.

()

()











-



()

 13 136


1 : 14 153
1 2
15 -- 164
2 10

3 19 16 173


17 184
4 30
18 194
5 40
19 207
6 61
20 212

21 221
7 67
22 238
8 76
23 249
2:
9 100 24 268

10 109 25 279

11 117 26 294

12 126 27 317


 28 332 43 573

44 580
29 342
45 594
30 352

31 365 46 605

32 377
47 615
33 383

34 393 48 629

3 : 49 642
35 406
50 651
36 421
51 662
37 432

38 442 52 673

39 483 53 681

54 687
40 499 gene-based vectors

41 506 55 695

42 567

 4 : 66 820
56 714

67 833
57 729
HIV-exposed babies 68 841

58 737 69 851

59 742
869

60 750


61 767

62 Community Immunity 775

63 786


5 :

64 794




65 812


 3

.. 2337 Edward Jenner

Jenner
(cowpox)
Jenner
Sarah Nelmes

8 James
Phipps 14 .. 2339
10 ..James Phipps
(smallpox)
..James Phipps
2 Jenner
..James
Phipps ..James Phipps
(variolation) Jenner

.. 2264
Lady Mary Wortley Montagu Jenner
Royal Society of London

Jenner
Lady Mary Wortley Montagu An Inquiry into the Causes
and Effects of the Variolae Vaccine 75

Cotton Mather Jenner
Onesimus

4

Jenner .. 2264 Lady Mary Wort-

ley Montagu variolation primary immune response




Jenner
protein, polysaccharide
Jenner (recombinant technology)

Jenner .. 2343 Jenner 11-3
vaccine
vacca .. 2378
vaccination
2
.. 2378 (Dr. Dan Beach Bradley)
.. 2420 Louis Pasteur
(attenuation)

Joseph Lister antiseptic
200 400

diphtheria, tetanus diphtheria
antitoxin, tetanus antitoxin
diphtheria tetanus 9
variolation
immunization
variolation
Paul Ehrich
active passive immunization
antiserum 1
..2469 Alexander Glenny alum
(adjuvant)
adjuvant
Glenny second-
ary immune response
 1 5

1
Live, Attenuated Killed Whole Organism Protein or Polysaccharide Genetically Engineered
Smallpox (1798)
Rabies (1885) Typhoid (1896)
Cholera (1896)
Plaque (1897)
BCG (1927) Pertussis (1926) Diphtheria toxoid (1923)
Influenza (1936)
Yellow fever (1935) Typhus (1938) Tetanus toxoid (1926)
OPV IPV Pneumococcal polysaccharide HBV
Measles Rabies (cell culture) Meningococcal polysaccharide Lyme OspA
Mumps JE Hib polysaccharide Cholera
Rubella Tick-borne encephalitis Meningococcal conjugate
Adenovirus HAV Hib conjugate
Typhoid (Ty21a) HBV
Varicella Typhoid (Vi)
Rotavirus Acellular pertussis
Cholera Anthrax
Cold-Adapted Influenza (2003) PCV (2000) HPV (2006)
Rotavirus Meningococcal quadrivalent
(new reassortants) (2006) conjugates (2005)
Zoster (2006)

(.. )
2

.. 2385
.. 2444
.. 2446




..
2453


2
() .. 2456
6

26 .. 2456
.


.. 2460


1 .. 2445 (Louis Pasteur)


.. 2456
( 1)4
.. 2454
24 .. 2463







4
46 3 71

258,000








( 2)

 1 7

and Research5
.. 2520
(Expanded Program on Immunization,
EPI)



2
(Compulsory vaccines)
10




6
(Optional vaccines)

7 .. 2465


Hemophilus influenzae type b

Acellular Pertussis Vaccine, Inactivated Poliomyelitis
Vaccine (IPV), Pneumococcal Conjugate Vaccine
(PCV), Influenza Vaccine, Rotavirus Vaccine, Human
GMP (Good manufacturing practice) Papillomavirus Vaccine Live attenuated Japanese
Encephalitis Vaccine Optional vaccine

ISO/IEC 17025
ilac MRA DMSc
Optional vaccine


WHO Collaborating Center for Research
on Rabies Pathogenesis and Prevention WHO (Vaccine for
Collaborating Center for Venomous Snake Toxicology special situation) Rabies Vaccine, Meningococcal
8

Vaccine

207,8


..
2520




(herd immunity)


6 DPT, IPV, Hib, HBV







anaphylaxis hypotonic-
hyporesponsive episode
1:1000 1: 1,000,000 1. Plotkin SA, Orestein WA, Offit PA, Editors.
Vaccines.5th ed. China: Saunders Elsevier Inc., 2008.
2. . .
: , . .
: ; 2519. . 13-25.
3. Ada GL. Vaccines. In: Roitt MR, Delves
PJ, editors. Encyclopedia of immunology. London:
Academic press; 1992. p.1540-4.
4. .
(-)
. http://www.nham.or.th/content/
detail/print/88/
 1 9

5. . http://www.
saovabha.com/th/aboutus.asp
6. .. :
, , . Lead-
ership in Medicine 2010. :
; 2553. . 184-90.
7. Tantawichien T, Thisyakorn U. Vaccines for
everyone. In: Joint TPAA-Chula International Medical
Congress 2011. Safety and quality in health-care prac-
tice; 2011 Feb 7-8; Bangkok: Chulalongkorn University
Press; 2011. p. 27.
8. Centers for Disease Control and
Prevention(CDC). Ten great public health achieve-
ments-- United States, 1900-1999. MMWR Morb
Mortal Wkly Rep.1999;48:241-3.
 11

adaptive immune response
2 innate (specificity)
innate immune response adaptive immune (memory)
response innate

adaptive immune response innate immune system
lymphocyte T cell B cell macrophage, dentritic cell, neutrophils, eosinophils
(specificity) (memory) monocytes 3



pathogen-
innate immune response associated molecular pattern (PAMPs)1

pattern-recognition receptor (PRR)
PRR PRR Toll-like
receptor (TLR)
2

TLR 11, 3 TLR 1, 2, 4,
2 5, 6
innate immune response adaptive immune TLR 3, 7, 8, 9
response

1. Innate immune response mutation
innate
PRR
4
12

1 Toll-like receptor
Toll-like receptors Ligands Microbial sources
TLR1 Lipoproteins, lipoteichoic acid Gram-positive bacteria, mycoplasma
TLR2 Lipoproteins Bacterial cell walls, mycoplasma
Peptidoglycan, lipoteichoic acid Gram-positive bacteria cell walls
Zymosan Fungi
Lipoarabinomannan Mycobacteria cell walls
TLR3 Double-stranded RNA Viral RNA
TLR4 Endotoxin Gram-negative bacteria cell walls
Viral coat proteins Respiratory syncytial virus
TLR5 Flagellin Bacteria
TLR6 Lipoproteins, lipoteichoic acid Gram-positive bacteria, mycoplasma
TLR7 Single-stranded RNA Viral RNA
TLR8 Single-stranded RNA Viral RNA
TLR9 Unmethylated CpG DNA Bacterial and viral DNA
TLR10 Unknown Unknown
( 1, 3)

T cell B cell clone

innate adaptive (diversity) T cell B cell
gene rearrangement
2. Adaptive immune response (random) T cell B cell
adaptive T cell gene rearrangement
B cell V(D)J recombination combination
receptor T cell B cell receptor
(antigen specific receptor)
gene rearrangement
(diversity) (specificity) diversity
innate (memory) multiple mutation
adaptive somatic hypermutation
(Antibodies)
plasma cell
(antigen recognition) B cell 11 Y
adaptive heavy chain light chain
(specificity) 2 5
(diversity) antigen-binding sites
(specific) receptor heavy chain
 2 13

1 Y
heavy chain light chain disulfide bonds
(1)

heavy chain B cell germinal center

class isotype memory B cell
isotype secondary immune response
21,6-8 affinity
Humoral immune response isotype switching IgM IgG IgA
effectors B
2 T-cell lymphocyte T lymphocyte
independent T-cell dependent
2 31 B cell T cell
T cell independent response B cell
B cell T-independent9,10 T-cell
plasma cell protein, toxoid
inactivated live attenuated virus vaccine
B cell T-dependent
T-cell independent immune memory
response affinity affinity T-independent
IgM (memory) live attenuated vaccine
secondary immune response CD8 cytotoxic T cell
T-dependent pathway CD8 cytotoxic T cell
T cell dependent response
T cell B cell T cell
14

2 isotype
Item IgM IgD IgG1 IgG2 IgG3 IgG4 IgA1 IgA2 IgE
Subunit form 5 1 1 1 1 1 1, 2 1, 2 1
Molecular weight (kd) 950 175 150 150 150 150 160, 400 160, 400 190
Concentration in 2 0.03 10 4 1 0.5 2 0.5 0.003
serum (mg/dL)
Complement activation ++/- -/+ ++/+ +/+ ++/+ -/+ -/+ -/+ -/-
a
(C/A)
Macrophage + - ++ ++ ++ - ++ ++ -
FcR binding
Mast cell sensitizing - - - - - - - - +++
Placental transport - - ++ + ++ +/- - - -
b b
Mucosal transport - - - - - - +++ +++ -
c
ADCC - - + + + + - - +
Half-life (days) 5 3 23 23 8-9 23 6 6 2
Function 1 immune Lymphocyte 2 immune response Mucosal immunity Immediate
response surface Major form of circulating antibodies Secretory Ig allergic
Lymphocyte reactions
surface
a: C=complement pathway, A= alternative pathway
b: Dimer only
c: ADCC= antibody-dependent cell-mediated cytotoxicity
(1, 6-8)

2 T-cell independent B cell activation

( 1)
 2 15

3 T cell dependent B cell activation

( 1)

2. CD4 T cell

cytokine B cell
1. Antibody CD8 T cell macrophage

(extracellular pathogen) 3. CD8 T cell
intracel-
1.1 lular pathogen
(inactive)
T cell
1.2

1.3 opsonization
macrophage neutrophil
1.4 complement complement

16

antigen presenting cell dendritic cell (DC) DC

immature mature
DC (intradermal injection)
Tcell B cell DC
(dermis) DC
danger signals
/ (adjuvants)
inflammation 10 DC
(DC, monocyte (intramuscular)
neutrophil) receptor (subcutaneous)11
self antigen pathogen- asso-
ciated molecular pattern (PAMPs)1
(danger signal)
receptor
TLR
inflammation inflammation 1.
maturation DC T cell live vaccine
B cell non live vaccine live vaccine
live virus vaccine
viral RNA TLR 12

target tissue T-dependent pathway
DC
T B cell live vaccine T-independent pathway
immuno- T- dependent antigen
genicity non-live vaccine memory B cell 13

2.
immunogenicity 3
10
Non-live vaccine pathogen recognition primary response
patterns danger signal 14
live vaccine non-live primary booster dose
vaccine 4
live vaccine affinity maturation memory B cell
secondary response 14
 2 17

subversion of pattern-recognition receptor signalling.

Nat Rev Immunol. 2008;8:911-22.
5. Amzel LM, Poljak RJ. Three-dimensional
structure of immunoglobulins. Annu Rev Biochem.
1979;48:961-97.
6. Torres RM, Imboden J, Schroeder HW.
Antigen receptor genes, gene products, and
co-receptors. In: Rich RR, Fleisher TA, Shearer
WT, Schroeder HW, Frew AJ, Weyand CM, editors.
Clinical Immunology: Principles and Practice. 3rd ed.
Philadelphia: Elsevier; 2008. p. 53-77.
T cell B cell immunogenicity 7. Bankers-Fulbright JL, Li JT. Immunoglobu-
lin structure and function. In: Adkinson NF, Bochner
adaptive BS, Busse WW, Holgate ST, Lemanske RF, Simon
system (adjuvant) FER, editors. Middletons Allergy: Principles&Practice.
innate immune response 7th ed. Philadelphia: Elsevier; 2009. p. 73-87.
maturation dendritic cell 8. Chaplin DD. Overview of the immune
response. J Allergy Clin Immunol. 2010;125
(2 Suppl 2):S3-23.
9. Lee CJ, Lee LH, Lu CS, Wu A. Bacterial
polysaccharides as vaccines--immunity and chemical
characterization. Adv Exp Med Biol. 2001;491:453-71.
10. Weintraub A. Immunology of bacterial
polysaccharide antigens. Carbohydr Res.
1. Moser M, Leo O. Key concepts in 2003;338:2539-47.
immunology. Vaccine. 2010;28(Suppl 3):C2-13. 11. de Lalla F, Rinaldi E, Santoro D, Pravettoni
2. Akira S, Uematsu S, Takeuchi O. Pathogen G. Immune response to hepatitis B vaccine given at
recognition and innate immunity. Cell. 2006;124:783- different injection sites and by different routes:
801. a controlled randomized study. Eur J Epidemiol.
3. Liu AH, Zasloff MA, Johnston RB. Innate 1988;4:256-8.
Immunity. In: Adkinson NF, Bochner BS, Busse 12. Manz RA, Hauser AE, Hiepe F, Radbruch
WW, Holgate ST, Lemanske RF, Simon FER, A. Maintenance of serum antibody levels. Annu Rev
editors. Middletons Allergy: Principles&Practice. Immunol. 2005;23:367-86.
7 t h e d. Philadelphia: Elsevier; 2009. 13. Southern J, Deane S, Ashton L, Borrow
p. 19-35. R, Goldblatt D, Andrews N, et al. Effects of prior
4. Bowie AG, Unterholzner L. Viral evasion and polysaccharide vaccination on magnitude, duration,
18

and quality of immune responses to and safety

profile of a meningococcal serogroup C tetanus toxoid
conjugate vaccination in adults. Clin Diagn Lab
Immunol. 2004;11:1100-4.
14. Siegrist CA. Vaccine immunology.
In: Plotkin SA, Orenstein WA, Offit PA, editors. Vacines.
5th ed. Philadelphia: Elsevier; 2008.
 31

(new delivery systems)

intradermal route, mucosal route
vaccine antigen
20
live attenuated pathogen
(disease burden) pathogen toxin whole killed pathogen
inactivate pathogen
live attenuated vaccine
(pathophysiology of infection), vaccine immunology

(high reactogenicity)


(specific immunogen from pathogen
to specific receptor) split antigen, subunit
live cowpox virus inoculation antigen, recombinant protein vaccine
antigen vaccine antigen
1
(antibody generator)

(immunogen) ( )
basic immunology,
pathogen and host interaction, immune response to in-
fection
molecular technique and genetic engineering tech-
nique Human Papillomavirus
recombinant
purified antigen protein (L1 protein) vaccine
(new adjuvants), antigen
32

1 vaccine antigen

1 Highly purified antigens

naked pathogen-derived DNA live vector attenuated live intracellular

vaccine antigen organism target antigen
(DNA vaccine) target live vector uptake host cell
antigen circular plasmid expression vector
vector host cell activate gene purified antigen
expression
humural immunity (HMI) cell
mediated immunity (CMI)
DNA vaccine pathogen toxin
1
 4 33

1,2 (DNA)
1.
(tetanus toxin, diphtheria toxin) purified antigen
Hib vaccine, (immuno-
conjugated pneumococcal vaccine genicity)
2. Immunologic structure immunogenicity aluminium
virus-like particle (VLP) salt
VLP HPV vaccine L1 protein 2.
VLP
3. (adjuvant)

ASO3

aluminium salt (aluminium hydroxide,
aluminium sulfate) 80 3.
avian influenza H5N1 vaccine
2 3 MF-59 influenza vaccine pandemic influenza
combina- influenza H5N1 vaccine
tion adjuvant (ASO) 1
2,3


(adjuvants)
4.
(adjuvants)
(mucosal immunity)


cell-mediated immunity (CMI) T lymphocyte



1

( 2)2-5 3 3-5
1. 1.

34

3
 4 35

(persistence of antigen) alu- Aluminium salt

minium salt emulsion-based adjuvant 80 aluminium salt
aluminium hydroxide
pertussis, diphtheria and tetanus vaccines,
aluminium phosphate hepatitis A (HAV) and
B (HBV) virus vaccines, aluminium hydroxyphosphate
sulphate quadrivalant human papillomavirus
(HPV) vaccine aluminium salt
(depot mechanism)
2. APC macrophage
(antigen presenting cell, APC)

APC aluminium T lym-
T lymphocyte phocyte, cell-mediated immunity
(direct activation of innate immune cells)
intracellular
MF59 infection 6
APC dendritic cell macrophage Liposome virosome artificial vesicles
3. innate immunity
lipid layers lipid
adaptive immunity membrane liposome virosome
APC B cell
cytokines 3-5,7
cytokines Th1 (type 1) Emulsion ( oil in water water in oil
Th2 (type 2) ) aluminium salt
cytokines IFN-gamma delayed-type hyper- APC
sensitivity (DTH) oil in water
Th1 cell- MF59 oil in water
mediated immunity cytotoxic-T lymphocyte APC
IgG1 subtype innate immunity
cytokines squalene pandemic influenza
IL-2, IFN-gamma, GM-CSF, IL-12 H1N1 vaccine3-5,7
bacterial toxins cholera toxin, pertussis toxin Bacterial product
Th2 Toll-like receptor
(TLR) APC T lymphocyte
microbial products
( 2, 3) DNA CpG motifs,
36

2
Types of adjuvants
Mineral salt : Aluminum salt adjuvants :
Aluminum hydroxide adjuvant
Aluminum phosphate adjuvant
Alum adjuvant
Mechanisms : depot mechanism
promote uptake of Ag by APC
inflammation at injection site
Oil-emulsion/surfactant based adjuvants :
MF-59, Virus-Like Particle
Microbial products/TLR agonist :
Monophosphoryl lipid A (MPL), AGP, CpG,
CT, LT (heat-labile toxin)
Saponin (QS21)
Cytokines : IL-2, IL-12,.

3
Adjuvant Vaccine
Aluminium salts DTaP (paediatric diphtheria, tetanus and acellular pertussis)
DTaP, polio and Haemophilus influenza type b
DTaP, polio, Haemophilus influenza type b and hepatitis B
Hepatitis A
Hepatitis B
Human papillomavirus-6/11/16/18
Influenza (H5N1)
Pneumococcus (conjugated)
Virosomes Hepatitis A
Influenza (seasonal)
Oil-in-water emulsion (MF59) Influenza (H5N1, H1N1)
Influenza (seasonal)
Adjuvant System AS04 Hepatitis B
Human papillomavirus-16/18
Adjuvant System AS03 Influenza (H5N1, H1N1)
Thermo-reversible Influenza (H1N1)
oil-in-water emulsion
 4 37

endotoxin monophospho-
ryl lipid A (MPL) modified derivative of lipopoly- ( 2 MPL
saccharide (LPS) endotoxin aluminium salt)
Salmonella spp. (detoxified LPS) 10,11 3, 4
innate immune system MPL AS04
toll-like receptot-4 (TLR4) endotoxin aluminium salts MPL
APC cytokines
adaptive immunity Th-1 response
humoral and cellular immune responses HPV, HBV, HSV, H5N1
MPL HPV AS04
vaccine, malaria vaccine, herpes virus vaccine
exotoxins seroprotection rates
cholera toxin, E.coli heat-labile toxin, pertussis toxin aluminium salt
muramyl dipeptide (MDP)8,9 AS04-adjuvanted
Cytokine HPV 16/18 vaccine VLP HPV
IL-2 16 HPV 18 20 AS04
aluminium hydroxide 0.5
MPL 50 AS04
HPV 16/18 vaccine
aluminium salt system
ASO3, ASO4
memory B lymphocyte 11,12
1
4
38

Innovative vaccine production technologies: the evo-

(delivery) lution and value of vaccine production technologies.
Arch Pharm Res. 2009;32:465-80.
(intradermal injection) 2.Vogel FR, Hem SL. Immunologic adjuvants.
In: Plotkin SA, Orenstein WA, Offit PA, editors. Vac-
cold-adapted trivalent influenza cines. 5th ed. New York: Elsevier; 2008. p. 5971.
vaccine (CAIV-T) 3.Marciani DJ. Vaccine adjuvants: role and
1,2 mechanisms of action in vaccine immunogenicity. Drug
(adverse reaction) DiscoveryToday. 2003;20:934-43.
aluminium salt 4.Reed SG, Bertholet S, Coler RN, Friede M. New
( horizons in adjuvants for vaccine development. Trends
) Immunol. 2008;30:23-32.
5.Schmidt CS, Morrow WJW, Sheiks NA.
Smart adjuvants. Expert Rev Vac. 2007;6:391-400.
MF-59, virosome 6.Noe SM, Green MA, Esch MH, Hem SL. Mech-
anism of immunopotentiation by aluminum-containing
ASO4 adjuvants elucidated by the relationship between an-
3,548 AS04 tigen retention at the inoculation site and the immune
13 response. Vaccine. 2010;28:3588-94.
ASO4-HPV vaccine 7.Garcon N, Goldman M. Boosting vaccine
power. Sci Am. 2009;301:72-9.
autoimmune diseases 8.Mata-Haro V,Cekic C,Martin M,Chilton PM,
Casella CR, Mitchell TC. The vaccine adjuvant mono-
phosphoryl Lipid A as a TRIF-biased agonist of TLR4.
Science. 2007;316:1628-32.
9.DidierlaurentAM,MorelS,LockmanL. AS04,an
aluminum salt- and TLR4 agonist-based adjuvant system,
induces a transient localized innate immune response
leading to enhanced adaptive immunity. J Immonol.
2009;183:618697.
10.Garcon N. Change and necessity. Human
Vac 2008;4:173-5.
11.Schwarz TF, Leo O. Immune response to
human papillomavirus after prophylactic vaccination
1.Bae KD, Choi JY, Jang YS, Ahn SJ, Hu BK. with AS04-adjuvanted HPV-16/18 vaccine: Improv-
 4 39

ing upon nature. Gynecol Oncol. 2008;110(3 Suppl

1):S1-10.
12.Schwarz TF. Clinical update of the AS04-
adjuvanted human papillomavirus-16/18 cervical can-
cer vaccine, Cervarix. Adv Ther. 2009;26:983-98.
13.Verstraetena T, Descampsa D, Davida PM,
et al. Analysis of adverse events of potential autoim-
mune aetiology in a large integrated safety database of
AS04 adjuvanted vaccines. Vaccine. 2008;26:6630-8.
 41

--
(passive immunization)


4
(active immunization) 1. (compulsory vaccines)


-
- -
1 -
3 2. (optional
vaccines)
1. (toxoid)




2. (killed vaccine)



(genetic engineering) 3. (vaccines in special
circumstances)

3. (live vaccine)
42

lot number
4.
(investigational vaccines)





1-4
70%

1





5
1. (oral route)
-
- - 2.
--


3. (intradermal)
27

(cell-
lot number mediated immune response)


 5 43

1


Bacillus Calmette Guerin 2-8O. 2-8O.
Diphtheria, tetanus pertussis 2-8O.
(DTwP, DTaP, DT, Td, Tdap, TT)
Haemophilus influenza type b 2-8O. 2-8O.
Hepatitis A (HepA) 2-8O.
Hepatitis B (HepB) 2-8O.
HepA-HepB 2-8O.
Human papillomavirus 2-8O.
Influenza, inactivated 2-8O.
Influenza, live attenuated 2-8O.
Japanese Encephalitis(JE), 2-8O. (
inactivated () 2-8O.)
JE, live attenuated 2-8O. 2-30O.
Measles, mumps, rubella 2-8O. 2-25O.
(MMR, M) 6 .
Measles, mumps, rubella, < -15O. 2-25O.
varicella (MMRV)
Meningococcal conjugate 2-8O.
Meningococcal Polysaccharide 2-8O. 2-8O.
Pneumococcal conjugate 2-8O.
Pneumococcal Polysaccharide 2-8O.
Polio, inactivated 2-8O.
Polio, live attenuate 2-8O.
Rabies 2-8O. 2-8O.
Rotavirus 2-8O. RV1 20-25O.
RV5
Typhoid 2-8O.
Varicella 2-8O. () 2-25O.
Yellow fever 2-8O. 2-8O.
Herpes Zoster < -15O. 2-25O.
: RV1= monovalent rotavirus; RV5 = pentavalent rotavirus
( 4)

44

4. (subcutaneous)

adjuvant -- 24
26G 3
45


5. (intramuscular)
lidocane
() 5-7
()
6,8 lidocane
1 met
hemoglobin methemoglobinemia 9

2

(18 )
* 5/8 (16 .) 26
1-12 1 (25 .) 25
1-2 111/4 (2532 .) 24-25
5/81 (1625 .) 24-25 (Deltoid)
3-18 5/81 (1625 .) 24-25 (Deltoid)
111/4 (2532 .) 24-25
(19 )
, 1 (25 .) 23-25
<60 .
, 1 (25 .) 23-25 (Deltoid)
6070 .
, 70118 . 111/2 (2538 .) 23-25
, 7090 . 23-25
, >118 . 11/2 (38 .) 23-25
, >90 . 23-25
* 28

5/8 <60 .
( 4)
 5 45

3

Bacillus Calmette Guerin Live bacteria 0.05 0.1 .* ID
Diphtheria, tetanus, pertussis Toxoids and 0.5 . IM
(DTwP, DTaP, DT, Td, Tdap, TT) inactivated bacterial
component
Haemophilus influenza type b Polysaccharide protein 0.5 . IM
conjugate
Hepatitis A (HepA) Inactivated viral antigen 1-18 : 0.5 . IM
19 : 0.5-1 .
Hepatitis B (HepB) Recombinant viral antigen : 0.5 .** IM
: 1.0 .
HepA - HepB Inactivated HepA antigen 18 : 1. IM
and recombinant HepB antigen
Human papillomavirus Recombinant viral antigens 0.5 . IM
Influenza, inactivated Inactivated viral component 6-35 : 0.25 . IM
3 : 0.5 .
Influenza, live attenuated Live-attenuated virus 0.2 . 0.1. Intranasal spray
Japanese Encephalitis(JE), Inactivated virus < 3 : 0.5./0.25 . SC
inactivated 3 : 1.0 ./ 0.5 . SC
JE, live attenuated Live-attenuated virus 0.5 . SC
Measles, mumps, rubella Live-attenuated virus 0.5 . SC
(MMR, M)
Measles, mumps, rubella, Live-attenuated virus 0.5 . SC
Varicella (MMRV)
Meningococcal conjugate Polysaccharide 0.5 . IM
protein conjugated
Meningococcal Polysaccharide 0.5 . SC
Polysaccharide
Pneumococcal conjugate Polysaccharide 0.5 . IM
protein conjugated
Pneumococcal Polysaccharide Polysaccharide 0.5 . IM
Polio, inactivated Inactivated virus 0.5 . IM
Polio, live attenuate Live virus2-3 Oral
Rabies Inactivated virus 0.5-1 . IM
0.1 . ID
Rotavirus Live-attenuated virus RV1: 1. Oral
RV5 : 2 .
Typhoid polysaccharide 0.5 . IM
Varicella Live-attenuated virus 0.5 . SC
Yellow fever Live-attenuated virus 0.5 . SC
Herpes Zoster Live-attenuated virus 0.65 . SC
: IM = intramuscular, ID = intradermal, Sc = subcutaneous
RV1= monovalent rotavirus; RV5 = pentavalent rotavirus
*
** 11-15 1.0 . 2 0 4-6
46

10
11,12 6




2-3

< 4
4
> 5

4
2
6
() 4

28
9 13 1 11 2
1
12-15 4
14

1

1 15,16
2



17

5-7
4


 5 47

4 1

(vaccine&dose no.) (recommended age) (minimum age)
(recommended interval) (minimum interval)
BCG - -
HepB-1 1-4 4
HepB-22 1-2 4 2-17 8
HepB-33 6-18 24 - -
DTwP, DTaP -1 2 6 2 4
DTwP, DTaP -2 4 10 2 4
DTwP, DTaP -34 6 14 6-12 6
DTwP, DTaP -4 15-18 12 3 6
DTwP, DTaP -5 4-6 4 - -
Tdap5 11 10 - -
Td 11-12 7 10 5
OPV, IPV -1 2 6 2 4
OPV, IPV -2 4 10 2 4
OPV, IPV -3 6 14 6-12 6
OPV, IPV -46 15-18 12 3 6
OPV, IPV -5 4-6 4 - -
MMR-1 9-12 9 3-5 4
MMR-27 4-6 12 - -
Inacitvated JE-1 12-18 12 4 1
Inacitvated JE-2 13-19 12 11 3
Inacitvated JE-3 24-30 24 - -
Live JE -1 12 9 3-12 3
Live JE-2 12-24 12 - -
Hib-18 2 6 2 4
Hib-2 4 10 2 4
Hib-3 6 14 6-9 8
Hib-49 12-15 12 - -
PCV-18 2 6 2 4
PCV-2 4 10 2 4
PCV-310 6 14 6 8
PCV-4 12-15 12 - -
PPSV-1 - 2 5 3
PPSV-2 - 5 - -
RV-111 2 6 2 4
RV-2 4 10 2 4
RV-3 6 14 - -
( pentavalent)
Var-1 12-18 12 3-5 12
Var-212 4-6 15 - -
HepA-1 12-23 12 6-12 6
HepA-2 18-41 18 - -
TIV 6 - 18 6 1 13 4
LAIV 2-49 2 1 4
48

(vaccine&dose no.) (recommended age) (minimum age)
(recommended interval) (minimum interval)
MCV4-1 - 2 5 8
MCV4-2 - 11 +8 - -
MPSV4-1 - 2 5 5
MPSV4-2 - 7 - -
HPV-1 11-12 9 1-2 4
HPV-2 11-12 (+1-2 ) 109 4-5 12
HPV-3 11-12 (+6 ) 114 - -
Herpes zoster > 60 60 - -

: BCG= Bacillus Calmette Guerin Vaccine; DTwP= Diphtheria and Tetanus toxoids, and whole cell Pertussis; DTaP =
Diphtheria and Tetanus toxoids and acellular pertussis; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus influenzae
type b; HPV = human papillomavirus; IPV = inactivated poliovirus; JE=Japanese Encephalitis Vaccine; LAIV = live, attenuated
influenza vaccine; MCV4 = quadrivalent meningococcal conjugate vaccine; MMR = measles, mumps, and rubella; MPSV4
= quadrivalent meningococcal polysaccharide vaccine; OPV=Oral Poliomyelitis Vaccine; PCV = pneumococcal conjugate
vaccine; PPSV = pneumococcal polysaccharide vaccine; RV= rotavirus; Td = Tetanus and diphtheria toxoids; TIV = trivalent
inactiated influenza vaccine; Tdap = Tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis; Var = varicella vaccine.
1


2
HBsAg HBIG HBV 1
3
DTP+HBV HBV 4 24
4
DTwP DTaP 3 4 6 DTwP DTaP
4 DTwP, DTaP-3 4
5
Tdap dT 1 DTP 4-6
6
IPV 4 4
7
MMRV
8
Hib PCV 7
9
Hib-4
10
PCV-3 ( 2+1)
11
RV 15 8
12
Varicella vaccine 1-12 1-2 2 4-6
4 3 > 13 2 4
13
Influenza vaccine 9 2 1
( 1)

5


+

+

( 4)
 5 49
6
1 2


+,#
2 +
+

# 7
( 4)

7
+

/ (. IgG/.) ()
Tetanus IG 250 (10 . IgG/.) IM 3
Hepatitis A IG
- 0.02 ./. (3.3 . IgG/.) IM 3
- 0.06 ./. (10 . IgG/.) IM 3
Hepatitis B IG 0.06 ./. (10 . IgG/.) IM 3
Rabies prophylaxis (HRIG) 20 IU/. (22 . IgG/.) IM 4
Varicella IG 125 /10 . (20-40 . IgG/.) 5
IM ( 625 )
Measles prophylaxis IG
- () 0.25 ./. (40 . IgG/.) IM 5
- () 0.50 ./. (80 . IgG/.) IM 6

- Red blood cells (RBCs),washed 10 ./. ( IgG ) IV 0

- RBCs adenine-saline added 10 ./. (10 . IgG/.) IV 3
- Packed RBCs (Hct 65%) 10 ./. (60 . IgG/.) IV 5
- Whole blood (Hct 35-50%) 10 ./. (80-100 . IgG/.) IV 6
- Plasma/platelet products 10 ./. (160 . IgG/.) IV 7
Replacement therapy for immune deficiencies (IVIG) 300-400 ./. IV 8
Respiratory syncytial virus prophylaxis 750 ./. IV ( RSV-IGIV) 9
Immune thrombocytopenic purpura (IVIG) 400 ./. IV 8
1,000 ./. IV 10
Kawazaki desease (IVIG) 2 /. IV 11
: IG = immune globulin; IgG = immune globulin G; IVIG = intravenous immune globulin; IM = intramuscular; IV =
intravenous

( 1, 4)
50

3
2 Trivalent
inactivated influenza vaccine Live-attenuated
7 influenza vaccine
2



18,19




20,21 28


2 9-31


1.

2.
3.
22,23-27




3 T cell


outer membrane protein Neisseria menin-
20,21 gitidis

30,32

 5 51

delayed-type
8 anaphylaxis
48,49
4. Thimerosal
.. 1930 preservative
systemic .. 1999
anaphylaxis thimerosal
anaphylaxis
-- - 50
33

anaphylaxis
34,35 51-53

-- 54-56
36-39
angioedema
40,41
2 1

( HBIG )
1. 3 2
Anaphylaxis 1-2 2 3
42-44 1-2 6
2 desensitization 4

fibroblast
anaphylaxis skin test 57-59
45-47
30 2
2. Latex
latex
latex 60
3.

52

8

1. Bacillus Calmette 1. local reation: - BCG
Guerin (BCG) osteitis 3-4
2. disseminated fatal infection
severe - BCG
combined immune deficiency syndrome INH
2-3
3 .
2. Hepatitis B 1. local reaction: sudden infant
2. systemic reaction: death syndrome demyelinating disease
3. allergic reaction: anaphylaxis multiple sclerosis
3. Diphtheria, tetanus 1. local reaction: , acellular
pertussis (DTP) whole cell
(sterile abscess)
2. systemic reaction :
encephalopathy, hypotonic
hyporesponsive episode
3. allergic reaction: anaphylaxis
4. Polio, live attenuate Vaccine-associated paralytic poliomyelitis
(OPV) (VAPP)

5. Polio, inactivated - VAPP
(IPV) - streptomycin, neomycin polymyxin
B


6. Measles, mumps, 1. systemic reaction: 5-12 -
rubella (MMR) transient thrombocytopenia Inflammatory bowel disease
encephalitis -
encephalopathy MMR
2. allergic reaction: skin test

neomycin 30

7. Japanese 1. local reaction: 2
Encephalitis(JE), 20
inactivated 2. systemic reaction:
10
3. allergic reaction: angioedema
0.2-0.6 2
 5 53

8. JE, live attenuate 1. local reaction:
2. systemic reaction:
9.3 6.7
hypersensitivity

9. Haemophilus 1. local reaction:
influenza type b 25
24
2. systemic reaction:
10. Pneumococcal 1. local reaction:
conjugate
2. systemic reaction: 1-2

11. Pneumococcal 1. local reaction:
polysaccharide 2. systemic reaction:

3. allergic reaction: arthus-like

2

12. Rotavirus

13. Varicella 1. local reaction:
2. systemic reaction:
(maculopapular rash vesicle)
14. Hepatitis A 1. local reaction:

2. systemic reaction:

15. Influenza, 1. local reaction:
inactivated (TIV) 2. systemic reaction:
13 6-24 .
Guillain-Barre
syndrome 1
3. allergic reaction:
anaphylaxis
16. Human 1. local reaction:
papillomavirus 2. systemic reaction:
30
54

17. Rabies 1. local reaction:
15-25
2. systemic reaction:

10-20
3. allergic reaction: immune complex like
reaction HDCV
2-21
angioedema
18. Typhoid 1. local reaction:
(Vi capsular 7
polysaccharide vaccine) 2. systemic reaction:
1.5-3 0-1
48
19. Meningococcal
1-2
20. Yellow fever 1. local reaction:
2 - 5 5 - 10

2. systemic reaction:

25

6
3. allergic reaction:
anaphylaxis serum
sickness
1
21.Zoster
( 1)

-
-
- 10
2 3

 5 55

-
- 6.
7.
1
14,61 8.

1 9.
2,000

4 2,000 1-2
14,62
10.
1,2
1.

11.

2.
12.




13.
-
3. -



4.

14.
5.

56

vention (CDC). General recommendations on immuni-

15. zation: recommendations of the Advisory Committee
on Immunization Practices (ACIP). MMWR Recomm
Rep. 2006;55:1-48.
4. National Center for Immunization and
Respiratory Diseases. General Recommendations on
Immunization --- Recommendations of the Advisory
16. Committee on Immunization Practices (ACIP). MMWR

Recomm Rep. 2011;60:1-64.
5. Taddio A, Nulman I, Goldbach M, Ipp M,
17.
Koren G. HYPERLINK http://www.ncbi.nlm.nih.gov/
pubmed/8151485 Use of lidocaine-prilocaine cream
for vaccination pain in infants. J Pediatr. 1994;124:643-
8.
6. Halperin SA, McGrath P, Smith B, Hou-
ston T. Lidocaine-prilocaine patch decreases the
18. pain associated with the subcutaneous administra-
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adversely affect the antibody response. J Pediatr.
19. 2000;136:789-94.
7. Uhari M. A eutectic mixture of lidocaine and
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8. Halperin BA, Halperin SA, McGrath P, Smith
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1. , , affect the antibody response to diphtheria-tetanus-
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62. Marin M, Gris D, Chaves SS, Schmid

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(ACIP). MMWR Recomm Rep. 2007;56:1-40.
 61

6
,

(Vaccine reaction)

(Programmatic error)
(Injection reaction)
(Coincidental events)
(Unknown)

1. (Vaccine reactions)

(Immune system)


(Adverse Events Following Immu- (systemic reaction)
nization : AEFI) Surveillance of adverse events
following immunization : Field Guide for Managers of
Immunization Programmes, WHO Geneva 1997 (antibiotic) (adjuvant)
An adverse events following immunization is a (preservative)
medical incident that takes place after an immunization
and is believed to be caused by the immunization.


1.1 (Mild, common vaccine
1 reactions)

(systemic reaction)
5

62

1

( )
BCG 90-95 % - - -
Hib 5 - 15 % 2 - 10 % - -
Hepatitis B 30 % 1-6% - -
5 %
Measles/MMR 10 % 5-15 % 5
Oral Polio Vaccine (OPV) <1 % <1
Tetanus/DT 10 % * 10 % - 25
DTP 50 % 50 % - 55
* 50 - 85 Tetanus/DT
( 2)

2
1 2

measles/MMR 5 - 12
10
DTP (whole
cell)
50 ( 1)
1.2 (More serious, rare vaccine
reactions)


(Thrombocytopaenia)
/ (Hypotonic Hyporesponsive Episodes) (Bacterial abscess)
(Persistent screaming) ( 2) sepsis
toxic shock syndrome
2.
(Programmatic error) (sterile
abscess) ( 3)
(cluster)
3.
(Injection reactions)

 6 63

2


BCG Suppurative Lymphadenitis 2-6 100-1,000
BCG Osteitis 1-12 0.01-300
Disseminated BCG-infection 1-12 0.19-1.56
Hib None known
Hepatitis B Anaphylaxis 0-1 1-2
Measles/MMR/MR Febrile Seizures 6-12 330
Thrombocytopaenia 15-35 30
Anaphylactoid (severe allergic reaction) 0-2 ~10
Anaphylaxis 0-1 ~1
Encephalopathy 6-12 <1
Oral Polio (OPV) Vaccine-Associated Paralytic Poliomyelitis (VAPP) 4-30 ~0.4
Tetanus Brachial Neuritis 2-28 5-10
Anaphylaxis 0-1 0.4-10
Tetanus-diphtheria Tetanus vaccine
DTP Persistent (>3 hours) inconsolable screaming 0-24 1,000-60,000
Seizures 0-2 80-570
Hypotonic Hyporesponsive Episode (HHE) 0-24 30-990
Anaphylaxis 0-1 20
Encephalopathy () 0-2 0-1
( 3)

3


(Programmatic error) (Adverse event expected)

toxic shock syndrome

BCG
DTP/DT/TT sciatic nerve


( 2)
64

1. (Local Adverse Events)
5 1.1 (Bacterial Abscess)




Neutrophil ( 50)
5
Hyperventilation
1.2 (Sterile Abscess)


5

1.3 (Lymphadenitis;
Includes Suppurative Lymphadenitis)
4. (Coincidental events) 1.5
.
2 - 6
(
)
.. 2539 (National 1.4 (Severe
Immunization Days) Local Reaction)
OPV
wild polio virus 3
wild polio virus 5
OPV

(coincidental event) 2.
(Central Nervous System Adverse Events)
5. (Unknown) 2.1 Vaccine-Associated Paralytic Poliomyelitis
(VAPP)


 6 65

4 - 30 OPV 2.8 Brachial (Brachial

4 - 75 Neuritis)
OPV 60


2.2 Guillain-Barr Syndrome (GBS)

2
6 2-28

2.3 (Encephalopathy) 3. (Other Adverse Events)

3.1 (Fever)

1 72 1-2 measles MMR
measles/MMR 5-12
7-12 3.2 (Allergic Reaction)
2.4 (Encephalitis)


30 24
3.3 Anaphylactoid Reaction (Acute Hypersen-
2.5 (Meningitis) sitivity Reaction)

(wheezing)
30 Stridor

2.6 Febrile Seizures 2
38.5 . 3.4 Anaphylaxis (Anaphylactic Shock)
() 15

2.7 Afebrile Seizures

15 (wheez-
ing) Stridor

66
3.5 (Arthralgia) ..

8
10 8

3.6 Disseminated BCG-itis
1.Information for health-care workers manag-
1 - 12 ing adverse events [Internet]. Available from: http://
Mycobacterium www.who.int/immunization_safety/aefi/managing_AE-
bovis FIs
3.7 / (Hypotensive- 2.Immunization Safety Surveillance: Part 2:
Hyporesponsive Episode : Shock Collapse) Adverse events following immunization (AEFIs). WHO
48 Regional Office for the Western Pacific; 2009.
3.Supplementary information on vaccine safe-
ty: Part 2: Background rate of adverse event following
3.8 (Osteitis/ immunization. Geneva: World Health Organization;
Osteomyelitis) 2000.

8 - 16
Mycobacterium bovis

3.9 (Persistent Screaming)

3
24
3.10 (Sepsis)


5

3.11 Toxic Shock Syndrome

2 - 3

3.12 (Thrombocytopaenia)
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1 ()
(allergens) (antigens) (vaccines) (antigens)
(hormones) (cytokines) (adjuvants) (preservatives)
(enzymes) (stem cells) (suspending fluid)
(tissues)
(human whole blood and plas-
ma derivatives) (immune sera)
(immunoglobulins)
(monoclonal antibodies)
(fermentation
or recombinant DNA) (vaccine)2
vaccin-us vacca cow
(.. 2339)
1. (cowpox)
(eukaryotic cells) (smallpox)
2. (cowpox)
(extraction of substances from Biological (cow-
tissues including human, animal and plant tissue (al- pox)
lergen) (smallpox)
3. (recombinant DNA
or rDNA techniques)
4. (hybridoma tech-
nique)
5. (EPI NIP)
(propagation of microorganisms in embryo or animals)
6.


78

()
(MMR)
(OPV)


(cold chain) 3. (Toxoid vaccines)
(toxin)
3 (toxoid)

5

1. (Inactivated vaccines)
(Diphtheria) (Tetanus)








4. (Subunit vaccines)

(Pertussis) (whole cell)


2. (Live-attenuated vaccines)







 8 79

5. (Conjugated vaccines)
(subunit) (DTP)
(MMR)

3
(polysaccharide capsule)
(Haemophilus influenzae type b) (Immunization)
100 100
(NRA)


2

1.
(Pre-clinical phase) (fully functional system
+ 6 regulatory functions)



UN Prequalified

Technical Report Series (TRS)
WHO Good Manufacturing Practices
(GMP)
2. (Clinical preclinical clinical
phase)
United Nation (UN
1, 2, 3 Tender)


4

80

GMP
complex mixtures of proteins, lipids, and
biological materials
(pathogenic)
(transmissible microorganisms)
aseptic process
()

4
(Building 1 (
Quality into the Products) )

unidirectional airflow (UDAF) systems
environmental monitoring 2 (
(EM) )

(Risk management)






3 (
)




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(AEFI) )
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factures protocols)
(Validation)
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2.

(manufactures protocols)
(Good manufacturing practice GMP) 3.
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Practice) NCL
(manufactures protocols)
4. NCL
(Pharmacopoeia)

1. 5. NCL

1.1 (potency) 6.
(safety) (NRA)

(manufactures protocols) 7.
In vitro In vivo test
1.2 8.
1.3 antibody responses preclinical potency (
1.4 immunity ) sterility, innocuity, pyrogen-
2. unfinished bulk icity stability test
materials 9.



(NCL)


strain (origin) master and
(NCL) Lot release working seeds batches

1.
 8 83

(certificate of analysis)

(valida-
tion) strain






(Clinical phase) GCP
(Good Clinical Practice)
pharmacokinetic, pharmacodynamic, clinical safety
efficacy



1.



2.




master formula









84

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(Air lock)
(Air lock) 2 (Double HEPA Filter)


Waste
(Killed
tank) 132 .
(Spore)






(U-shape)






(Curve)



 8 85

(Batch production record)

(Intermediate products)







(Fumigation)
(lint-free)





(Validation)
(Hot Air
or Steam Sterilizer) 2 (Double Doors)




Quarantine Area




86

Endotoxin



9
(EM)
LF (Classification
and environmental monitoring (EM) of clean rooms
and laminar flow work Stations) ISO
14644-1
(in operation) (at rest)
(identification) (seed) 4
Grade A:
laminar air flow
work station 0.36-0.54 /

Grade B: larminar air flow
grade A aseptic preparation

Grade C and D:

(validation)
 8 87

1 EN ISO 14644-1

(Maximum permitted airborne particulate concentration per air grade)1
At rest In operation
Grade Max. permitted particles /m3 Max. permitted particles /m3
0.5 m 5.0 m 0.5 m 5.0 m
A 3,520 20 3,520 20
B 3,520 29 352,000 2,900
C 352,000 2,900 3,520,000 29,000
D 3,520,000 29,000 Not defined Not defined

HVAC

(validation) 12

A B 6
ISO 14644-1 (clean room
routine environmental monitoring according
ISO 14644-1)
(out of trend = OOT)
(validation)














88

2
(Commended limits for microbiological monitoring of clean areas during operation)
Recommended limits for microbial contamination (a)
Air sample Settle plates Contact plates Glove print
Grade cfu/m3 (diam. 90 mm), (diam. 55 mm), 5 ngers
cfu/4 hours (b) cfu/plate cfu/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
: (a) These are average values
(b) Individual settle plates may be exposed for less than 4 hours

3
(Recommended clean room grades for general activities in the manufacture of prequalified vaccines)2
 8 89
90
 8 91

4 (Vaccine - specifie production

activities)
92
 8 93

:
(1)
UDAF in C or D or UNC (unclassified) refers to the situation where a unidirectional airflow system may not be classified as
Grade A (due to the lack of a Grade B surrounding) but can provide significant additional protection to operations.

campaign basis

(seed lot)
(cell bank)

Bacillus
anthracis, Clostridium botulinum Clostridium
tetani


campaign basis
(bio-
logical substances)

94

3 4






(air extraction)

(air-
vent filter) (hydrophobic)


(aero-
sol)




(bioburden)

(positive pressure)

(negative pressure)

(containment requirements)
(air-handling units) (inoculation room)
(process- (postmortem room)
ing area)





4
 8 95

Revised Requirements for Biological
Substances No.7






..
2510








25(3) .. 2510



(preservatives)
(additives)



96










monitor


Quarantine
(Lot Release)




1.


.. 2549.
2. Stern AM, Markel H. The history of vaccines
and immunization: familiar patterns, new challenges.
Health Aff (Millwood). 2005;24:61121.
(Batch 3. Good manufacturing practices for sterile
packaging records) pharmaceutical preparations in: WHO Expert Com-
mittee on Specifications for Pharmaceutical Prepa-
rations. Forty-fourth Report, Geneva, World Health
1 Organization, 2010, Annex 4 (WHO Technical Report
Series 957). Available from: http://whqlibdoc.who.int/
(Follow-up-stability study) trs/WHO_TRS_957_eng.pdf
4. Guided by Experts Committee on Stand-
ardization of Biological (ECBS) recommendations on
safety, efficacy issued in WHO Technical.
 8 97
5. The Washington Post [Internet]: Three ways
to make a vaccine. Available from: http://www.wash-
ingtonpost.com/wp-dyn/content/graphic/2009/11/24/
GR2009112401834.html
6. Thimerosal in vaccines. Center for Biolog-
ics Evaluation and Research, U.S. Food and Drug
Administration; 2007.
7. Muzumdar JM, Cline RR. Vaccine supply,
demand, and policy: a primer. J Am Pharm Assoc.
2009;49:e8799.
8. Bae K, Choi J, Jang Y, Ahn S, Hur B.
Innovative vaccine production technologies: the
evolution and value of vaccine production technologies.
Arch Pharm Res. 2009;32:46580.
9. WHO [Internet]. Environmental monitoring
of clean rooms in vaccine manufacturing facilities;
2011. Available from: http://www.who.int/immunization_
standards/vaccine_quality/env_monitoring_
cleanrooms_draft.pdf
 8 79

5. (Conjugated vaccines)
(subunit) (DTP)
(MMR)

3
(polysaccharide capsule)
(Haemophilus influenzae type b) (Immunization)
100 100
(NRA)


2

1.
(Pre-clinical phase) (fully functional system
+ 6 regulatory functions)



UN Prequalified

Technical Report Series (TRS)
WHO Good Manufacturing Practices
(GMP)
2. (Clinical preclinical clinical
phase)
United Nation (UN
1, 2, 3 Tender)


4

80

GMP
complex mixtures of proteins, lipids, and
biological materials
(pathogenic)
(transmissible microorganisms)
aseptic process
()

4
(Building 1 (
Quality into the Products) )

unidirectional airflow (UDAF) systems
environmental monitoring 2 (
(EM) )

(Risk management)






3 (
)




4 (
(AEFI) )
Lot
release
(Laboratory
assessed)
 8 81

Staphylococcus
6,7
( )
( )5
(
H.influenzae type b)
(recombinant)



8
(ultrafiltration)
(column chromatography)







(pathogen-associated molecular pattern)8

(Good Manufacturing
Practice GMP) PIC/S (Pharmaceutical
International Convention/Scheme)

(Good manufacturing practices, GMP)



82

(manu-
factures protocols)
(Validation)
(Quality Assurance)
2.

(manufactures protocols)
(Good manufacturing practice GMP) 3.
(Good Laboratory
Practice) NCL
(manufactures protocols)
4. NCL
(Pharmacopoeia)

1. 5. NCL

1.1 (potency) 6.
(safety) (NRA)

(manufactures protocols) 7.
In vitro In vivo test
1.2 8.
1.3 antibody responses preclinical potency (
1.4 immunity ) sterility, innocuity, pyrogen-
2. unfinished bulk icity stability test
materials 9.



(NCL)


strain (origin) master and
(NCL) Lot release working seeds batches

1.
 8 83

(certificate of analysis)

(valida-
tion) strain






(Clinical phase) GCP
(Good Clinical Practice)
pharmacokinetic, pharmacodynamic, clinical safety
efficacy



1.



2.




master formula









84

Lint-free
(Air lock)
(Air lock) 2 (Double HEPA Filter)


Waste
(Killed
tank) 132 .
(Spore)






(U-shape)






(Curve)



 8 85

(Batch production record)

(Intermediate products)







(Fumigation)
(lint-free)





(Validation)
(Hot Air
or Steam Sterilizer) 2 (Double Doors)




Quarantine Area




86

Endotoxin



9
(EM)
LF (Classification
and environmental monitoring (EM) of clean rooms
and laminar flow work Stations) ISO
14644-1
(in operation) (at rest)
(identification) (seed) 4
Grade A:
laminar air flow
work station 0.36-0.54 /

Grade B: larminar air flow
grade A aseptic preparation

Grade C and D:

(validation)
 8 87

1 EN ISO 14644-1

(Maximum permitted airborne particulate concentration per air grade)1
At rest In operation
Grade Max. permitted particles /m3 Max. permitted particles /m3
0.5 m 5.0 m 0.5 m 5.0 m
A 3,520 20 3,520 20
B 3,520 29 352,000 2,900
C 352,000 2,900 3,520,000 29,000
D 3,520,000 29,000 Not defined Not defined

HVAC

(validation) 12

A B 6
ISO 14644-1 (clean room
routine environmental monitoring according
ISO 14644-1)
(out of trend = OOT)
(validation)














88

2
(Commended limits for microbiological monitoring of clean areas during operation)
Recommended limits for microbial contamination (a)
Air sample Settle plates Contact plates Glove print
Grade cfu/m3 (diam. 90 mm), (diam. 55 mm), 5 ngers
cfu/4 hours (b) cfu/plate cfu/glove
A <1 <1 <1 <1
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
: (a) These are average values
(b) Individual settle plates may be exposed for less than 4 hours

3
(Recommended clean room grades for general activities in the manufacture of prequalified vaccines)2
 8 89
90
 8 91

4 (Vaccine - specifie production

activities)
92
 8 93

:
(1)
UDAF in C or D or UNC (unclassified) refers to the situation where a unidirectional airflow system may not be classified as
Grade A (due to the lack of a Grade B surrounding) but can provide significant additional protection to operations.

campaign basis

(seed lot)
(cell bank)

Bacillus
anthracis, Clostridium botulinum Clostridium
tetani


campaign basis
(bio-
logical substances)

94

3 4






(air extraction)

(air-
vent filter) (hydrophobic)


(aero-
sol)




(bioburden)

(positive pressure)

(negative pressure)

(containment requirements)
(air-handling units) (inoculation room)
(process- (postmortem room)
ing area)





4
 8 95

Revised Requirements for Biological
Substances No.7






..
2510








25(3) .. 2510



(preservatives)
(additives)



96










monitor


Quarantine
(Lot Release)




1.


.. 2549.
2. Stern AM, Markel H. The history of vaccines
and immunization: familiar patterns, new challenges.
Health Aff (Millwood). 2005;24:61121.
(Batch 3. Good manufacturing practices for sterile
packaging records) pharmaceutical preparations in: WHO Expert Com-
mittee on Specifications for Pharmaceutical Prepa-
rations. Forty-fourth Report, Geneva, World Health
1 Organization, 2010, Annex 4 (WHO Technical Report
Series 957). Available from: http://whqlibdoc.who.int/
(Follow-up-stability study) trs/WHO_TRS_957_eng.pdf
4. Guided by Experts Committee on Stand-
ardization of Biological (ECBS) recommendations on
safety, efficacy issued in WHO Technical.
 8 97
5. The Washington Post [Internet]: Three ways
to make a vaccine. Available from: http://www.wash-
ingtonpost.com/wp-dyn/content/graphic/2009/11/24/
GR2009112401834.html
6. Thimerosal in vaccines. Center for Biolog-
ics Evaluation and Research, U.S. Food and Drug
Administration; 2007.
7. Muzumdar JM, Cline RR. Vaccine supply,
demand, and policy: a primer. J Am Pharm Assoc.
2009;49:e8799.
8. Bae K, Choi J, Jang Y, Ahn S, Hur B.
Innovative vaccine production technologies: the
evolution and value of vaccine production technologies.
Arch Pharm Res. 2009;32:46580.
9. WHO [Internet]. Environmental monitoring
of clean rooms in vaccine manufacturing facilities;
2011. Available from: http://www.who.int/immunization_
standards/vaccine_quality/env_monitoring_
cleanrooms_draft.pdf
 101

Enterobacteriaceae Yersinia
3 Y. pestis, Y. enterocolitica
Y. pseudotuberculosis

Y. pestis1
Y. pestis 3 biovars (orientalis,
mediaevalis antigua) 3 biovars
2
Yersinia pestis .. 2437
Yersin & Hitasato

3
6

24 50
2 14
The Black Death ()


25
3
(Plague) .. 2439
Yersinia pestis bi-
polar staining safety pin
Congo red agar 26-28 . .. 2443-2444
(bull-eye) 60,000
.. 2453-2454 10,000
48 Y. pestis

102

- .. 2552
pneumonic plague

3
9 3
1. (Bubonic plaque)
. 2447


.. 2495

3,4 50-60
2. (Pneumonic plaque)

1-7





95-100
5

3. (Septi-
cemic plaque)




bubonic
plague

6-9

(Septicemic plague) Y. pestis
bipolar-staining coccobaccilli
 9 103

safety-pin cell vaccines; KWC)

Haemagglutination inhibition test 195/P Y. pestis17
Fluorescent antibody United States Pharmacopoeia (USP)
polymerase chain reaction immuno- ..1999
histochemical staining KWC Common-
wealth Serum Laboratories (CSL, Australia)
195/P
10-16 3 x 109/.
streptomycin 30 0.5 . 1-4
././ gentamicin, tetracycline, 6
doxycycline, chloramphenicol, trimethoprim- 1
sulfamethoxazole ciprofloxacin Live attenuated vaccines
chloramphenicol .. 1908
EV76 Y. pestis18


Sub-unit vaccines
sub-unit


recombinant proteins
.. recombinant F1 V proteins alhy-
1946 drogel adjuvanted19-22
phase I 145


sub-unit
( 2 )
sub-unit
phase 1 KWC23


Pre-exposure prophylaxis

Y. pestis
Killed whole-cell vaccines
(Killed whole-
104

1
(Killed whole-cell vaccine)


6 - 2 0.1 . 0.1 .a 0.1 .a 0.1 .b
3-6 0.2 . 0.2 .a 0.2 .a 0.2 .b
7-11 0.3 . 0.3 .a 0.3 .a 0.3 .b
> 12 0.5 . 0.5 .a - 0.3 .c
a
1-4
b
6
c
6 0.1 . (intradermal)

F1
24 1:128 27,28

F1 V
bubonic form
F1 V
Post-exposure prophylaxis
KWC sub-
unit recombinant F1 V proteins phase I
32
sub-unit ( 21
) 1 F1 29

Y. pestis
KWC KWC
6
passive
sub-
unit recombinant F1 V proteins
8-12 30
KWC
F1
25
F1 26 .. 1961-1971
 9 105

(333
/106 person-year of exposure) 18

KWC
(1 /106 person-year of exposure) 24,31

KWC
KWC
sub-unit
32
KWC
EV76 sub-
unit Y. pestis
KWC 33
sub-unit recombinant
F1 V proteins

25,34

35

KWC

1036,37 KWC
EV76
20 38 sub-unit

33,38 Yersinia secretory protein
sub-unit recombinant F1 V F
proteins 39
39

106

12. Koirala J. Plague: disease, management,

1. Brubaker RR. Factors promoting acute and
chronic diseases caused by yersiniae. Clin Microbiol
Rev. 1991;4:309-24.
2. Perry RD, Fetherston JD. Yersinia
pestis--etiologic agent of plague. Clin Microbiol Rev.
1997;10:35-66.
3. Prentice, MB, Rahalison, L. Plague. Lan-
cet. 2007; 369:1196-207.
4. , Am J Med. 1953; 14:284-93.
15. Boulanger LL, Ettestad P, Fogarty JD,
. Dennis DT, Romig D, Mertz G. Gentamicin and tetra-
. 2552;40:497-50. cyclines for the treatment of human plague: review of
5. Ratsitorahina, M, Chanteau, S, Rahalison,
L, Ratsifasoamanana L, Boisier P. Epidemiological
and diagnostic aspects of the outbreak of pneumonic
plague in Madagascar. Lancet. 2000;355:111-3.
6. Crook, LD, Tempest, B. Plague. A clinical
review of 27 cases. Arch Intern Med. 1992; 152:1253-6.
7. Centers for Disease Control and Preven-
tion (CDC). Human plague--United States, 1993-1994.
MMWR Morb Mortal Wkly Rep. 1994;43:242-6.
8. Weniger, BG, Warren, AJ, Forseth, V,
Shipps GW, Creelman T, Gorton J, et al. Human bu-
bonic plague transmitted by a domestic cat scratch.
JAMA. 1984;251:927-8.
9. Butler, T. Yersinia infections: centennial
of the discovery of the plague bacillus. Clin Infect Dis.
1994;19:655-61.
10. Anisimov AP, Amoako KK. Treatment of
plague: promising alternatives to antibiotics. J Med
Microbiol. 2006;55:1461-75.
11. Meyer KF. Modern therapy of plague. J
Am Med Assoc. 1950;144:982-5.
and recognition of act of terrorism. Infect Dis Clin North
Am. 2006;20:273-87.
13. Mwengee W, Butler T, Mgema S, Mhina G,
Almasi Y, Bradley C, et al. Treatment of plague with
gentamicin or doxycycline in a randomized clinical trial
in Tanzania. Clin Infect Dis. 2006;42:614-21.
14. Mccrumb FR, Mercier S, Robic J, Bouillat
M, Smadel JE, Woodward TE, et al. Chloramphenicol
and terramycin in the treatment of pneumonic plague.
75 cases in new Mexico, 1985-1999. Clin Infect Dis.
2004;38:663-9.
16. Nguyen-Van-Ai, Nguyen-Duc-Hanh,
Pham-Van-Dien, Nguyen-Van-Le. Letter: Co-trimox-
azole in bubonic plague. Br Med J. 1973;4:108-9.
17. Williams JE, Altieri PL, Berman S, Lo-
wenthal JP, Cavanaugh DC. Potency of killed plague
vaccines prepared from avirulent Yersinia pestis. Bull
World Health Organ. 1980;58:753-6.
18. Meyer KF, Smith G, Foster LE, Marshall
JD Jr, Cavanaugh DC. Plague immunization. IV. Clini-
cal reactions and serologic response to inoculations
of Haffkine and freeze-dried plague vaccine. J Infect
Dis. 1974;129(Suppl):S30-6.
19. Leary SE, Williamson ED, Griffin KF, Rus-
sell P, Eley SM, Titball RW. Active immunization with
recombinant V antigen from Yersinia pestis protects
mice against plague. Infect Immun. 1995;63:2854-8.
20. Simpson WJ, Thomas RE, Schwan TG.
Recombinant capsular antigen (fraction 1) from Yer
sinia pestis induces a protective antibody response in

BALB/c mice. Am J Trop Med Hyg. 1990;43:389-96.
21. Miller J, Williamson ED, Lakey JH, Pearce
MJ, Jones SM, Titball RW. Macromolecular organisa-
tion of recombinant Yersinia pestis F1 antigen and the
effect of structure on immunogenicity. FEMS Immunol
Med Microbiol. 1998;21:213-21.
22. Carr S, Miller J, Leary SE, Bennett AM, Ho
A, Williamson ED. Expression of a recombinant form of
the V antigen of Yersinia pestis, using three different
expression systems. Vaccine. 1999;18:153-9.
23. Heath DG, Anderson GW Jr, Mauro JM,
Welkos SL, Andrews GP, Adamovicz J, et al. Protec-
tion against experimental bubonic and pneumonic
plague by a recombinant capsular F1-V antigen fusion
protein vaccine. Vaccine. 1998;16:1131-7.
24. Prevention of plague: recommendations
of the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep. 1996;45:1-15.
25. Williamson ED, Eley SM, Griffin KF, Green
M, Russell P, Leary SE, et al. A new improved sub-
unit vaccine for plague: the basis of protection. FEMS
Immunol Med Microbiol. 1995 ;12:223-30.
26. Williams JE, Cavanaugh DC. Measur-
ing the efficacy of vaccination in affording protection
against plague. Bull World Health Organ. 1979;57:309-
13.
27. Meyer KF. Effectiveness of live or killed
plague vaccines in man. Bull World Health Organ.
1970;42:653-66.
28. Marshall JD Jr, Cavanaugh DC, Bartel-
loni PJ, Meyer KF. Plague immunization. 3. Serologic
response to multiple inoculations of vaccine. J Infect
Dis. 1974;129:(Suppl):S26-9.
29. Williamson ED, Flick-Smith HC, Lebutt
C, Rowland CA, Jones SM, Waters EL, et al. Hu-
9 107
man immune response to a plague vaccine compris-
ing recombinant F1 and V antigens. Infect Immun.
2005;73:3598-608.
30. Williamson ED, Vesey PM, Gillhespy KJ,
Eley SM, Green M, Titball RW. An IgG1 titre to the
F1 and V antigens correlates with protection against
plague in the mouse model. Clin Exp Immunol. 1999
;116:107-14.
31. Cavanaugh DC, Elisberg BL, Llewellyn CH,
Marshall JD Jr, Rust JH Jr, Williams JE, et al. Plague
immunization. V. Indirect evidence for the efficacy of
plague vaccine. J Infect Dis. 1974 ;129(Suppl):S37-40.
32. Cohen RJ, Stockard JL. Pneumonic
plague in an untreated plague-vaccinated individual.
JAMA. 1967;202:365-6.
33. Russell P, Eley SM, Hibbs SE, Manchee
RJ, Stagg AJ, Titball RW. A comparison of Plague
vaccine, USP and EV76 vaccine induced protection
against Yersinia pestis in a murine model. Vaccine.
1995;13:1551-6.
34. Williamson ED, Eley SM, Stagg AJ, Green
M, Russell P, Titball RW. A sub-unit vaccine elicits IgG
in serum, spleen cell cultures and bronchial washings
and protects immunized animals against pneumonic
plague. Vaccine. 1997;15:1079-84.
35. Jones SM, Griffin KF, Hodgson I, Wil-
liamson ED. Protective efficacy of a fully recom-
binant plague vaccine in the guinea pig. Vaccine.
2003;21:3912-8.
36. Reisman RE. Allergic reactions due to
plague vaccine. J Allergy. 1970;46:49-55.
37. Marshall JD Jr, Bartelloni PJ, Cavanaugh
DC, Kadull PJ, Meyer KF. Plague immunization.
II. Relation of adverse clinical reactions to multi-
ple immunizations with killed vaccine. J Infect Dis.
108

1974;129(Suppl):S19-25.
38. Meyer KF, Cavanaugh DC, Bartelloni
PJ, Marshall JD Jr.Plague immunization. I. Past and
present trends. J Infect Dis. 1974;129(Suppl):S13-8.
39. Matson JS, Durick KA, Bradley DS, Nilles
ML. Immunization of mice with YscF provides protec-
tion from Yersinia pestis infections. BMC Microbiol.
2005;5:38.
 109

10

.. 2264 Lady Mary Wortley
Variolation Montagu

Dr. Zabdiel Boylston
Cotton Mather
(Mode of In- Variola-
fection) tion 23

(Rinderpest,
) (sheep pox)

1 Lady Mary Wortley Montagu 2

( )
110

.. 2339
Edward Jenner Berkeley, Gloucestershire
Vaccinia virus
(Cow pox)
neurovirulence
(post-vaccinal encephalitis)

(Vaccine) Vacca (generalized vaccinia)
2 (eczema vaccinatum)
75
An Inquiry into the Causes and Effects of the Vari-
olae Vaccinae, A Disease Discovered in Some of the
Western Countries of England, Particularly Glouces- 1.
tershire and Know by the Name of the Cowpox
2.
(cow-to-human)
3.
(Human-to-Human arm-to-arm)
6 4.


1.
arm-to-arm

(Humanized Vaccinia Virus)
(chorioallantoic
membrane)
Vaccinia virus
(original cowpox virus)

Variolation
.. 2383 Variolation
avian leukosis virus
(cross-
immunization)
 10 111

11.5 108 pock forming unit pfu

0.03 1 .

(jet injector) (scar) 4 .
3 - 6
(killed vaccine) (live vaccine)

Ehrengut (freeze-dried lyophilization in vacuo)
(primary vaccination)


(Lister Institue, Estree)
45 . 6





2.



.. 2517
5

1. 3.

2.
3.

4. chorioallan-
toic membrane 12 48
35 . (pock)
112

Thomas Rivers

The first revived strain
CV1
3 The second revived strain CV2

1. (Primary vaccination)

Modified Vaccinia Ankara Virus
MVA
(.. 2553) Primary take
Papule 5
(Vesicle) 7 - 10

(multilocular)
0.5 1.5 .
Jennerian vesicle
Pustule

major reaction

1

crust
3

foveation smallpox
vaccination scar
pox mark

8

2. (Revaccination)

 10 113

pox mark

2.1 (Successful revaccina-
tion) major reaction 1
(vesicle)
(pustule) (induration)
(congestion)
( vaccinoid
reaction accelerated reaction (non-endemic area)
major reaction) 1-2
2.2 (Equivocal reaction) (Post vaccinal
encephalitis, PVE)
2 - 3 1 2-10

(allergic reaction)
( Reaction of
immune Immediate reaction Allergic reac-
tion)
2-3
6






/
Dysgamma globulinemia
Blood dyscrasia
Eczema dermatitis

(Immunosuppressive agents)


114

vaccinia immune
gamma globulin
2.
(Live at- dermatotro-
tenuated virus vaccine) pism


2.1 Generalized vaccinia

1.
6
2. 6-9
2.2 Eczema vaccinatum
5
3.
3
2.3 Vaccinia gangrenosa


1.

() vaccinia
immune gamma globulin

( 70%

3. Post Vaccinal Encephalitis (PVE)
) PVE
8-15

Clostridium tetani, Escherichia 10 1
coli, hemolytic Streptococci Bacillus anthracis Vaccinia gamma
(non-pathogenic globulin
bacteria) 500 1 .
 10 115

4. Post vaccinal myocarditis ed needle) (

)

5.


3 4
(Bifurcated needle) (Hagedorn needle)




1. Multiple pressure method

Hagedorn needle 6
6-10 10 .
(
50 )
2. Scratch method 7
Hagedorn needle
6.5 . 40 Glycerin M/30 dil. Mc Ilvaine buffer, pH 7.6



1. , .
3. Multiple puncture method .
(Bifurcat- . 2464;4:75.
116

2. Brown CM. Smallpox immunization. The

practitioner. 1959;183:253-7.
3. Kempe CM. Studies on smallpox and
complication of smallpox vaccination. Pediatrics. 1960;26:
176-89.
4. Cox CR. WHO expert committee on smallpox.
First report. World Health Organ Tech Rep Ser. 1964;283:
1-37.
5. Kaplan C. Smallpox vaccine:present status,
suggested use, desirable development. lbid. 144.
6. . .
. 2517;2:342.
7. Ehrengut W, Weise HJ. Am Ende der
Pockenimpfpflicht. Kongress-dienst Bayer. 1975;36:1.
 117

11

1,2
(Tick-borne
encephalitis, TBE)


Tick borne encephalitisvirus
(TBE virus)
3 TBE


Langat virus (LGTV)
TBE LGTV .. 1937

.. 1956 1 Russian Spring and Summer
encephalitis (RSSE)


2 .. 1974 2003
4
2,755 ( .. 1973) 8,755
( .. 1996 10,298 )
(hard tick)

accidental host
3
.. 1980

118

TBE
LIV
10 1,3
TBE FE-TBE
15 S-TBE W-TBE 1,2
10,000-12,000 TBE
3
larva nymph adult
TBEV family
Flaviviridae, genus Flavivirus

50 nymph
structural protein prM E protein
capsid protein
RNA 1 Ixodes persulcatus
11 FE-TBE
structural nonstructural protein (NS1-5) Ixodes ovatus Ixodes ricinus
4
genus Flavivirus TBE 0.1-0.52 TBE
(Ixodes spp.)
5

TBE

3 (subtype) Far Eastern (FE-TBE),
Siberian (S-TBE) Western European (W-TBE)
Flavivirus
TBEV 1,2
Louping ill virus (LIV), Langat virus (LGTV), Powassan
(POWV), Omsk hemorrhagic fever virus (OHFV),
Kyasamur Forest disease virus (KFDV), Kadan virus TBE
Langerhans cells
TBE (Regional
( lymph node)
80) T lymphocyte, B lymphocyte
 11 119

mediator
TBE febrile form

blood brain barrier 7-14

(ataxia) Meningoencephalitis form
(paresis, paralysis)
(coma)


gray matter lymphocyte 30
glial cell

2,5
60
Poliomyelitic form
7-10 (4-28) 5
2-7
( 38-39o .)

(fasciculation) 2

1-2 (wrist drop) (hanged head)
2-10 2-3


1-2 o .
Polyradiculoneuritic form
6
(biphasic) 3-7
Febrile form 1/3
1-5
1-2

Meningeal form
120

Chronic form Siberia
Far East
subtype Siberian
10-20 ()

75 C-reactive protein
80 ESR 90




mononuclear cell
(Kozshevnikovs epilepsy) ,
Parkinson syndrome
60 /.. 31
severe dementia
100 /..


1,000 /.. neutrophil
Siberia S-TBE febrile form mononuclear cell
80 paralytic form
7-8 chronic form 4-5
7 ELISA IgG IgM
Far East
meningoencephalitis IgG

601,2

cross reaction
flavivirus neutralization test
6
RNA RT-PCR
systemic infection 1/3 2,7
 11 121

10



(secondary prophylaxis) 96
60 TBE S-TBE
FE-TBE W-TBE
antibody dependent enchancement3 ( W-TBE)
W-TBE

FSME-immun

(inactivated)
.. 1940
TBE




TBE
active antigen
FSME-immun (TicoVac) Encepur



96-99
3 TBE

TBE far-eastern 205
3 Sofjin 1
60
FSME-immun
2 FSME-immun
Encepur
122

- FSME-immun
.. 1970
Neudoerfl 2,8-10

- Encephur TBE 12
.. 1994 (Encepur-adults)/ 16 FSME-immun-adults)
Novartis ( Chiron) 1.5 (Encepur-adults)
K53 2.4 (FSME-adults) 0.5 .
Karlsruhe 12 (Encepur-children)/ 16
(FSME-immun-junior)
master seed virus embryonic 0.25 .2
fibroblast cell inactivated formaldehyde 1
ultracentrifugation
sucrose gradient
adjuvant (aluminium hydroxide) 2-8o .

1 inactivated TBE vaccine

Vaccine Encepur adult Encepur children FSME-immun adult FSME-immun junior
Type of vaccine Inactivated vaccine
Manufacturer Novartis, Germany Baxter AG, Austria
Composition
Antigen details
Strain K-23 K-23 Neudoerfl Neudoerfl
Amount of 1.5 0.75 2.4 1.2
antigen (g)
Excipients
Adjuvant Al(OH)3
Stabilizer sucrose Human serum albumin
Adjusted (mL) 0.5 0.25 0.5 0.25
Vaccine Schedule
Age limit (years) >12 <12 >16 <16
nd
Standard vaccine 0, 1-3 month, 5-12 months after 2 dose
schedule (Booster) (every 5 years for adults and every 3 years for children/elders)
Rapid vaccine 0, D7, D21 (12-18 month*) 0, WK2 (5-12 month after 2nd dose*)
schedule
(* for long term protection)
Route IM
( 2, 7)
 11 123

99
7-9,11
3 0, 1-3
5-12
1

5 16-50
(FSME-immun-adult) 12-50 (Encepur-
adult) 3 35-45

FSME-immun-adults
FSME-immun Encepur-adults
Encepur 2
FSME-immun 8
38o .

15, 5 2-5 1-2 , 3-11
FSME-immun 0, 2 12
5-12
Encepur 15
0, 7 21 12-18 7,8
2 .. 1997-1998
Encepur-children

Polygeline stabilizer
aluminum hydroxide
2
(seroconversion) 90-100 encepur .. 2001 stabilizer

( 85-95)

stabilizer10

TBE


124

1 3


1 : 10,0001 LGTV
TBE
category C

12










0.9 : 1,000
.. 1970
Langat virus (LGTV) Elantcev15-20/3 1 : 10,000
TBE
LGTV flavivirus
TBE
12-18 7
6


(Future vaccine)

10 Live attenuated vaccine
20

100 1

 11 125

immunogenicity of the modified adult tick-borne en-
cephalitis vaccine FSME-IMMUN: results of two large
phase 3 clinical studies. Vaccine. 2006;24:5256-63.
viral like particle recombinant 9. Pllabauer EM, Pavlova BG, Lw-Baselli A,
subviral particles, DNA vaccine, Fritsch S, Prymula R, Angermayr R, et al. Comparison
non structural protein subunit of immunogenicity and safety between two paediatric
DEN-4 TBE vaccines. Vaccine. 2010;28:4680-5.
TBE 13,14 10. Zent O, Hennig R, Banzhoff A, Brker
M.Protection against tick-borne encephalitis with a new
vaccine formulation free of protein-derived stabilizers.
J Travel Med. 2005;12:85-93.
11. Demicheli V, Debalini MG, Rivetti A.
1. Gritsun TS, Lashkevich VA, Gould EA. Vaccines for preventing tick-borne encephalitis.
Tick-borne encephalitis. Antiviral Res. 2003;57:129-46. Cochrane Database Syst Rev. 2009;(1):CD000977.
2. Kaiser R.Tick-borne encephalitis.Infect. 12. Dumpis U, Crook D, Oksi J.Tick-borne
Dis Clin North Am. 2008;22:561-75. encephalitis. Clin Infect Dis. 1999;28:882-90.
3. Mansfield KL, Johnson N, Phipps LP, 13. Pletnev AG, Bray M, Hanley KA, Speicher
Stephenson JR, Fooks AR, Solomon T.Tick-borne J, Elkins R. Tick-borne Langat/mosquito-borne den-
encephalitis virus - a review of an emerging zoonosis. gue flavivirus chimera, a candidate live attenuated
J Gen Virol. 2009;90:1781-94. vaccine for protection against disease caused by
4. Gould EA, Solomon T.Pathogenic members of the tick-borne encephalitis virus complex:
flaviviruses. Lancet. 2008;371:500-9. evaluation in rhesus monkeys and in mosquitoes.
5. Haglund M, G nther G. Tick-borne J Virol. 2001;75:8259-67.
encephalitis--pathogenesis, clinical course and 14. Pripuzova NS, Tereshkina NV, Gmyl LV,
long-term follow-up. Vaccine. 2003;21(Suppl 1):S11-8. Dzhivanyan TI, Rumyantsev AA, Romanova LIu,et
6. Holzmann H. Diagnosis of tick-borne al. Safety evaluation of chimeric Langat/Dengue 4
encephalitis. Vaccine. 2003;21(Suppl 1):S36-40. flavivirus, a live vaccine candidate against tick-borne
7. . encephalitis. J Med Virol. 2009;81:1777-85.
Tick-Borne Encephalitis. :
, , ,
, , . Travel and
adult immunization.:;
2552. .210-3.
8. Loew-Baselli A, Konior R, Pavlova BG,
Fritsch S, Poellabauer E, Maritsch F, et al. Safety and
76
 127

12

2,000

4-6 .. 2552

Japanese encephalitis (JE) 543 0.86
arbovirus family Flaviviridae, genus 106
Flavivirus Culex tritaeniorhynchus ( 19.52) 0.17

10-35 15 0-4
30-501-3 1.1
5-9 15 10-14
0.3, 0.09 0.08
7

18

.. 2468
19 1 : 300 1 : 1000

Culex




.. 2512


5-15 1-3

128

8,9 4,9

(inapparent infection) aseptic meningitis
(encepha-
litis) 3
1. Prodromal stage

1-6
2. Acute encephalitic stage
10-1,000 / ..

pyramidal tract signs, flaccid
paralysis deep tendon reflex
10
1 2 9
2

3. Late stage and sequele


(viral isolation)

10
1. JE virus-specific IgM antibody
4 7
.. 2522
(AFRIMS)
anti-JE IgM IgG
ELISA
anti-JE IgM 80
antidiuretic hormone (SIADH) 5 11
2. JE virus antigens
immunohistochemistry
3. JE vius genome

 12 129

reverse transcriptase polymerase chain reaction placebo-controlled trial

(PCR)
4. interferon alpha 2a 16
ribavirin salicylates
5. 4 JE
virus-specific IgG antibody 10
hemagglutination inhibition (HI) plaque reduction
neutralization assay (PRNT) 17
14 (acute convalescent sera)

cross reactivity 1.
Flavivirus
2. amplifying host
3.
4 4.

(JEV)
mannitol .. 2473
10 dexamethasone


12
controlled clinical
trials Neutralizing murine monoclonal
antibodies .. 2495

13
interferon 10

uncontrolled series
14 recombinant
interferon-alpha 13 14,15
randomized double-blind
130

SA14-14-2
vero cell Intercell

IXIARO

2.
1. (Inactivated vaccine) (Live-attenuated vaccine)
1.1 (Inactivated 2.1
mouse brain JEV)
SA14-14-2 primary hamster kidney cells
(PHK) Biogenetech
CD.JE VAX
2.2
Nakayama Acambis
Cosma medical 0.5 ./ PrM E SA14-
3 1 ./ 3 14-2 PrM E
DS Japanese Encephalitis vaccine 17D structural protein
Beijing non-structural
0.25 ./ 3 protein
0.5 ./ 3 Flavivirus
JE (Beijing)-GPO vaccine Chimeri Vax
1.2 (Inactivated IMOJEV
cell culture-derived JEV)
SA14-14-2 1
hamster kidney cell

1


Nakayama Beijing SA14-14-2
DS JEV (Nakayama) CD.JE VAX
JEV-GPO (Beijing)
 12 131

Inactivated mouse brain JEV Inactivated mouse brain JEV 2
2-8o . 9419
(lyophilized) -10o . 80-9120,21
90-100 22,23
Live-attenuated JEV 2-8o . Nakayama Beijing
20,21
Live-attenuated JEV
2 150 seroconversion 89.3
Live-attenuated JEV Inactivated 95.0 30 90
mouse brain JEV 100 2
Inactivated mouse brain JEV 9922
Live-attenuated JEV
3 99.3 96.5 12-15 5

2

*
12-18 9-12
2 1-4 3-12
1
Beijing 0.5 . 0.5 .
Nakayama 1 .
3
:
* 1. 1 ( 4) 3 3-5
5
2. Nakayama Beijing

3 Live-attenuated JEV
Inactivated mouse brain JEV
Inactivated JEV Live-attenuated JEV
2 3-12
1 2 3-12
2-3 1 1
4
( 18)
132

1 23,24 95-100
2 25

IXIARO Inactivated cell
culture-derived JEV Inactivated mouse brain JEV
0, 28 1
phase III 23
83, 53 48 13
6 1 2 angioedema 2
0.2-0.6
100 29,30

9 6
11 1:50-
99 75,000 1: 1

11 Live-attenuated JEV
26 9.3 6.7
hypersensitivity
ChimerivaxJE (IMOJEV) 18


1 1. 12-18

99.1 2. 1
3 ( 95.1)
1
93.6 10
14
1 Inactivated mouse
brain JEV 3 0, 7 30
27,28 0, 7 1431

1 28
1
 12 133

Japanese Encephalitis Virus .

1. 12. 2541;9:65-71.
2. 7. , ,
3. . Situation of encephalitis and Japanese B
4. Live-attenuated JEV Encephalitis, Thailand, 2009. Weekly Epidemiological
Surveillance Report. 2010;41:33-5.
5. 8. , . Viral
1 meningitis encephalitis .
. 2528;2:6-10.
9. Thisyakorn U, Nimmannitya S. Japanese en-
cephalitis in Thai children, Bangkok, Thailand. Southeast
Asian J Trop Med Public Health. 1985;16:93-7.
10. Halstead SB, Jacobson J. Japanese
1. Thisyakorn U, Thisyakorn C. Japanese encephalitis vaccines. In: Plotkin SA, Orenstein WA,
encephalitis. In: Dupont HL, Steffen R, editors. Offit PA, editors. Vaccines. 5th ed. Elsevier Inc.; 2008.
Textbook of Travel Medicine and Health. 2nd ed. p.311-52.
Hamilton: B.C. Decker Inc.; 2001. p.312-4. 11. Burke DS, Nisalak A, Ussery MA. Antibody
2. Thisyakorn U, Thisyakorn C. Diseases capture immunoassay detection of Japanese encephalitis
caused by arboviruses: dengue haemorrhagic fever and virus immunoglobulin M and G antibodies in
Japanese B encephalitis. Med J Aust. 1994;160:22-6. cerebrospinal fluid. J Clin Microbiol. 1982;16:1034-42.
3. Thisyakorn U, Thisyakorn C. Studies on 12. Hoke CH Jr, Vaughn DW, Nisalak A,
Flaviviruses in Thailand. In: Miyai K, Ishikawa E, Intralawan P, Poolsuppasit S, Jongsawas V, et al.
editors. Progress in Clinical Biochemistry: Proceedings Effect of high-dose dexamrthasone on the outcome of
of the 5th Asian-Pacific Congress of Clinical Biochemistry; acute encephalitis due to Japanese encephalitis virus.
1991 Sept 29-Oct 4; Kobe, Japan. Amsterdam: Ex- J Infect Dis. 1992;165:631-7.
cerpta Medica; 1992. p.985-7. 13. Ma WY, Jiang SZ, Zhang MJ, et al.
4. . Preliminary observations on treatment of patients with
. : , , . Japanese B encephalitis with monoclonal antibody. J
. : ; 2536. Med Coll PLA. 1992;7:299-302.
.89-97. 14. Harinasuta C, Nimmanitya S, Thisyakorn
5. , , U. The effect of interferon-alpha A on two cases of
, Hoke CH, Gingrich J, Leake E. Outbreak Japanese encephalitis in Thailand. Southeast Asian J
of Japanese encephalitis-Bangkok Metropolis. Trop Med Public Health. 1985;16:332-6.
. 2527;15:573-6. 15. Harrington DG, Hilmas DE, Elwell MR,
6. , . Whitmire RE, Stephen EL. Intranasal infection of
134

monkeys with Japanese encephalitis virus: clinical control study. Lancet. 2005;366:1375-8.
response and treatment with a nuclease-resistant 24. Tandan JB, Ohee H, Sohn YM, Yoksan
derivative of poly (I).poly (C). Am J Trop Med Hyg. S, Ji M, Nam CK, et al. Single dose of SA14-14-2
1977;26:1191-8. vaccine provides long-term protection against
16. Solomon T, Dung NM, Wills B, Kneen Japanese encephalitis: a case-control study in Nepalese
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, , V, Gartner-Woelfl G, Kaltenboeck A, Schuller E, et
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31. American Academy of Pediatrics. Arbovi-

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SS, editors. Red Book 2009 Report of the Committee
on Infectious Diseases. 28th ed. Elk Grove Village, IL:
American Academy of Pediatrics; 2009. p.214-20.
76
 137

13
,

(Influenza)

influenza virus (Influenza virus) RNA
1-3 Orthomyxoviridae matrix
protein (M) internal antigen
5-7 7-8 influenza virus 3 A,
2 B C influenza A B 8
4-6 influenza C 7 (surface anti-
gen) haemagglutinin (HA) neuraminidase (NA)
(Antigenic drift) haemagglutinin
A
B
(Seasonal influenza) C
(Antigenic shift)
(Pandemic influenza)
10 - 40 A
.. 2552 A (H1N1) subtype surface antigen haemagglu-
2009 tinin neuraminidase haemagglutinin
7,8 16 subtype (H1-H16) neuraminidase
9 subtype (N1-N9) haemagglutinin
neuraminidase A
A
haemagglutinin H1-H3 neuraminidase
N1 N2 subtype

H1N1, H2N2 H3N2
A surface antigen H1
138

H16 N1-N9 (..-..)

.. 2461 (1918) H1N1 Spanish flu
H5N19 .. 2500 (1957) H2N2 Asian flu
.. 2511 (1968) H3N2 Hong Kong flu
.. 2520 (1977) H1N1 Russian flu
A B
. .. 2552-2553
A/New Calidonia/20/99/ [H1N1]
A New Calidonia A H1N1
20 . 1999 H1N1/09 (pandemic H1N1/09 virus)
H1N1 H1N1 2009


30 (reassortment)
10 13 H1N1 2009
14




900,000

36,000 1
300 11 .. 2552
120,400
189.73 columnar
.. 2552 3 - 5

A(H1N1) 2009 231 3-4
0.36
0.1912
1-4 2
2-3
20

 13 139

40


26-29

90
Influenza virus
Influenza-like illness
6,7
3
.. 2461, 2500 255215-20 nasal swab nasopha-
ryngeal aspirate throat swab
3 viral culture, rapid diagnostic (antigen) testing,
reverse transcription polymerase chain reaction (RT-
PCR) immunofluorescence assays30

10-14


(influenza rapid diagnostic
2 test kit)
65 21-25 immunochromatography
15- 30 influenza A
influenza B

90
20-70
RT-
(encephalitis) PCR viral culture31-35 rapid diagnostic
(encephalopathy) test 36
Guillain-Barr (Reye
syndrome) A (H1N1)
2009 rapid diagnostic test
A (H1N1) 2009 62.7
99.2 < 2
76.737
140

2-49

38-45
(oseltamivir)
(zanamivir) 3
Influenza A 2 H1N1
46 H3N2 Influenza B 1




antigenic drift
shift
48

1 .. 2010
(- ..
2553) 2010-11
( .. 2553-
.. 2554) 2011

(-
.. 2554)
2011-12 ( ..
.. 1940 2554- .. 2555)
inactivated whole virus
vaccine 47,48
.. 1970 -A/California/7/2009 (H1N1)-like virus
split vaccine subunit vaccine -A/Perth/16/2009 (H3N2)-like virus
-B/Brisbane/60/2008-like virus
haemagglutinin circulating antibody A B
.. 2010-2012
circulating antibody
2
 13 141

1. (Live-attenu-
ated influenza vaccine; LAIV)
2. (Trivalent
inactivated influenza vaccine; TIV)

Live-attenuated influenza vaccine (LAIV) LAIV

TIV (mucosal immunity)
(humoral immunity) LAIV
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146

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 153

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2-3 1,5 neutralization test

2. (period of remission)
1-2 RT-PCR
7
15

3. (period of intoxication)


- Passive antibody
monoclonal antibody
20-50
7-10 passive antibody

- Immunomodulators
1,6,7
interferon




- Ribavirin
hepatitis C
Flaviviridae


Ribavirin


2
(delay onset encephalitis)

IgG IgM Nonstructural protein fla-
vivirus
flavivirus flavivirus
156

8
secondary seed .. 1957

(seed virus)
neurovirulence viscerotropism


19
.. 1927
human serum
2

French neurotropic vaccine (FNV) human serum
17D3,4
.. 1962
FNV
Dakar passage avian leukosis virus oncogenic virus


passage viscerotropic 3
(neurotropic) .. 1982 17 D (2
sub-strains YF 17DD YF 17D-204)1
.. 1940

( 56 .. 1953)
.. 1985

.. 1950
(Backbone

17D .. 19824
virus) flavivirus
17 D (YFV 17D)



Ghana

100 passage 3
.. 1940 YF 17DD
YF 17D-204
( .. 1937-1941)
passage 7


YF 17D-204
human serum passage Stamaril
 14 157

Stamaril YF
17D-204 1,000 LD50
lactose, sorbitol, L-histidine hydrochloride, 1
L-alanine, sodium chloride, potassium chloride, diso-
dium phosphate, monopotassium phosphate, calcium
chloride, magnesium sulphate 10

(Sodium chloride solution) prefilled
syringe



2-8 .
10

25 3-7

0.5 .
1
10 ( 100 PFU/.)
3-7
IFN-,
86-90 TNF- T- cell
10 1
99-100 30
10 6,9,10 10
3
9 (hypersensitivity)
(yellow fever vaccine associated neurotropic disease;
30 8011 YEL-AND)
(yellow fever vaccine associated viscerotropic
disease; YEL-AVD)
Hypersensitivity

158

( 10 ) 7
1: 58,000-131,000
stabilizer
YEL-AND
1/
(0.5-4 subsahara
1,000 ) .. 1999-2006 10
29 6-78

1 (CD4
< 200/..)6,7

2 E protein
YEL-AND
10
YEL-AND
3-28 1. 6
YEL-AND)

(100-500 /..) 6-12

IgM
6
YEL-AVD 2.
.. 200112 YEL-AVD 10
.. 2010
YEL-AVD 57 3.
13 YEL-AVD
3-4 /14
YEL-AVD



(prednisolone 10 ./ )
65 7-30 2
 14 159

(CD4 <200 /..)

10
1. 6-12
(International Certificates of Vaccination; yellow book)

10
9 9-12 10
6
6-9
2. ( 60 )
9-12
YEL-AVD



3.


1 41

1.

. 02-3069146-7
2.

1 . 02-5903430 (
)
3.
.. 2008 .
1 . 02-2873101-3
YFL-AND7 4.
4. . 02-252-0161-4
5. 10 .
. 053-276364 106
160

6.
- . 02-535-1482,
02-535-4245
- () . 02-249-4110,
02-249-4418 .. 2008
- . 053-922-133,
053-200-647 17DD
- . 074-251-548
- . 076-351-128 15
- . 038-401-112 .. 2010
- . 074-331-206, 074-332-641 inactivate beta-
- . 076-212-108 propiolactone adjuvant (aluminum hydroxide)






2,15

1
Contraindication
Age <6 months
Thymus disease or history of thymus disease
Immunosuppression
Precautions
Age 6-12 months
Age 60 years for first dose vaccine
Pregnancy
Lactation
Asymptomatic HIV infection with laboratory verification of adequate immune system function
Hypersensitivity to eggs
Hypersensitivity to gelatin
( 10)
 14 161

2 *
Country US CDC Yellow Fever Vaccine Recommendations
Africa
Angola For all travelers 9 months of age
Benin For all travelers 9 months of age
Burkina Faso For all travelers 9 months of age
Burundi For all travelers 9 months of age
Cameroon For all travelers 9 months of age
Central African Republic For all travelers 9 months of age
Chad For all travelers 9 months of age traveling to areas south of the Sahara Desert
Congo (Democratic For all travelers 9 months of age
Republic of Kinshasa)
Congo (Republic of For all travelers 9 months of age
the Brazzaville)
Cte dIvoire (Ivory Coast) For all travelers 9 months of age
Equatorial Guinea For all travelers 9 months of age
Ethiopia For all travelers 9 months of age
French Guiana For all travelers 9 months of age
Gabon For all travelers 9 months of age
Gambia For all travelers 9 months of age
Ghana For all travelers 9 months of age
Guinea For all travelers 9 months of age
Guinea-Bissau For all travelers 9 months of age
Kenya For all travelers 9 months of age. The cities of Nairobi and Mombasa have lower
risk of transmission than rural areas.
Liberia For all travelers 9 months of age
Mali For all travelers 9 months of age traveling to areas south of the Sahara Desert
Mauritania For all travelers 9 months of age traveling to areas south of the Sahara Desert
Niger For all travelers 9 months of age traveling to areas south of the Sahara Desert
Nigeria For all travelers 9 months of age
Rwanda For all travelers 9 months of age
So Tom and Prncipe For all travelers 9 months of age
Senegal For all travelers 9 months of age
Sierra Leone For all travelers 9 months of age
Somalia For all travelers 9 months of age
Sudan For all travelers 9 months of age traveling to areas south of the Sahara Desert,
EXCLUDING the city of Khartoum
Tanzania For all travelers 9 months of age. The city of Dar es Salaam has a lower risk of
transmission than rural areas.
Togo For all travelers 9 months of age
Uganda For all travelers 9 months of age
162

2 * ()
Country US CDC Yellow Fever Vaccine Recommendations
South America
Argentina For all travelers 9 months of age traveling to the northern and northeastern forested
areas of Argentina, including Iguassu Falls and all areas bordering Paraguay and Brazil.
Bolivia For all travelers 9 months of age traveling to areas east of the Andes Mountains.
Vaccination is NOT recommended for travel only to the cities of La Paz or Sucre.
Brazil For all travelers 9 months of age traveling to areas at risk for yellow fever transmission.
Colombia For all travelers 9 months of age. Travelers whose itinerary is limited to the cities of
Bogot, Cali, or Medelln are at lower risk and may consider foregoing vaccination.
Ecuador, including For all travelers 9 months of age traveling to the following provinces in the Amazon
the Galpagos Islands Basin: Morona-Santiago, Napo, Orellana, Pastaza, Sucumbos, and Zamora-Chinchipe,
and all other areas in the eastern part of the Andes Mountains, NOT including the cities
of Quito and Guayaquil or the Galpagos Islands.
Guyana For all travelers 9 months of age
Panama For all travelers 9 months of age traveling to the provinces of Darien, Kuna Yala
(old San Blas), Comarca Ember, and Panama east of the Canal Zone, EXCLUDING
the Canal Zone, Panama City, and San Blas Islands
Paraguay For all travelers 9 months of age
Peru For all travelers 9 months of age traveling to the areas east of the Andes Mountains and
for those who intend to visit any jungle areas of the country <2,300 m (<7,546 ft).
Travelers who are limiting travel to the cities of Cuzco and Machu Picchu do NOT need
vaccination.
Suriname For all travelers 9 months of age
Trinidad and Tobago For all travelers 9 months of age whose itinerary includes Trinidad. Port of Spain has
lower risk of transmission than rural or forested areas. Cruise ship passengers who do
not disembark from the ship or travelers visiting only the urban area of Port of Spain (in
cluding passengers in-transit only) may consider foregoing vaccination. Vaccination is
NOT recommended for those visiting only Tobago.
Venezuela For all travelers 9 months of age traveling to Venezuela, EXCEPT the northern coastal
area 3. The cities of Caracas and Valencia are NOT in the endemic zone.

(16)
*

 14 163

11.Poland JD, Calisher CH, Monath TP, Downs

WG, Murphy K. Persistence of neutralizing antibody
1.Barnett ED. Yellow fever: epidemiology and 30-35 years after immunization with 17D yellow fever
prevention. Clin Infect Dis. 2007;44:850-6. vaccine. Bull World Health Organ. 1981;59:895-900.
2.Monath TP, Lee CK, Julander JG, Brown 12.Hayes EB. Acute viscerotropic disease
A, Beasley DW, Watts DM, et al. Inactivated yellow following vaccination against yellow fever. Trans R Soc
fever 17D vaccine: development and nonclinical safety, Trop Med Hyg. 2007;101:967-71.
immunogenicity and protective activity. Vaccine. 13.Kitchener S. Viscerotropic and neurotropic
2010;28:3827-40. disease following vaccination with the 17D yellow fever
3.Frierson JG. The yellow fever vaccine: a vaccine, ARILVAX. Vaccine. 2004;22:2103-5.
history. Yale J Biol Med. 2010;83:77-85. 14.Lindsey NP, Schroeder BA, Miller ER,
4.Staples JE, Monath TP. Yellow fever: 100 Braun MM, Hinckley AF, Marano N. Adverse event
years of discovery. JAMA. 2008;300:960-2. reports following yellow fever vaccination. Vaccine.
5.Gould EA, Solomon T. Pathogenic flavivi- 2008;26:6077-82.
ruses. Lancet. 2008;371:500-9. 15.Hayes EB. Is it time for a new yellow fever
6. , vaccine?. Vaccine. 2010;28:8073-6.
. : , 16.Yellow Book [Internet]. Atlanta: US CDC.
, , , [update July 27, 2009; cited 2011 April 5] Available
, . Travel and adult from: http://wwwnc.cdc.gov/travel/yellowbook/2010/
immunization.:;2552. chapter-2/yellow-fever-vaccine-requirements-and-
.202-9. recommendations.aspx
7.Staples JE, Gershman M, Fischer M. Cent-
ers for Disease Control and Prevention (CDC).Yellow
fever vaccine: recommendations of the Advisory
Committee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2010;59:1-27.
8.Monath TP. Treatment of yellow fever. An-
tiviral Res. 2008;78:116-24.
9.Lang J, Zuckerman J, Clarke P, Barrett P,
Kirkpatrick C, Blondeau C. Comparison of the immuno-
genicity and safety of two 17D yellow fever vaccines.
Am J Trop Med Hyg. 1999;60:1045-50.
10.Monath TP, Cetron MS. Prevention of yel-
low fever in persons traveling to the tropics. Clin Infect
Dis. 2002;34:1369-78.
76
 165

-
- 15

(nontoxigenic strain)

Corynbacterium
diphtheria

diphtheria pseudomem-
toxin brane Tinsdale medium

antitoxin C. diphtheria1

2-6 diphtheria toxin

C. diphtheria
Elek test (in vivo
pseudomembrane neutralization assay)
polymerase chain reac-
tion (PCR) (tox gene)
diphtheria antitoxin erythromycin
penicillin G 14
2,3
(congestive heart failure)
(myocarditis)
C. diphtheria
cutaneous diphtheria 5
0.1
3
90 4,5
C. diphtheria
166

.. 2553
78 10 0.12 7,8
14 0.02 10

5 ( 21.05) 5-9 ( 14.47) .. 2553 168
10-14 ( 11.84 ) 97.4 0.26 0.01
1.3 1.3 65
70 (6.95 ) 55 - 64
45 - 54
6 0.01
0.17 6


Clostridium tetani
Bordetella pertussis



tetanus toxin tetanospasmin

90
(spastic paralysis) 6-20 ( 7-10 )
3-21 Catarrhal
stage 1-2
generalized tetanus Paroxysmal stage
2-6


Convalescent stage 4-6
Localized tetanus
Cephalic tetanus
Neonatal tetanus (Tetanus
neonatorum) generalized tetanus
(encephalopathy)
 15 -- 167

(apnea) 1

(Cocoon strategy)12
(nasopharyngeal aspirate) .. 2552
(nasopharyngeal wash) Bordet-
Gengou (BG) agar 16,858 12 13
B. pertussis
PCR ..2549 60
DNA probe ( 83.3 )
9,10 ..2553 0.01
macrolides 5
catarrhal stage 6

--

11 - -
(DTP) purified diphtheria toxoid,
purified tetanus toxoid Inactivated B. pertussis


1

1 DTP Tdap

FHA PT Pn Fim 2&3
Acelluvax Biocine 2.5 g 5 g 2.5 g - DTaP
Tripacel/Actacel/ SP 5 g 10 g 3 g 5 g DTaP / DTaP +Hib/
Pediacel DTaP +IPV+Hib
Tetraxim/ SP 26 g 25 g - - DTaP+IPV/
Pentaxim/ DTaP+IPV+Hib/
Hexavac DTaP+IPV+Hib+HB
Adacel/Adacel polio SP 5 g 2.5 g 3 g 5 g Tdap/Tdap-IPV
Infanrix/ GSK 25 g 25 g 8 g - DTaP/
Infanrix-IPV-Hib/ DTaP+IPV+Hib/
Infanrix-Hexa DTaP+IPV+Hib+HB
Boostrix/ Boostrix polio GSK 8 g 8 g 2.5 g - Tdap/Tdap-IPV
168

1. Tetanus toxoid (TT) 17-21

2. Diphtheria-tetanus toxoid (DT) 1. 7 DTwP
DT Td DTaP DTaP
3. Diphtheria-tetanus-pertussis vaccine
(DTP) whole cell pertussis DTwP
vaccine (DTwP) DTwP 2, 4, 6 18
acellular pertussis vaccine (DTaP) 4 DTwP, DTaP Tdap
11-12

Pertussis toxin (PT), Filamentous
hemagglutinin (FHA), Pertactin (Pn) Fimbria
(Fm) DTaP 2
HBV, Hib IPV 5 --
4. Diphtheria-tetanus-pertussis vaccine 4 5
(Tdap) 6 7
2. 7
Td Tdap 7-10
Td 3 0, 1, 6
2-8 . Tdap Td 1
Tdap
18 11-18 (11-12 )
Tdap Td
Td Tdap

DTwP, DTaP Tdap
0.5 .
DTaP Td 22,23
1 Arthus hypersensitivity reac-
tion tetanus diphtheria containing
(primary series) vaccine 10
( 18 )
Td 10
DTaP Tdap Td 1 ( Tdap)
DTaP 1
14-16
 15 -- 169

Td 3 0, 1, 6
Tdap Td 1 sterile abscess
adjuvant
3. Tdap Arthus hypersensitivity reaction
Tdap

Tdap 2 3 Guillain-Barr Syndrome (GBS) Brachial
( 36 ) neuritis tetanus toxoid
10 DTP GBS
tetanus-containing vaccine
10

2 anaphylaxis 2
95 DTwP
100 DTaP
50-90 40.5o. 48
10 3 48
5-7
Hypotonic-hyporesponsive episode (HHE)
DTwP DTaP24,25 shock-like state 48
72
acellular
Guillain-Barr Syndrome (GBS)
Tdap Tdap-IPV 6 tetanus-containing vaccine
DTaP 4-6 Tdap
seroprotective antibody level 3 26-30 Td
Tdap
5 32,33
10 pertussis
toxin, fimbriae, filamentous hemagglutinin 10
pertactin31 1.
(progressive neurological disorder)
--
DTP (encephalopathy) 7

170

- () . 1.:
2. -- . ..; 2549. . 547-65.
anaphylaxis 8. American Academy of Pediatrics. Tetanus.
purified diphtheria In: Pickering LK, Baker CJ, Long SS, Kimberlin DW,
toxoid, purified tetanus toxoid Inactivated editorss. Red Book: 2009 Report of the Committee
B. pertussis on Infectious Diseases. 28th ed. Elk Grove Village, IL:
American Academy of Pediatrics; 2009. p. 555-60.
9. . Bordetella. :
. 1.:
. ..; 2549. . 477-87.
1. . Corynbacterium. : 10. American Academy of Pediatrics. Pertussis.
. 1.: In: Pickering LK, Baker CJ, Long SS, Kimberlin DW,
. ..; 2549. . 307-16. editors. Red Book: 2009 Report of the Committee on
2. American Academy of Pediatrics. Diphtheria. Infectious Diseases. 28th ed. Elk Grove Village, IL:
In: Pickering LK, Baker CJ, Long SS, Kimberlin DW, editors. American Academy of Pediatrics; 2009. p.504-19.
Red Book: 2009 Report of the Committee on Infectious 11. .
Diseases. 28th ed. Elk Grove Village, IL: American Academy .
of Pediatrics; 2009. p.280-3. : , ,
3. Overturf GD. Corynbacterium diphtheria. , ,
In: Long SS, Pickering LK, Prober CG, editors. , . Travel and adult immunization.
Principles and Practices of Pediatric Infectious : ;
Diseases. 3rd ed. China: Churchill livingstone Elsevier; 2552. . 59-69.
2008. p.754-9. 12. Yeh SH, Mink CM. Shift in the epidemiology
4. . of pertussis infection: an indication for pertussis
2545. vaccine boosters for adults? Drugs. 2006;66:731-41.
. 13. Centers for Disease Control and Prevention
2545;38:602-6. (CDC). Final reports of internationally notifiable
5. Tharmaphornpilas P, Yoocharoan P, diseases. MMWR Morb Mortal Wkly Rep. 2010;59:
Prempree P, Youngpairoj S, Sriprasert P, Vitek 1025,1027-39.
CR. Diphtheria in Thailand in the 1990s. J Infect Dis. 14. Greenberg DP, Feldman S. Vaccine
2001;184:1035-40. interchangeability. Clin Pediatr (Phila). 2003;42:93-9.
6. 15. Halperin SA, Tapiero B, Law B, Diaz-Mitoma
. .. 2553. F, Duval B, Langley JM, et al. Interchangeability of
: ; 2553. two diphtheria and tetanus toxoids, acellular pertussis,
7. . Clostridium. : inactivated polioviruses, Haemophilus influenzae type
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B conjugate vaccines as a fourth dose in 15-20-month- toxoid, reduced diphtheria toxoid and acellular pertussis
old toddlers. Vaccine. 2006;24:4017-23. (Tdap) vaccine from the Advisory Committee on
16. Greenberg DP, Pickering LK, Senders Immunization Practices, 2010. MMWR Morb Mortal
SD, Bissey JD, Howard RA, Blatter MM, et al. Wkly Rep. 2011;60:13-5.
Interchangeability of two diphtheria-tetanus-acellular 22. Beytout J, Launay O, Guiso N, Fiquet
pertussis in infancy. Pediatrics. 2002;109:666-72. A, Baudin M, Richard P, et al. Safety of Tdap-IPV
17. - - given one month after Td-IPV booster in healthy
. : , young adults: a placebo-controlled trial. Hum Vaccin.
, , , 2009;5:315-21.
. 23. Talbot EA, Brown KH, Kirkland KB,
2550. : Baughman AL, Halperin SA, Broder KR. The safety of
; 2550..84-92. immunizing with tetanus-diphtheria-acellular pertussis
18. Prevention of pertussis among adolescents: vaccine (Tdap) less than 2 years following previous
recommendations for use of tetanus toxoid, reduced tetanus vaccination: Experience during a mass
diphtheria toxoid, and acellular pertussis (Tdap) vaccination campaign of healthcare personnel during a
vaccine. Pediatrics. 2006;117:965-78. respiratory illness outbreak. Vaccine. 2010;28:8001-7.
19. Broder KR, Cortese MM, Iskander JK, 24. Bisgard KM, Rhodes P, Connelly BL,
Kretsinger K, Slade BA, Brown KH, et al. Preventing Bi D, Hahn C, Patrick S, et al. Pertussis vaccine
tetanus, diphtheria, and pertussis among adolescents: effectiveness among children 6 to 59 months of
use of tetanus toxoid, reduced diphtheria toxoid and age in the United States, 1998-2001. Pediatrics.
acellular pertussis vaccines: recommendations of 2005;116:e285-94.
the Advisory Committee on Immunization Practices 25. Casey JR, Pichichero ME. Acellular pertussis
(ACIP). MMWR Recomm Rep. 2006; 55:1-34. vaccine safety and efficacy in children, adolescents
20. Kretsinger K, Broder KR, Cortese MM, Joyce and adults. Drugs. 2005;65:1367-89.
MP, Ortega-Sanchez I, Lee GM, et al. Preventing tetanus, 26. Kosuwon P, Warachit B, Hutagalung Y,
diphtheria, and pertussis among adults: use of tetanus Borkird T, Kosalaraksa P, Bock HL, et al. Reactogenicity
toxoid, reduced diphtheria toxoid and acellular pertussis and immunogenicity of reduced antigen content
vaccines: recommendations of the Advisory Committee diphtheria-tetanus-acellular pertussis vaccine (dTpa)
on Immunization Practices (ACIP) and recommenda- administered as a booster to 4-6 year-old children
tions of ACIP supported by Healthcare infection control primed with four doses of whole-cell pertussis vaccine.
practices advisory committee (HICPAC) for use of Tdap Vaccine. 2003;21:4194-200.
among health-care personnel. MMWR Recomm Rep. 27. Snger R, Behre U, Krause KH, Loch HP,
2006;55:1-34. Soemantri P, Herrmann D, et al. Booster vaccination
21. Centers for Disease Control and Prevention and 1-year follow-up of 4-8-year-old children with a
(CDC).Updated recommendations for use of tetanus reduced-antigen-content dTpa-IPV vaccine. Eur J
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Pediatr. 2007;166:1229-36. containing reduced quantities of pertussis antigens as

28. Langley JM, Predy G, Guasparini R, Law B, a booster in adolescents. Pediatrics.1999;104:e70.
Diaz-Mitoma F, Whitstitt P, et al. An adolescent-adult
formulation tetanus and diphtheria toxoids
adsorbed combined with acellular pertussis vaccine has
comparable immunogenicity but less reactogenicity in
children 4-6 years of age than a pediatric formulation
acellular pertussis vaccine and diphtheria and
tetanus toxoids adsorbed combined with inactivated
poliomyelitis vaccine. Vaccine. 2007;25:1121-5.
29. Meyer CU, Habermehl P, Knuf M, Hoet B,
Wolter J, Zepp F. Immunogenicity and reactogenicity
of acellular pertussis booster vaccines in children:
standard pediatric versus a reduced-antigen content
formulation. Hum Vaccin. 2008;4:203-9.
30. Scheifele DW, Halperin SA, Ochnio JJ,
Ferguson AC, Skowronski DM. A modified vaccine
reduces the rate of large injection site reactions to the
preschool booster dose of diphtheria-tetanus-acellular
pertussis vaccine: results of a randomized, controlled
trial. Pediatr Infect Dis J. 2005;24:1059-66.
31. Bailleux F, Coudeville L, Kolenc-Saban A,
Bevilacqua J, Barreto L, Andr P. Predicted long-term
persistence of pertussis antibodies in adolescents after
an adolescent and adult formulation combined tetanus,
diphtheria, and 5-component acellular pertussis vaccine,
based on mathematical modeling and 5-year observed
data. Vaccine. 2008; 26 :3903-8.
32. Turnbull FM, Heath TC, Jalaludin BB,
Burgess MA, Ramalho AC. A randomized trial of
two acellular pertussis vaccines (dTpa and pa) and
a licensed diphtheria-tetanus vaccine (Td) in adults.
Vaccine. 2000;19:628-36.
33. Tran Minh NN, He Q, Ramalho A, Kaufhold
A, Viljanen MK, Arvilommi H, et al. Acellular vaccines
 173

16
,

2 Enders

(mumps) (complement-fixing antibodies)
3
mumps
mump
to mump

mumps

epidemic parotitis


(mumps
virus) family Paramyxoviridae genus
Rubulavirus ( mumps virus, New Castle
disease virus, human parainfluenza virus types 2, 4a,
and 4b) enveloped negative single-
stranded RNA
90-300 200
Hippocrates nucelocapsid envelope 3 4
glycoprotein hemagglu-
1700 Hamilton tinin, neuraminidase cell fusion activity
.. 1934 host cell
Johnson Goodpasture cytoplasmic membrane
1 nonglycosylated membrane
protein
.. 1945 Habel genome nucleocapsid
174

continuous linear molecule of single- 6 16 17

stranded RNA genome repeating protein 18
subunits 8 .. 2006 6,584 18-24
hemagglutinin-neuraminidase protein (HN), fusion 29
protein (F), nucleocapsid protein (NP), phosphoprotein 8317
(P), matrix protein (M), hydrophobic protein (SH) genotype G16 13
L proteins5 F HN 2 63
1
13 (A to M) 18,19
SH protein (waning immunity)
6-8
ether lipid
envelope 4o. Jeryl Lynn strain (A)
-65 o. G
embryonated hens eggs9

monkey kidney, human embryonic kidney .. 2008 376
HeLa cell cultures (cytopathic effects) .. 2010
intracytoplasmic New York New Jersey20
eosinophilic inclusions, rounding of cells giant .. 2009 - .. 2010 1,521
multinucleate syncytial cell10 11

17-18 61 76

1 88 2
.. 1967 2-5 11 75
-
12 .. 2514
.. 2540
(MMR)
13,14 .. 1967
99
.. 2001-2005
265 15
21 .. 2552
 16 175

20,383 32.1
10
(.. 2543-2552) 1-2
.. 2543-2546 (14.74-17.59 5
) .. 2551 (21.93 7
) .. 2552 9
10 .. 2548-2552
.. 2551 16-18 ( 12-25 )24
Stensens duct 1
.. 2552 5


15
5-9 5
10-14 22 viremia
G .. 2550-2551 J
1
25,26

50 5-9
90 14 80-90 diffuse
20
interstitial edema serofibrinous exudates
mononuclear leukocytes
.. 2001 49 neutrophil necrotic debris
15



23
multinucleate syncytia
intracytoplasmic eosinophilic inclusions
-
9
interstitial hemor-
rhage polymorphonuclear leukocytes

(direct contact) perivenous demyeliniza-
(droplet nuclei) fomites tion perivascular mononuclear cuffing
176

microglial cells 27

neuronolysis demyelinization28 29 10
30 ( 1)
submandibular sublingual
sublingual
6 pre-
24 sternal pitting edema
submandibular
lymphatic drainage31

2-3 32-36
1 4 1-10
Stensens duct
Trismus 40-50



4
1 1 2

1
()
(Glandular)
60-70
submandibular sublingual 10
Epididymo-orchitis 25 ()
Oophoritis 5 ()

50
1-10
0.1
Transient high-frequency deafness 4

5-15
60
( 30)
 16 177

1 6
3 75

10-2,000 /..
lymphocyte 20-25 neutrophil

70 ./. 85 epididymitis
6-30 3-4
5 84 5 20
3-10 2 50


37,38 1 6,000 1 400 51 5
2
early onset
7-10 52,53
migratory polyarthritis
late onset postinfec- 10-14
tious demyelinating process 5

30

1-2

1.4

Transient high-frequency-range deaf- endocardial
ness 4.4 39 fibroelastosis (EFE)
1
20,000 40 cerebellar ataxia41, facial palsy42, RNA 70
transverse myelitis43, ascending polyradiculitis44 EFE
poliomyelitis-like syndrome45 aque-
ductal stenosis hydrocephalus EFE
46-48 EFE 54, 55
Epididymo-orchitis49,50 20-30 juvenile diabetes mellitus
178

Reverse transcriptase
juvenile diabetes mellitus 56, 57 (RT)PCR assays

24,30
3
6
2-3 2 72
5
2
RNA
PCR


amylase 24,30

2-3 Parainfluenza
amylase lipase type1 3, coxsackieviruses
cytomegalovirus, enterovirus, lymphocytic
choriomeningitis virus, human immunodeficiency
virus, Staphylococcus aureus, nontuberculous myco-
bacterium, Burkhoderia pseudomallei,


(serologic studies) phenylbutazone, thiouracil, iodides
IgM phenothiazines
enzyme-linked immunosorbent assay (ELISA) uremia
4 acute
convalescent serum complement fixation,
hemagglutination inhibition (HAI), ELISA neutrali- Mikuliczs syndrome,
zation testing Parinauds syndrome, uveoparotid fever of sarcoidosis
parainfluenza 3 HAI Sjogrens syndrome
parainfluenza
heterologous antibody
parainfluenza 3 HAI
 16 179

58 .. 1945 Habel
2
(CDC), American Academy of (killed virus
Pediatrics (AAP) Healthcare Infection Control vaccine) .. 1948 ..
Practices Advisory Committee (HICPAC) 1950
5

.. 1966 Buynak Hilleman
5 (lived attenuated
vaccine) 59,60
Jeryl Lynn
standard droplet precautions
.. 1967
12
26 cell culture chick
embryo
Urabe, NK-M46, S-12, Rubini, Leningrad-
Zagreb, Leningrad-3
5 Jeryl Lynn, Urabe,
Rubini, Leningrad-Zagreb Leningrad-3
Rubini
2
9-12 4-6 Jeryl Lynn

2
1

.. 2553 MMR
1 Masu
Leningrad-Zagreb

180

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 16 183

MMR
2553.
41, 2553.
76
 185

17

1.2-4.8/1000 / > 60
7.2-11.8/1,000 /8,12,13
Herpes zoster
Herpes zoster .. 2552 20,804
32.78
2000
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55-64, 45-54 35-44 14
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immunity (CMI) VZV 1-3 15
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root ganglia
17

(dermatome) 18 19-24
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26-30,36-38
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ruses family herpesviridae
double-stranded DNA envelope
glycoprotein spikes
4-6 150-200
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5,7-11
186

PHN) 39,40 PHN

VZV 13,40,41
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dorsal root ganglia) 50 <50
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PHN
mononuclear dorsal root ganglion 79 35
ganglion
demyelination axon




(dermatomal
distribution)
48-72 (macule) Tzanck smear
(papule) (vesicle) multinucleated
3-5 10-15 giant cells

(thoracic lumbar immunofluorescent polymerase chain
dermatome) reaction

VZV VZV
50

ophthalmic
nucleoside analogs acyclovir,
valacyclovir famciclovir42

postherpetic neuralgia 72
50
PHN
meta-analyses
PHN
(postherpetic neuralgia; 42,43-47
 17 187

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acyclovir
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PHN 66.5 (27 80 )
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 17 189

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in England and Wales. Vaccine. 2009 25;27:1454-67.
64. Pellissier JM, Brisson M, Levin MJ.
Evaluation of the cost-effectiveness in the United
States of a vaccine to prevent herpes zoster and
postherpetic neuralgia in older adults. Vaccine.
200728;25:8326-37.
65. Rothberg MB, Virapongse A, Smith KJ.
Cost-effectiveness of a vaccine to prevent herpes
 17 193

zoster and postherpetic neuralgia in older adults. Clin

Infect Dis. 2007;44:1280-8.
66. Hornberger J, Robertus K. Cost-
effectiveness of a vaccine to prevent herpes zoster
and postherpetic neuralgia in older adults. Ann Intern
Med. 2006;145:317-25.
76
 195

18

400 HBsAg
1 10 . 20 .

4-5 2.5

0.5 . ( 18 )
1 . 3 0, 1 6
.. 1981 (plasma derived)
recombinant (.. 1986)



(
)


HBsAg 2
1. Plasma derived vaccine2,3
HBsAg 10



2. Recombinant vaccine

196

1 (
) 20
2
2
4 (occult infection)
9-11
6

9-12 --

2
2 1 .. 2531 12 .. 2533
3 5 .. 2535
2 1 ( 24
2 6 )
90

0.7 .. 2551
()

4
(systemic adverse events)
24 1
( HBIG)
24
2, 4
6 ( 5 )


2, 4 6 4
94 97
hepatitis B immune globulin (HBIG) 6-8
HBIG 5
 18 197

(Post exposure prophylaxis)

1.

HBeAg 2.
3.

HBIG HBIG 4. HBIG
24
HBIG
HBIG HBIG
HBIG HBIG
HBIG
12
6-8


HBeAg
2 3 2 6 HBIG
HBIG
72
plasma derived 13,14
yeast derived6,12



24


1. HBeAg
2. DNA polymerase activity 5 .
3. HBV-DNA antiHBs HBsAg
HBIG 0.06 ./. 3-5 .
(200 /.)
24-48
198

1

HBsAg +ve HBsAg-ve
HBsAg
HBIG + HBV HBV HBV

Responder

Nonresponder HBIG + HBV
HBIG 2
HBsAg +ve
anti-HBs anti-HBs
(Response unknown)
1. >10 mIU/. 1. <10 mIU/.
HBV
2. <10mIU/. 2. >10 mIU/.
HBIG + HBV
HBIG 0.06 ./. IM ( Hepatitis B vaccine : Mahoney FS, Kane M.
Vaccine, 13th edition, plotkin 1999).

HBIG

0, 1, 6 0, 1, 2, 12 12
1

24

HBIG
(
) HBIG
72
HBIG 24 0.06 ./. 5
.
HBIG
HBIG
HBIG 15,16
HBIG
 18 199

HBIG
HBIG gamma globulin (intradermal injection)17


HBIG (subcutaneous)
HBIG cold ethanol
fractionation anti-HBs
anti-HIV
gamma globulin aluminium
passive anti-HIV hydroxide
HBIG

HBIG

(Pre-exposure prophylaxis)



-
(anterolateral of thigh)
- 1-5

-



18

(Nonresponder)19

nonresponder

1-3

200

1


- HBV marker

-
HBeAg
-
1.
HBIG HBV-DNA

Genetic prediction 20 HBV-DNA


major
histocompatibility complex (MHC) HLA HBV-DNA
HLA B8, SC01, DR3

21 HBV-DNA mononuclear cells
HBV-DNA
mononuclear cells

HBV-DNA mononuclear cellas
HBV-DNA mononuclear cells
(1,800 - 2,200 )
intrauterine infection
seroconversion 2. Escape mutant
6-12
S

HBIG

22,23


 18 201

1. lamivudine (3TC)
HBV-
DNA
HBIG

HBV-DNA



( 90)
25
3TC

2. HBIG
( 50)


24



aluminium hydroxide HBsAg 15
adjuvant tetanus toxoid HBeAg
26
HBeAg






2

CD4
202

4
3-4
27
3 4




GSK
2
3-4

immunizing dose 1 6-12
5

2
1



3-4


.. 2000




37 .




 18 203

(HBsAg) 0.7 10-18

()
3.5 18
2.527,28

29



80 .. 2528 10.4
100,000 4.5
100,000 .. 2538
4 215 100,000
90.4 14
100,000
5 1

.. 2541

.. 2533
85
15 0.5


vertical horzontal 2527
0.70
100,000 0.57 100,000
.. 2542 .. 2529 - 2532 0.36 100,000
.. 2533 - 2537

6 18 5
6-19
2229 0.52 100,000
3 .. 2517-2527 0.13 100,000
82.5 6 10 .. 2527-252930
204

(HCV)

170
5
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 207

19

2,3

4,5





2
1. (inactivated vaccine)
2. (lived vaccine)
0.1
0.1-0.4
1 40

1 ,
H2
6,7

4
1 5 - 5 0


(virus suspension)
ELISA,
RIA unit
2 phenoxyethanol



208

2
2 0.5
18 1.0 .
18
ELISA, RIA
unit ( 0.5
1 immunizing dose (1-2 )
18 ) (0.5 .) 1 . ( 4
18 ) (systemic adverse events)
virosome 24

8 1-13.9


1. 2-4 1
0.5 . ( 1-18 ) 0.5 . 1
6-12
() 2
6-12 20
2.
1 . ( 18 )
1.0 .
2 6-12

1


subclinical
8.6
9,10 subclinical 6.714
94-100 2-4
10011-13

 19 209

Maternal passive antibody


1
6-12 17

1 (
)
1 15



18,19

2
30 2 6

3 0, 1 6
36,16 1
2 24
7
20

210

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76
 213

20

19
Typhoid Mary ..1907
Mary Mallon New York
430 53 3
Ethiopia Egypt Libya Mary
Greece Greece quarantine
Pericles Mary 26 Mary Pneumonia2
Athens 30
Athens
Athens Thucydides Chicago 65-174
epidemic typhus 100 1
.. 2006 Manolis Papagrigorakis
Athens DNA 10 -100 1
DNA sequence Salmonella
typhi 21
2 .. 20003
..1829 Pierre
Charles Alexandre Louise
138 50 .. 1989 Chloramphenical, ampicillin,
85 trimethoprim
cipro-
.. 1808-1882 William Budd floxacin 4



..1885
Theobald Smith
Salmonella cholerasuis genus Salmonella Salmonella 2,460
Daniel Elmer Salmon O-somatic
1 5 A E group D
214

Salmonella subspecies enterica serotype typhi host cell

facultative anaerobe MacConkey agar
Non lactose fermentor Salmonella
reservoir
endotoxin 8
Vi antigen (virulence)
invasin non phagocytic cell .. 2552 6,486
oxidative burst 10.26
Salmonella 3,624 ( 55.87)
14
ampicillin, tetracycline, nalidixic acid, trimeth-
oprim-sulfamethoxazole, cefotaxime, ciprofloxacin
chloramphenicol 4
5 15-20
DNA 12.28 5-9
plasmids bacteriophage bacteria 12-15
Salmonella
Salmonella typhi (600-800 )

animal model Salmonella 22.80, 14.36,
typhimurium Salmonella 9.40 2.32
typhi
Stephen J Libby5 .. 2521 20-40 10
Proceeding of the National Academy of Sciences
Humanized Mouse Model Stem cell
()
Salmonella typhi Salmonella typhi
Stem cell (
virulence factor Professor David ) 1000-1 9
Holden6,7 Imperial College London
tract bacterial membrane transport helicobacter pylori10
channel host cell virulence
factor host cell defense mechanism duodenum
host cell Salmonella (Peyers Patch)
 20 215

2
reticulo endothelial system11 1015
70 17
18

reticulo endothelial system ( 3 - 35)
T cell ( 1-5) ( 1-86)
( 1)
3-60 ( 1-26)19
2
5 45
12 5 Salmonella typhi
5 12



40-80
10 Widal test
-20 Rose spot 5 -1012-15 O-somatic
..1896
59 23 Widal test
(259 ) 1 -75 3 cut off point O 1 : 80 H 1 : 200
50
()
/ (delirium) (normal curve dis-
90 10 tribution) 97.5 cut off point


10 ( 7
) Widal test
screening positive
50 16 predictive value negative predictive value



216

10 indirect name linked MDR S.typhi (multidrug resistance)

immunosorbent assay 13
6520 chloramphenicol .. 1948
serial .. 1960
Widal test positive predictive value plasmids
negative predictive value Widal test amoxicillin 20-50 ././
3-4 14
Widal test trimethoprim - sulfamethoxazole 15-20
Widal test ././ 3-4 14
21 ciprofloxacin 20-30 ././
IgM commercial test 2 14 5-7
Typhidot 67- uncomplicated typhoid fever
90 54-100 22,23 azithromycin 10 ./.
Tubex 60 5822 5 ./. 2 -5 7
Real Time PCR Specific DNA sequence 8-10 ./. uncomplicated typhoid fever
fli C gene ceftriaxone 50 -75 ./. /
24 12 7

3-5
100 10
model 6
dexamethasone

dexamethasone
(reliability)

26




Salmonella typhi
200325 18
fluoroquinolone nalidixic acid
38 ampicillin Salmonella typhi
chloramphenicol trimethoprim sulfamethoxazole
 20 217

.. 1897 Almroth Edward Wright analysis32 4

.. 1909 Frederick F Russel 3 55
428
Typhim Vi
Whole cell vaccine field trial 1-10 48
.. 1960
58-81

25-50 12 27
Field trial Ty21a live attenuated (
6 )

96 3 28 67-96 5 42 -53
2.5 29
634 2-6
seroconversion 69
14 seroconversion

6930 meta-

analysis 5
2.5 - 3 4831
5
UDP-
galactose 4-epimerase

buffer

(enteric coated)
( 37 .) 2
Vi capsular polysaccharide 1. Vi-CRM 197 Violence Capsular
2 0.5 . (25 ) Polysaccharide S.typhi recombinant mutant
3 2-8 . Pseudomonas aeruginosa exoprotein A
72 17 Vi-rEPA Novartis 2 2-5
Nepal32 64 21 South Africa33 1 2
meta- 94 87
218

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8 IgG 100 , ,
0 , .
18 (Enteric fever) (Typhoid
26 14 2234 fever) .
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 221

21

(Streptococcus pneumoniae)
(cochlear implants)
1,2

lancet pneumolysin
alpha 1
partial hemolysis
ethyl hydrocupreine (optochin) population-based sur-
bile salts catalase veillance 5

90 3
penicillin .. 2548
.. 2550 7,319

10.6-28.9 100,000
5 (
4
)

7.5-14.0 100,000
5 6

(asymptomatic
carriers) .. 2523-2533
35 2 (22.2%) Hemophilus
2-95 influenzae type b (42.3%)7
222

.. 2530-2540 ANSORP 11
.. 2543-2544
(42.5%)8 penicillin
90 26.9 26.9
14
penicillin

4, 6B, 9V, 14, 18C,
19F 23F - .. 2551 sterile
6A, 6B, 9V, non-sterile site
14, 19A 19F 23F penicillin 170 170 3
19A 94
60 (29.4%)
7-valent 9 2-5 (20.0%) 2 (12.4%)
disk
sterile diffusion chloram-
site 5 1 .. phenicol, linezolid, oflaxacin vancomycin
2543 31 .. 2548 71.8, 100, 100 100
6B erythromycin, penicillin, tetracycline trimethoprim/
27.8 23F 20.0 sulfamethoxazole 35.5, 31.1, 28.8
14 10.4 19F 9.610 24.1 minimal inhibitory con-
centration (MIC) broth microdilution
6B sterile site penicillin
11 92.0 cefotaxime 90.0
non-sterile site penicillin
penicillin (MIC > 0.1 ./ .) 6.7 cefotaxime 26.9 76.9 15
.. 2521 10.6 .. 2530
.. 2535-2537 penicillin cefotaxime
37.2 pbp2b
23F 9V 16
12
170
.. 2535-2542
10.5-69.2 .. 2551 ofloxacin
10.5-51.3 0-28.013 93.5 gyrA
 21 223

parC fluoroquinolone respiratory tract infection) (pneu-

4 gyrA monia)
Ser81Phe Glu85Gly 3. (upper res-
parC Ser79Tyr piratory tract infection) (sinusitis)
3 (otitis media)
4 6B 2
nonvaccine type 2 17

9 .. 2529-2540 61
24 19
10
8 6
10.221

.. 2514-2543
138 137
51 38
35 13
/ 2 66

.. 2531
.. 2539-2543 7122


18-20
penicillin23
3
1. 13
(invasive pneumococcal disease, IPD)
(bacteremia)
(meningitis)
(endocarditis)
(pericarditis) (peritonitis)
(osteomyelitis, arthritis)
2. (lower
224

penicillin oxacillin disk 1 .
zone of inhibition 20 .
9,24 penicillin MIC
zone of inhibition 20 . MIC
penicillin sterile
sites sterile sites
MIC penicillin cefotaxime
ceftriaxone 1

vancomycin meropenem

polymerase chain reaction (PCR) (nonsusceptible) penicillin
rifampin
MIC
broth
microdilution antimicrobial gradient strips

1 MIC
(./.)
./.
Penicillin (oral) 0.06 0.12-1.0 2.0
Penicillin (intravenous)
- Nonmeningeal 2.0 4.0 8.0
- Meningeal 0.06 None 0.12
Cefotaxime or ceftriaxone
- Nonmeningeal 1.0 2.0 4.0
- Meningeal 0.5 1.0 2.0
( 9)
 21 225

amoxicillin 26
30-40 ././ 2-3 5-7


(craniofacial abnormalities) amoxicillin, amoxicillin-clavulanate
macrolides
10 ampicillin
ceftriaxone DRSP
50 ././ 1 cefotaxime
Drug ceftriaxone 27
resistant Streptococcus pneumoniae (DRSP)
2 3 13

DRSP
amoxicillin 80-90 ././ 27
type I hyper- cefotaxime ceftriaxone
sensitivity cefdinir, cefpodoxime vancomycin
cefuroxime type I hypersensi-
tivity azithromycin clarithromycin 9
penicillin-resistant penicillin, cefotaxime ceftriaxone
S.pneumoniae clindamycin cefotaxime
ceftriaxone
3 vancomycin

27
DRSP
amoxicillin/ DRSP
clavulanate ( amoxicillin 80-90 ./ penicillin, cefotaxime ceftriaxone
./ DRSP) vancomycin
cephalosporins cefdinir, cefuroxime, 29
cefpodoxime ceftriaxone
50 ./. 3 25 vancomycin rifampin

226

2


penicillin vancomycin cefotaxime ceftriaxone
penicillin vancomycin + cephalosporin
penicillin cefotaxime vancomycin cefotaxime ceftriaxone
ceftriaxone
penicillin, cefotaxime ceftriaxone vancomycin cefotaxime ceftriaxone
rifampin rifampin vancomycin
24-48

( 9)
meropenem chlorampheni-
col chloramphenicol MIC 1.
4 ./. 9 (23-valent pneumococcal polysaccha-
dexa- ride vaccine, PS-23) polyvalent polysaccharide
methasone 23
6 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14,
15B, 17F, 18C, 19A, 19F, 20, 22F, 23F 33F
25 .
Pneumo 23
dexamethasone 28
9 2.
48 (Pneumococcal conjugate vaccine, PCV)19
1. 3
penicillin oxacillin disk 2.1 PCV7
MIC
cefotaxime ceftriaxone 2. 7 4, 9V, 14, 18C, 19F, 23F 2
3. dexamethasone . 6B 4 .
CRM 197 (a nontoxic mutant of
9 diphtheria toxin) 20 . alumi-
num phosphate 0.125 . adjuvant
thimerosal

Prevnar
2 2.2 PCV10 (PHiD-CV)

 21 227

10 1, 5, 6B, 7F, 9V, PCV10 PCV13

14, 23F 1 . 4 3 . PCV7
non-typeable Haemophilus
influenzae 18C 19F PCV7
3 . tetanus diphtheria 31,32
toxoid IgG
Synflorix enzyme-linked immuno-
2.3 PCV13 sorbent assay (ELISA) 0.35 ./.
PCV7
1
13 6 PCV7 3
1, 3, 5, 6A, 7F 19A
1, 3, 4, 5, 6A, 7F, 9V, 14,
18C, 19A, 19F 23F 2.2 . 3
6B 4.4 . aluminum phosphate adjuvant PCV7
Prevnar 13
T-cell 1.
independent antigens mature IgG
B-lymphocytes T-lymphocytes 0.35 ./.
T-lymphocyte B cells
PCV7 10
IgM affinity PCV10 (PHiD-CV; GSKs ELISA with
maturation memory B cells (anamnestic 22F-inhibition assay)
or booster response) PCV7 (non 22F-inhibition assay)
PCV10 cut-off level
2 immunological memory IgG
0.2 ./.
5-10 29 0.35 ./.
boosting effect 2. geometric mean
concentration (GMCs)
T-cell independent 3. functional antibodies (Opsonophago-
T-cell dependent cytic activity) PCV
2
B cell memory booster response opsonophagocytosis
30
228

3-5 2


opsonophagocytosis activity assay (OPA) 0.5 ./
opsonic titer
1:8 cut-off level 3

50 34:
-
PCV opsonic
titer 1:8 PCV7
4.

immunologic memory (cochlear implants)
PCV - PCV13 PCV7
PCV10 PCV7
PCV10 PCV7 2
3 PCV10 PCV7

- PCV7 4
2-8 o . PCV13 1 PCV7
8
9,33

PS-23 0.5 ./ - PCV
2 2- 18
PS-23
3
()
2-6 PCV 3 6-8 PCV 1 12-15
7-11 PCV 2 6-8 PCV 1 12-15
12-23 PCV 2 6-8
24-59 () PCV7 PCV13 1
24-71 () PCV7 PCV13 2 PS-23 1
8 PCV 8
( 33,34)
 21 229

PCV
PS- PCV7
23 1 5 PCV
PS-23 97
PS-23 PS-23
PCV 89.1
- 2+1 3537,38,45
2, 4 12-15
57
35,36 34
6-7 9-23
tympanostomy tube 2037,45
-- PS23

PCV7
--

37,38
5 9846


2 78 93.4 47,48

85-9039 penicillin 2
68-85 81 49
40,41 PCV7

56-8142 2
42 65
2 3950
boosting effect
2
4251 PCV7 7
43
44
230

5 65 7F
100 92 52 97.3, 99.0 99.5 32
(indirect or herd effect)
PCV10
5 0.2 ./. PCV7
7 1, 5
PCV7 7F 99.6
PCV10
74
( 52) 6B 23F
PCV10 PCV7
53
PCV7
18C 19F
PCV10
PCV757
19A PCV10
opsonic titer 1:8 7
PCV7 87.7-100
54,55 19A PCV7 92.1-100
5 1, 5 7F opsonic titer
65.7, 90.9 99.6
PCV7 .. 2003 91.0, 96.3
56 100 32
PCV13 19A PCV10
PCV10 Pneu-
PCV7 head-to-head comparative trial mococcal Otitis Media Efficacy Trial (POET)

PCV7 6B 23F 11
ELISA PCV10 2, 3 4
cut-off level 51.5
(0.2 ./.) 6B 23 F 65.9
81.4 PCV7 3 33.6
79 94.1 Haemophilus influenzae
1, 5 35.6 PCV10
 21 231

1.

POET58 2.
PCV13
3.
cut-off level, opsonic
titer immunologic memory PCV7 4.
59

PCV7, PCV10 1. 24
PCV13 2.
5 70.3, 70.3 PS-23
81.2 60

PS-23

1.
9,61

PS23 2.
3.

2
1. PCV PS-23
(elective splenectomy)
cochlear implant 2
1-2 2. PCV


diphtheria CRM 197
3.
PCV PS-23
optional vaccine
PS-23 2

4.
232

penicillin adjuvants
penicillin V 125 . intranasal
2 5
250 . 2 5
immunogens
1. whole-cell pneumococcal bac-
62 teria
2. DNA vaccines
3. Protein-based vaccines pneumo-
coccal surface protein A (PspA), pneumococcal sur-
face protein C (PspC), pneumococcal surface adhesion
A (PsaA), pneumolysin (Ply), neuraminidase enzymes
(NanA and NanB)
PspA
.. 2549
optional vaccine
5 5 PspA

cost benefit PspA
( capsular polysaccharide
) (herd immunity) pneumococcal protein

63
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62. Wongsawat J, Chokephaibulkit K. Implica-
tion of pneumococcal conjugate vaccines to public
health: Thailand perspective. J Med Assoc Thai. 2010;
93(Suppl.5):S53-S60.
63. Black S, Eskola J, Whitney C, Shinefield H.
Pneumococcal conjugate vaccine and pneumococcal
common protein vaccines. In: Plotkin SA, Orenstein
WA, Offit PA, editors. Vaccines. 5th ed. Elsevier Inc.;
2008. p.531-67.
76
 239

22

(OPV) (Inactivated
Poliovirus (IPV) vaccine)

World Health Assembly
..
25431

Acute Flaccid Paralysis ( AFP surveillance) Poliovirus
(Oral Poliovirus (OPV) vac- human enterovirus, family Picornaviridae
cine) single - stranded, positive sense RNA genome
( .. 2554) protein capsid 3 1, 2 3
fecal to oral
transmission oral to oral transmission
pre eradication era 4

OPV (Wild poliovirus
type poliovirus, WPV) 2

fecal - oral
( 1)5
.. 2552 -
imported case 2554 20 4
endemic countries Afghanistan, India,
Nigeria Pakistan
WPV 1 3
2013 (.. 2556)3
2 Imported cases
240

1
( 5)
Enterovirus 109
imported cases
.. 2552 15
2553 1 - 72 7 169 409
AFP ( 41.3 )
2552 2553 Russis,
Nepal, Kazakhstan, Tajikistan, Turkmenistan ( 2554)
Senegal endemic 3 8
Pakistan 1. Endemic countries
Afghanistan, India, Nigeria Pakistan
.. 2553 2. Countries with re-established transmission
nonendemic imported cases
12 Angola,
Chad, Democratic Republic of the Congo Sudan
3. Countries with imported poliovirus
10 imported cases
.. - .. 2553 Kazakhstan, Liberia, Mali, Mauritania, Nepal, Niger,
AFP 409 Russian Federation, Senegal, Sierra Leone, Tajikistan,

1 (WPV)6
2552 2553
(23 ) (20 )
1,604 1,294
Endemic countries 1,256 232
Nonendemic countries 348 1,062
( 6)
 22 241

Turkmenistan, Uganda OPV myocardium

WPV 11,12
.. 2540
WPV (Af- 95
ghanistan, India, Pakistan)
(AFP surveillance) 3-6
OPV 2-3 (abortive
.. 25469 poliomyelitis) 1-5
AFP 18 aseptic meningitis
2-10
( Vaccine Derived Poliovirus, VDPV) (asymmetric
OPV flaccid paralysis with areflexia)
0.1 - 2
(Hypogammaglobulinemia) 7 - 21
..
2522 1 (WPV 1)
imported cases
vaccine associated paralytic poliomyelitis (VAPP) 80 10
IPV .. 2540 2-10 10
(IPV-OPV) IPV
.. 254310
aseptic meningitis
11

mucosa lymphatic tissue 1-2


paralytic poliomyelitis
motor neurons paralytic disease 100 : 1 1,000 : 110
anterior horn cell
intermediate gray ganglia posterior
horn dorsal root ganglia (cell culture)
reticular formation, vestibular ()
nuclei, cerebellar vermis deep cerebellar nuclei
242

( 14 )
2 24
Inactivated Poliovirus Vaccine (IPV)

3
OPV


OPV
standard precaution
contact precaution
Outbreak 13
mass immunization OPV OPV .. 2493
MRC 5
IPV vero cell serial passage
neurotropic character Sabin

WHO ..
2 2504 .. 2512 WHO
1. (OPV, Sabin) OPV VAPP
2. (IPV, Salk) IPV OPV

Oral Poliovirus Vaccine (OPV) (1st generation IPV) Salk

3
.. 2493 - 2495
monkey kidney cells
.. 2498 paralytic cases (Cut-
ter incidence)

( inactivation)
Sabins oral poliovaccine
2 (2nd generation
enhanced potency IPV)
 22 243

well characterized cell line

vero cells OPV
microcarriers biogenerators 2-8 .
Mahoney strain 1
type 1, Mef 1 strain type 2 Saukett strain IPV 2-8 .
type 3 ultrafiltra-
tion gel filtration
inactivate (1:4,000) 2

(DTP ) OPV IPV
(HBV) Haemophilus influenza type b (Hib)
OPV

OPV 3 2 2, 4, 6, 18 4 - 6
(1, 2 3) > 106, 105 105.8 3 6-8
IU/ 4 6 -12 3 4
trivalent mono- 4 5 4 - 6
valent OPV (mOPV) bivalent OPV (bOPV) IPV 3
mass im- 2, 4, 6-18 4-6
munization OPV
BCG, DTP, HBV, IPV
Measles, Hib Rota VAPP IPV 2 2, 4
IPV 2 3 OPV 6-18 4-6
(1, 2 3) 40, 8 32 D unit (Sequential IPV - OPV)
( 2) VAPP 5010
IPV 4

2 IPV

Tetraxim Sanofi Pasteur DTaP, IPV
Pentaxim, Pediacel Sanofi Pasteur DTaP, IPV, Hib
ADACEL - Polio Sanofi Pasteur Tdap, IPV
Infanrix IPV/Hib GlaxoSmithKline DTaP, IPV, Hib
Infanrix Hexa GlaxoSmithKline DTaP, IPV, Hib, HBV
Boostrix - Polio GlaxoSmithKline Tdap, IPV
244

2 2 2
3 6-18 OPV
4 4-6 ( 3 4
4) ( WPV)

4 1. VAPP
OPV WPV
VAPP
4 / 1/ OPV
OPV 2 3 22 Sabin 3 ( 60 )4
90 97 OPV VAPP
3 14 1 2.4
VAPP
15 1 750,000 12
73 70 VAPP
1 3 4,16 3,200-6,800 23
VAPP ..
2540-2543 1 3-15
4 2. VDPV Sabin virus
4
OPV
neurovirulence
IPV 2 seroconversion circulating VDPV (cVDPV)
95 replicate
2 ( neurovirulence
immunodeficiency-associated VDPV (iVDPV)
) 3
9917,18 IPV
OPV19,20
streptomycin, polymyxin B
neutralizing antibodies IPV 3 neomycin
18 21 IPV


OPV
 22 245

IPV preeradicating era
OPV (
IPV OPV
VAPP OPV OPV
severely im-
munosuppressed )24 OPV (WHO)
25 WPV 2
IPV WPV 1 3 WHO
low risk
12 pre eradication era
2 ( 2)4
2

primary series OPV IPV 1. Imported cases
1
3 4
2.

12
OPV Imported cases
OPV
IPV
Imported cases
( IPV)
IPV Imported
IPV anaphylaxis cases ( India, Pakistan
streptomycin, neomycin Afghanistan)
polymyxin B (
90 - 95) 3
IPV
OPV () 7226 )
WHO
IPV
OPV OPV Sequential
246

2 WHO
( 4)

IPV - OPV
fractional dose
1. OPV3 90 (1/5 full dose) IPV (intrader-
) 2. AFP mal) IPV
AFP 2 /100,000 seroconversion ( > 95)
15 80 ( 100)
) 3. 27
mop up adjuvants oil in water emulsions
90 )4 (MF59 like emulsion)28, Chitosan29
26
1.
Imported WPV 2. VAPP
VDPV 3. cost effectiveness analysis
IPV
IPV
1. World Health Assembly. Global eradication
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resolution WHA 41.28.
2. Modlin JF. The Bumpy Road to Polio Eradi-
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tion.org/Portals/0/Document/StrategicPlan/StratP-
lan2010_2012_ENG.pdf
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html
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. 2546;34:835-50. 17. Faden H, Modlin JF, Thoms ML, McBean
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oral polio vaccine: recommendations of the Advisory
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Recomm Rep. 1997;46:1-25.
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Pathogenesis. Philadelphia: Lippincott Raven; 1997.
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on Infectious Diseases. 28th ed. Elk Grove Village, IL:
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14. American Academy of Pediatrics. Poliovi-
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Report of the Committee on Infectious Diseases.
26th ed. Elk Grove Village, IL: American Academy of
Pediatrics; 2003. p.505-9.
15. .
2550. :
, , ,
, .
.:
; 2550. 100-7.
16.Patriarca PA, Wright PF, John TJ. Factors
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18. Modlin JF, Halsey NA, Thoms ML, Me-
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1997;175(Suppl1):S228-34. 27. Mohammed AJ, AlAwaidy S, Bawikar S,

19. Onorato IM, Modlin JF, McBean AM, Kurup PJ, Elamir E, Shaban MM, et al. Fractional doses
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November 2002. Geneva: WHO; 2003. Available from:
http://www.who.int/vaccines-documents/DocsPDF03/
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 249

23

(zoonosis)
Lyssavirus


() virus-laden
saliva
55,000 1



2.2-3


10
14


(intermittent salivary excretory)



.. 2535 62 .. 2524 46 ..
2538 18.8 .. 2547


250

()
1 12
1
2 (contact route)


0-14

4
500
3-6


(cell-culture rabies vaccines)
( 1) (purified duck embryo vaccine)
( 2 1 )

(vampire) 20 60,000
300,000-400,000
(superficial bite ( 0.5 100
scratch)

( 30 )
) .

Australian bat Lyssavirus 4
1
10

(non-bite exposure)
(intradermal Thai
( Red Cross regimen, TRC)
) 100,000


 23 251

10-30
3-4 (
300 )

90
(
67-85
) (), 10-23
3 ( 2)8
1-40 ( 20 10
(bite prevention) )

WHO categories
( 1) 50-60

80
70 (
5-80) ( 0.1-1)
96.57 50
2.5 ( 60) ( 12.7)
5

( 25) ( 10) 70 8-10








(pre-exposure vac-
cination) ()

252

povidone-iodine 7-28 nested

(active immunization) PCR latex
(rabies immune globulin; agglutination test
RIG) (passive immunization)
FA test
RIG 13
2 FA test
( 1) ( pre-
1. exposure vaccination)

3
categories11,12 1 FA test

RIG 1 WHO
category 1 (
) 10

10-20

3
14
1.
WHO category 2 3
1 2.
2. ( 1) 2
3. (provoked condi-
tion)
( 3
) 10
20
fluorescent antibody test (FA test) 3
1 (
) 10
(mouse
inoculation test) 3-12
 23 253

- ()
() 3-7
- amoxicillin, amoxi/clav, 2ndor3RD cephalosporins
- (Td or TT)

rabies post-exposure treatment

WHO Categories

1
2 3
( pre-exposure)

(FA test)

post-exposure6 ( pre-exposure)

post-exposure post-exposure

post-exposure

post-exposure 3
1)
2) 2
3)

3 3

10 post-exposure6
post-exposure 10
( 0, 3
7 pre-exposure
vaccination)

1
254

1 (rabies immunoglobulin, RIG)

(WHO categories)
/ RIG

I a
II b
, 10
c

III / b
10
( ) c



a
(pre-exposure vaccination)
b
3 ( 2
) 10
c

3
(provoked condition) 1
(unprovoked condition)

10
( (Post-exposure vaccination)
3-4 2
primary immunization 4 HDCV (human diploid cell vaccine
1 . ) PCECV (purified chick embryo cell
pre-exposure ) vaccine 1 . ) PVRV (purified Vero
10 cell vaccine 0.5 . ) PDEV (puri-
fied duck embryo vaccine 1 .
preservation)
( 10 )
10-14 (intradermal)
14
 23 255

rabies neutralizing antibody (Nab)

titer 1/5 0.5 IU/.
10-14 rabies Nab titer
21
12 10-14
rabies Nab titer 0.5 IU/.
14
rabies Nab titer 0.5 IU/
4 . 1 1-2
11 (standard 17
intramuscular regimen: ESSEN) RIG 7
2-1-1 (multisite intramuscular regimen; Zagreb)
(intradermal) Thai Red Cross
(original TRC regimen: 2-2-2-0-1-1 modified TRC 5
2-2-2-0-2-0) 2-1-1 (multisite intramus-
(8-site intradermal, Oxford) cular regimen; Zagreb: 2-0-1-0-1)
2 11,12,15
1. (standard (PDEV) 1 2
intramuscular regimen: ESSEN: 1-1-1-1-1) ( 0)
1 (deltoid muscle) 2 1 1
(1 . 0.5 . 7 21 28
1 )
(deltoid) (antero- (rabies Nab titer)
lateral of thigh muscle)

RIG 3
1-1 0 () 3, 7, 14
28 30 2-1-1 RIG
28 ( 4 WHO category 2
0, 3, 7 14: 1-1-1-1-0) PCECV PVRV (
rabies antigenicity 10 IU/) RIG
5 2-1-1
(immunocom- 14 rabies Nab titers 0.5 IU/
petent host) . 0.5 IU/
16 . 1
256

2. (intradermal) Thai = 6.9 IU/.) PCECV ( rabies antigenicity

Red Cross (original TRC regimen: 2-2-2-0-1-1 3.6 IU/.) 0.1 .
modified TRC 2-2-2-0-2-0)12 TRC RIG
(intradermal)
0.1 . 0.2 . immunogenicity
2 ( 0) 3 PCECV 0.1 .
7 1 28 30 90 TRC ( rabies antigenicity = 10 IU/)
2 28 30 (2-2-2-0-2) RIG
RIG PCECV TRC
HRIG rabies antigenicity
7 IU/. 0.1 . (0.7 IU/1 )
2-8o . 6 PCECV 0.1 .
- 8 TRC
14 1
4-10o. ( 7 ) rabies antigenicity HRIG PCECV
2.5 IU/ PVRV TRC intradermal
18 0.1 . (PCECV = 0.91 IU/0.1 .)
rabies antigenicity HRIG 0.1 . PCECV
19,20
TRC
rabies antigenicity 1

pre-exposure prophy- 0.7 IU/21
laxis 3-4 2 (multisite in-
primary immunization tradermal regimen)
8-site intradermal regimen (Oxford regimen)
0.1 . HDCV, PVRV
TRC ID PCECV (intradermal)
15 100,000 2
1 2 ( 8 ) (
0) (
TRC ID 0.1 . PVRV, PCECV 4 ) 7 30 90
1 (8-0-4-0-1-1)
0.7 IU/ RIG
PDEV (1 ./ rabies antigenicity RIG
 23 257

3, 7 28 TRC regimen
WHO categories 3
RIG

WHO
categories 3 RIG

(
)
purified ERIG
22-26 PVRV 0.05
. 1
0.05 .
1 (4-0-2-0-1-1) RIG
4 0, 3 7
27 202 (59
3 )
PVRV+RIG (
0.39 )
1
ESSEN RIG
TRC

post-exposure 1 1
TRC
3, 7 28 ( 1IM-2ID-2ID-0-2ID)
rabies Nab titer HDCV, PDEV , PCECV
intramuscular ESSEN regimen intradermal
TRC regimen28 RIG
500 29

.. 2549
(Rabies immune globulin, RIG)
0 RIG

258

category 3 neutralize receptor

RIG (
RIG )
(WHO category 3) RIG
RIG ()
RIG (equine rabies immune RIG
globulin; ERIG) RIG
ERIG RIG ( )
(RIG) 2
RIG
1. Human rabies immune globulin (HRIG) RIG
HRIG 20 IU/. HRIG
(
HRIG RIG RIG 2-3
2. Equine rabies immune globulin (ERIG)
ERIG 40 IU/.
purified ERIG anaphylaxis serum sickness
( 1.6-6.9) (type III hypersensitivity intradermal skin
purified ERIG highly testing ERIG
purified heat-treated ERIG ( intradermal skin testing
)30
purified ERIG wheal
purified ERIG 5 . 30-40
anaphylaxis purified ERIG
(crude ERIG anaphylaxis ( 30-40
3.8) HRIG )
RIG 1
ERIG ( purified ERIG)
( 10-14) 26 ERIG
RIG 0.02 . ( 1:100 )
10
7 wheal flare
RIG 2
anaphylaxis
serum sickness 1.41
 23 259

wheal 5 . 10 6
. 2 ( 0 3)
5 . 6
negative control test wheal 5 . PVRV 4
25.9 (0.1./) 0
PVRV 2 ( 0
HRIG wheal 10 . flare 3)
20 . PVRV pre-exposure ID (0.1./) 1
anaphylaxis rabies Nab titers ID 4
anaphylaxis 2
(conventional booster regimen)
5 1 31
4

.. 2541
WHO category 3 5,000

rabies Nab 32,33
titer 0.5 IU/.
WHO 4
category 2 3 12
RIG
12

5 10
1 0.2
. PDEV PVRV 1
0 3 rabies Nab titers
14
7
5-10 10 34,35

1 4 0
1 1 ( 1 0
0.1 .) 1 ( 0) 3
260

(pre-exposure post-exposure)


36
(
17 )
8.7 1.3 37,38
(Pre-exposure prophylaxis)
9-17

(
)

WHO category 1 (
)

(
2-4 )
(DPT-IPV)
RIG


( )

2-3


3 4 1-2 (pri-
mary immunization)
2

1
(
)
 23 261

PVRV (ID) 0.1 . 1
0, 7 21 28
RIG ( RIG 1 40-50 rabies
) Nab titers 0.5 IU/.
3 ( 87-100)
HDCV
0.1 . rabies Nab titer

1 0.1 .
(deltoid) 0, 7 21 0.1 0.2 .
28 () 1 0 3
0.1 . 4
3 2 0
( 0 28)
3 ( 0, 7 28) HDCV PVRV
1 1 rabies Nab 5-7
titer 14 ( 379)
rabies Nab titer 30 IU/. (pre-booster
( 0.5 IU/.) 10 rabies Nab titer)
2
tetanus toxoid (
aluminium hydroxide tetanus
toxoid ) (rabies
rabies Nab titers Nab titer) 0.5 IU/.
3 39
0.1 . Nab titer 6
1 0, 7 21 rabies Nab titer 0.5 IU/.
28 chloroquine 1
0.1 . 1
( 1
mefloquine
rabies Nab titers)

262

anaphylaxis serum sickness 41

rabies Nab HRIG
titer 1-2 rabies Nab titer
0.5 IU/. ERIG
( purified ERIG 1.6-6.9
) purified ERIG

serum sickness 90
rabies Nab titer 1-2
3
serum sickness

WHO category 2 3

42,43

HDCV
15-25
2-8
serum sickness 1
2-3

serum sickness 6-11 (
2-21 ) PVRV primary immuni-
zation

( 23-39)
( 3) 6-10 ()
( 1) ( 1:80,000 1:12,000-30,000
5-9)
30-32
 23 263

1.
WHO category III


44,45
2.

(Immunocompromised host)


2-3
rabies Nab titer
3.

2
(deltoid region) (anterolateral 46,47
thigh)
4.


5. CD4 300-400/..

(PVRV) TRC ID RIG
PCECV ESSEN
(rabies Nab)

CD4 300-400/.
.48-50 post-expo-
sure treatment
2 51,52
2 TRC-ID (2-2-2-0-1-1)
( 10 ) 4-4-4-0-2-2 ID
2
tetanus toxoid (2-2-2-2-2-0;
double doses ESSEN regimen)
264

Nab CD4 1968;217:954-5.

200/.. Briggs PJ 5. Phvangsab A, Panas-Ampol K, Lawha-
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rodents and shrews trapped in Bangkok. J Med Assoc
Thai. 2003;86:1008-12.
pre-exposure vaccination 7. Coleman PG, Dye C. Immunization coverage
CD4 ( required to prevent outbreak of dog rabies. Vaccine.
15)55,56 1996;14:85-6.
Nab 8. Benjavongkulchai M, Kumphai W, Tanta-
CD4+T-lymphocyte counts wichien T. Animal - bite injuries at Queen Saovabha
viral load Memorial Institute. 75th Anniversary Research
Conference, December 16,1887 (Abstract).
9. Bhanganada K, Sakolsataydorn P, On-
57 sumbat P. Dog-bite injuries at a Bangkok teaching
hospital. Acta Tropica. 1993;55:249-55.
10. Tepsumethanon S, Tepsumethanon V,
Wilde H. Risk of rabies after mammal bites in Thai
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. 25. 14. .
, . 25-28 (
2542. ). , ,
4. Smith PC, Lawhaswasdi K, Vick WE, , , .
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 269

24

B
3 4
Neisseria menin- C, Y W-1351
gitidis
B A C, Y W
135
5 - 10


0.03-0.19
16-100 2 .. 2552

24 34 0.05
5 0.01
14.71
9 ..
2543-2551 ..
2552 .. 2551

N. meningitidis 0 - 4 10-14, 5-9,
25-34, 15-24 35 3


13 A, B, C, D, E, X, Y, Z, W-135, N. meningitidis
H, I, K L 5
A, B, C, W-135 Y A
Sub-Sahara W-135 2-10 (
3-4 )
270

petechiae /



4
30
20 cefotaxime ceftria-
petechiae purpura xone penicillin
20 (meningococcemia) penicillin
purpura fulminans penicillin 6-8

(Waterhouse Friderichsen syndrome) Disseminated intravascular coagulation
(DIC)

13
.. 2537-2542 33 2 -75
11.2 45.5 meningo- (close contact)
coccemia 54.5 24
24.2 rifampicin 600 . 12
33.3 12.1 2 >1 rifampicin
3 9.15 10 . 12 2
1 rifampicin 5 . 12
2
quinolone,
ceftriaxone azithromycin9-11
10-20 2

30

 24 271

(..1900-1940) killed whole 2

cell12,13 1. Bivalent
..1930 A C
2. Quadrivalent 4 A, C, Y
inactivated endo- W-135 Menomune
toxin A/C/Y/W-135 (MPSV4)
..1940 Scherp Rake A, C, Y,
W-135 50 .35
14 A, C, Y,
15,16 W-135

17 .. 1960 2-8o .

1
18,19 2 MPSV4 2
bivalent (A C) quadrivalent (A, 0.5 .
C, W135 Y)

T cell20
memory T cell21-23 4
2-3 5

A C24 C25-28 1,35
A, C, Y W-13529-34 MPSV4 7-10
MPSV4
(A, C, Y W-135) 11-55
..2005 (MCV4)
2-10 32
MPSV4 3-5 9,36
MPSV4
2


272

B



terminal complement deficiency


2
1. Monovalent

serogroup C
C
(CRM 197)
(tetanus toxoid) 35
2, 3 4

B
2. Quadrivalent meningococcal (A, C, Y
W-135) conjugate vaccine
1,35
.. 2005 Menactra (MCV4)

A, C, Y W-135
3 4 .
MCV4 48 .1,35 Menveo (MenACWY)
Guillain-Barr syndrome (GBS) Novartis .. 2010
MCV437 38

2-8 o .


momovalent serogroup C conjugate
1 vaccine (Menjugate) 0.5 .
2 -12 3
1 12 0.5
. 1
 24 273

Quadrivalent meningococcal conjugate W135)

vaccine 0.5 . MCV4
Menactra (MCV4) 2-55 40
Menveo (MenACWY) 11-55

1 11-12
1 16 2-54 MenACWY
anatomical .. 2010
functional asplenia, terminal complement component 11-55
(C5-C9) deficiency properdin deficiency MCV4 11-17
primary series MenACWY
2 2 39 MPSV441 MenACWY

42

MCV4 MCV4 (serogroups A, C, Y
(MPSV4) W-135) .. 2005
11 18 18-55 33 .. 1998 .. 2007
11-18 64 0.92
80 0.33 100,000 43
A, C, W135 Y meningococcal se-
rogroup C conjugate vaccine
3 9
MCV4 ( 92)
W135 44 21 MPSV4 ( 97)44 2,
C Y 3 4
34 49
2-10 5-11
MCV4 12 45,46
MPSV4 C
C
MCV4 4 46
(1700 893
A, 354 231 C, 637 19 C
408 Y, 750 426 47
274

75 3
2-18
C 67 35 1 17 MCV4 MPSV4
> 25 2-5 GBS
herd immunity48 MCV4 6 49,50
GBS
MCV4 MPSV4 51
MCV4
2-55



anatomical functional asplenia, terminal 2
complement component (C5-C9) deficiency GBS
properdin deficiency, GBS MCV4


2
1,35

11-18

A, C, Y W 135
55 MCV
Menveo MPSV4 > 55

MCV4
N. meningitidis
2-10

2-3



MPSV4 A B


herd immunity


MCV4

 24 275

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of group B meningococcal disease. N Z Med J. 2009;
122:48-59.
 279

25

core VP1, VP2 VP33,4
(group)
(Rotavirus) (subgroup) (serotype)
5 VP6 7 A-G
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1,205
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A G
family Reoviridae, genus G1, G2, G3, G4 G9 P
Rotavirus double - stranded RNA P4 P810,11 G P
12 65-75 80
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capsid) inner core G1P[8], G2P[4], G3P[8] G4P[8] 12,13

(Rota .. 2538
) 2 G9P[8]
VP7 VP4 VP6 inner
280

14-21 27-3418 .. 2544-2546

.. 2520-2540
G1
G2, G4 G3 .. 6
2539-2540 G9 3
G1 G218 .. 2541-2542
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G9 23
..
2544-2546
4,057

1,950
5 838 43
1 5
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1 206
24 6-13
2 213 1
200 12
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1 1 67 131,000
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1
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5 25

The Asian Rotavirus Surveillance 6
Network (ARSN) 2 18,26-28

4526

.. 2520-2540

 25 281

(fecal-oral-route)



4-57 29
5,30






necrotizing enterocolitis
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34-40
disaccharides

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-
nonstructural rotaviral protein (NSP4)
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31
ELISA, latex agglutination, Polyacrylamide gel elec-
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32,33

282

.. 2541
9
2
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.. 2542 rhesus rotavirus
probiotic hyperplasia lymphoid tissue
41-46 payer patch 55

56-60
1. Human-derived monovalent live-attenuated
oral vaccine RotarixTM

12 2547
(RIX4414)
G1P[8]
70,000

2. Bovine-human reassortant pentavalent
live-attenuated oral vaccine RotaTeq
Merck G1, G2, G3, G4
P[8] 3
Tetravalent Rhesus 3. Lamb-derived, monovalent live-attenuated
Rotavirus Vaccine (RotashieldsTM) oral vaccine G10P[12] Lanzhou Institute of
Biomedical Products
G3 reassorted . 2544
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2, 4 6 60

46-68 2
70-10047-51 Live, attenuated human rotavirus vaccine
Bovine- human reassortant rotavirus vaccine

 25 283

1


Rotarix Human-derived Lyophilize 1 ./ 2 6-15 2, 4
monovalent Oral suspension 8
G1P[8] 1.5 ./
> 106 CCID50/. 4
RotaTeq Bovine-human Oral suspension
reassortant 2 ./ 3 6-15 2, 4, 6
pentavalent 8
G1 2.2x106
infectious units 4
G2 2.8x106
infectious units
G3 2.2x106
infectious units
G4 2.0x106
infectious units
P8 2.3x106
infectious units
( 63)

2. Bovine- human reassortant rotavirus

1.Live, attenuated human rotavirus vaccine vaccine RotaTeq Merck
RotarixTM (Bovine rotavirus
WC3 strain) reassorted
G1P[8] G1, G2, G3, G4 P[8]
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1.5 .
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.. 2548 RotarixTM
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24
61
284

63
1. Live, attenuated human rotavirus
vaccine
2
6-15 2 8 1. Live, attenuated human rotavirus
4 vaccine
2. Bovine- human reassortant rotavirus Vesikari score
vaccine 2 .
3 6-15
8
4 0-20

6-15 8 11 55,66
4 RotarixTM
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3,994

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90

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2 OPV 94, 83 96
63,65
OPV RotarixTM
RotarixTM

 25 285

G1 100 74
non-G1 94
RotarixTM ( >16) 98

G1 83
non-G1 80 G1, G2, G3, G4 G9 74, 63, 82, 48
65
G1 96 G1, G2, G3, G4
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2,036
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2. Bovine-human reassortant rotavirus RotaTeqTM Cochrane Collaboration
vaccine 34 175,944

0-24

73

16

286

immunodeficiency disease
74-78 79-81
3. latex RotarixTM
77,78 oral applicator latex
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4.




(intussusception) RotaTeqTM 5.
TM 61,62
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7.
6
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9.


3 10.


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 25 287

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2
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PCV1

Rotarix WHO Human-bovine reassortant
.. 2553 tetravalent oral vaccine National Institutes
of Health
DNA PCV1 RotaTeq G1, G2, G3 G4 Human neonatal strain-derived
PCV2 live-attenuated vaccine Graeme Barnes &
PCV1 PCV2 PCV2 Ruth Bishop
monovalent strain G3P[6]
50

2 2
Rotarix human-bovine
RotaTeq neonatal-derived strains

.. 2553

288

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26

.. 1921
(WHO) Calmette Guerin
.. 2010/2011 1.7
4,700 Mycobacterium bovis
9.4 1 culture medium
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38.0 .. 1921
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(lyophilize)
22
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3.3
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rifampicin bacterium bovis 4

.. 1921 virulence immunogenicity 5,6
100
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bovis

296

1
( 4)

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1 M. bovis BCG
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.. 1961
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phylogenetic tree 4 deletions
molecular fingerprint M .bovis, M. tuberculosis deletions polymorphisms
restriction-fragment-length-polymorphism
(RFLP)
IS6110 MPT64 .. 1921
IS6110 MPT64
IS6110 MPT64 2 early strain late
IS6110 strain BCG Pasteur 1173 P2
.. 1925-1926 MPT64 late strain Tokyo 172-1
.. 1927-1931 24 early strain genome sequence
.. [BCG Pasteur 1173 P2 contain
1921 two separate genetic populations with double and triple
tandem duplications in the DU2 region (a protein en-
coding region with 58 genes) BCG Tokyo 172-1
 26 297

contain two separate genetic population with differ in munogen

the protein encoding RD16 region, one variant having immunogen
the full RD16 region the other with a 22 bp deletion in .. 193114 ESAT-6 CFP-10
this region. ] morphology M. bovis
growth characteristic 7-11 MPT64, MPB70, MPB83

culture medium


.. 1921
2
(lyophilized) vaccine immunogenicity


reactogenicity conversion
1.
90-95
- protective immunity
2512 172 lot-to-lot consistency
30 1 final lot
.
12-15 1 .
2 biomarker panels mycobacterium growth
syringe inhibition bioassay
2. molecular biology
(genectic information)
mycolic acid virulent
M. bovis mycobacterium 15

.. 1931 BCG sub-strain sub-strain
methoxymycolic acid M. bovis
methoxymycolic acid (guinea pig)
(macro- early strain
phage)13 (BCG Tokyo 172-1) late strain (BCG Danish 1331,
3. im- BCG Pasteur 1173 P2, BCG Connaught, BCG Tice)
298

2
( 4)

aerosol challenge
16
BCG Glaxo (late strain)
(regional suppurative adenitis)
0.1-38 1,000
(BCG-osteitis) 0.01-330 1,000,000

(WHO) (prevalence) (disseminated BCG) 2
(TB disease) 1,000,000 18 (
40 )

.. 2545 49.95 .. 2551
54.3017 .. 2552 63.112



(disseminated tubercu-
losis) (TB meningitis)
60-90 19
(primary tuberculosis) 1
2-3
 26 299

1
Category Description
Regional disease Persistent ulcer, abscess, fistula,
or lymphadenopathy limited to the region of inoculation
Extra regional localized disease Infection of a single anatomic site, such as osteitis or
cutaneous abscess, outside the region of inoculation
Disseminated disease See detailed in table 2
Other BCG syndrome Syndromes following vaccination in which bacteria are
not identified, such as keloid, uveitis. These syndromes
may have an immune basis
( 18)

(bluish-red pustule)
5-15 .
crust formation
3-4 6-10 crust erythromycin, cloxacillin
3-7 . ( ) isoniazid
10 . 20
3 isoniazid
28-33 hypertrophic scar
2-4 keloid scars 22
(infants)

1 21
2 2,500
well baby clinic

2
Incidence per 1 million vaccinations
Complication
Age < 1 year Age 1- 20 years
Local subcutaneous abscess, regional lymphadenopathy 387 25
Musculoskeletal lesions 0.39 0.89 0.06
Multiple lymphadenitis, nonfatal disseminated lesions 0.31 0.39 0.36
Fatal disseminated lesions 0.19 1.56 0.06 0.72
( 21)
300

3 conversion rate
40
intradermal conversion rate
3 83 lympho-
proliferative response M. tuberculosis
IFN -response
2 percutaneous
intradermal
subcutaneous
intradermal
intradermal
8-9 90 ( M. tuberculosis24
10 .) 23
(BCG lymphadenitis)
(outbreak) 1-4


(Pasteur-1173P2)
Mozambique, Zimbabwe, Zaire
Caribbean 0.013 2325-27


(Pasteur-1173P2) 19
Tokyo Moreau 22
Copenhagen AFB
Pasteur-1173P2 M. bovis
Staphylococcus aureus, Strepto-
coccus group A M. bovis

M. bovis
percuta-
neous multiple-puncture device


intradermal 20
 26 301

3.8 Russian BCG-osteitis

( 1-6 ) 2-4 . 35 : 1,000,000
10 15 . 9 BCG-osteitis19
10-15 . 1 10 . .. 1960-1970
17 ( 85) Gothenburg
9.1 ( 2.5-19 ) BCG osteitis 7.3 : 100,000 ..
3 20 1971-1978 Gothenburg
11.8 ( Copenhagen
5-23 )28 spontaneous BCG-osteitis 36.9 : 100,000
regression 20-85 29 BCG-osteitis


M. bovis

BCG osteitis 222
.. 1960-1988 30,31
96 0-1
1.5 ( 0.25-5.7)
isoniazid, rifampicin 1
2.5 ( 1.7-3.6)

1.5-2
14
24 arthritis


sinus tract lower extremity ( 57.6)
femur 26.7
metaphysis epiphysis long bone29
(BCG Osteitis) 3
BCG osteitis 3-4
pyrazinamide BCG M. bovis
0.01 : 1,000,000 12 ( 6-24
300 : 1,000,000 ) 97
BCG osteitis
Czechoslovakia
Prague .. 1982 keloid
302

3 BCG osteitis
BCG Osteitis
1.
2.
3. osteitis
4.
4.1 M. bovis BCG
4.2 AFB +ve
4.3 (epithelioid cell granuloma)
( 30)

(Disseminated BCG) (failure to thrive)

disseminated BCG
3 418
(disseminated BCG) 2 M. bovis first-
1,000,000 18 line pyrazinamide
disseminated BCG
severe isoniazid, rifampin, ethambutol, streptomycin
combined immunodeficiency (SCID), chronic granu- 70
lomatous disease (CGD)
.. 1921-1982 60 pyrazi-
.. 1980-1995 27 namide
5,000
84 immunocompromised drug interaction
71 2

4 Disseminated BCG
3
1.
2.
2.1
2.2 2

3. systemic

( 18)
 26 303

2
outbreak BCG
adenitis

(lot number)

(potency)
PPD

conversion rate 90-95
Glaxo, Tokyo, Pasteur, Copenhagen
conversion rate
Pasteur
Pasteur-1173 P2 conversion rate 64
conversion rate
88 conversion rate

intradermal
immunogenicity hypersensitivity
indura-
syringe tion
Zimbabwe outbreak 0-4, 5-9, 10-14 15
. 32
19
.. 2553
(Serum Insti- 15
tute of India) (Russian 1) (BCG scar)

( Tokyo 172)
0.05 . 50-6033
(0.1 .) 5334


20-5035,36
304

(induration)

50 37

(TB
meningitis) (miliary TB)
52-100
2-8021
( 0-80) 1



5 38
1-2


5








1 -2



intrader-
mal
T-cell 1-2
1-2
 26 305

5
_________________
________________________ .
induration
induration
(abscess)

(hypopigmented patch)

(keloid)

1


1-2
1. (induration)


2. 15 .


(active disease)

2 (LTBI) isoniazid 6-9

3. 1-9 .
53 ( 6-12
10 .31,39)
(miliary TB) (TB
meningitis) 37

1 4. 10-14 .

(environmental mycobacterium)
Kagina BM .. 2009
306

44
10
(endemic area)
BCG-specific CD4
T cells 40 ( polyfunctional T cells co-
expression IFN-gamma, TNF-alpha IL2)
immunity mature

BCG-specific
T cells ( : wane)
disseminated
BCG disease 41

2 7

1 7-14
42
( ..
1931)
.. 1921

9043 (over-attenuated vac-
cine)
45

(sanatoria)

10-20
(endemic area) 46-48


Wuchere-
ria bancrofti, Schistosoma haematobium
49
cytokines
 26 307

Th2-type immune activation Th1 (CMI)

albendazole ( 3)
(Ascaris lumbricoides)
(live oral cholera vaccine)
IFN- 43
50,51 Blocking hypothesis
Ferreira AP52 (environmental mycobac-
Ascaris lumbricoides, Enta- terium)
moeba histolytica, Strongyloides stercoralis
IFN- IL-10
IL-10
type-2 cytokines response
IFN-

(vaccine strain) (CMI)
(block)


(M. tuberculosis)

3 Blocking hypothesis Masking hypothesis

( 43)
308

(nave recipient) responses

(BCG dissemination) waning 54 30
(latitude) (equator)
Masking hypothesis

30 (higher latitudes)
( 55
blocking hypothesis)
Blocking hypothesis



(nave recipient) (nave recipient)
Masking hypothesis




Blocking hypothesis Masking hypothesis
Blocking hypothesis

(tropical regions)
(skin test con-

version rate)
(wane)


Malawi
2-3 10-20
waning

waning /
53 T-cell (boost existing immunity: Late
 26 309

booster vaccine) (postexposure

vaccine)

6
Type Description Developer Improvement over Stage of development
available vaccines
rBCG30 Live, recombinant BCG- University of Stimulates a stronger, Phase I trials
Tice, over-expressing California, LA, USA longer-lasting response completed
Ag85B from M.tb than conventional BCG
rBCG::D Live, recombinant BCG,
ureC-llo+ urease-deficient mutant that Max Planck Institute Promotes leakage of Clinical trial
express lysteriolysin O gene of Infectious Biology, antigens from phagosome to scheduled for 2006
from Listeria monocytogenes Berlin, Germany improve CD8 responses
via cross-priming
MVA-85A Live, recombinant, Oxford University, Stimulates strong primary Completed phase I
replication-deficient vaccinia Oxford, UK immune response, but trials in UK and in
virus, expressing Ag85A\ intended primarily as a clinical trials in The
from M.tb booster vaccine for individuals Gambia
previously vaccinated with
BCG
Ag85B-ESAT6 Recombinant protein, Statens Serum Stimulates strong primary In phase I trials in
composed of a fusion of Institue, immune response, but Leiden, Netherlands
ESAT-6 and Ag85B from M.tb Copenhagen, intended primarily as a
Denmark booster vaccine for individuals
previously vaccinated
with BCG
Mtb72f Recombinant protein, GlaxoSmithKline Stimulates strong primary Completed phase I
composed of a fusion of Biologicals, immune response, but trials in USA and
Rv1196 and Rv0125 from Rixensart, Belgium intended primarily as a recruiting for phase II
M.tb and delivered in oil-in- booster vaccine for individuals trials in Lausanne,
water emulsion, containing previously vaccinated with Switzerland
immunostimulant 3- BCG
decacylated-monophosphoryl
lipid A and a purified fraction
of Quillaria saponaria
SRL172 Autoclaved M vaccae SR Pharma, London, Enhances Th1 response to Phase I completed.
UK. Current trial led shared mycobacterial Phase II running in
by Dartmount- antigens, but also drives Tanzania (DarDar
Hitchcock Medical regulatory T cells that project) in patients
Center, Lebanon, inhibit Th2 infected with HIV
NH, USA
( 57)
310

MHC class I MHC class II
6 cytotoxic T lymphocytes, helper T cells
primary immune response
(acute phase)
( 4 - A)

HSP65, Ag85, 38 kDa, PstS-3, (ESAT-6, KatG,
3-5 (TB
disease)


(prophylactic vaccination)


(latent phase) ( 4 - A)




(dormant state)
(LTBI: latent TB infection)

(reactivation phase)

( 4 - B)
(post-exposure, therapeutic vaccination)
reactivation
phase ( 4 - B)

(acute phase)
(acute and
reactivation phase) multiphase vaccination ( 4
4 - C)
DNA vaccine ( 56)
 26 311

MPT63, MPT64, MPT83), (Mtb39a, HSP65, MPT70, T-cell immunity

IL-12), (65 kDa, Ag85), 35 kDa B-cell
58 DNA vaccine (M.tuberculosis)
HSP65 MPT70 CD4+ T-cells CD8+ T
DNA cells MHC class II
59 molecules ( CD4+ T cells) MHC class
I molecules ( CD8+ T cells)

phagosome
prime subunit acid-dependent enzymes phagosome
booster vaccine
60-62 mycobacterial urease pH phagosome
cytoplasm

(Replacing BCG) MHC class II molecules
MHC class I molecules
cytoplasm
MHC class I molecules

Kaplan G.
rBCG30 vaccine, rBCG::ureC-llo+ vaccine MHC class I molecules
MHC class II molecules
M. tuberculosis cy-
toplasm phagosome
M. tuberculosis
(virulent lysine gene
form) Listeria monocytogenes
rBCG30 vaccine63 phagosome
M. tu- MHC class I
berculosis: 30-kDa major secretory protein gene molecules MHC class II molecules
recombinant vaccine phase I
(guinea pig) 64

rBCG::ureC-llo+ vaccine64
Kaplan G.
312

Th1-
response
MVA-85A, Ag85B-ESAT6,
Mtb72f

primary immune response
recombinant protein vac-
cine Th1-response
(booster vaccine) adjuvant adjuvant
subunit vaccines
(Augmenting BCG: Late booster alum (aluminum hydroxide), MF59, virosomes
vaccines or postexposure vaccines) Th2-response
50 adjuvant
65
56
(endemic area)
(Postexposure vaccines)

25-35


(postexposure vaccines)


(TB disease)
(primary immune
response) preexposure vaccine
(multiphase
vaccination)
immunological memory



Mycobacterium vaccae (heat-
recombinant killed) (therapeutic
 26 313

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 317

27
,

Measles virus
(measles) ( Rubeola) genus Morbillivirus
Paramyxovirus4 single-stranded RNA
(spherical) 100-250
5 envelope glyco-
200,000 - 500,000 protien 3 6
450 1 H protien
F protien
M protien
measles masel viral maturation
2 (spots) envelope (>37.)


( 2 )
2,000
Rhazed ..
1954 Panum 3


2
1,4,7


2
(Expanded Program on Immunization EPI)
.. 25528
6,071
318

9.57
11.6 .. 15-17
2542 - 2552 2
.. 2543 .. 2545 4
16.49
.. 2551
11.81 8-12
39 . - 40.5. 14,15

1-4 8 (photophobia)

2-4
Koplik spots16,17
(airborne transmission)

(first molar) 1
4 2-3
4 9 3-4
18 maculopapular rash

48-72
respiratory epithelium
(first viremia) confluent maculopapular rash
2-3 discrete maculo-
reticuloendothelial papular rash
10,11 25-507
2 (second viremia) 5-7
monocyte 18 3-7
12 7-14 (hyperpigmenta-
tion)


lymphoid biphasic9 24-48
hyperplasia 24
13
multinucleated giant cells 2-3
 27 319



10 7

9

14-20 25
1. Atypical measles 1-2
Koplik spots
(formalin-inactivated measles vaccine)
..1963-
1968 19 3.

(pleuritic chest pain) 2-3 giant cell pneumonia26
maculopapular rash
(petechiae) (vesicle) 27,28

Koplik spots (hemiplegia) (slurred speech)
(ataxia) (aphasia)
19-21 atypical (encephalitis)
measles 1-7
hemagglutination inhibition (HI)
5-6 22 2 30-40
40-70 1
atypical measles
T-cell29

antigen-antibody immune complexes23,24


30
5 20 7

2. Modified measles (epithelial surface)
30-32
320

4140 pneumomediasti-
1. num subcutaneous emphysema41-44
(acute otitis media)

14 5 2.
(diarrhea)
eustachian tube 5
30 30-70
eustachian tube
45
Laryngotracheobronchitis (measles croup)
2 (appen-
9-3233-38 dicitis) lymphoid hyperplasia46
inspiratory stridor
giant cell 7
(tracheitis) mesenteric adenitis, hepatitis, pancreatitis
(pneumonia) stomatitis
Staphylococcus aureus
(pneumonia) 3.
Febrile seizure 0.1-2.335,37,46
39 9
5
Encephalitis 1:1,000

(chest x-ray) lymphocyte
interstitial infiltration 25
15
parainfluenza, 4,22
adenovirus Acute dissseminated encephalomyelitis (ADEM)
25-35 Streptococcus postinfectious encephalomyelitis
pneumoniae, Staphylococcus aureus, Haemophilus demyelinating
influenzae 47 5-14
bronchopneumonia 1-3:1,000 22,48
consolidation
 27 321

multi- (wild type)

focal neurological signs meningeal irritation SSPE57
ataxia, myoclonus,
choreoathetosis myelitis
paraplegia, quadriplegia, sensory loss 4.
bowel bladder dysfunction (keratitis)
lymphocyte
(vitamin A deficiency) 58
(MRI) multiple hyperintense signal
white matter T2 5.
(immune process)47,49,50 -
(myocarditis)59 (pericarditis)
myelin - 60
25 disseminated intravascular coagulation (DIC)
- 61
22,48 (severe desquamation) cellulitis
-
Subacute sclerosing panencephalitis (SSPE)
1-8.5 : 1,000,000 51-53 - T-cell
degenerative disease 2-6

demyelination
22,54
20
2 55,56
maculopapular rash 3-4
7-10 Koplik spots


myoclonus, dementia,
mutism, central blindness, decorticate rigidity 1.
(EEG) enzyme immunoassay
high-voltage complex of slow waves (EIA)
and sharp waves IgM acute
phase serum IgG 2
322

acute convalescent phase serum 2 2

(fourfold rising of 67 2
antibody) 62
(WHO) 1
IgM62,63 1 2
3
14 1 - 50,000 IU 6
7 - 100,000 IU 6-11
IgM - 200,000 IU 1
3
rheumatoid factor
parvovirus B1964 2-4
2. (viral culture) Ribavirin
ribavirin 67 ribavirin

(aerosol)
68,69
3.
immunofluorescent randomized controlled trial
4. ribavirin
polymerase chain reaction (PCR)65

Passive immunization

Immune globulin (IG) IG
0.25 ./.
6
0.5 ./. 15 .
IG
1


cochrane review .. 200566

2 IG
 27 323

Immune Globulin Intravenous (IVIG) vaccine (MMR)67,71

IG
IVIG
3 400 ./. .. 2527 1 9-12
.. 2539 2
1 .. 2540
--

(MMR) 9-12
(history of 4-6
vaccine developement) 1 - -

..1960
..1963
(killed vaccine) 2
(live attenuated vaccine) - - (MMR)
2 4 Trimovax TM
PriorixTM
atypical measles
monovalent live attenuated measles vaccine
Edmonston B (MMR)
chick embryo cell
1

Edmonston 70
2-8o .
..1971
trivalent live attenuated measles-mumps-rubella

1 MMR


measles mumps rubella
(1,000 TCID50) (5,000 TCID50) (1,000 TCID50)
Priorix GSK Schwarz Jeryl-Lynn (Modified) Wistar RA 27/3
Trimovax sanofi pasteur Schwarz Urabe AM 9 Wistar RA 27/3
324

Rubini Urabe
0.5 . 75-9973
9-12 4-6
9 .. 2527
MMR 1
.. 2526
34,713
CDC clinical category class C 1 2,331 .. 2553
CDC immunological 2,255 1
category class 367 395

9-12
1
MMR
4-6 12-15
MMR
(primary failure)

(secondary failure)
(cocooning) 2



95
-- 9 12 98
85-95 15 74
96-99 63-95 ( 1 ) 4
Moraten 99 5
Edmonston B-Zagreb
Jeryl-Lynn
Rubini 72 12


Rubini 6.3
Jeryl-Lynn 61.6
 27 325

anaphylaxis 1:1,000,000
MMR
autism inflammatory
5-15 bowel disease76-78
6-12 1-2 75
5
1.
2
9-12 4-6
2. MMR
febrile
convulsion
3.
(thrombocytopenia)
2 1 30,000-100,000
4.


MMR

MMR
25 1-3 5. MMR
1-3 72
MMR
aseptic meningitis
mumps Urabe 74
1:11,000-1:100,00075 L-Zagreb
1:3,000 Jeryl-Lynn
Rubini 1. MMR
MMR Jeryl-Lynn
Jeryl-Lynn
Urabe
encephalopathy / encephalitis 28
6-15 MMR
1:1,000,000 3
326

6.
67,71 MMR
2. egg cross-reacting protein chick
embryo cell culture
WI-38 human diploid
3. neomycin anaphylaxis lung fibroblasts skin test
4.
( 2) 30 67,71
5. 7.
prednisolone 2 ./.

2
MMR ()67
(. IgG/.)
()
Tetanus prophylaxis (TIG) 250 (10 . IgG/.) IM 3
Hepatitis A prophylaxis (IG)
- 0.02 ./. (3.3 . IgG/.) IM 3
- 0.06 ./. (10 . IgG/.) IM 3
Hepatitis B prophylaxis (HBIG) 0.06 ./. (10 . IgG/.) IM 3
Rabies prophylaxis (HRIG) 20 IU/. (22 . IgG/.) IM 4
Varicella prophylaxis (VZIG) 125 /10 . (20-40 . IgG/.)
IM ( 625 ) 5
Measles prophylaxis (IG)
- () 0.25 ./. (40 . IgG/.) IM 5
- () 0.50 ./. (80 . IgG/.) IM 6

- Red blood cells (RBCs),washed 10 ./. ( IgG ) IV 0
- RBCs adenine-saline added 10 ./. (10 . IgG/.) IV 3
- Packed RBCs (Hct 65%) 10 ./. (60 . IgG/.) IV 5
- Whole blood (Hct 35-50%) 10 ./. (80-100 . IgG/.) IV 6
- Plasma/platelet products 10 ./. (160 . IgG/.) IV 7
Replacement therapy for
immune deficiencies (IVIG) 300-400 ./. IV 8
Respiratory syncytial virus
prophylaxis 750 ./. IV ( RSV-IGIV) 9
Immune thrombocytopenic purpura (IVIG) 400 ./. IV 8
1,000 ./. IV 10
Kawazaki desease (IVIG) 2 /. IV 11
 27 327

20 ./ 14 MMR
1 67
MMRV 4-6

8.
MMR (
) 2
9.
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76
 333

28
,

Rubivirus 2 clades 13 4
single-stranded RNA spherical
60
lipoprotein nucleocapsid
(rubeola)
helix RNA structural protein
3 C (capsid protein), E1 E2
(transmembrane protein) 24S subgenomic
De Bergen Orlow mRNA nonstructural protein 2
replication transcription
..1750 E1 attachment, fusion,
German measles1 hemagglutination neutralization
measles scarlet fever structural protein 3 hemagglutinin
Third Exanthematous Disease of Childhood complement-fixing antigen5,6
three day measles .. 1866 Veale
Rubella
little red2 amantadine7 cytopathic effect
..1941 Norman McAllster rabbit kidney cell line RK-13 primary African
Gregg green monkey cell5
Rubella
(congenital cataract)3

Congenital Rubella Syndrome (CRS)

5 9
80 90


6 9 30
..1964 12.5 8 ..1969
family Togavirus genus
334

.. 2005 1.5 1
5,11-13 0 4 2.19
(mathematical model) 3

90 5,14
.. 2004
387
309 97

orthodox protestant 2 14 - 18 ( 12 -
23 ) (droplet
14 (11 nuclei) (direct contact)
)
99.3
(95%CI= 95.3-99.9) 5 - 7
genotype 1G15 5.7 reticuloendothelial system
9.1 .. 2007 2008
81 15 bronchoalveolar
6 10 lavage
genotype 1E16 1 2 1 20-22
.. 2527 IgG

9,033 3
0.03 ..2529
23,24
6
17 ..2540

-- 9 5 - 7
1 2 4 6
1 18 25-28
..2552
594 0.94 10

8
 28 335

18
momonuclear cell
18 20 29,30 36,37
2. 1
cytopathic effect 3,000 38,39
apoptosis 31,32
immunological mediated

38
3. 1
5,000 38,40,41
20 50
2
maculopapular
1 5 1 42
33,34 4.
43
24 3 5.
44
(Forchheimer spots)
(Congenital rubella
syndrome: CRS)

1 5 3
70 65-85
21 8 45 30 - 35
12

16
10
1. 1 3 20 46
35

1
47,48
50 45
336

HLA-DR3
HLA-DR2 80
49

scarlet fever parvovirus, herpesvirus
6 7 enterovirus infectious
mononucleosis toxoplasmosis 51,52

atypical lymphocyte

1.
50 1

5,7

1

()
60
45
-patent ductus arteriosus 20
-peripheral pulmonary stenosis* 12
27
25
(<2,500 ) 23 -
19
17
13
10
7
5






* pulmonary arterial hypoplasia, supravalvular stenosis, valvular stenosis, and peripheral
branch stenosis ( 57 58)
 28 337

2. reverse IG
transcriptase polymerase chain reaction (RT-PCR)
6
3.
hemagglutination inhibition (HAI)
enzyme linked immunosorbent assay (ELISA),
passive latex agglutination test radial hemolysis
test
IgG ..1962
IgM
fourfold IgG actue convalescent
serum 6,53 ..1969

rubella titer

rubella titer RA 27/3
rubella IgM HPV 77 DE5 Cendehill

12 monoclonal -- (MMR)
antibody rubella antigen 2 9-12
rubella RNA in situ hybridization PCR54,55 4-6
2 MMR 1
.. 2001

3

3 28 57
680
2
2 6 3
2
0.5

immune globulin (IG) --

viremia 56
338

2



Category A: ( patent ductus arteriosus peripheral
pulmonary artery stenosis) pigmentary retinopathy
Category B:
(radiolucent bone)
()

rubella IgM
rubella IgG
Polymerase chain reaction

(suspected)
(probable)

- 2 Category A
- 1 Category A B

(confirmed)
(infection only)

1
20 rubella IgM 1
( 59)

rubella viruses found in the United States between

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76
 343

29

7
.. 1884
comma
enterotoxin (Vibrio cholerae)
rice water stools 2
(pandemic)
7 6
.. 2360 (.. 1817) .. 2469 (.. 1923)
V. cholerae O1 classic biotype

1 7
.. 6 V. cholerae O1 El Tor biotype (
2397 (.. 1854) EL Tor
Broad street, Golden Sqaure section .. 1905)
.. 2504 (.. 1961)
2
Thames 100 2
.. 2514 (.. 1971)
.. 2534 (.. 1991)
3,4
Cambridge Broad .. 2535 (.. 1992)
500 10
Broad
1 O1395
.. 2427 (.. 1883) 3,4 6
V. cholerae O17
Robert Koch 3-5
344

1 .. 1989-2009
( WHO weekly epidemiological record in 30 July 2010)

100,000-120,000 8
90 ( V. cholerae
1) 5 1-3
35 -1,428 9 0.5-0.8 facultative anaerobe
V. cholerae
flagellum
family Vibrionaceae
family Enterobacteriaceae
10 O somatic H flagella antigen
dormant Vibrio enzyme oxidase glucose,
11 sucrose mannitol polar flagella O
biofilm 12 antigen V. cholerae 200
3 O1 O139

non O1 sporadic
14 V. cholerae O1
13 specific phenotype characteristic 2 biotype
classical biotype El Tor biotype15 biotype
8,13
subspecificity O1 antigen 3
Ogawa O antigen A, B Inaba O
 29 345

antigen A C Hikojima antigen A, B C cholera toxin heat

shift biotype 16 labile toxin E. coli A subunit
1 B subunit 5 17,18 B subunit
GM1 ganglioside receptor
Bacteriophage CTX encode gene A subunit 2 component A1 A2 linked
cholera toxin ctx A ctx B toxin disulfide bond A2 component A1
co-regulated pilus (tcp) inte- component B subunit, A1 component active
grate V. cholerae genome encode A enzyme persistent
B subunit cholerae toxin ace gene activation adenyl cyclase17,19 cyclic
encode accessory cholera toxin, zot gene AMP crypt cell
zonula occludens toxin cep gene
chemotaxis proteins genes villi
copies V. cholerae O1 V. cholerae O13917
V. cholerae
mucosa toxin co- ( 2)
regulated pili chemotaxis proteins cholerae toxin V.

2 ( Butterton, JR, Calderwood,

SB. Vibrio cholerae O1. In : Infections of the Gastrointestinal Tract,
Blaser, MJ, Smith, PD,Ravdin, Ll, et al (Eds), Raven Press, New York, 1995, p. 649.)
346

cholerae O1 cholerae toxin

zonula occludens toxin tight junction
permeability IgA anticholerae toxin 23
accessory cholerae enterotoxin V. cholerae El Tor biotype
17 1 20-100
classical biotype 1
2-4
5
1-3

wet mount dark-
field phase contrast microscopy
(darting shooting star)
antiserum V. cholerae O1 O139
V. chelorae O1
V. chelorae O139 24


3,4
Cary-Blair
transport media
rotavirus, adenovirus, enterotoxigenic E. coli, 7 25 plate Thiosulfate Citrate
campylobacter Bile Salt (TCBS) media Tellurite Taurocholate
Gelatin Agar (TIGA)
enteric bacteria 25 V. cholerae
sucrose TCBS colony
109 TIGA V. cholerae
collagenase colony
20 cloudy halo20 sub-
H. pylori21 culture V. chol-
erae serotyping specific antisera
cholerae O1 O139
PCR, ELISA Latex agglutination
O A, B AB22 assay
GM1 ganglioside receptor O vibriocidal antibody
 29 347

7 Na 75, Cl 65, K 20, HCO3 10 glucose 75 ./

1-5 7-21 osmolarity 250 /26
4 27 rehydration ORS
4


1
2 rehydration
phase 2-4 maintenance phase
Ringers
lactate solution
normal saline tetracycline 30-50 ././ 3 doxycy
20-40 ./. cline 5 ./. norfloxacin 10-20 ././
3 ciprofloxacin 20 ./.
4 azithromycin 20 ./. erythromycin
rehydration phase 30 ././3,4 3
0.5 ./ 29
./. maintenance phase
normal hydration ongoing loss 6
ORS .. 2553 V. cholerae El Tor

5% 5-10% 10%



2






Capillary refill 1-5 3
( Greenbaun M. Nelson textbook of Pediatrics 18th ed. 2007 313)
348

Ogawa Inaba ampicillin, chloram 3

phenicol norfloxacin ciproflxacin
cotrimoxazole Inaba 32
tetracycline Ogawa
classical 30 2-3
31

Oral vaccine


2

1.
1.1 DukoralTM (WC- rBS) monovalent
oral vaccine V. cholerae O1
recombinant cholera toxin
B subunit 150 .
6 2
7 6
100 2 2-5 3
6 33 34
Parenteral vaccine 66-86 4-6
killed whole cell adjuvant 45-62 1 58-77 2
purified lipopolysaccharide herd protection B subunit
polysaccharide-cholera toxin conjugate vaccine ETEC 60
35
V. cholerae O1 (Inaba, Ogawa, Classical 1.2 Shanchol TM mORCVAXTM
El Tor) 10 9 31 bivalent oral vaccine serogroup O1 O139
50 3-6
V. cholerae O139 2 B subunit
7-28 ETEC
1 2 7
4 6 6 booster 6
(yellow fever vac- 5
cine) DukoralTM, SchancholTM
 29 349

WHO oral
mORCVAXTM vaccine 2 WHO
CDC
33
8,39
2.
JBK 70 (V. cholerae O1, El Tor, 31
Inaba & CtxAB), EVD 101 (V. cholerae O1 classical
Ogawa & CtxA), O395-N1 (V. cholerae classical
O395 & CtxA) O395-NT (V. cholerae classical 8,39
O395 & CtxA) V. cholerae
O1

31
CVD111 (V. cholerae 1. Brody H, Rip MR, Vinten-Johansen P,
O1 El Tor), CVD112 (V. cholerae O139), Peru-15 Paneth N, Rachman S. Map-making and myth-making
(V. cholerae O1 El Tor), Bengal15 (V. cholerae in Broad Street: the London cholera epidemic, 1854.
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1984;288:379-81.
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3-5 tious Disease 7th ed. New York Churchill Livingstone;
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6 36 Textbook of Pediatrics 18th ed. Philadelphia, Saunders;
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37 25 38 16 5. Cholera Working Group, International
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p. 727-9.
76
 30 353

30

89,246
140.64 4
Varicella- 0.004 5
zoster (VZV) 1-3
5-9 578.95
5
10-14 15
487.13, 338.45 58.81


10

(congenital varicella
syndrome) VZV 10-21 ( 14-16 )4
dorsal root ganglia varicella zoster immune globulin (VZIG)
21 28
48

5,6

VZV - her- 7
pesviruses family Herpesviridae VZV
double-stranded DNA envelope
glycoprotein spikes
1,2 150-200


(epidermis)
.. 25523 multinucleated
354

giant cells eosinophilic intranuclear inclusion

(cornified) 9
(basal)
(vesicles) 8 - 20

polymorphonuclear (cicatricial skin lesion)

(dermatome)
chorioretinitis horner (microphthal-
VZV mos) nystagmus
hypoplasia
cortical atrophy
24
(macules) (papules)
(vesicles)
(pustules)
42
Streptococcus pyogenes Staphylococcus aureus

4 0.6 2.2
10 S. pyogenes
hemorrhagic 11-15
vesicles
910,16
VZV
(Neonatal varicella) 17,18 acute cerebellar ataxia
25 1 4,000
VZV 15 19 acute cerebellar
ataxia
16,20
8 21,22

VZV 10 (vasculitis)
28 Reye salicylate
 30 355

Reye

23,24 12
salicylate acyclo-
vir 80 ././ ( 3,200 ./)
16,25,26 4 5
1-6 26,27
acyclovir
1,500 ./2/ 8
28-31 30 ././ 8 7-10



Passive immunization
1,32

VZIG



Tzanck VZIG
smear VZV33,34
multinucleated giant cells 5
immun- 2
ofluorescent >28
polymerase chain reaction (PCR)
enzyme linked immunosorbent
assay (ELISA), complement fixation test, indirect <28
fluorescent antibody latext agglutination <1,000


VZIG 96
antihistamine 96
125 / 10 . 125
acyclovir 625 VZIG
12 (Intravenous
356

1

OKAVAX sanofi pasteur OKA > 1,000 PFU
Varilrix GlaxoSmithKline OKA > 2,000 PFU
Varicella Vaccine-GCC Green Cross/ MAV/06 > 1,400 PFU
Biogenetech

Immune Globulin, IVIG)

acyclovir33
(lyophilized)
(IVIG 400 3
./.) 1. Varilrix 1 2,000 pfu
VZIG 3 2. OKAVAX 1 1,000 pfu
IVIG 3. Varicella Vaccine-GCC 1
1,400 PFU
1
(Varicella vaccine)

-
.. 1974 -- (MMRV)
Oka 44
Oka
35
Oka 2- 8o .
36-40

.. 1987
(subcutaneous)
.. 1989 0.5 . 1

MAV/06 41 1-12 1-2
12-18 2
42,43 4-6 2
4 3
13 2
4
 30 357

1-12 breakthrough disease
1
( VZV > 0.3 gpELISA units)
97 13
1 72-94
94-99 45,46
..1995-200451
> 5 gpELISA units 8-12
1-12 1 1 5
> 5 gpELISA units 85.7 5 [relative risk 2.6,
99.6 2 47 95% confidence interval (CI), 1.2-5.8]
meta-analysis
14
11 .. 1995-2006
20 48,49 1
72.5 breakthrough
disease
1 52
.. 2009
70-90
9537,40,50
97
39 2 53
booster effect 84
25
2 53
1
2 10.4
Breakthrough disease 1 14.6
42 10 (RR: 0.72, 95% CI: 0.44-1.15)
10 1-12 2 80
7.3 2.2 1
1 2 (p<0.001) 50
2-5 47
358

5 -
35 20 Post-exposure prophylaxis

3- 5 3
3- 5 5
2-5
maculopapular VZIG
5-26 96 VZIG IVIG
2 acyclovir 7-10 7

(wild type- VZV) 54 VZIG
37.8 o. acyclovir
10 ataxia,
erythema multiforme, Stevens-Johnson syndrome, 8-21 VZIG
28

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 30 359

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360

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4059



100

The Advisory Committee on Immunization
Practice
12 -12

13 1. Straus SE, Ostrove JM, Inchausp G,
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 31 365

31

2

(Human (virus-like particles- VLPs)
Papillomavirus - HPV)

recurrent respiratory papil-
lomatosis

(anogenital cancer)

(oropharynx) 1,2 11-12
2
26 high grade
500,000 50 dysplasia ( 16
250,000 18)

(type specific)


9,999 5,216 (oncogenic type)
.. 2551 24.5 70-75
100,000 3 8.6 16 18

73.8 16 18 5
16 184 DNA family
Papillomaviridae6 DNA
8,000 2 L1 L2
(oncogenic HPV genotype) 2 early protein
366

6 E1, E2, E4-8 cal intraepithelial neoplasia (CIN) I, II III

DNA 16 18
2 upstream
regulatory region (URR) 1,000 70 8

(disease burden)
1 (oncogenic human papilloma virus)
(basal
cell layer) 16 18
E1 E2 DNA 70 squamous cell carcinoma9
80 adenocarcinoma
(suprabasal) DNA Pap
16 18
50 high-grade precancerous lesion (cervi-
cal intraepithelial neoplasia 2/3 [CIN2/3])
E6 E7 p53 25 low grade CIN (CIN1) 45,
pRB tumor suppressor 33 31
(immortalized) 3, 4 5 10
7 E6 E7 high risk
() low risk ( ) 16
100 40
high risk HPV 10
(genital HPV) alpha genus 16
(cutaneous verruciformis) beta genus (anogenital cancer)
low risk vulva, vagina anus 40, 80
6 11 90 11,12
90
80 50 13

(16)
high risk 15
16, 18, 31, 33, 35, 45, 52, 56, 58, 59, (oropharyngeal cancer) 14
61 squmous
intraepithelial lesion (SIL) (low grade , LSIL) 16 42-74
(high grade, HSIL) cervi- 18 7-2015-17
 31 367

neoplasia VAIN2/3, vulvar intraepithelial neoplasia

VIN2/3)22 CIN1
50-80 18
CIN2 CIN3
19,20 CIN1
humoral cell CIN2 low grade high grade
mediated humoral
50 60
( HPV DNA)
21


(persistent infec- (persistent
tion) infection)
(high-grade cervical dysplasia)
high-grade precancerous
(adequate ablation
cell-mediated treatment)
23
latent infection basal epithelial
cell
Odds ratio
100
cell mediated (281.9 16 222.5
immunity 18)24

Odds ratio 10

high-grade CIN
(invasive cervical cancer- ICC)
( Chlamydia tracho-
2 6 matis, anogenital herpes simplex)
16
high grade intraepithelial neoplasia
(CIN2/3, vaginal intraepithelial
368

(low risk HPV) 1 (first-generation prophy-
(low-risk HPV) lactic HPV vaccine)
6 11 90 late protein L1
(condyloma accuminata) (capsid)
low-grade cervical lesion recur- baculovirus
rent respiratory laryngeal papillomatosis
(pediatric onset) (viral-like particles-VLPs)
(adult onset) 5
25 2
3 6 2
( 1)
1. 4 (Quadrivalent HPV
vaccine- GardasilTM Merck) VLPs
16 18 VLPs
6 11
amorphous aluminum hydroxyphosphate sulfate
(AAHS) 225
2. 2 (Bivalent HPV vac-
cine- CervarixTM GlaxoSmithKline) VLPs

1 ()
quadrivalent (GardasilTM) bivalent (CervarixTM)
Merck & Co, Inc. GlaxoSmithKline
0, 2 6 0, 1 6
0.5 . 0.5 .
(VLPs) 40 . HPV-16 20 . HPV-16
20 . HPV-18 20 . HPV-18
20 . HPV-6
40 . HPV-11
Amorphus aluminum hydroxyphosphate sulfate Aluminum hydroxide 500 . +
225 . 50 . ASO4 (Al(OH)3+ MPL)
Saccharomyces cerevisiae (bread yeast), Trichoplusia ni in insect cell line infected
expressing L1 with L1 encoding recombinant baculovirus
2-8o. 2-8o.

( 5, 46)
 31 369

16 18 intention- to- treat

aluminum hydroxide
500 3-deacylated monophosphoryl lipid bivalent 92
A (ASO4) 50 16/18 12
3
CIN2
I II quadrivalent
quadrivalent bivalent 6,11,16, 18

2 serocon- 6,11,16,18
version 99 7 8
26,27 100 (external genital lesion)
36
16 18 7 24-45
1 3 90.5 [95%CI 73,97]
50 100 6,11,16,18
III 83 [95%CI 50,95] 16,18
quadrivalent bivalent 37
quadrivalent
2 100 CIN2+, adenocarcinoma in situ (AIS),
VIN2/3, VAIN2/3 16, 18
3.6 34,36
99-100 29


2 100
high-grade dysplasia 16 18 ( 2)
(per-protocol population) quadrivalent bivalent
28-35 Pap
intention to treat


A7 A9
2 31 42.6 [95%
CI 15.3,66.4] (CIN1-3, AIS)
370

31 56.9 [95%CI 28,74]38 32 bivalent

bivalent 92.5 31
[96%CI 79.9,98.3] CIN2+ (6-12 ) 78.7
16,18 [96.1%CI 70.2, 85.2] 70.4 [96.1%CI 66.1, 88.1]
98.1 [96%CI 88.4,100] 6 12

2 bivalent humanpapillomavirus vaccine (HPV2)

quadrivalent papillomavirus vaccine (HPV4)
Vaccine Control Vaccine efficacy
Vaccine/Endpoint/HPV type
No. Cases No. Cases % (CI*)
Bivalent vaccine (HPV2) (96.1%CI)
CIN2/3 or AIS32
HPV 16 and /or 18 7,344 4 7,312 56 92.9 (79.9-98.3)
HPV 16 6,303 2 6,165 46 95.7 (82.9-99.6)
HPV 18 6,794 4 6,746 15 86.7 (39.7-98.7)
Quadrivalent vaccine (HPV4) 95%CI)
CIN2/3 or AIS**
HPV 6,11,16,18 7,864 2 7,865 110 98.2 (93.3-99.8)
HPV 16 6,647 2 6,455 81 97.6 (91.1-99.7)
HPV 18 7,382 0 7,316 29 100.0 (86.6-100)
VIN 2/3 or Vain2/3**
HPV 6,11,16,18 7,900 0 7,902 23 100.0 (92.6-100.0)
HPV 16 6,654 0 6,647 17 100.0 (76.5-100.0)
HPV 18 7,414 0 7,343 2 100.0 (<0-100)
Genital warts
HPV 6 and/or 11 6,932 2 6,858 189 99.0 (96.2-99.9)
*Confidence interval
Phase III trial. According to protocol efficacy analysis including females aged 15-25 years who received all 3 vaccine doses,
were seronegative at day 1- month 6 for respective HPV type, normal or low grade cytology at day 1, with case counting
beginning day 1 after 3rd vaccine dose; mean duration of follow up post first vaccine dose: 34.9 months
Combined analysis of one phase II trial and two phase III trials. Per protocol efficacy analysis included females aged 16
-26 years who received all 3 vaccine doses, were seronegative at day 1 and HPV DNA negative at day 1 through month 7
for respective HPV type, with case counting beginning 1 month after third vaccine dose; mean duration of follow-up post first
vaccine dose:42 months.
** Source: Kjaer SK, Sigurdsson K, Iversen OE, et al. A pooled analysis of continued prophylaxis efficacy of quadrivalent
human papillomavirus (type 6/11/16/18) vaccine against high-grade cervical and external genitalial lesions. Cancer Prev Res
2009;868-78.
Source: FDA. Product approval-prescribing information [package insert]. Gardasil [human papillomavirus (Type 6/11/16/18)
vaccine recombinant], Merck & Co, Inc: Food and Drug Administration 2009. Available from: http://www.fda.gov/biolocsblood-
vaccine/aprovedproduct/ucm09042.htm. Accesssed May 25,2010.
( 46)
 31 371

45 75.7 [96.1%CI 60.4,85.7] 40

63 [96.1%CI 18.4,84.7] 6 12
immune memory
16,18 41
5



1 quadrivalent
3
4,065
6 16-26 5 18
27,39 randomized placebo controlled, double
blinded external genital
lesion 6, 11, 16, 18
quadrivalent 3
external genital lesion
90.4 2.8
5 condyloma accuminata
89.4
quadrivalent 42
III


2 2
quadrivalent 120
48 18
40
CIN2/3
18

98.4 [95%CI 90,100]34
monovalent 16 43
8.5 .. 2006
(US FDA)
372

quadrivalent Advisory committee on Immu-

nization Practice (ACIP) 1 10,000
11-12 13-26
IV
9
HPV 6,11,16,18 (
quadrivalent 23
)44
.. 2009 ACIP quadrivalent 49
9-26
45
.. 2009 quadrivalent bivalent
ACIP 0.5 .
bivalent 10-26 3
46 2 1 ( bivalent) 2
( quadrivalent) 3
6
11-12 2
4 2 3
quadrivavalent 24
9-18
47

1 2

3

quadrivalent 20

bivalent
16 18
45,988 ASO4 6 11
48 III 2 quadrivalent 3
47

 31 373

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 377

32

Bacillus anthracis
B. anthracis
..1876 ..1881
B. anthracis .. 2535-2543 0.02-0.17
102 .. 2538
1 7 .. 2537
.. 25444

..2544 ..2551

24 10

2,3

12 - 7

60
B anthracis

sheep blood agar




edema
toxin lethal toxin
378

3 protective antigen, lethal factor, edema
factor

3
1. (cutaneous anthrax) 20
5,6




penicillin G tetracycline 7-10



systemic ciprofloxacin doxycycline
2. (gastroin-
testinal anthrax) ciprofloxacin doxycycline
rifampin, penicillin, ampicillin, vancomycin, imipenem,
chloramphenicol, clindamycin clarithromycin
cephalosporins trimethroprim-
3. (inhala- sulfamethoxazole 7-11
tion anthrax)



3-5 .. 2447
B. anthracis
inhalation anthrax .. 2497
oropharyngeal (alum) adjuvant
anthrax anthrax meningitis septicemia .. 2500-2503
 32 379

protective antigen (PA)

(pre-exposure
anthrax vaccine adsorbed (AVA) prophylaxis)
.. 2508 AVA

0.5 . 5 0, 4 6,
.. 251312 12 18 13 1

0.5 . 4 0, 3, 6
Anthrax vaccine adsorbed (AVA) 6 3 1

BioThraxTM
V770-NP1-R (toxigenic 2 0 3 1
non encapsulated)
0.83 ./ 0.5 . adjuvant 2 0 6-12
PA, lethal factor (LF) edema factor (EF)13

.. 2522 (post-exposure
14,15
Center for Applied Microbiological Research prophylaxis)
AVA 10
Sterne 34F2 adjuvant 0.5 .
LF EF thimerosal preservative 3 0, 2 4 13
60
STI-1
Sterne
suspension AVA 2
.. 249616-18 95-10020

.. 2500 Lanzhou Institute of Biological
Product 1-2 2 12
A16R AVA
21
AVA 1,563
6 AVA
3-4
AVA 2-8o .12,19 6
380

AVA (Post-exposure prophylaxis)

.. 2505
3 0, 2 4
92.5 3


18
65 22 1.

23 2. 1
anaphylaxis

3.
24,25



4.
1-2


2


(Pre-exposure prophylaxis)

12
1. alum precipitation
B. anthracis 90
2 .
- .. 1999
-

- B. anthracis

3 .
 32 381

Suppl 1990;68:95.
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 383

33

typeable)6 6

(Haemo- -
philus influenzae type b, Hib)
2






6-18
1,2
90 .. 2543
8.13
371,000 7


.. 2543-2544
35-44 3.8
3-5 5 100,000 8

90

.. 2530
5 41
100,000
(coccobacilli) 5 .. 2550
chocolate agar 0.11 100,000 1,2
(non- 7,9
384

hypogammaglobulinemia cerebral
10-16 palsy 28,29

17-22 330
20-6031

11,12,23



75-9032

nonciliated columnar
epithelium

pleomorphic
coccobacilli


latex
particle agglutination countercurrent immuno-
electrophoresis
24

beta
25,26 - lactam ( amoxicillin 2nd 3rd generation
cephalosporins)

(Odds ratio 2.2; 95% CI: fluoroquinolones, macrolides, tetracyclines
1.2-3.9)27 aminoglycosides



 33 385

Cross reactive material 197 (CRM197)

non-toxic mutant
VaxemHibTM

.. 1985
18 --
39 1
18
B cell T-lymphocytes memory T
cell 2-8o .
18-71 24 .
9033,34

7-9535-37 0.5 .
2
T- dependent 6

38 3 ( PRP-OMP 2 )
polyribosylribitol phosphate 40-42
(PRP) 2

(outer mem-
brane protein) Neisseria meningitidis
3 (congenital or acquired immunode-
1. Polyribosylribitol Phosphate Chemically ficiency)
conjugated to Tetanus Toxoid (PRP-T) 1 18
HiberixTM Act- 2
HIBTM
2. Polyribosylribitol Phosphate conjugated to 2 2 4-8
an outer-membrane protein complex of N. meningi- 1
tidis (PRP-OMP) outer membrane protein 7-10 43-49
N.meningitidis Pedvax HibTM
PRP-T PRP-OMP
3. Haemophilus b oligosaccharide conjugate PRP-T50
vaccine (HbOC)
386

1 Hib
Carrier
Hiberix GlaxoSmithKline Tetanus toxoid -
Act-HIB sanofi pasteur Tetanus toxoid -
VaxemHib Novartis/ Biogenetech Non toxic mutant of -
Diphtheria toxin (CRM-197)
Infanrix-IPV/Hib GlaxoSmithKline Tetanus toxoid DTaP, IPV
Infanrix-Hexa GlaxoSmithKline Tetanus toxoid DTaP, HBV,IPV
TETRActHib sanofi pasteur Tetanus toxoid DTwP
Pediacel sanofi pasteur Tetanus toxoid DTaP, IPV
Pentaxim sanofi pasteur Tetanus toxoid DTaP, IPV
Quinvaxem Novartis/ Biogenetech (CRM-197) DTwP, HBV
DTwP= Diphtheria and Tetanus toxoids, and whole cell Pertussis; DTaP = diphtheria and tetanus toxoids and acellular
pertussis; HepB = hepatitis B; Hib = Haemophilus influenzae type b; IPV = inactivated poliovirus
( 39)

2 Hib

() PRP-T, HbOC PRP-OMP
2-6 0, 2, 4, 0, 2,
12-18 12-18
7-11 0, 2 0, 2
12-24
24 0, 2 0, 2
*
* (con-
genital or acquired immunodeficiency) 1 18
2 2
2 2 1 7-10
1 3
( 39)

PRP-T 2
DPT


1 43,46,51
2 6

 33 387

DTP

PRP-OMP 2 43,63

70-80 1.
0.1 ./. 90
2 4 2.
0.1 ./.52-54
PRP-T (congenital or acquired immu-
HbOC PRP- nodeficiency)
OMP 3 3. 2

PRP-OMP
3 PRP-T

55,56
3 ( PRP-OMP 2 )
40-42 PRP-T


-

PRP-OMP
outer membrane protein N.meningitidis57

9558-61 25
6462



99
herd im-
munity2


25
56

388

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. : , ,
, . Update
on Pediatric Infectious Diseases 2008.
; 2551. .123-5.
 393

34

DTwP Hib
PRP-T Haemophilus b oligosaccharide conjugate
vaccine (HbOC) 2-5
-- (DTaP)
Hib PRP-T Hib
6
(HepB) DTaP
(IPV)
HepB
1 7 HepA
HepB
8



polyribosylribitol phos-
phate-tetanus toxoid (PRP-T)
-- (DTwP) --
Act-HIBTM DTwP - (MMRV)
(D.TCOQTM) HiberixTM -
DTwP - (MMR) 9
--
DTwP-HBV (TritanrixTM-HB)


394

DTaP 10 Hib, IPV, HepB

() 3


( 18 4-6 )




DTwP+HepB 3 1
2, 4 6 HepB 1




(DTwP)

1

DTwP- HepB DTP-HB SII/Masu
DTwP- HepB Tritanrix-HB GlaxoSmithKline Hiberix

DTwP-Hib (PRP-T) TETRAct-HIB sanofi-pasteur
DTwP- HepB -Hib (CRM197) Quinvaxem Biogenetech
DTaP-IPV Infanrix-IPV GlaxoSmithKline
DTaP-IPV Tetraxim sanofi-pasteur
Tdap-IPV Adacel Polio sanofi-pasteur
Tdap-IPV Boostrix Polio GlaxoSmithKline
DTaP-IPV-Hib (PRP-T) Pediacel sanofi-pasteur
DTaP-IPV-Hib (PRP-T) Pentaxim sanofi-pasteur
DTaP-IPV-Hib (PRP-T) Infanrix-IPV/Hib GlaxoSmithKline
DTaP-IPV-Hib-HBV (PRP-T) Infanrix-Hexa GlaxoSmithKline
HepB-HepA Twinrix GlaxoSmithKline
MMRV - GlaxoSmithKline
: CRM197= Non toxic mutant of Diphtheria toxin; DTwP= Diphtheria and Tetanus toxoids, and whole cell Pertussis;
DTaP = Diphtheria and Tetanus toxoids and acellular pertussis; HepA = hepatitis A; HepB = hepatitis B; Hib = Haemophilus
influenzae type b; IPV = inactivated poliovirus; MMRV = measles, mumps, rubella, and varicella; PRP-T = polyribosylribitol
phosphate-tetanus toxoid conjugate; Tdap = tetanus toxoid, reduced diphtheria toxoid, and acellular pertussis.
( 1)
 34 395

23 primary series

Hib
Hib PRP-T
DTwP HbOC
2-5,11,12 DTwP Hib Hib
DTwP-HBV 24-26
DTwP-
Hib (PRP-T) DTaP/IPV/ Hib
DTwP-HepB-Hib (CRM197) 2, 4, 6 27
1 6 (DTaP/IPV/HepB/Hib)
28-34
6
(DTaP, Tdap) DTaP
6
HepB
IPV, HepB Hib HexavacTM Infanrix hexaTM
IPV DTaP, DTaP/ Hib Tdap HepB Infanrix
hexaTM HexavacTM35
13-16 HexavacTM
DTaP DTaP/IPV 6
DTaP/ IPV/ Hib 36

HepB DTaP DTaP/IPV
DTaP IPV (HepA/
HepB HepB)
HepB 7
Twinrix
HepB 0, 1 TM
6 2, 4 720 EU
6 3, 4 5 20
Hib DTaP DTaP/IPV
6,17-22 DTaP/ HepA/HepB
Hib DTaP/IPV/ Hib () HepA HepB
396

0, 1 6
100
HepA/HepB (Hep A) Salmonella typhi capsular poly
37-40 saccharide Vi (Vi)
HepA/HepB Vi Hep A
HepA HepB
0, 7 21 2 HepatyrixTM
99 Viatim
(
GMT 854 mIU/ml Hepatyr-
512 mIU/ml) 82 ixTM GMT
HepA/HepB seroconversion
84 94
( GMT 65 9747
mIU/ml 98 mIU/ml) ViatimTM
HepA/HepB
seroconversion 14
HepA/ 86.4
41
HepB 87 72 95.6 seroconversion 14
100 88.2
89 94.2 (
81 60
100 HepatyrixTM serocon-
95 version )48 3
41 99
10 94
86 32 36

3 0, 1
6 2 0, 6
0,12 42-46 2 3 -- (MMR)

---
(MMRV)
 34 397

15 - 12
(MMRV) > 48 CDC
Priorix TetraTM MMRV
ProQuadTM MMRV
49,50
MMRV 12-23
5-12 MMR
MMR
MMRV 4-6
MMR


15-26
MMRV
MMR 51 C (MnC) (MnC/Hib)
MMRV Menitorix TM
MMR 53-54
DTaP3/IPV DTaP3/IPV/HepB (DTaP3;
3 )
MMRV 2, 3 4 2, 4 6

MMRV C
Advisory Committee on Immunization Practices (MnC)+ Pediacel TM MnC+ Infantrix hexa TM
(ACIP)
--
12-15 4-6
52 12-47
MMRV MMR 7
MMRV
(DTaP/HepB/IPV + Hib/ MnC)
MMRV 7
MMRV
CDC
(DTwP/HepB/IPV/Hib-MnAC)55
MMRV
398

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 407

35

50- (dengue hemorrhagic fever,
100 DHF)
10,000
RNA family Flaviviridae 4 DHF
DEN1, DEN2, DEN3, DEN4
.. 2497
(homotypic immunity)
(dengue fever, DF)
(heterotypic immunity)

.. 2501


Aedes aegypti


7-10


28-35
3-15 ( 5-6 )
1
1-3


408

1-3 T B cells chemokines
T cell
autoantibody
vasculopathy
autoantibody
Lei HY


cytokines
monocytes, endothelial cell 1-
4 2 3,5,8


aspartate aminotransferase (AST)
alanine aminotransferase (ALT)
5 AST ALT

partial prothrombin time (PTT) prothrombin
time (PT) 9
alkaline phosphatase (AP)

6-9
AST/ALT
(non-neutralizing antibody) PTT
enhancing antibody DHF
DF1-3
Antibody dependent enhancement


6
enhancing antibody
10
5,6

7
 35 409

11 coagulopathy



DHF 3
1. (febrile stage)
39-41
2-7 17
1-3,10,11 7

90 (flushing)
3

1. Undifferentiated fever viral syndrome

maculopapular 80-85
2. DF 2. (shock or hemorrhagic stage)


breakbone fever
pulse pressure

4
1

3. DHF 2
3
(dengue shock pulse pressue
syndrome, DSS) 4
DHF 3 4 DSS
3. (convalescent stage)
24-48
12
petechial rash

410

convalescent rash
1-3

( .. 2530
)



DF DHF




6-9 11-13


(neutralizing antibody)
enhancing antibody


1-3 stress ulcer





.. 2513

(ARDS)

amylase

lymphoid hyperplasia
(co-infection, dual
infection)
 35 411

enzyme-linked immunosorbent
assay (ELISA) hemagglutination inhibition (HI)
interstitial PCR
infiltration


5-14
ELISA

(rapid test)


1-3





PCR


PCR
atypical lymphocyte
100,000/..
(
)

aspartate transaminase (AST) alanine
transaminase (ALT)
1-3
412

24-48
1

7

Normal saline, Ringers lactate,
Ringers acetate 5% D/NSS
10-20 ././. 1-2

.. 1943


14

1-3


non-steroidal anti-inflammatory drugs






recombinant activated
factor VII (rFVIIa)

1-3



 35 413

2-3

PCR


1-3

Dengue infection: A new classification


New classification
Dengue infection

15

414

-






-


.. 2472 toxicity testing

1
16-18 -
.. 2495 (genome stability
2 data)


19 viremia


Primary dog kidney cell culture (PDK) - II

2
deletion/substitution
mutant
(chimeric virus) -
Recombinant
subunit protein DNA
-
IIB I
4 20 II

IIB
 35 415

I II



-
1.


.. 2523

.. 2537
4 5 Walter Reed Army Institute
of Research (WRAIR)
.. 2527

1.1

- I 1, 2 4
PDK
3 Primary green monkey kidney
(PGMK) cells passage
- II 30 Fatal Rhesus lung cell 3
passages

4


21
.. 2539 phase I
- III 1
5
Flavivirus 40
Flavivirus 4
seroconversion (neutralizing
antibody, NAb 1:10) 90
416

(wild-type)
3 NAb 21 2
3 22 25
phase I/II .. 2541 1.2 WRAIR
2 6 .. 2527-2535
Flavivirus
49 PDK 26

seroconversion .. 2540-2542
1, 2, 3 4
77, 60, 100 40 Flavivirus 49
seroconversion 85, 78, 1 1
100 71 seroconversion 100,
1, 2, 3 4 3:2:1:2 92, 46 58 1-4
30 90
23 seroconversion
phase I .. 2542
2 (3:2:1:2 3:3:1:3) 2
3 5-12 Flavivirus 1
82 3-5 Flavivirus 10
3 8-12
1
2 3 seroconversion
seroconversion 4
2 4 51 66
3:2:1:2 3:3:1:3 27
3 seroconversion
4 89 100
3:2:1:2 3:3:1:3 Flavivirus 28
3:3:1:3 .. 2547 17

3:2:1:224 6 phase I
5 Flavivirus 4
23 ( 22)
6-9 7
 35 417

2
1
6 100 seroconversion Flavivirus
4 (YF 17D)
29 prM E
phase II 1-4 prM E
ChimeriVax-DEN1-4 tetrevalent
vaccine

2. endemic
non-endemic area
structural proteins 3
capsid (C), membrane (M) envelope (E) 3 ( 0, 3-4 1 )30,34,35
prM E IIB
10 National 4,002
Institutes of Health (NIH) National Institute of 36
Allergy and Infectious Diseases (NIAID)
4 full-length infectious DNA
clone 30 nucleotides Recombinant subunit
3 untranslated region infectious protein DNA vaccine
cDNA rDEN430 Recombinant subunit protein

recombinant vaccine

prE NS1
1-3

prM E cDNA
prM E
wild-type
.. 2534 37,38
rDEN430 DNA vaccine DNA
1-3 wild-type uptake DNA

30-33 plasmid
418

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 421

36

Coronavirus 3
4 Phylogenetic
Severe Acute Respiratory Syndrome (SARS) SARS-CoV
(Zoonosis) 5,6
( live wild-game animal markets)
.. 2545 palm civets raccoon dog
.. 2547 7


SARS-CoV
7-9

2
1

.. 2545
SARS-associated coronavirus 305 5
( SARS-CoV)1 Corona virus Co- (16 .. 2545-9 ..
rona virus 1-3 Coro- 2546) SARS
navirus order Nidovirales, family Coronaviridae,
genus Coronavirus enveloped , single-stranded
RNA virus 60-220 coronavirus
3 1 human coronavirus 229E , SARS 21 .. 2546
porcine epidermic diarrhea virus feline infectious 2
peritonitis virus 2 bovine coronavirus, 10
murine hepatitis virus human coronavirus OC43 SARS
3 avian infectious bronchitis virus ()
422

1 SARS
( 10)

() ( 4 .. 2546
SARS)
( 1)10 11 .. 2546 (
SARS
.. 2546 SARS 12 .. 2546 )
29 ..
(World Health Organization, 254612 WHO
WHO) 12 .. 2546
(Dr. Carlo Urbani)11 SARS
13
 36 423

nasopharyngeal wash1,2

300 14 SARS
SARS


25
SARS
2625 4
.. 2546
.. 2545- .. 2546 10
WHO 26 8,098 2-3
27 SARS
774 ( 9.6)
20-50

15
21
30-100 16 Polymerase Chain Reaction
2 1 spo-
(PCR) nasopharyngeal wash
47, 67 21 26
radic SARS cases 4 3
17,18 19
10-15
20 1
nasopharyngeal

aspirates
secondary transmission21
28
29

10 diffuse alveolar

17,22
damage, lung edema hyaline membrane

formation In situ Hybridization

electron microscope viral replication
(Early human SARS-CoV)
SARS pneumocyte enterocyte
30

Receptor SARS metallopeptidase
ACE-2 pneumocyte type 1 & 2 enterocyte
(late human SARS-CoV)
(
)31,32 cytokines ( IL-1, IL-6
1 SARS

IL-12) chemokines (MCP-1, IP-10)
SARS 33,34

23,24 3


SARS neutralizing
Bronchoalveolar lavage (BAL) antibody 2
424

35-40 4
2- 10 41
2 prodro- 28
mal phase 1-2 SARS
3.
(shortness of breath) mild
hypoxemia 3-7 Biosafety level 3
respiratory phase
(
nonproductive cough)
Atypical manifestation

SARS 1)

70-80 2-3 2) 3)
20-30 respiratory care
5 -10 38
SARS
42
Anti S protein monoclonal antibody,
interferons protease inhibitors 43 -45

3 46-48
1. (Nucleic acid tests)
RT-PCR
standard precaution,
2 41 droplet precaution, contact precaution air-
2. (Seroconversion) borne precaution ( high risk procedures)
SARS droplet contact
Enzyme-linked immunosorbent assay precaution
(ELISA) Immunofluorescence assay (IFA) 48
10
10-20 gold standard
2
acute phase convalescent phase
 36 425

2 SARS-CoV
( 49)

.. 2546
7 SARS - CoV 7 structural proteins
( 2)49
Spike protein (S), Membrane
1. protein (M), Envelope protein (E), Nucleoprotein (N),
3a, 7a 7b S, M, E 3a viral membrane
proteins express
2. animal model Neutralizing antibody
S protein target 50,51
3.
immunogenicity efficacy 149, 52-55

1 SARS


Neutralizing antibody Protective efficacy
Inactivated virus Mice , Ferret, Monkey + + + ( phase I)
Subunit Mice +
Viral or bacterial vectors Mice, ferret, primates + +
DNA vaccine Mice, primates + + + ( phase I)
Live attenuated virus hamsters + +
( 49, 52-55)
426

Inactivated virus vaccine DNA vaccine

plasmid DNA encoding
inactivate virus biosafety level humoral
3 cellular immunity SARS-CoV
(good immunogenicity) DNA candidate vaccine
( intranasal)56,57 encode S, N M proteins
efficacy challenge humoral cellular immunity M
protein strongest T cell response64
viral replication DNA vaccine expressing S protein
58-60 36 54 65
3 1) 2) 16 10 phase I clinical trial
SARS-CoV unit (SU) 3) 32 SU DNA vaccine expressing S protein 3
2 28 ( 0, 4 . 0, 28 56 immunogenicity
28) 0, 7, 14, 28, 35, 42, 56 neutralizing antibody
210 42 2 3 seroconversion 3 (9 10 ) T cell
100 geometric mean titer (GMT) 2 response SARS -CoV CD4+ T cell response
2 4 20 CD8+ T cell response55
prime/ boost
Subunit strategy 66

structural protein express target S, M, Live attenuated virus
N protein immunogenicity
strong 61 vaccinia virus
small pox
Viral or bacterial vectors SAR-
humora cel- CoV
lular immunity intranasal virulence strain
Adenovirus vectored SARS-CoV vac- recombinant
cines ( N, S M protein)62 SARS-CoV deletion E gene at-
58 ferret59 tenuated mutant hamster immunogenicity
prime/ boost strategy different protective efficacy67
vectors DNA vaccine immunogenicity
platform
Poxvirus vector , Newcastle disease virus, Baculovirus
63
 36 427

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 433

37

CMV

(Cytomegalovirus; CMV)
-herpesvirus human
CMV
herpesvirus 6A (HHV-6A), HHV-6B, HHV-7 CMV
double stranded DNA virus :
200-300 CMV
DNA (linear, double-stranded DNA)
(capsid) 20
162 capsomeres CMV CMV

T lymphocyte 1,250
1,3,4
CMV CMV
(congenital CMV infection) CMV
47 .. 1981
1 71.8 .. 1998
mononucleosis2
20-25
3
CMV CMV
4

CMV
CMV
CMV
CMV
CMV (host defense mechanism)
434

CMV (persistent viremia)

CMV

(persistent latent infection)
CMV (attachment) (reactivation) (reinfection)
(envelop) 1
glycoprotein gB gH (cell mediated immune response)
neutralizing CMV
antibody viral genome CMV-specific cytotoxic T lymphocyte
transcription
CMV CMV6 CD4
(immediate early) proteins 100 /..
(delayed early) CMV 7
proteins DNA
(late phase phase)
DNA CMV
nonenveloped particles CMV
owls eye intranuclear
inclusion 1 CMV CMV
CMV
microcephaly, intracranial
calcification
viral shedding cytomegalic cell
4-6 shedding
CMV
CMV
(primary infection) neuronal migration
CMV (seronegative) neuronal stem cell
(secondary infection)
CMV CMV
CMV CMV Temporal cochlear,
vestibular, auditory canal (Mondini dysplasia)
5 CMV

CMV
 37 435

Barr Virus (EBV)

tonsillar patch
CMV
CMV EBV1
lymphocyte atypical
intrauterine growth retardation lymphocyte
hepatic transaminase 300 IU/L
heterophile
optic atrophy intracranial antibody
calcification
ALT 100,000/.. CMV
direct bilirubin ( 49
CMV 94 )
1
CMV

4

CMV
CMV
CMV 3-4 8

CMV
CMV

retinal necrosis

2
1 CMV
(mononucleosis syn-
drome)

CMV intranuclear inclusion CMV
2
Epstien- CMV
436

CMV /
CMV
plaque-like pseudomembranes CD4
50 /.. CMV

CMV CMV
85
CMV

mononuclear cells infiltration, scattered DNA CMV
microscopic granuloma giant cells 9
CMV
CMV
CMV 50-
CMV 100

viral shedding
CMV 4-12
interstitial pneumonitis
intracellular CMV
inclusion body
pancytopenia

CMV
CMV
pyramidal tract
Pneumocystis jirovecii, Aspergillus spp.
DNA CMV

CMV

CMV

CMV
CMV (R+ D+)
 37 437

IgM IgG CMV
enzyme immunoassay CMV
CMV

CMV IgG PCR DNA
CMV antigenemia assay
CMV IgM IgG pp65 CMV
antibody avidity testing monoclonal antibody
CMV nucleic acid sequence-based
amplification (NASBA) real-time PCR
3

2
CMV CMV
(typical cytopathic change)
DNA CMV

CMV
PCR CMV
3 CMV

CMV
ganciclovir 12 ././
CMV CMV
6
CMV viral gangciclovir
shedding 68 ( 21)
DNA CMV 1 10
CMV CMV
CMV
CMV ganciclovir
CMV
CMV ganciclovir
IgG CMV
438

DNA CMV
gangciclovir CMV (preemptive therapy)
ganciclovir CMV
gangciclovir 100 11
CMV CMV
(early onset)
1 valgangciclovir ( late onset)
CMV ganciclovir 5 ./.
12
CMV
CMV 2
ganciclovir 5
- ganciclovir valganciclovir
CMV
CD4 50 /.. ganciclovir CMV
CMV CMV
CMV
ganciclovir CMV (D+/R-)
CD4 CMV (R+)
6
CMV
ganciclovir 7.5-15 ././
14-21 CMV
maintenance
5-6 ././ 5-7
5 CMV
ganciclovir implant ganciclovir
cidofovir
foscarnet CMV
CMV
ganciclovir 6 ./.
Passive immunization
12 6
CMV CMV immunoglobulin randomized,
placebo-controlled clinical trials CMV
CMV immunoglobulin (CMV IGIV)
 37 439

CMV
1 CMV IGIV
CMV chimeric CMV
CMV 2 Towne
CMV IGIV Toledo
15
CMV 12 2. Subunit vaccine
Purified recombinant glycoprotein B ( gB)
glycoprotein B
neutralizing antibody
CMV
CMV CMV
2
gB MF59 adjuvant
CMV CMV
16
3. DNA vaccine
CMV
DNA
CMV gB DNA
CMV
CMV 17 1
bivalent CMV DNA
CMV 18
CMV Towne DNA
pp65, IE1, gB
pp65 T cell gB
1. Live attenuated virus vaccine Towne
CMV Towne 19 DNA
CMV
CMV CMV
13,14 Towne 4. Vector system
CMV vector
CMV
CMV
440

2 modified vaccinia virus Ankara children born to HIV-1 infected women. Asian Pac J
MVA20 alphavirus vector attenuated variant Allergy Immunol. 2003;21:127-30.
Venezuelan equine encephalitis virus 5. Clyde S, Crumpacker II, Jie LZ. Cytome-
galovirus in Mandell GL, Bennett EJ, Dolin R, edi-
humoral celluar21,22 tors. Mandell, Douglas, and Bennetts principles and
practice of infectious diseases 7th ed. Philadelphia:
Elsevier Inc;2010. p.1071-87.

6. Boeckh M, Leisenring W, Riddell SR, Bowden
CMV RA, Huang ML, Myerson D, et al. Cytomegalovirus
disease and mortality in recipients of allogeneic
hematopoietic stem cell transplants: importance of viral
load and T-cell immunity. Blood. 200315;101:407-14.
Towne subunit 7. Erice A, Tierney C, Hirsch M, Caliendo AM,
Weinberg A, Kendall MA, et al. Cytomegalovirus (CMV)
CMV and human immunodeficiency virus (HIV) burden,
humoral CMV end-organ disease, and survival in subjects with
advanced HIV infection (AIDS Clinical Trials Group
Protocol 360). Clin Infect Dis. 2003;37:567-78.
8. Fowler KB, Stagno S, Pass RF, Britt WJ, Boll
1. Pass RF. Cytomegalovirus in Long SS, Lar- TJ, Alford CA. The outcome of congenital cytomegalovirus
ry K Pickering LK, Prober CG, editors. Long: Principles infection in relation to maternal antibody status. N Engl
and Practice of Pediatric Infectious Diseases 3rd ed. J Med. 1992;326:663-7.
Philadelphia: Elsevier Inc;2009. p.1029-36. 9. Deayton JR, Prof Sabin CA, Johnson MA,
2. American Academy of Pediatrics. Emery VC, Wilson P, Griffiths PD. Importance of
Cytomegalovirus infection. In: Pickering LK, cytomegalovirus viraemia in risk of disease progression
Baker CJ, Kimberlin DW, Long SS, editors. Red Book: and death in HIV-infected patients receiving highly active
2009 Report of the Committee on Infectious Diseases. antiretroviral therapy. Lancet. 2004 ;363:2116-21.
28th ed. Elk Grove Village, IL: American Academy of 10. Nassetta L, Kimberlin D, Whitley R.
Pediatrics; 2009. p. 275-80. Treatment of congenital cytomegalovirus infection:
3. Amarapal P, Tantivanich S, Balachandra K. implications for future therapeutic strategies.
Prevalence of cytomegalovirus in Thai blood donors by J Antimicrob Chemother. 2009;63:862-7.
monoclonal staining of blood leukocytes. Southeast Asian 11. Goodrich JM, Mori M, Gleaves CA, Du
J Trop Med Public Health. 2001;32:148-53. Mond C, Cays M, Ebeling DF,et al. Early treatment
4. Likitnukul S, Bhattarakosol P, Poovorawan with ganciclovir to prevent cytomegalovirus disease
Y. Seroprevalence of cytomegalovirus infection in after allogeneic bone marrow transplantation. N Engl
 37 441

J Med. 1991;325:1601-7. 20. Wang Z, La Rosa C, Li Z, Ly H, Krishnan A,

12. Nigro G, Adler SP, La Torre R, Best Martinez J, et al. Vaccine properties of a novel marker
AM; for Congenital Cytomegalovirus Collaborating gene-free recombinant modified vaccinia Ankara
Group. Passive immunization during pregnancy for expressing immunodominant CMV antigens pp65
congenital cytomegalovirus infection. N Engl J Med. and IE1. Vaccine. 2007;25:113241.
2005;353:135062. 21. Reap EA, Morris J, Dryga SA, Maughan M,
13. Plotkin SA, Smiley ML, Friedman HM, Talarico T, Esch RE, et al. Development and preclinical
Starr SE, Fleisher GR, Wlodaver C, et al. Towne-vac- evaluation of an alphavirus replicon particle vaccine for
cine-induced prevention of cytomegalovirus disease cytomegalovirus. Vaccine. 2007;25:74419.
after renal transplants. Lancet. 1984;1:528-30. 22. Schleiss MR, Lacayo JC, Belkaid Y, McGregor
14. Plotkin SA, Starr SE, Friedman HM, A, Stroup G, Rayner J, et al. Preconceptual administration
Brayman K, Harris S, Jackson S, et al. Effect of Towne of an alphavirus replicon UL83 (pp65 homolog) vaccine
live virus vaccine on cytomegalovirus disease after induces humoral and cellular immunity and improves
renal transplant. Ann Intern Med. 1991;114:52531. pregnancy outcome in the guinea pig model of congenital
15. Heineman TC, Schleiss M, Bernstein DI, cytomegalovirus infection. J Infect Dis. 2007;
Spaete RR, Yan L, Duke G, et al. A phase 1 study of 4 live, 195:78998.
recombinant human cytomegalovirus Towne/Toledo
chimerc vaccines. J Infect Dis. 2006;193:135060.
16. Pass RF, Zhang C, Evans A, Simpson T,
Andrews W, Huang ML, et al. Vaccine prevention of
maternal cytomegalovirus infection. N Engl J Med.
2009;360:11919.
17. Schleiss MR, Bourne N, Bernstein DI.
Preconception vaccination with a glycoprotein B (gB)
DNA vaccine protects against cytomegalovirus (CMV)
transmission in the guinea pig model of congenital CMV
infection. J Infect Dis. 2003;188:186874.
18. Wloch MK, Smith LR, Boutsaboualoy S,
Reyes L, Han C, Kehler J, et al. Safety and immunogenicity
of a bivalent cytomegalovirus DNA vaccine in healthy
adult subjects. J Infect Dis. 2008;197:163442.
19. Jacobson MA, Adler SP, Sinclair E, Black
D, Smith A, Chu A, et al. A CMV DNA vaccine primes
memory immune responses to live-attenuated CMV
(Towne strain). Vaccine. 2009;27:15408.
76
 443

38


21


(disability-adjusted life
year DALY)
HIV/AIDS 84.5 DALY
HIV 46.5
(human immunodeficiency virus) DALY
(acquired immunodeficiency syndrome, AIDS) 43.5 DALY

(neglected
tropical diseases)


1,2

7
(ascariasis)
(trichuriasis) (hookworm disease/
infection)
(lymphatic filariasis)
(onchocerciasis) (dracunculiasis)
(cognitive development) (schistosomiasis)
3
(Chagas disease) (African
sleeping sickness) (leishmaniasis)
444

(amoebiasis)

Entamoeba 44 4
histolytica Entamoeba
dispar

5
1




(Taenia solium)
(cysticercosis)
echinococcosis
(food-borne trematode infections) mucocutaneous
2,3 onchocerciasis
HIV/AIDS




HIV/AIDS
3


1
antipoverty vaccines
(mass treatment)

(re-infection)
(eukaryote)
reverse vaccinology

eukaryotic expression vectors
 38 445

6
(caudal bursa) 7 7
2
Necator americanus Ancylostoma duodenale
Ancylostoma ceylanicum


Ancylostoma braziliense
Ancylostoma caninum

creeping eruption
(definitive host)8

3









Ebers (prevalence)
papyrus 1600 (intensity of infection worm
burden)
Dubini 1
.. 1843
7
order Strongylida 4 superfamilies 9,10
superfamily Ancylostomati-
dea Necator americanus
subglobular buccal capsule Ancylostoma duodenale
(cutting plate) (teeth)
genus species (sub-Saharan Africa)
446

Ancylostoma duodenale



13,14

8

( 1)
1. Ancylostoma duodenale
8-11 . 0.4-0.5 .
10-13 . 0.6 .



Necator americanus buccal capsule
Ancylostoma duodenale ventral chitin
Ancylostoma duodenale 2
Necator americanus 1
accessory teeth dorsal
dental plate
filariform larva
species

8 bursa dorsal ray
3 tripartite
Ancylostoma duodenale spicule 2
65,000 7,8
Ancylostoma
caninum 10 . 0.4
. 14 . 0.6 .
22 DALY buccal capsule 3 ventral
576 11,12 species bursa
(slender ray)
 38 447

1 Necator
americanus (A)
cutting plate (B)
(C)

bursa (D) filariform (E)
rhabditoid rhabdi-
tiform (F) (
)

Ancylostoma braziliense Ancylostoma duodenale 60

8 . 0.27 . 40
10 . 0.3 . buccal capsule 2
ventral teeth Ancylostoma Necator americanus 64-76
ceylanicum Ancylostoma ceylanicum 36-40
Ancylostoma bra-
ziliense7,8 species 7,8
Necator americanus 3. (rhabditoid larva)
genus Ancylostoma 1 2
1 (first stage larva)
buccal 0.25-0.30 . 17
capsule cutting plate dorsal 1
ventral 1 1 3
species 7-9 . 0.3 .
bursa dorsal ray (bulbous type)
2 bipartite spicules 2
2 genital primordium
9-11 . 0.4 . 2 (second stage larva)
Ancylostoma duo- 0.5-0.6 .
denale7,8 7,8
2. (hookworm egg) 4. (filariform larva)
448

(lung migration) filariform larva

3 (third stage larva )
(infective stage) Necator americanus (alveolus)
500-600 Ancylostoma
duodenale 600-700 epiglottis

(sheath) filariform larva 1
filariform type buccal
2 capsule
buccal spears epithelium (fourth stage larva)

(striation) 1
7,8 buccal capsule cutting plate


filariform
larva ( 2) hair 5
follicle epidermis Ancylostoma duodenale
corneum
subcutaneous tissue Ancylostoma duodenale
(venule) (neonatal infection)

2 () (
2 10) APR1: aspartic protease; CP3: cysteine
protease; MEP1: metalloproteinase; OPT1: putative transport protein; GST: glutathione-S-transferase; GSH: glutathione
GSSH: glutathione disulphide ( )
 38 449

Ancylostoma caninum Ancylostoma

ceylanicum 2
Ancylostoma duodenale 5 8 2
3

Ancy- 7,8
lostoma duodenale Ancylostoma caninum

filariform larva



Necator hyaluronidase
americanus 4-20 Ancylostoma hyaluronic acid keratino-
duodenale 5-7 7,8 cyte epidermis
dermis15

Necator americanus 10,000- neutrophil inhibitory factor (NIF)
20,000 Ancylostoma duodenale glycoprotein 41
10,000-25,000 neutrophil endothelium
Necator americanus hydrogen peroxide
0.03 . Ancylostoma duodenale neutrophil serum
0.15-0.26 . opsonized particle
(unembryo- neutrophil integrin receptor CD11b/CD1816-18
nated egg) early cleavage
2-3
anticoagulant peptide (ACAP-1)
coagulation factor XA



platelet dense granule

1-2 1 fibrinolysis
3
450

glutathione-S-transferase
IgG acethylcholinesterase

35-40 eosi-
nophilia 38-64
6


10,18-22 acute
gastrointestinal hemorrhage


filariform larva
cutaneous larva migrans creeping (hypoalbuminemia)
eruption ground itch malabsorption8





Ancylostoma caninum
Ancylostoma braziliense

8

lung miqration

pulmonary
infiltrate eosinophilia
lung migration
Loefflers syndrome8 8,22


epigastrium 3 8

 38 451

(Strongyloides stercoralis)
buccal cavity
koilonychia (angular stomatitis) genital primordium

charcoal culture
filter paper culture 7,23
congestive heart failure agar plate culture
1-2
peptone, beef extract
8,22 25-35o .
3-5
Strongyloides stercoralis
(hypochromic micro- Strongyloides stercoralis
cytic erythrocytes) reticulocyte direct smear formalin-ether
ferritin transferrin sedimentation method 10.2 1.9
eosinophilia agar plate culture
8 direct smear formalin-ether
sedimentation method 14 1.5

2 agar plate culture
direct smear filter
concentration formalin-ether paper culture 1.14 24
sedimentation ethyl-acetate sedimentation
direct smear


1,200 8
1 Mebendazole Ancylostoma
duodenale Necator americanus
100 . 2 3
1 Stoll dilution egg 76-95
count Kato thick smear 8


rhabditoid teratogenic effect
452

Albendazole benzimidazole Necator americanus (Na-ASP2)

mebendazole 200 29
. IgG4
mebendazole
Pyrantel pamoate IgG4
Ancylostoma duodenale Necator americanus
11 ./. 1 Th2
lymphocyte
liver enzymes IgE IgG4

Bephenium hydroxynaphthoate 29,30
pyrantel pamoate 5 IgD
(2.5 ) An- IgD cross-link basophil
cylostoma duodenale Necator interleukin-4 (IL-4) IL-4
americanus 3
Th2 cell31,32 secretory
IgA
ferrous sulfate IgA

3 33
2. cytokines

Th2 lymphocyte
packed red blood IL-4, IL-5, IL-13 IgE
cells 8 IL-5

interferon
1. gamma (IFN-)
IgM
6
IgG Th1 Th2 cells
8 22-27 IgE Th2 cell
IgE
27,28 IgE Th1 cell
Ancylostoma secreted protein-2 34,35
 38 453

3. (cell-mediated 41
immune response)
eosinophil

eosinophil
antigen-presenting cells effector 42
cells basophil
Th2 cell basophil
protease allergens IL-4 thymic 2543
stromal lymphopoietin
natural killer (NK) cells

NK cells
1.
IFN- NK cells IFN- .. 1965
Ancylostoma caninum
(irradiated larvae)
Th1 cell36,37

9044
1970





49.238
sterile
Necator americanus 95.8 immunity
Ancylostoma duodenale 0.5 Ancylos-
toma ceylanicum 0.339

40


45
454

2.
Na-ASP-2
45


IgE
2.1
filariform larva
Ancylostoma caninum Na-ASP-2
21
metalloproteinase MTP-1
3 metalloprotease IgG2
(MTP-1) 2 pathogenesis-
related proteins 43.9
Ancylostoma secreted protein-1 (ASP-1) MTP-1
21.3 Ancylostoma
secreted protein-2 (ASP-2)46-48
Necator IgE
americanus Na-ASP-1 Na-ASP-2
2
53,54
2.2
49-51
Na-ASP-1

Na-ASP-2

52 Na-ASP-2

Na-ASP-2

filariform larva
48 recombinant
Na-ASP-2 alhydrogel adjuvant

 38 455

19
hemoglobinases (
2) aspartic protease (APR1) 19,56
cysteine protease (CP3) GST1
metalloprotease (MEP1)
Wuchereria bancrofti 57

OPT1 membrane-spanning amino acid 10
transporter APR1 45
heme haematin

oxygen aspartic acid
radicals alanine aspartic acid
APR1 58
glutathione APR1
S-transferase 1 (GST1) 58
heme haematin 10 59 APR1


GST1 APR1 protease
GST1 24
(recombinant protein)
Pichia pastoris
GST1 peroxi-
dase reduced GST1 APR1
glutathione electrophiles
heme haematin 54,60
oxygen radicals 19,55

GST1





456

genus Leishmania 2 subgenus
subgenus Leishmania subgenus Viannia
subgenus Viannia hindgut
61 Leishmania (
Leishmania ) subgenus
(flagellate) Leishmania Leishmania (
order Kinetoplastida ) species 2
kinetoplast circular subgenus Leishmania
DNA mitochondria
Leishmania family Trypanosomatidae reticuloendothelium visceral leishma-
Trypanosoma family niasis
genus Leishmania Ross .. 1903 mucosal mucocutaneous leishmaniasis
Leishman cutaneous leish-
maniasis Leishmania species
Dum Dum
Donovan
Ross 62

Leishman-Donovan (LD) body .. 1904 Rog-
ers amastigote genus Leishmania
promastigote ..1911 2 amastigote Leishma-
Wenyon Baghdad nial form promastigote leptomonad form
(sand fly) ( 3) amastigote reticuloendothelial
..1925 Adler Theodor promastigote cell 2-5
7
Leishmania Giemsa Wright kinetoplast
species basal body
axoneme amastigote
binary fission
Leishmania amastigote
species species amastigote promastigote

kinetoplast basal body
 38 457

3 Leishmania (A) amastigotes phagocytic cell

(B) promastigotes
( )

flagellum 1 promastigote 32 base pairs63

15-20 1.5-3.5 flagellum Leishmania mexicana groups 34
15-28 8 29
promastigote 4-5 20 36 Leishmania braziliensis
flagellum groups 35 20
mitochondria 1 3464
kinetoplast promas- Leishmania
tigote longitudinal binary fission species 20 species
65
metacyclic promastigote
metacyclic promastigote

amastigote phagolysosome metacyclic promastigote
phagocytic cell7 ( 4) family Psychodidae
Leishmania donovani Leishmania subfamily Phlebotominae 2 genus
major groups 36 genus Phlebotomus
458

4 Leishmania ( )

genus Lutzomyia
1.5-2.5 . pupa
pupa
2-3
2
600 species Leishmania 7-10
60 species
7,62


Leishmania
15-80
larval instars 4 Leishmania
 38 459

Leishmania major 2-3 promas-

tigote wet
Th1 lymphocyte NK cell mount Giemsa
IFN- interleukin-12 (IL-12) 7
naive T lymphocyte Th1 cell 3.
NK cell IFN-
naive T lymphocyte Th2 cell
IL-4 IL-10 golden hamster

Leishmania 7,66-69 7
4.
(intradermal test)
1. Leishmanin skin test Montenegro test

amastigote delayed-type
Giemsa Romanovsky hypersensitivity promastigote

48-72
Histoplasma capsulatum mi- cutaneous leishmaniasis mucosal leish-
crosporidium Leishmania maniasis diffuse cutaneous leishmaniasis
kinetoplast visceral leishmaniasis 7
amastigote 5.

indirect immunofluorescence test
23 promastigote
2.
Leishmania
counterimmuno electrophoresis,
Leishmania enzyme-linked immunosorbent assay (ELISA)
direct agglutination test 23,70,71
Novy-MacNeal- 6. DNA
Nicolle medium (NNN medium)
fibrin Schneiders Dro- DNA Leishmania
sophila medium fetal bovine serum (PCR)
(Hockmeyers medium)
460

species Leishmania niasis

viscerotropic leishmaniasis7,62
kinetoplastid DNA72, small subunit ribosomal RNA73 1.2
74
mini-exon genes genus Phlebotomus
Phlebotomus argentipes, Phlebotomus pernisiosus
Leishmania donovani Leishmania
Leishmania species infantum genus Lutzomyia Lutzomyia longi-
20 species species palpis Leishmania chagasi7,62
1.3
Leishmania donovani
Leishmania
Leishmania infantum
(subclinical infection) Leishmania chagasi

viscerotropic Leishmania tropica
62 62
1.4
1. Visceral leishmaniasis (kala-azar) visceral leishmaniasis
Leishmania 90
donovani
75
(hypergammaglobulinemia) 1.5
kala-azar ( black visceral leishmaniasis Leish-
62
sickness) Dum Dum fever mania donovani complex
1.1
3 species Leishmania donovani
complex
Leishmania donovani
Leishmania infantum promastigote
reticuloendothelial cell
Leishmania chagasi granuloma histiocyte
Leishmania 3 amastigote epithelioid cell
species giant cell
Leishmania
tropica visceral leishma-
 38 461

granulomatous reaction murmur

hyperplasia reticuloendothelial cell
amastigote


hypersplenism autoimmune hemo-
Kupffer cell lysis
amastigote
granuloma

amastigote
granulomatous reaction giant pancytopenia
cell
62
reticuloendothelial cell
portal 62
visceral leishmaniasis

reticuloendothelial cell (latent
submucosa infection)
villous atrophy hyperplasia crypt

62
1.6 76
2-6
neutrophil
eosinophil



62
7,62 post-kala-azar dermal leishmaniasis



462

2-10 62
1.7 62
1.9
visceral leishmaniasis
eosinophil 100 /..
3 ./. 4 ./. .. 1960
62 17
1. amastigote 6
98 stibophen 77
amas- 6
tigote 80-85 78
2. indirect im-
munofluorescence test (IFA) promastigote
79 .. 1999
1:256 95 2 9

.. 1996 2
3. Montenegro test
6
1 90 9.7 38.5o .
1.8 4 .
pentavalent antimony 7 .
sodium stibogluconate meglumine antimoni- 6.9 %
ate 84,000 /.. 4.1 %
diamidine pentamidine 5.5 %
isethionate paromomycin amastigote Leishmania DNA
Leishmania PCR
visceral leishmaniasis Leishmania indirect
amphotericin B lipid immunofluorescence 1:16384
formulation pentamidine isethionate
amphotericin B deoxycholate 3 ./.
3
miltefosine sitamaquine 15
75 2
1
 38 463

9.6 % 168,000 /.. Phlebotomus sergenti

Leishmania Phlebotomus papatasi (2) Leishmania (tropica) minor
1:32 1:16 Leishmania (tropica) tropica
10 (relapse)79 Phlebotomus papatasi
visceral leishma- Phlebotomus caucasicus (3) Leishmania (tropica)
niasis aethiopica hyrax

Phlebotomus longipes Phlebotomus pedifer
898 (New World cutaneous
9 80 leishmaniasis) subgenus Viannia
visceral leishmaniasis Leishmania mexicana complex Leishmania
braziliensis complex genus
Lutzomyia 62
2.2
Phlebotomus argentipes Phlebotomus major cutaneous leishmaniasis
major 90
80

83
2.3
visceral leishmaniasis
Leishmania infantum81
Leishmania species lymphocyte, plasma cell mononuclear cell
82 visceral leishmaniasis fibrosis granuloma
fibrosis
granuloma

2. Cutaneous leishmaniasis
2.1 leishmaniasis recidivans

2 (Old World amastigote
cutaneous leishmaniasis) Leishmania lymphocyte
tropica complex 3 species diffuse cutaneous
(1) Leishmania leishmaniasis62
(tropica) major
464

2.4 10-20 visceral

2-8 Leishmaniasis 28
3 pentavalent antimony 20
./. 4
Leishmania major 84

2-3 Leishmania tropica pentamidine isethionate amphotericin
B fluconazole
Leishmania aethiopica 200 . 2 4 6
ketoconazole 600 ./
62 28 itraconazole 200 .
2 28 dapsone
100 . 2 6 84
(papule) ointment paromo-
mycin methylbenzethonium chloride
leishmaniasis recidivans pentavalent antimony

20-40 84
2.7
diffuse cutaneous leishmaniasis cutaneous Leishmaniasis

7,62
2.5 40
1. amastigote

Giemsa7,62
2. NNN medium
2-7 Schneiders medium
21 promas- .. 1981
tigote7,23 199778
3. Montenegro test
3 7 3. Mucosal leishmaniasis
2.6 mucosal leishmaniasis
pentavalent antimony
visceral Leishmaniasis
 38 465

mononuclear cell
plasma cell lymphocyte
epithelioid cell Langerhans giant cell
mu- granuloma
cosal leishmaniasis necrotizing granulomatous
espundia, chiclero ulcer bay sore 62 7
3.1 3.3
cutaneous
2 Leishmania leishmaniasis
mexicana complex (1) Leishmania mexi-
cana

Lutzomyia olmeca olmeca (2) Leishmania
amazonensis Leishmania braziliensis

Lutzomyia flaviscutellata
(3) Leishmania venezuelensis

Leishmania olmeca bicolor 2
Leishmania braziliensis complex
(1) Leishmania braziliensis 7,62
diffuse cutaneous leishmaniasis
Lutzomyia
wellcomei Lutzomyia intermedius Lutzomyia
pessoai (2) Leishmania panamensis
sloth 62
Lutzomyia trapidoi (3) Leishmania guyanensis 3.4
pentavalent antimony
Leishmania umbratilis sloth (4) visceral leishmaniasis
Leishmania peruviana 28 amphotericin B deoxycholate
Lutzomyia verrucarum
Lutzomyia peruensis7,62 pentamidine isethionate
3.2 2-4 ./.
hyperplasia epidermis 3 15 84
necrosis dermis neutrophil eosinophil
466

87,88
3.5 Leishmania
mucosal
leishmaniasis Leishmania metacyclic promastigote
1,000 89
1 90
Leishmania
Leishmania
genome Leishmania
Leishmania Trypanosoma brucei Trypano-
soma cruzi proteome
6,200 63 promastigote maxadilan
Leishmania 91,92
filamentous proteophosphoglycan
(fPPG) (secretory gel)
promastigote

2 promastigote
86 89 promastigote
3 dermal macrophage
Leishmania keratinocyte Langerhans
Leishmania promastigote dermal
macrophage 93
Leishmania C3 94
phagocytosis promastigote
promastigote lipophos- amastigote
phoglycan (LPG) promastigote phagosome LPG
promastigote lipid
promastigote microdomains phagosome
promastigote phagosome promastigote
lysosome
(receptor) hydrolases
LPG galectin promastigote
phagosome lysosome promas-
Leishmania tigote amastigote
 38 467

phagolysosome 102
95-97 neutrophil Leishmania braziliensis
promastigote tumor necrosis
keratinoeyte factor alpha (TNF-) superoxide103
IL-12, neutrophil Leishmania donovani
IL-1, IL-4, IL-6 osteopontin IL-6 neutrophil extracellular traps
(NETs) fibrous traps DNA his-
IL-6 tone granule neutrophil
Leishmania 104,105 NETs neutrophil
LPG Leishmania
IL-6 Th2 cell NETs Leishmania
Leishmania NETs DNase
98 Leishmania NETs
Langerhans neutrophil
dendritic cells Leishmania
phagocytosis
Langerhans NETs
(interstitial space) neutrophil
promastigote
Langerhans monocyte
promastigote vacuole 2 mono-
(pseudopod) cyte dendritic cell
Langerhans amastigote 106

Leishmania T lymphocyte
Langerhans 16
99,100 CD4+ T lymphocyte Leishmania

T helper lymphocyte
1 Th1 cell IFN-
neutrophil mono- TNF- Leishmania
cyte 101
promastigote MCP-1
CXCL1 (chemoat- T lymphocyte
tractant) monocyte neutrophil Th2 IL-4, IL-5
468

IL-13107-110 Leishmania
dendritic cell IgG
Leishmania CD4+
T lymphocyte IL-12 IFN 1 B lymphocyte
( IFN-, IFN- and IFN-) Leishmania117
nave T lymphocyte Th1
lymphocyte Leishmania major
Leishmania
dendritic cell nuclear factor kappa-
light-chain-enhancer of activated B cells (NF-B) Leishmania
IL-12 111-113
Leishmania donovani Leishmania tropica 1. macrophage
dendritic cell
IL-12 dendritic cell LPG Leishmania
CD4+ lymphocyte macrophage CD40 signalosome
IL-12 IL-12
Th1 lymphocyte Leishmania major macrophage
dendritic cell NK cell CD40 signalosome
IFN- CD4+ lym- Erk1/2 mitogen activated protein kinase
phocyte Leishmania IL-10
IFN- NK cell Leishmania 118
IL-12 dendritic cell 2. cytokine
IL-2 CD4+ T lymphocyte
Leishmania promastigote
Leishmania species macrophage
(innate immunity)
transforming growth factor
(acquired immunity)114,115 beta (TGF-) cytokine
T lymphocyte
T lymphocyte
apoptosis Th1 lymphocyte lymphocyte, NK cell, dendritic cell, macrophage,
mast cell granulocyte
nitric oxide L-asparagine 119
inducible nitric oxide synthase (iNOS)116 TGF-
cytokine
B lymphocyte promastigote
B lymphocyte Leishmania
 38 469

TGF- cytokine apoptosis

cysteine protease 125
TGF- Leish- promastigote fPPG
mania 120 maxadilan
TGF- cytokine IL-6, IL-10 TGF- iNOS
Leishmania maxadilan
major TGF- monocyte dendretic cell
respiratory burst IL-6, IL-10, IL-1 IL-10
phagocytosis TGF- IL-12, TNF- IFN-
iNOS Leish- Leishmania
mania121 126,127
3. regulatory T (Treg) lymphocyte
Treg
lymphocyte 5-10
CD4+ T lymphocyte Treg cell


Leishmania CD4+CD25+ Treg lymphocyte (zoonotic transmission)
FoxP3, TGF- IL-10R1 88
CD4+CD25- lymphocyte IL-2 1.5-2
IFN- 122 Treg 7
cell Leishmania 350
TGF-
Treg lymphocyte 2-4
Leishmania CD4+CD25+ DALY85
Treg lymphocyte

CD4+CD25- T cell IL-10
IL-10
Leishmania CD4+CD25+ Treg
cell 123,124 Adler (Hebrew University)
4.
Leishmania major
macrophage migration inhibitory factor (MIF)
Lm1740MIF MIF
470

128 Leishmania 3 (phase

III)

leishmanization 134,135
..1967

Leishmania subgenus Vannia
species
leishmanization 136 Leishvacin

leishmanization 80 Th1 lymphocyte
Leishmania major
leishmanization
Th1 lymphocyte
promastigotes Leishmania major
Leishmania tropica
leishmanization
129,130 137,138

1 2
(first-generation vaccines) (second-generation vaccines)

promastigote Leishmania leishmanization
(axenic 136
culture)

Leishmania gentamicin
5
Leishmania
Leishmanin skin
test dihydrofolate reductase-thymidylate synthase
50 (DHFR-TS)139 cysteine proteinase140
LPG Leishmania major141
Leishmania amazonensis Leishmania DTFR-
IFLA/BR/67/pH8 Leishvacin131-133 TS
 38 471

3 Leish-111f thiol-
specific antioxidant (TSA), Leishmania major stress
130 inducible protein 1 (LmST11) Leishmania major
elongation factor (Le1F) emul-
sion adjuvant monophosphoryl lipid A (MPL-SE)
(subunit vaccine) subunit vac- Leish-111f
cine visceral cutaneous leishmaniasis
Th1 lymphocyte
1. gpb3 protease IFN- TNF-
Leishmania amastigote 99148
promastigote

gpb3
142 3
BCG 143 (third-generation vaccine)
2. Leishmania homologue for receptors of DNA
activated C kinase (LACK)
amastigote pro-
mastigote LACK
IL-12
LACK plasmid DNA DNA
vaccinia Th1 lymphocyte
144,145 LACK DNA
Leishmania species LACK 3
visceral leishmaniasis DNA
Th1 lymphocyte 146 LACK,
3. Cathepsin L-like cysteine proteinase A Leish-111f, CPA CPD DNA
B (CPA CPB) adjuvant
CPA CPB DNA LACK
Leishmania major
Leishmania
CPA CPB CD8+T cell
Th1 cell DNA
147 IFN- IL-12 129
4.
472

dendritic cell
Leishmania
3,149
dendritic cell
Th1 cell
dendritic cell




129-131




DALY








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 483

39

(Respiratory syncytial virus; RSV)
RSV HPIVs
1,2
31-41 5 RSV HPIV3
RSV3,4 25
1
RSV5 RSV (bronchiolitis) (pneumonia)
6
(human stem cell transplant)6
RSV 3,7 HPIV1 HPIV2
1, 2 3
(human parainfluenza viruses type 1, 2 3; HPIV1, croup 8,9
HPIV2 HPIV3 ) RSV HPIV
25 RSV 14
HPIV RSV
1
8 HPIV1 HPIV2 15,16
Croup 6 17 18
2 HPIV3 19,20
(bronchiolitis) (pneumonia) RSV
1 9-11 (reactive airway
HPIV3 disease) RSV

RSV12,13 (pulmonary function)
RSV HPIVs
21 RSV
484

RSV RSV genus Pneumovirus

15,222 nucleotides
21,22 transmembrane surface proteins (F, G SH), matrix
RSV HPIV proteins (M M2), nucleocapsid proteins (N, P L)
nonstructural proteins (NS1 NS2)
23 neutralizing antibody
1024,25 surface fusion (F) attachment (G)
(hema- glycoproteins
tologic malignancies)
(lung trans- RSV 2 A
plant) RSV B
HPIV3 12,13,26 35 G glycoprotein
RSV A RSV B 53
(amino acid) 36 RSV A
RSV cytomegalovirus RSV B
(CMV)6,7,27-30 HPIV1 HPIV3 genus Respirovirus
HPIV2 HPIV4 genus Rubulavirus
HPIV 15,500 nucleotides
HPIV3 RSV 24-7912,31 HPIV3 transmembrane surface
proteins (F HN), matrix protein (M) nucleocapsid
proteins (N, P L) surface fusion (F)
(acute allograft rejection) hemagglutinin-neuraminidase (HN) glycoproteins
bronchiolitis obliterans 32 neutralizing
antibody hemagglutination-inhibiting (HI) antibody
RSV HPIVs33,34 ( HN)


HPIVs RSV RSV
HPIVs RSV family Paramy- 2 50
xoviridae single strand RSV 2 37 HPIV3
of negative-sense RNA nucleo- 60 2 80
capsid envelope 4 HPIV3 1 38,39
plasma membrane-derived lipid bilayer HPIV1 HPIV2 5
virally encoded transmembrane proteins HPIV2
 39 485

75 5 HPIV1
1 38,39
28,51 RSV


23
RSV
RSV lymphocyte
(temperate climates) (lymphocytic peribronchiolar infiltration)
RSV
(bronchiolar epithelium)52
(tropical climates)
40,41
RSV
4,5 RSV A
B
5,42,43 HPIV3
(hyperinflation) RSV
HPIV1 (ciliary apparatus) 53
HPIV2
HPIV2 44 RSV
RSV HPIVs
RSV HPIVs
lymphocyte 48

RSV cellular humoral
RSV cellular
54 antibody

RSV 45 IgG secretory IgA RSV
HPIV3 RSV RSV
55,56
40,46,47 HPIV
RSV

RSV


57 croup
48 RSV mononuclear subglottic
monocyte macrophage
49,50
486

(ciliated epithelial cells) HPIV1 HPIV2 HPIV359,67

lymphocytes, HPIVs
plasma cells macrophages RSV

mononuclear nasal flaring, intercostals
57 retractions (prolonged
HPIV antibody expiration) wheezing
IgG secretory IgA hyperinflation
58 (peribronchiolar
thickening)
crepitations RSV HPIVs
59,60 IgE (apnea)
parainfluenza 6

61 RSV HPIVs
(cell-mediated) 31,68-72

62-65
croup HPIV HPIVs RSV

66
direct immunofluorescence assays,
reverse transcription-polymerase
HPIVs RSV chain reaction (RT-PCR) RSV antigen

73,74
(laryngitis)
HPIVs HPIV1
HPIV2 croup HPIVs RSV
6 2 67
RSV HPIVs

2
RSV 6 HPIV3
6-18
 39 487

ribavirin (aerosol) RSV RSV

HPIVs palivizumab
RSV
92 motavizumab
75-77 (hypersensitivity adverse reaction)
palivizumab

Passive immunization HPIVs RSV
RSV
78-80 .. 2010
81 RSV neutralizing antibody AstraZeneca motavizumab

2 RSV neutralizing antibody motavizumab RSV
RSV Immune Globulin Intravenous motavizumab
(RSV-IGIV; RespiGamTM) monoclonal RSV RSV
neutralizing antibody (palivizumab; SynagisTM) HPIV
RSV-IGIV

750 ./.82,83
palivizumab

RSV

84,85 palivizumab
RSV-IGIV 50-100 RSV HPIV3
2-3
palivizumab HPIV1 HPIV2
RSV86 1
palivizumab ..1960
RSV 87,88 RSV
RSV monoclonal (formalin-inactivated RSV vaccine)
antibody motavizumab (MEDI-254)
RSV palivizumab RSV
RSV RSV RSV
89-91 93
motavizumab
palivizumab
488

CD8+ cytotoxic RSV meta-analysis
T-cell type 2 helper T-cell
interleukin (IL)-4, IL-5 IL-10 RSV
94,95 114
RSV RSV co-purified F,
neutralizing antibody G M proteins RSV A
CD8 RSV-specific cytotoxic T cell alum polydicarboxylatophe-
noxyphosphazene (PCPP)
RSV subunit RSV neutralizing antibody 105
alum
neutralizing
RSV glycoprotein F G antibody alum 103,104
RSV BBG2Na

subunit 2-3
purified F glycoproteins96-102, co-purified F, G, 4
M proteins103-105 BBG2Na peptide (hy-
G glycoprotein conjugated albumin-binding persensitivity reaction)
domain streptococcal protein G106-111
RSV subunit F
purified F protein (PFP)-1, PFP-2
HPIV RSV
PFP-3
(live attenuated)
12
(
cystic fibrosis) 96-102,112,113
purified F protein


PEP-2 geometric RSV
mean titers RSV F antibody HPIV3
4 115,116
2 6
RSV neutralizing antibody102
meta-analysis PFP-1 PFP-2
 39 489

37 .
37 .
PIVs
2 HPIV3 cp45
(cp45) bovine PIV3 (BPIV3) cp45
(cold-passaged; cp) HPIV3 JS127
20
(temperature-sensitive; ts) 128,129 BPIV3
(genetically engineered) HPIV3 130
RSV 1 2
cpRSV, RSV ts-1 RSV ts-2117-121 HPIV3 cp45 1
BPIV3 2
RSV
cptsRSV HPIV3
cpRSV cpts248/404 HPIV3
6 115 116,131-134
70
1 HPIV3 cp45
cpts248/955 HPIV3
cpts530/1009 6
116
RSV 122 2 HPIV3134 BPIV3
RSV RSV cp45
(deletion;) hemagglutinin-neuraminidase
nonessential gene (SH, NS1, NS2 M2-2) (HN) proteins HPIV3 130
cp ts recombinant
123-126 bovine-human PIV-3 HN F genes
1-2 rA2cp248/404/1030SH HPIV3 internal genes BPIV3
1 135
125 rA2cpNS2, rA2cp530/1009NS2 PIVs
rA2cp248/404NS2 NS2 gene
RSV human metapneumovirus
(HMPV)
126
RSV
490
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114. Simoes EA, Tan DH, Ohlsson A, Sales
V, Wang EE. Respiratory syncytial virus vaccine: a
systematic overview with emphasis on respiratory
syncytial virus subunit vaccines. Vaccine. 2001;20:954-60.
115. Wright PF, Karron RA, Belshe RB,
Thompson J, Crowe JE, Jr., Boyce TG, et al. Evaluation
of a live, cold-passaged, temperature-sensitive,
respiratory syncytial virus vaccine candidate in infancy.
J Infect Dis. 2000;182:1331-42.
116. Karron RA, Belshe RB, Wright PF,
Thumar B, Burns B, Newman F, et al. A live human
parainfluenza type 3 virus vaccine is attenuated and
immunogenic in young infants. Pediatr Infect Dis J.
2003;22:394-405.
117. Murphy BR, Hall SL, Kulkarni AB, Crowe
JE, Jr., Collins PL, Connors M, et al. An update on
approaches to the development of respiratory syncytial
virus (RSV) and parainfluenza virus type 3 (PIV3)
vaccines. Virus Res. 1994;32:13-36.
118. Wright PF, Shinozaki T, Fleet W, Sell
SH, Thompson J, Karzon DT. Evaluation of a live,
attenuated respiratory syncytial virus vaccine in infants.
J Pediatr. 1976;88:931-6.
119. McIntosh K, Arbeter AM, Stahl MK,
Orr IA, Hodes DS, Ellis EF. Attenuated respiratory
syncytial virus vaccines in asthmatic children. Pediatr
Res. 1974;8:689-96.
120. Kim HW, Arrobio JO, Brandt CD, Wright
P, Hodes D, Chanock RM, et al. Safety and antigenicity
of temperature sensitive (TS) mutant respiratory
syncytial virus (RSV) in infants and children. Pediatrics.
1973;52:56-63.
121. McKay E, Higgins P, Tyrrell D, Pringle
C. Immunogenicity and pathogenicity of temperature-
sensitive modified respiratory syncytial virus in adult
volunteers. J Med Virol. 1988;25:411-21.
122. Karron RA, Wright PF, Crowe JE, Jr.,
Clements-Mann ML, Thompson J, Makhene M, et al.
Evaluation of two live, cold-passaged, temperature-
sensitive respiratory syncytial virus vaccines in
chimpanzees and in human adults, infants, and
children. J Infect Dis. 1997;176:1428-36.
123. Bukreyev A, Whitehead SS, Murphy
BR, Collins PL. Recombinant respiratory syncytial
virus from which the entire SH gene has been deleted
grows efficiently in cell culture and exhibits site-specific
attenuation in the respiratory tract of the mouse. J
Virol. 1997;71:8973-82.
124. Whitehead SS, Bukreyev A, Teng
MN, Firestone CY, St Claire M, Elkins WR, et al.
Recombinant respiratory syncytial virus bearing a
deletion of either the NS2 or SH gene is attenuated in
chimpanzees. J Virol. 1999;73:3438-42.
125. Karron RA, Wright PF, Belshe RB,
Thumar B, Casey R, Newman F, et al. Identification
of a recombinant live attenuated respiratory syncytial
498

virus vaccine candidate that is highly attenuated in
infants. J Infect Dis. 2005;191:1093-104.
126. Wright PF, Karron RA, Madhi SA, Treanor
JJ, King JC, OShea A, et al. The interferon antagonist
NS2 protein of respiratory syncytial virus is an
important virulence determinant for humans. J Infect
Dis. 2006;193:573-81.
127. Belshe RB, Hissom FK. Cold adaptation
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phenotypic markers. J Med Virol. 1982;10:235-42.
128. Skiadopoulos MH, Durbin AP, Tatem
JM, Wu SL, Paschalis M, Tao T, et al. Three amino
acid substitutions in the L protein of the human
parainfluenza virus type 3 cp45 live attenuated
vaccine candidate contribute to its temperature-
sensitive and attenuation phenotypes. J Virol.
1998;72:1762-8.
129. Skiadopoulos MH, Surman S, Tatem JM,
Paschalis M, Wu SL, Udem SA, et al. Identification
of mutations contributing to the temperature-
sensitive, cold-adapted, and attenuation phenotypes
of the live-attenuated cold-passage 45 (cp45) human
parainfluenza virus 3 candidate vaccine. J Virol.
1999;73:1374-81.
130. Coelingh KJ, Winter CC, Murphy BR,
Rice JM, Kimball PC, Olmsted RA, et al. Conserved
epitopes on the hemagglutinin-neuraminidase proteins
of human and bovine parainfluenza type 3 viruses:
nucleotide sequence analysis of variants selected with
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131. Clements ML, Belshe RB, King J,
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parainfluenza type 3 viruses in adult volunteers and
in chimpanzees. J Clin Microbiol. 1991;29:1175-82.
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M, Thompson J, Burns BA, et al. A live attenuated
bovine parainfluenza virus type 3 vaccine is safe,
infectious, immunogenic, and phenotypically stable in
infants and children. J Infect Dis. 1995;171:1107-14.
133. Karron RA, Wright PF, Newman FK,
Makhene M, Thompson J, Samorodin R, et al. A
live human parainfluenza type 3 virus vaccine is
attenuated and immunogenic in healthy infants and
children. J Infect Dis. 1995;172:1445-50.
134. Belshe RB, Newman FK, Tsai TF, Karron
RA, Reisinger K, Roberton D, et al. Phase 2 evaluation
of parainfluenza type 3 cold passage mutant 45 live
attenuated vaccine in healthy children 6-18 months
old. J Infect Dis. 2004;189:462-70.
135. Schmidt AC, McAuliffe JM, Huang A,
Surman SR, Bailly JE, Elkins WR, et al. Bovine
parainfluenza virus type 3 (BPIV3) fusion and
hemagglutinin-neuraminidase glycoproteins make an
important contribution to the restricted replication of
BPIV3 in primates. J Virol. 2000;74:8922-9.
 499

40

Interferon (IFN) Tumor necrotic factor

(TNF) activated CTLs


(cellular immune system) CTLs granzymes perforins
death receptors target cells

Ebstein-Barr virus (EBV)
1 CTLs 100 (1-10/100 CTLs)2
monoclonal antibody
3






(cancer (cancer vaccine)
vaccine)1
cell-mediated (Tumor antigen)
immune response (CMIR) (viral cancer antigen viral antigen
antigens) antigen-reactive T cells peptides
antigen presenting cells (APCs) Human leukocyte antigen (HLA)
dendritic cells (DCs) activated APCs T cells peptides
T cell DCs T cell intracellular proteins ribosome
activated T cells HLA class I heavy chain domains endoplasmic
cytotoxic effector cells (CTLs) reticulum (ER) CD8+ T cells
CMIR cytokines peptides endocytosed membrane
500

extracellular proteins ribosomes

HLA class II CD4+ T cells4 melanoma tyrosinase
2

1. Tumor-specific antigen TSA5 melanoma antigen (MAGE)

fusion chimeric bcr - abl oncoprotein
chronic myeloid leukemia (CML) oncofetal antigen
p53 protein tumor suppression gene
p53
transformation
host cell
carcinoembryonic
Li-Fraumeni syndrome Idiotype (Id) antigen (CEA)
secreted monoclonal immunoglobulin (Ig) alfa-fetoprotein (AFP) oncogenic
surface Ig clonal B cells virus antigen
B cells (B cell malignancies)6 EBV
2. Tumor-associated antigen (TAA) Burkitts lymphoma, Human papilloma virus (HPV)
( 1)

polysaccharides Antigen presentation and T cell proliferation
tumor reactive CTLs
tyrosinase melanin tumor cells

1
Tumor specific antigens
Mutated oncogenes
Immunoglobulin idiotype
Cryptic frameshift sequences
Tumor associated antigens
Cancer testis antigens
Differentiation antigens
Oncofetal antigens
Widely expressed antigens
Viral antigens
mRas mutation p210 (Bcr-abl), mutated P53 (mP53)
Idiotype (Id)
(may be tumor specific)
melanoma antigen 1 (MAGE) 1, MAGE 3
Gp 100, tyrosinase
Carcinoembryonic antigen (CEA), alpha-fetoprotein (AFP)
mP53
Epstein - Barr virus (EBV), Human papilloma virus (HPV)
 40 501

antigenic signal signal 17 co-stimulatory molecules

second signals cell surface effector cells co-stimulatory molecules
molecules cytokines, chemokines effector T cell
Professional APCs cytokines
dendritic cells (DCs) 8 activated memory T cells
co-stimulatory molecules APCs effector cells cytokines
antigen activated T cells C4+ helper T cells inflammatory
cell cycle cells eosinophils macrophages
fibroblasts T cells 16
9
Negative regulation of T cell activation
T cell differentiation cytokines co-stimulatory molecule
cell cycle gene negative regulators
antigen-activated T cells effector cells Transforming growth factor (TGF)
T cell differentiation 2 T cells (proliferate)
Type 1 (TH1 / TC1) Type 2 (TH2 / TC2)10 lymphocyte
Type 1 cell mediated macrophage IL 10
immune response (CMIR) immunosuppressive
anti-tumor 11 anti-viral 12 co-stimulatory molecule cytokines
type 1 effector cytokines IFN APCs16 cytokines
TNF chemokine receptor CSCR3, regulatory T cells (Tregs) 2 classes
CXCR513 perforin Tr 1 cells separate T cell lineage
14 17 Tr 2 cells
Type 2 (periphery)
humoral immune response (HMIR) T cells
type 2 effector cells adaptive
interleukin (IL) 4, IL 10, IL 5, IL 13 express immune response
chemokine receptor CCR3, CCR4 CCR815
T cell trafficking
Maintenance of effector T cells
effector cells cytokines co-stimulatory molecule
(lymphoid organ)18 activated
T cells
CTL activity
(anti-tumor) co-stimulatory molecular families
502

lectins integrins recruiting

T cells tertiary whole cell vaccine cytokines
chemokines class
effector cells19 3
1.1 Autologous vaccine
(Immunotherapy)

APCs T cells
2
1. Passive immunotherapy
() 1.2 Allogenic vaccine
mature T cells
monoclonal antibody
(McAb) autologous vaccine
Rituximab (Rituxin) chimeric anti-CD 20 1.3 Gene modified vaccine
receptor B lymphocyte
B cell Trastuzumab
(Herceptin) Humanized anti-HER2
Gemtuzumab (Mylotary)
Humanized anti-CD33 (tumor-specific antigen)
acute myeloid leukemia (AML) Interleukin-2 (IL2),
2. Active immunotherapy granulocyte-macrophage colony-stimulating factor
(GM-CSF) (stimulatory
molecules)

(tumor vaccine) 20 pre-clinical model
GM-CSF cytokine
(immunogenicity)
21 GM-CSF modi-
fied tumor cell vaccine effector cells

22
1. Whole cell vaccine phase III trials

whole cell whole cell vaccine
vaccine APCs
 40 503

receptor (CD91 DCs)23

CD8 + T cells24
2. Antigen Based Vaccines 2.3 DNA vaccines DNA
purified tumor specific protein plasmid vector
tumor protein immunogen DNA
APCs DNA
T cells tumor protein
tumor-specific tumor-specific T cells
antigen APCs
2.4 Viral and bacterial vector vaccines
DNA vaccines DNA
DNA viral bacterial vector
T cells viral bacterial vector
tumor-specific 2 DNA
antigen melanomas vaccine 2
20 4 20
2.1 Peptide-based vaccines tumor- pox virus family vector
derived protein fragments
APCs 25
peptide
3. Antigen Presenting Cell Based Vaccines (Dendritic
cell vaccine)
2.2 Heat shock protein vaccines Heat shock Dendritic cells
protein
CMIR DCs
tumor cells antigen-specific T cells
Heat APCs 1,000 26
shock protein dendritic cells
tumor protein APCs dendritic cells
dendritic cells receptor heat shock (tumor-specific antigen)
proteins DCs
tumor-specific
tumor protein heat shock protein T cells 27
DCs heat shock protein clinical trial
(tumor protein) melanoma, myeloma
504

B7 family revisited. Annu Rev Immunol. 2005; 23:

515-48.
9. Kndig TM, Bachmann MF, DiPaolo C, Simard
JJ, Battegay M, Lother H, et al. Fibroblasts as efficient
antigen-presenting cells in lymphoid organs. Science.
1995;268:1343-7.
10. Murphy K, Reiner S. The lineage decisions
of helper T cells. Immunol Cell Biol. 2002; 2:933-44.
11. Berzofsky J, Terabe M, Oh S. Progress
on new vaccine strategies for the immunotherapy and
prevention of cancer. J Clin Invest. 2004;113:1515.
12. Berzofsky J, Ahlers J, Janik J. Progress
on new vaccines strategies against chronic viral infec-
1. Zinkernagel R. Immunology taught by tions. J Clin Invest. 2004;114:450-62.
viruses. Science. 1996;272:634-5. 13. Moser B, Wolf M, Walz A, Loetscher P.
2. Callan M, Tamn L, Annels N. Direct visualization Chemokines : multiple levels of leukocyte
of antigen-specific CD8+ T cells during the primary immune migration control. Trends Immunol. 2004;25:75-84.
response to Epstein-Barr virus in vivo. J Exp MMed. 14. Lieberman J. The ABCs of granule-mediated
1998;187:1395-402. cytotoxicity : new weapons in the arsenal. Immunol.
3. Kolb H, Holler E. Adoptive immunotherapy with 2003;3:361-70.
donor lymphocyte transfusions. Curr Opin Oncol. 1997;9: 15. Luther S, Cyster J. Chemokines as
139-45. regulators of T cell differentiation. Nat Immunol 2001;
4. Germain R, Margulies D. The biochemistry 2:102-7.
and cell biology of antigen processing and presentation. 16. Pardoll D, Topalian S. The role of CD4+
Annu Rev Immunol. 1993;11:403-50. T cell responses in antitumor immunity. Curr Opin
5. Van den Eynde B, van der Bruggen P. Immunol. 1998;10:588-94.
T cell defined tumor antigens. Curr Opin Immunol. 17. Sakaguchi S. Naturally arising Foxp3-
1997;9:634-93. expressing CD25+CD4+ regulatory T cells in
6. Tao MH, Levy R. Idiotype / granulocyte- immunological tolerance to self and non-self. Nat
macrophage colony-stimulating factor fusion protein Immunol. 2005;6:345-52.
as a vaccine for B-cell lymphoma. Nature. 1993; 18. Zinkermagel R, Ehi S, Aichele P. Antigen
362:755-8. localisation regulates immune responses in a dose-
7. Janeway C. Immunogenicity signals 1,2,3 and time- dependent fashion: a geographical view of
and 0. Immunol Today. 1989;10:283-6. immune reactivity. Immunol Rev. 1997;156:199-209.
8. Greenwald R, Freeman G, Sharpe A. The 19. Bacon K, Baggiolini M, Broxmeyer H.
 40 505

Chemokine/chemokine receptor nomenclature. Dendritic cells resurrect antigens from dead cells.
J Interferon Cytokine Res. 2002;22:1067-8. Trends Immunol. 2001;22:141-8.
20. Ribas A, Butterfield LH, Glaspy JA,
Economou JS. Current developments in cancer
vaccines and cellular immunotherapy. J Clin Oncol.
2003;21:2415-32.
21. Dranoff G, Jaffee E, Lazenby A, Golumbek P,
Levitsky H, Brose K, et al. Vaccination with irradiated
tumor cells engineered to secrete murine granulocyte-
macrophage colony-stimulating factor stimulates
potent, specific, and long-lasting anti-tumor immunity.
Proc Natl Acad Sci U S A. 1993;90:3539-43.
22. Soiffer R, Lynch T, Mihm M, Jung K,
Rhuda C, Schmollinger JC, et al. Vaccination with irra-
diated autolgous melanoma cells engineered to secrete
human granulocyte-macrophage colony-stimulating
factor generates potent antitumor immunity in patients
with metastatic melanoma. Proc Natl Acad Sci U S A.
1998;95:13141-6.
23. Binder RJ, Han DK, Srivastava PK. CD91:
receptor for heat shock protein gp96. Nat Immunol.
2000;1:151-5.
24. Mazzaferro V, Coppa J, Carrabba MG,
Rivoltini L, Schiavo M, Regalia E, et al. Vaccination
with autologous tumor-derived heat-shock protein
gp96 after liver resection for metastatic colorectal
cancer. Clin Cancer Res. 2003;9:3235-45.
25. Paoletti E, Tartaglia J, Cox WI. Im-
munotherapeuticstrategies for cancer using pox-
virus vectors. Ann N Y Acad Sci. 1993;690:292-
300.
26. Dhodapkar MV, Bhardwaj N. Active
immunization of humans with dendritic cells.
J Clin Immunol. 2000;20:167-74.
27. Larsson M, Fontenaeu JF, Bhardwaj N.
76
 507

41

(Alexander the Great
of Macedonia)7 340

6,000-8,000 1
(Crusades)
2,700 (Holy
Land)
2 11-13


7
2,000 (Ayurveda) .. 1880

(king of (Charles Louis Alphonse Laveran)8
diseases)
3 1,600

4


(Ebers Papyrus)5
(Hippocrates Epidemics)
400
(tertian fever)
(quartan fever)
6
508

genus Plasmodium (sexual development)
species 120 species (definitivehost)
5 Plasmodium
falciparum, Plasmodium vivax, Plasmodium malariae, (asexual
Plasmodium ovale Plasmodium knowlesi development)
(intermediate host)8

( 1) 3
.. 2009 225
781,000 1.
9
2.
10 (ookinete)
5 (merozoite) (sporozoite)
10 (apical organelle)
4
P.falciparum 3.
35 P.vivax 7 (gametocyte)
P.falciparum P.vivax 4.1 .. ookinete
1965 0.8 .. 200211 .. 1998

131,055 .. 2008 1. (oocyst)
25,449 10 sporogony
2. tissue
schizogony exo-erythrocytic schizogony
5 pre-erythrocytic schizogony
12,13 1 3. erythrocytic
species schizogony14
2413 gametocytes
gametocyte
(female gamete)
gametocyte
 41 509

1 Plasmodium falciparum [A]

[B] [C] [D]
(1) sporozoite (2) hepatic trophozoite (3) hepatic schizont with merozoites (4) free merozoite (5) ring
stage (6) growing trophozoite (7) growing schizont (8) mature schizont with merozoites (9) immature gametocytes (10) ma-
ture gametocytes (11) exflagellation of male gametocyte (12) male gamete (13) female gamete (14) zygote (15) ookinete
(16) oocyst (17) salivary gland sporozoite ( )

exflagellation (male sporozoite 1 oocyst sporozoite

gamete) 8 1 2 15 oocyst
1 sporozoite
oocyst
(zygote)
sporozoite
ookinete sporozoite


oocyst
510

1 2 14
merozoite
8 35 14 vacuole

sporozoite giemsa

ring stage (ring form
hepatic stage exoerythrocytic stage young trophozoite)

(pinocytosis)
(schizont) growing trophozoite

merozoite
schizogony malarial pigment
merozoite P.falciparum hemozoin18,19
merozoite 30,000 40,000 sporozoite growing
1 P.ovale P.malariae merozoite trophozoite
15,000 P.vivax 10,000 giemsa
sporozoite 1 P.knowlesi P.falciparum
Maurers
sporozoite merozoite cleft P.vivax P.ovale
14 Schuffners dot
sporozoite P.falciparum, P.malariae P.malariae
P.knowlesi Ziemanns dot P.knowlesi
P.vivax P.ovale
Sinton and Mulligans stippling14
P.falciparum, P.malariae P.knowlesi
schizont
schizogony
schizont

(relapse) schizont (late schizont)
merozoite merozoite
(hypnozoite)16,17 merozoite P.falciparum
merozoite 8 26 P.vivax
merozoite 12 24 P.malariae P.ovale
 41 511

merozoite 6 12 P.knowlesi
merozoite 6 16 14 merozoite
18.00-04.00 .
(hemolysis) 1.2 An.minimus


asexual erythro- 18.00-22.00 .
cytic cycle P.knowlesi 24 1.3 An.maculatus
P.falciparum 36 48
P.vivax P.ovale 48
P.malariae 72 18.00-21.00 .
merozoite 2. (secondary vectors)
2.1 An.sundaicus
20,21

(asexual erythrocytic cycle) 2.2 An.aconitus
merozoite
gametocyte
gametocyte P.falciparum 2.3 An.pseudowillmori
(crescent form) gametocyte An.maculatus
microgametocyte P.falciparum P.vivax
gametocyte macrogametocyte
gametocyte P.vivax, P.malariae, P.ovale
P.knowlesi macrogametocyte
microgametocyte 1. sporozoite
gametocyte
22-24
2.


3.
25
1. (primary vectors)


1.1 Anopheles dirus
512

30

2 (malarial
paroxysm) 1-2 2-4 28
P.falciparum 2.
(severe normocytic anemia)
hematocrit 15
hemoglobin 5 ./.
parasitemia 10,000 1
1) (splenectomy) 2)
(primigravida) 3)
(immunosuppression) 4) (thalas-semia)
(non-immune (hemoglobinopathy)
to malaria)26
.. 1990 29
26 3. (acute renal failure)
1. (cerebral malaria with 400 . 24
unrousable coma) 12 ./. 24

creatinine 3.0 ./.

P.falciparum
30
creatinine 2
10 blood urea nitrogen 40 ./.

80

2 30,31
4. (pulmonary edema)

27 P.falciparum


 41 513

adult respiratory distress syndrome (ARDS) 8. (repeated

generalized convulsion)
2
(fluid overload) 24
32,34 (febrile convulsion)
5. (hypoglycemia)
(whole blood glucose) 2.2
40 ./. 26
9. (acidemia/acidosis)
arterial pH 7.25 bicarbonate
15

(coma) extensor
(hyperparasitemia) 40-42
10.
(quinine) (quinidine) (malarial hemoglobinuria, blackwater
fever)
35-38 hemoglobin
6. (circulatory
collapse, shock, algid malaria)
systolic 50
5 70

(core-skin temperature)
10 . quinine halofantrine G-6-PD
deficiency
metabolic acidosis septicemia
43-45
27 11. (hyper-
7. (spon- parasitemia) parasitemia
taneous bleeding, disseminated intravascular
coagulation)
disseminated parasitemia
intravascular coagulation (DIC) 5
10 parasitemia
39
514

P.falciparum 49
sequestration visceral blood 1.
26
12. (jaundice)
(bilirubin) 50 giemsa
3.0 ./. 1.1 (thin blood film)




total bilirubin indirect bilirubin 1.2 (thick blood
46 film)
13. (hyperpyrexia)
rectum 40 .
200
giemsa
schizogony hyperpyrexia
38.5 .
39.5 42 .
42 . 40 1
P.falciparum P. vivax
fetal distress47,48


1.
(mixed species infection)
2.
3. 2.

4.
immunochromatographic
5. test monoclonal antibody circulating
antigen



 41 515

histidine-rich protein II (HRP II) chloroquine sulfadoxine-

lactate dehydrogenase (pLDH) pyrimethamine

giemsa
P.falciparum P.falciparum mefloquine, artemether
3. DNA artesunate, quinine

DNA
(polymerase chain reaction, PCR)
DNA 2. P.vivax P.ovale
chloroquine
primer oligonucleotide hypnozoite
DNA primaquine
complementary primer DNA 3. P.malariae P.knowlesi
polymerase chloroquine primaquine
DNA DNA hypnozoite
primers


small subunit ribosomal RNA (SSU rRNA)
primers mitochondrial cytochrome b
primers SSU rRNA

5
DNA
PCR primers mitochondrial
cytochrome b

PCR primers SSU rRNA 5





26 (clinical immunity)50-53 ..1961 1962
1. P.falciparum
P.falciparum clinical immunity
516

54,55 ..1991

IgG

3
56 1) pre-erythrocytic stage vaccines
sporozoite

.. 1941 1942
sporozoite Plasmodium gallinaceum
(ultraviolet)
2) asexual blood-

57,58 .. 1967 stage vaccines

Plasmodium berghei sporozoite

(X-irradiated sporozoite)

sporozoite sporozoite
3) transmission-blocking vaccines

gamete, zygote ookinete
(complete protection)59,60 sporozoite

sporozoite (precipitation)
sporozoite
circumsporozoite protein (CSP) ( 2)61
CSP sporozoite
60

P.falciparum sterile

immunity






 41 517

2
( )

merozoite
1. 30 sporozoite
(pre-erythrocytic stage
vaccine candidates) sporozoite
dendritic
P.berghei Plasmodium yoelii cells exo-erythrocytic
sporozoite stages sporozoite
sporozoite
50 62-64
2-3 6
1 10
sporozoite sporozoite
exo-erythrocytic stages 10 15
epidermis, 1 apical organelle
dermis hair follicle merozoite
merosomes sporozoite

518

circumsporozoite protein NANP NVDP

CSP, thrombospondin-related adhesive protein (TRAP) P.falciparum
sporozoite-threonine-asparagine-rich protein tetrapeptide repeats
(STARP) 40 51 66
1.1 circumsporozoite protein CSP
sporozoite P.falciparum
40 79
N-terminus C-terminus repeats repeats
CSP P.falciparum B cell epitope
CSP species
region I region II ( 3)65 sporozoite 67
sporozoite68
(repeats) CSP (monoclonal
P.falciparum 4 antibody) repeats CSP P.berghei
(tetrapeptide repeats)
asparagine alanine 69 (ligand)
asparagine proline (NANP) (recepter) sporozoite 70
asparagine valine aspartic acid sporozoite 71
proline (NVDP) C-terminus CSP

3 circumsporozoite protein RTS,S ( 2 61)

 41 519

T helper epitope 2 Th2R

Th3R cytotoxic T cell epitope CSP 83,84
Th3R epitope ( 3)72-76 pre-erythrocytic stages
T cell epitope sporozoite
codon epitope
1.2 thrombospondin-related adhesive protein
Th2R Th3R sporozoite
codon 66,77,78 90 85,86
TRAP
T cell epitope
6 (domain) 1) signal peptide
N-terminus 2)
altered peptide ligand antagonism78 von Willebrand factor type A-domain
codon 3) sulfated glycosaminoglycan
epitope region II CSP 4)
(natural selection) proline asparagine
epitope 66 5)
transmembrane domain 6)
79 C-terminus cytoplasmic tail
tetrapeptide repeats TRAP P.falciparum P.vivax
CSP P.falciparum
sporozoite
2
87-89

repeats domain 2, 3
4

80,81
repeats B cell immunofluorescence
T cell (T-independent B cell stimulation)82 immuno-electron micrograph CSP TRAP
T helper epitopes CSP microneme90,91 TRAP
B cell (T-B cooperation) sporozoite (patch)
avidity affinity cytotoxic CSP sporozoite92,93
T cell epitope cytotoxic T TRAP CSP P.yoelli
lymphocyte
CSP sporozoite 2
520

STARP
Hep G2
N-terminus C-terminus
repeats 10
pre-erythrocytic
stages STARP
sporozoite 1 CSP Aotus
TRAP 2 (owl monkey)
sporozoite T cell
region II plus repeats

heparan sulfate proteoglycan basolateral
domain
1.3 sporozoite threonine-asparagine-rich pro- CSP, TRAP STARP
tein (STARP) 78
sporozoite threonine as- pre-erythrocytic stages
paragine
STARP sporozoite and liver stage antigen
(SALSA)95 liver-stage-specific antigens 1, 2
sporozoite STARP intron 3 (LSA-1, 2, 3) sporozoite
5 2 exons exon 1 CSP
5 24 codons proteasome complex
exon 2 hepatocyte
2 45 (processing)
2
10 25-28 hepatocyte major histocompatibility
complex (MHC) class I
CD8+
cytotoxic T lymphocyte
repeats 5 86 CSP
IgG hepatocyte MHC class I CD8+
PfSTARP P.falciparum cytotoxic T lymphocyte
42.6 interleukin-1, interleukin-6 nitric oxide
6 94 hepatocyte 43
STARP sporozoite

 41 521

103
2. MSP1 P.falciparum
schizont precursor protein
(asexual erythrocytic stage vaccine candidates)

2
(primary processing) 83
30 38 42
2.1 merozoite surface protein 1 (MSP1) (secondary processing)
merozoite 42 2
33
merozoite 19
185 200 kDa97 97,104 merozoite
(antigenic (ring stage)
polymorphism) 98 19 PfMsp-119
MSP1 P. falciparum epidermal growth factor (EGF)-like domain
(PfMSP1) 2 2
(allelic dimorphism) PfMSP119

P.falciparum105-107
(variable block) merozoite
(semi-conserved block)
(conserved block) 104,108 PfMSP1
variable block semi-conserved block Aotus
2 17
(block)99 block 2 tripeptide repeats
3 P.falciparum
100 (partial protection)
MSP1
(allele) (intragenic recombination) 109-111

101 PfMSP1
P.falciparum block 2 C-terminus
102
recombination 105,112
522

MSP1 P.vivax (PvMSP1) merozoite

glycosylphosphatidylinositol (GPI) anchor122-124
PfMSP1 P.falciparum
PvMSP1 35 56
113,114 P.vivax
PvMSP1
MSP2
115-117 N-terminus C-terminus
C-terminus PvMSP1 42
(PvMSP142) 19 (PvMSP119) 2
repeats non-repeats
118 PvMsp-1
merozoite MSP2
2 FC27 3D7
PvMSP1 red cell reticulocyte FC27 repeats
binding motifs 119,120 2
PvMSP1 32 repeats 3
PfMSP1 12 repeats 1 5
3D7
PvMSP1 PfMSP1 repeats
alanine, glycine serine122-124
(allele) 2
PvMSP1 FC27 3D7
(mosaic organization) 125,126 MSP2
PvMSP1 merozoite 127
PvMSP1 merozoite
13 block121 conserved block 7 cross-link merozoite128
variable block 6 conserved MSP2
block codon
merozoite 129
5 Irian Jaya
2 P.falciparum
(dimorphic substitution) repeats Msp-2
PvMSP1 N-terminus C-terminus
intragenic recombination
2.2 merozoite surface protein 2 (MSP2) 130-132
 41 523

2.3 merozoite surface protein 3 (MSP3) MSP4/5

MSP3 P.falciparum (PfMSP3) MSP4/5 P.yoelii
43 re-
peats 7
alanine 1 5 repeats 142,145 MSP4 MSP5
Msp-3
coiled-coil alpha-helices133,134 MSP3 2.5 apical membrane antigen 1 (AMA1)
P.vivax (PvMSP3) microneme
3 PvMSP3-, PvMSP3- apical organelle 83
PvMSP3-135 merozoite
75 105 trophozoite
(coil motif) schizont

PfMSP3 66 merozoite
antibody-dependent cellular inhibition merozoite
(ADCI)136 AMA-1 merozoite
merozoite
cytophilic IgG1 IgG3 146,147 AMA-1
monocyte MSP3 merozoite 148
Fc receptor cytokines AMA-1
136,137 AMA-1
2.4 merozoite surface protein 4 (MSP4) P.falciparum 1) N-terminus
merozoite surface protein 5 (MSP5) 2 (extracellular domain) 546 2)
P.falciparum (PfMSP4 PfMSP5) (transmembrane domain)
40 21 3) C-terminus
merozoite C-terminus (cytoplasmic domain)
epidermal growth factor (EGF)-like 55 AMA-1
domain138 MSP1 PfMSP4 cysteine 16
PfMSP5 139-141
disulfide AMA-1
PfMSP4 3 loop 149

142 AMA-1 P.falciparum
MSP4 MSP5 PvMSP4
PfMSP4 PvMSP5
PfMSP5143,144 MSP4 MSP5 T helper epitopes
524

antibody-dependent cellular inhibition

MSP3160
T cell epitopes C-terminus CSP cytophilic antibody 138
P.falciparum66,150 AMA-1 P.vivax

erythrocyte-binding protein
intreagenic recombination AMA-1 (EBA-175), serine repeat antigen (SERA), ring-infected
P.knowlesi erythrocyte surface antigen (Pf155/RESA) rhoptry
rhesus proteins 161,162
151,152 AMA-1 3.
Plasmodium fragile recombinant (sexual stage vaccine
squirrel candidates)
153
AMA-1 P.chabaudi gametocyte
T cell

154,155 AMA-1

2.6 Glutamate-rich protein (GLURP)
parasitophorous vacuole 163,164 3
merozoite P.falciparum 1)
220 (pre-fertilization) gametocyte
156 GLURP gamete exflagellation
gametocyte
157 Pfs230 Pfs48/45 P.falciparum 2)
GLURP 5 9 zygote ookinete
(post-fertilization) Pfs25
Pfs28 P.falciparum 3)
GLURP 158 late-midgut-stage
chitinase ookinete
GLURP 159
repeats repeats proteinase chitinase
GLURP
merozoite
monocyte
P.falciparum
 41 525

3.1 Pfs230
48 gametocyte epitope Pfs48/45
363 172,173
310 3.3 Pfs25
gamete165,166 Pfs230 gametocyte P.falciparum
repeats glutamine exflagellation
zygote ookinete
N-terminus oocyst 174
gamete Pfs25 EGF-like
310 domain 4 domain 2
Pfs230 cysteine
motif cysteine 7 175 EGF-like domain
6 disulfide cysteine
167 Pfs230 B cell epitope conformational
gametocyte complement epitope epitope
antibody-dependent complement-mediated lysis epitope

168,169 discontinuous epitope176
repeats Pfs25
Pfs230 zygote 177
Pfs25
repeats
167
3.2 Pfs48/45 48 45 178,179
gametocyte, gamete zygote 3.4 Pfs28 P.falciparum
P.falciparum Pfs48/45 zygote
4-cysteine Pfs25180 secretory signal
motif 6-cysteine motif Pfs48/45 N-terminus GPI anchor C-terminus
Pfs230 EGF-like domain
Pfs48/45 4 180 Pfs28
complement170 Pfs25
epitope 180
epitope 171
ookinete oocyst
ookinete Pfs48/45

526

P.falciparum
P.vivax


merozoite
surface protein-1, merozoite surface protein-2, apical
1. (anti- membrane antigen-1 merozoite surface protein-5
genic diversity) 100,121,140,144,182-184
repeats


1.1
(allele) (intragenic interallelic
recombination) unequal
crossing-over slipped-strand mispairing
185

P.falciparum circumsporozoite
protein block 2 merozoite surface
protein-1 merozoite surface
protein-2 sporozoite threonine-asparagine rich
protein66,100,183,184,186 P.vivax merozoite
surface protein-1 repeats merozoite
surface protein 4 5 121,143,144,187
repeats
epitope
repeats
Hardy-Weinberg equilibrium repeats
genetic cross 1.2 (antigenic
variation)
181 subtelomere
P.falciparum
var
erythrocyte membrane protein 1 (PfEMP1)
epitopes rif Rifin (repetitive interspersed family)
 41 527

stevor (subtelomeric variable open reading

frame) Pfmc-2Tm Pfmc-2Tm
(Maurers cleft two transmembrane) Duffy-binding-like 1 domain DBL-1190
(switch)
PfEMP1
10-2
1

var 60 rif 149 stevor
28 Pfmc-2Tm 11 186,187
messenger RNA
(mRNA) mRNA

var
early growing trophozoite
rif mature trophozoite stevor
Pfmc-2Tm
Maurers cleft
(knob-like
structure) 188,189 191
PfEMP1

cytoadherence PfEMP1
knob




(visceral blood)
sequestration
receptor
CD36, ICAM-1 (intercellular adhesion molecule-1),
TSP (thrombospondin), CR1 (complement receptor-1),
VCAM1 (vascular adhesion molecule-1) CSA clinical immunity
(chondroitin sulfateA)189 PfEMP1
rosettes
528

gametocyte apex erythrocyte

192-194 binding ligands (EBLs) reticulocyte binding protein
homologs (RBLs PfRh) tight junction
var apical organelles 197
var2csa chondroitin EBLs 3
sulfateA EBA175, EBA140/BAEBL EBA181/JE SEBL
syncytiotrophoblasts EBLs glycoproteins
var2csa sialic
glycophorin A C sialic acid band
4.1 RBLs 4
PfRh1, PfRh2a, PfRh2b PfRh4
var2csa merozoite P.falciparum

195 sialic (sialic-acid-dependent
gametocyte pathway) EBAs PfRh1

var, rif stevor

sialic
(sialic-acid-independent pathway)
PfEMP1 merozoite PfRh2a
PfRh4
PfEMP1

gametocyte
196 1-2
2. 198-200
3. epitopes (cryptic epitopes)
merozoite epitope
apical organelles epitope
epitope

merozoite surface protein-1
merozoite epitope
apical membrane antigen 1 sporozoite P. yoelii
(re-orientation) merozoite
 41 529

T cell epitopes
CD8+ T lymphocyte T cell interleukin-10
CSP (IL-10) anti-inflammatory
sporozoite
204,205
5. dendritic cells
epitope MSP1, CSP AMA1 P.falciparum
T lymphocyte epitopes malarial pigment hemozoin
B lymphocyte maturation dendritic cell
epitopes T cell
dendritic cell
disulfide
epitopes MSP2, CSP, AMA1 dendritic cell
TRAP 155,201-203 maturation dendritic cell
4. T cell mimotopes altered peptide
ligands (APLs) T cell apoptosis
T cell (T cell receptor, TCR) dendritic cell merozoite
MHC-peptide complexes antigen maturation dendritic cell
presenting cells (APCs) 206-208
T cell 6. regulatory CD4+CD25+
(affinity) TCR Foxp3+ T cell (Treg) Treg
MHC-peptide complexes TCR cross- self-tolerance
linking cytokine 209 Treg
T cell thymus
TCR agonist T cells Treg thymus
TCR partial agonist transform-
TCR antagonist ing growth factor beta (TGF-) Treg
1 2 Th1, Th2 Th17 cells
T cell P.falciparum Treg TGF-
CD4+ T cell Th1 210 P.vivax
pro- inflammatory Th2 anti-inflammatory Treg
IL-10 211
Treg
P.falciparum MSP1
T cell
CSP
530

cinology)
1. (traditional vac- ge-
cinology) nome
Edward Jenner
(vaccinia virus) 214
(smallpox) ..1796 2.1 genome
Louis Pasteur




CD4+ T cell epitopes
CD8+ T cell epitopes HLA haplotype
2.2
recombinant peptide
212
(recombinant tetrameric staining repeats
protein) (adjuvant) T cells
ELISPOT intracellular cytokine staining (ICCS)
213
(cell-mediated immune
response)
B cell epitope

2.3



2.4



(molecular
(autoimmunity) epidemiology)
T cell epitope
2. (reverse vac- 2.5
 41 531

1
216 CSP
P.falciparum 3 dN/dS
1
phase I, II III CD4+ T cell epitopes (Th2R Th3R epitopes)
2.6 CD8+ T cell epitopes217

P.falciparum STARP, PfMSP4,
2.7 PfMSP5, PfAMA1 PfTRAP 87,140,182,186
P.vivax PvMSP4, PvMSP5 PvTRAP
2.8 89,143,144
epitopes
phase IV epitopes HLA haplotupe
PfMSP5 PvMSP5
(molecular evolution) 2. McDonald-Kreitman (MK) test
(population genetics)
(synonymous
polymorphism)
(nonsynonymous
polymorphism) species
(positive selection) (fixed difference)
species MK test
(neutrality index)

218
215
epitope
MK test
PvMSP5
(neutral evolution) Hudson-Kreitman-
Aguade test 219
3. Tajima Test
1.

(dN)
(dS) dN/dS
532

1 segregating
site Tajimas D D
reverse vaccinology
D

directional selection T cell
epitopes

Tajimas D

balancing selection220
Tajimas D reverse
PfMSP3 PfAMA1 vaccinology
extracellular domain 221,222
balancing selection genome
Fu and Lis tests adenine thymine
Tajima test codon
223 (codon usage) (
4. Wrights Fst F statistics )
fixation index
(cell-free expression)
2
214,226
Fst Fst
(Adjuvants)
balancing selection224 Fst
PfMSP1 adjuvant
balancing selection adjuvant
(potency)

PfMSP1

Wrights Fst
225
adjuvant
adjuvant
 41 533

adjuvant TLR
colloid emulsion (autoimmune responses)
adjuvant adjuvant Montanide ISA-720
water-in-oil emulsion sterile abscess
adjuvant 228,229
adjuvant adjuvant saponin
2 227 (QS21)
1. adjuvant
(immunostimulant) ligand oil-in-water liposome adjuvant
Toll-like receptor (TLR), saponin, cytokine AS01 AS02
exotoxin
adjuvant

2. adjuvant RTS,S
(vehicle) Alum monophosphosyl
adjuvant lipid A (AS04) Alum oil-in-water emulsion
adjuvant (AS03) adjuvant
adjuvant mineral salts, emulsion, RTS,S
virosomes, liposomes microspheres
polymer adjuvant monophosphosyl
adjuvant lipid A QS21 oil-in-water emulsion
227
adjuvant

(attenuated) 1. Alum Aluminum
(inactivated) adjuvant
adjuvant

unmethylated deoxy- adjuvant
cytidyl-deoxyguanosine (CpGs)

TLR9 Alum
species TLR9 Alum Th1 cell
species CTL
adjuvant 230
534

2. MF59 squalene-in-water glycosides adjuvant

emulsion 250 241 ISCOM
adjuvant Alum phospholipids, choleslerol Quil-A
IgG subclass (cage-like
helper T cell particle) 40
Th1 lymphocyte 242 QS-21 Quil-A
adjuvant
231 Th1
3. MPL adjuvant Th1 CTL adjuvant
cell MPL
lipopolysaccharide Salmonella minnesota 243
hydrophilic polysaccharide 3. MPL
hydrophobic lipid core232,233 MPL-SE Squalene oil, 3-deacylated
TLR4 adjuvant monophosphoryl lipid A carrier
oil-in-water emulsion
AS04 aluminum (leishmaniasis)244 AS02
oil-in-water emulsion MPL
adjuvant QS-21
adjuvant liposome Th1 lymphocyte
saponin 234-236 AS01 MPL QS21 lipo-
some236,245
4. (oligonucleotides)
1. Montanides (ISA51 ISA720) unmethylated CpG TLR9
water-in-oil emulsion squalene dendritic cell
mannide-monolate pro-inflammatory cytokines tumor necrosis factor
incomplete Freunds adjuvant237,238 alpha (TNF-), interferon gamma (IFN-) IL-12
Montanides CpGs Th1 CTL
ISA720 adjuvant

246,247
239,240 5. Imidazoquinolines
2. Saponins Quil-A, antigen presenting cells (APCs)
immunostimulating complexes (ISCOM), QS-21, inflammatory cytokines chemokines
AS02 AS01 adjuvant triterpene adjuvant imiquimod
glycosides saponin TLR7 resquimod TLR7/8
Quil-A imiquimod antigen
 41 535

presenting cell 235,240

.. 1941 248



(rhesus macaque) P.knowlesi
P.falciparum Aotus
Saimiri
P.chabaudi,
P.falciparum P.vinckei, P.yoelii P.berghei



transmission-blocking vaccines

adjuvant

1.
(whole parasite vaccines) .. 1976 Trager Jensen
P.falciparum

249



(whole
killed vaccines)


(live attenuated vaccines)


(infection-cure model)

536

sporozoite
(homologous parasite) 3
chloroquine
(heterologous parasite) chloroquine
1





cytokine
CD3+ CD45R0+ memory T
250-252 cells CD4+ CD8+ T
P.falciparum lymphocytes
30 254
5 sporozoite
chloroquine
3

94 sporozoite
PCR
1
sporozoite
cytotoxic CD8+ T cell
T cell
CD4+ CD8+ T cells 1
IFN- IL-4
IL-10 sporozoite
nitric oxide synthase mononuclear cells

sporozoite

cell-mediated immune response sporozoite

UIS3, UISE4 P3bp
253 sporozoite
 41 537

SanariaTM PfSPZ vaccine255
2. HLA class I class II
(recombinant protein vaccines) regulatory T cell
epitope
cryptic
epitope 3

epitope
cryptic epitope

altered peptide ligand
antagonism T cell mimotope


CD4+ T cell pro-inflamanatory
(Th1) anti-inflamanatory (Th2)
genome 256
P.falciparum adenine
thymine 80 codon
expression
vector 2.1 RTS,S
codon
Water Reed Army Institute of Research (WRAIR)
glycosylation sites GlaxoSmithKline (GSK)
.. 1984
MSP1 circumsporozoite
C-terminus 42 (PfMSP142), PfAMA-1 protein CS
PfEBA175 glycosylation sites


glycosylation sites Escherichia coli
CS
257
256
538

adjuvant
Phase IIb RTS,S/AS04 1 8
.. 1994 1996
258,259 CS RTS,S/AS03 2 7
RTS,S/AS02A
GSK ( 1)
6 7
HBsAg (S antigen) RTS,S/AS02A phase I/IIa
Saccharomyces cerevisae 40
HBsAg S protein 263-265
virus-like particle 260 phase IIb
GSK 3 0, 1 5

tetrapeptide repeats (NANP) CS 16 15 34
HBsAg R16-HBsAg

261 19 47

tetrapeptide repeats B cell epitopes 9
C-terminus CS T cell
epitopes 3 epitopes P.falciparum
RTS,S R NANP repeats CS HBsAg 5 266,267
T T cell epitopes CS RTS,S/
HBsAg S protein S AS02A
S protein CS
RTS,S/AS0D
RTS,S 1 4
Phase I/IIa 2,022 0, 1 2
6
.. 1995
2 8 RTS,S Alum 29
MPL 58
6 18
RTS,S Alum 35 49
262 adjuvant 45
26 38
 41 539

1 RTS,S
Formulation RTS,S MPL QS21 Final volume Adjuvant system
(g) (g) (g) (ml)
RTS,S/AS02A 50 50 50 0.5 oil-in-water emulsion
RTS,S/AS02D 25 25 25 0.5 oil-in-water emulsion
RTS,S/AS01B 50 50 50 0.5 liposome-based
RTS,S/AS01E 25 25 25 0.5 liposome-based
( 257)

50 RTS,S/AS02A
34268,269 32272
RTS,S/AS0D
18 4
Haemophilus influenzae type b (Hib) RTS,S/AS01E
8, 12 16

expanded program on immunization RTS,S/AS01 RTS,S/AS01E
(EPI) 5 17
66 3 8

270 53
RTS,S/AS02 EPI
adjuvant oil-in-water emulsion phase
RTS,S/AS01 III .. 2009
adjuvant liposome adjuvant 2 double-blind
MPL QS21 2
RTS,S/AS01B 16,000 7
T cell CS .. 2011 257
Th1 RTS,S/AS02A RTS,S/AS01E
271 50
phase IIa 1
RTS,S/AS01B
CD4+ T cell (insecticide
CS RTS,S/AS02A treated bed nets)
RTS,S/AS01B (intermittent preventive treatment)
540

2.2

273-275
clinical immunity 2.2.2 apical membrane
antigen1 E.coli Pichia pastoris
AMA1 P.falciparum 3D7
ectodomain N-terminus
2 3 AS02A AS01
HLA adjuvant phase I/IIa

P.falciparum
phase
II 1 6

2.2.1 merozoite
surface protein 1 MSP1
C-terminus
epidermal growth factor-like domain 3D7 FVO
disulfide 2 loops MSP119 2 3
19 AMA1
P.falciparum 3D7 FVO adjuvant AS02A
T cell epitopes tetanus toxoid Alhydrogel AMA1
phase I clinical immunity

C-terminus
MSP142 MSP119 MSP133 2 276-279
AS02 2.2.3 merozoite
adjuvant phase I surface protein 2 MSP2
E.coli
P.falciparum 3D7
1 3
phase IIb CS N-terminus
MSP1 RESA Montanide
MSP1 ISA720 adjuvant
 41 541

GLURP
280,281 MSP3
6 9 merozoite
phase I/IIb ADCI 286


P.falciparum 3
MSP2 3D7 1)
283

MSP2 MSP2 merozoite
FC27 MSP1 AMA1
MSP2 2 monocyte cytokines
2.2.4 ADCI 2)

P.falciparum

1) PfCP2.9
AMA-1 domain
3 MSP1 C-terminus 19 adjuvant
MSP119 P.pastoris 3
Montanide ISA720 adjuvant 2) GMZ2
GLURP repeats 3)
3
C-terminus MSP3
Lactococus lactis MSP1 AMA1
Alum adjuvant disulfide
CP2.9 3 disulfide
AMA1 MSP119
epitope
phase I 2 (discontinuous epitope)

2 epitope
284,285 PfMSP119 merozoite
GMZ2 ADCI (inhibiting antibodies)
phase I
542

merozoite tetrapeptide repeats CS

merozoite epitopes
(blocking antibodies) sporozoite
conformation-
dependent B cell epitopes epitopes sporozoite
domain repeats sporozoite
allotype
steric hindrance inhibiting sporozoite
antibodies sporozoite

(inhibitory) (blocking)
(neutral) CS sporo-
PfMSP119 P.falciparum zoite
sporozoite
EGF-like domain CD4+ T cells
257 cytokines B cell differentiation
3. (synthetic CD8+ memory T cells
peptide vaccines) cytokines IFN-
exo-erythrocytic stage

inducible nitric oxide
synthase (iNOS) nitric oxide
287,288
T cell epitopes B cell epitopes


epitopes sporozoite


epitope
3.1.1
(protein (branched peptide vaccines)
carrier)
P.falciparum repeats CS P.falciparum
3 tetanous toxoid
3.1 circumsporozoite peptide vaccines adjuvant (NANP)3-TT conjugate vaccine
 41 543

sporozoite precipitin
sporozoite sporozoite 291
3.1.1.2 (T1BT*)4-P3C
( anamnestic response) T1B universal T cell epitope
CST.3 epitope C-terminus CS
multiple antigen peptide (MAP) 20 292
non-cationic polylysine core matrix 48 lysine
oxime
(branched peptide)289 4
lipopeptide palmitoyl-S-glyceryl cysteine (P3C)
3.1.1.1 (TIB)4MAP NANP Toll-like receptor 2 (TLR2) agonist
3 B cell epitope TLR-2
T cell epitope NANPNVDP 2
B cell epitopes tetrapeptide
repeats CS T helper P3C adjuvant
epitope (T1BT*) 4 P3C
Th1 adjuvant
anamnestic response tetrapeptide repeats sporozoite
290 phase I
(T1B)4MAP Alum QS21 Phase I
sporozoite
sporozoite
HLA DQB1*0603, CD4+ T cell
DRB1*0401 DRB1*1101 IgG1 IgG3
25 35 IFN-
HLA CD4+ memory T cell T cell
291 epitope
CD4+
T cell Th1 CD4+ T cell
IgG1 IgG3 adjuvant QS21 sporozoite 291,293
3.1.2
Alum (linear peptide vaccines)
3.1.2.1 48 mers linear T1BT* peptide

sporozoite
NANP cross-link 48
544

T1BT* Montanide ISA720 adjuvant

phase I 2
repeats CS sporozoite 3.2.1
glutamate-rich protein (GLURP LSP vaccine)
Th2 IgG1 N-terminus
opsonization GLURP P.falciparum
sporozoite B cell epitopes
IgG1 IgG3
291 antibody dependent cellular
3.1.2.2 inhibition ADCI GLURP
C-terminus CS (long merozoite
synthetic peptides, CS LSP vaccine) monocyte
sporozoite
clinical immunity
GLURP LSP Alum
CD8+ T cells cytokines Montanide ISA720 adjuvant
IFN- CS LSP
100 T cell B cell
T cell epitopes C-terminus IFN- mononuclear cells
CS IgG1
CD8+ cytotoxic T lymphocytes
CS ADCI
IFN- 294-296
sporozoite 3.2.2
merozoite surface protein-3 (MSP3 LSP vaccine)
sporozoite
CS LSP phase I clinical immunity C-terminus
CD8+ T cell CS PfMSP-3 70
P.falciparum B cell epitopes IgG1 IgG3
T cell epitopes Th1
291
3.2 erythrocytic stage peptide vaccines MSP3 LSP Alum Montanide ISA720
adjuvant Alum adjuvant

MSP3
T cell IFN-
 41 545

Montanide ISA720 adjuvant

MSP3 CS
ADCI sporozoite 44
GLURP LSU 1
297-299 3 0, 2 6
3.3 multistage malaria peptide vaccines
AMA-1
2

2 306,307

2
3.3.1 SPf66 vaccine
tetrapeptide repeats (NANP) adjuvant
CS MSP1
2 35 55


phase I III
30

SPf66
300-302
3.3.2 malaria peptide virosomes
virosomes unilamellar (active case detection )
liposomal vesicles 150 (passive case detection )
hemagglutinin (HA) glycoproteins influenza
virosome
antigen presenting cells
virosomes
protein carrier adjuvant303-305

CS semi-conserved domain III apical
membrane antigen 1 AMA1
49 phosphatidylethanolamine 5
virosomes
546

1. Coluzzi M. The clay feet of the malaria giant
and its African roots: hypotheses and inferences about
origin, spread and control of Plasmodium falciparum.
PvAMA1, PvMSP1, Parassitologia. 1999;41:277-83.
PvMSP4, PvMSP5, PfCSP PfMSP2 2. Hoeppli R. Parasites and parasitic
infections in early medicine and science. Singapore:
University of Malaya;1959.
P.falciparum P.vivax 184 3. Russell PF. Mans mastery of malaria.
London: Oxford University Press; 1955.
4. Sallares R, Bouwman A, Anderlung C. The
5 spread of malaria to southern Europe in antiquity: new
approaches to old problems. Med Hist. 2004;48:311-28.
5. Garnham PCC. Malaria parasites and
other Haemosporidia. Oxford: Blackwell Scientific
Publications; 1966.
(bottleneck effect)184 6. Jones WHS. Malaria and Greek history.
5 Manchester: Manchester University Press; 1909.
7. Hackett LW. Malaria in Europe. London:
Oxford University Press; 1937.
8. Cox FEG. Illustrated history of tropical

diseases. London: The Wellcome Trust; 1996.

9. WHO [Internet]. Global malaria report 2010.

Available from: http://www.who.int/malaria/world.

malaria.report.2010/en/index.html.
intragenic recombination
10. Cui L, Yan G, Sattabongkot J, Cao Y,

Chen B, Chen X, et al. Malaria in the Greater Mekong

Subregion: Heterogeneity and complexity. Acta Trop.

2011. (in press)
11. Zhou G, Sirichaisinthop J, Sattabongkot
J, Jones J, Bjrnstad ON, Yan G, et al. Spatio-temporal
distribution of Plasmodium falciparum and P. vivax
malaria in Thailand. Am J Trop Med Hyg. 2005;72:256-
184 62.
12. Jongwutiwes S, Putaporntip C, Iwasaki

T, Sata T, Kanbara H. Naturally acquired Plasmodium
knowlesi malaria in human, Thailand. Emerg Infect Dis.
2004;10:2211-3.
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 567

42

2. (Immune
modulating vaccines)
(autoimmune
(non com- diseases) 1
municable disease) ( allergic diseases) 1
allergen specific immune therapy
desensitization
10

mucosal intolerance IgG blocking
1 antibody (allergen)
IgE cross link mast cell
1. (Antibody allergic inflammatory cascade 2
inducing vaccines) adjuvant
monophosphoryl lipid A Th2
(target molecule) antiinflammatory response
IgG blocking antibody
(neutralize) anaphylaxis3

3.

T effector cell
(autoimmune T cell mediated inflammation)
immune complex soluble
target overinhibit target enzyme

568

1 1
target antigen
(antibody inducing vaccines)
-amyloid
(Alzheimers disease)
(stroke) N-methyl D-aspartate receptor
(Parkinson disease) -synuclein
(atherosclerosis) Cholesteryl ester transfer
protein (CTEP)
Apo B100
Angiotensin I, II
Interleukin-5
rheumatoid TNF-
(Immune modulating vaccines)
(type I diabetes) Insulin, GAD
Multiple sclerosis Myelin basic protein
Myasthenia gravis Acetyl choline receptor
Environmental allergens

neurodegenerative disease
(personalized vaccine) 26
(loss of recent memory)


amyloid-A plaques (
beta-amyloid amyloid precursor
(adjuvant) protein )
grey matter intracellular
neurofibrillary tangles (NFTs)
hyperphosphorated tau protein
10
(clinical trial phase)
clinical trial 11
9,000 4

(Alzheimers disease vaccine) A beta 42/QS21 (AN-1792)
A 1-42 peptide amyloid precursor
progressive protein saponin adjuvant QS-21
 42 569

1 (Phase I clinical trial) HDL-cholesterol

80
6
5
2 (Phase IIa) LDL-cholesterol T cell receptor
300 LDL
.. 2545 10
A beta 42 HDL-cholesterol
6 aseptic cholesteryl ester transferring
meningoencephalitis leukoencephalopathy6,7 protein (CETP) cholesterol
B cell HDL LDL CETi-1
T cell 11-15 1 2
B cell epitope anti-A CETP
90 HDL
15-42 T cell epitope Th1-medi- 11
ated cellular immune response (T cell induced autoan- adjuvant CPG
tibody) IL-2 IFN 7909 pre-clinical phase12
meningoencephalitis
Th2 lymphocyte

response
2
CAD-106 A1-6
Qb virus like particle8
aminoterminus A (AD01, AD02)9 (Preventive cancer vaccine)




(Atherosclerosis vaccine)

(atherosclerosis) 13 (hu-
man papilloma virus) 14

(chronic H.pylori
inflammatory response) 15,16
LDL-cholesterol
570

(Therapeutic cancer vaccine) Sipuleucel-T

.. 2553
2. (Non
Hodgkins lymphoma, follicular type)
Biovax ID anti-idiotype
immune response
tumor specific immunoglobulin
B-cell idiotype (Id)
idiotype
(autologous
tumor cells) hybridoma

keyhole limpet hemocyanin (KLH)
Id-KLH (subcutaneous
long term administration) GM-CSF
memory cell (remission stage)
innate adaptive tumor specific humoral immunity
immunity cellular immunity
Phase II clinical trial
1. 22 62
Id-specific immune response
(Castration-resistant prostate cancer) Sipuleucel-
T immunotherapy17 (progession-free survival) 38 12
Biovax ID 318

leukapheresis 200
recombinant fusion protein PA 2024
prostate antigen, prostate acid phosphatase
granulocyte colony stimulating factor (G-CSF)
2 3
30
512 biotechnology
(3-year survival) 23
32 Sipuleucel-T

2009;5:P113-4.
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immunotherapy with a monophosphoryl lipid
A-adjuvanted vaccine: reduced seasonally boosted
immunoglobulin E production and inhibition of
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antibodies. Clin Exp Allergy. 2003;33:1198-208.
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meningoencephalitis in a subset of patients with AD
after Abeta42 immunization. Neurology. 2003;
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7. Gilman S, Koller M, Black RS, Jenkins
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immunization (AN1792) in patients with AD in an
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8. Bengt G. Results of the first-in-man
study with the active A immunotherapy CAD106 in
42 571
Alzheimer patients [abstract]. Alzheimers Dementia.
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Mattner F Schmidt W. Development of Alzheimer
AFFITOPE vaccines-from concept to clinical testing
[abstract]. Alzheimers Dementia. 2009;5:P257.
10. Hermansson A, Ketelhuth DF, Strodthoff D,
Wurm M, Hansson EM, Nicoletti A, et al. Inhibition of T
cell response to native low-density lipoprotein reduces
atherosclerosis. J Exp Med. 2010;207:1081-93.
11. Davidson MH, Maki K, Umporowicz D,
Wheeler A, Rittershaus C, Ryan U. The safety and
immunogenicity of a CETP vaccine in healthy adults.
Atherosclerosis. 2003;169:113-20.
12. Timmerman JM, Vose JM, Czerwinski DK,
Weng WK, Ingolia D, Mayo M, et al. Tumor-specific
recombinant idiotype immunisation after chemotherapy
as initial treatment for follicular non-Hodgkin
lymphoma. Leuk Lymphoma. 2009;50:37-46.
13. Mast EE, Margolis HS, Fiore AE, Brink
EW, Goldstein ST, Wang SA, et al. A comprehensive
immunization strategy to eliminate transmission
of hepatitis B virus infection in the United States:
recommendations of the Advisory Committee on
Immunization Practices (ACIP) part 1: immunization of
infants, children, and adolescents. MMWR Recomm
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14. Borleffs JC, Danner SA, Lange JM,
van Everdingen JJ; Commissie Richtlijnen van de
Nederlandse Vereniging van Aids Behandelaren. [CBO
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15. Czinn SJ, Blanchard T. Vaccinating against
Helicobacter pylori infection. Nat Rev Gastroenterol
Hepatol. 2011;8:133-40.
572

16. Del Giudice G, Malfertheiner P, Rappuoli R.

Development of vaccines against Helicobacter pylori.
Expert Rev Vaccines. 2009;8:1037-49.
17. Kantoff PW, Higano CS, Shore ND, Berger
ER, Small EJ, Penson DF, et al. Sipuleucel-T immu-
notherapy for castration-resistant prostate cancer. N
Engl J Med. 2010;363:411-22.
18. Lee ST, Jiang YF, Park KU, Woo AF,
Neelapu SS. BiovaxID: a personalized therapeutic cancer
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Ther. 2007;7:113-22.
 573

43

HSV-2

2
Herpes simplex virus (HSV) HSV-2
75 HSV-1
herpetic gingivostomatitis genital herpes 252 HSV 1
con-
genital herpes infection, neonatal herpes infection, :
herpes keratitis herpes simplex virus encephalitis HSV 2
HSV
(latent infection) 1
(asymptomatic 5,000 20,000
viral shedding) HSV
(reactivation)1 6 3

( Herpes simplex virus)

HSV

Herpes simplex virus family Herpesviridae persistent
double-stranded DNA enveloped virus latent infection
subfamily Alpha-
herpesvirinae herpes simplex virus type 1
2 varicella zoster virus subfamily
subfamily Beta-herpesvirinae (primary
( cytomegalovirus, human herpes virus 6 infection) 33-50
7) Gamma-herpesvirinae ( Epstein-Barr (secondary infection)
virus human herpes virus 8) 5
HSV-1
574

25 perineum
2 2 Herpetic whitlow HSV
1-2

3-5 4 Herpes encephalitis primary
recurrent infection


1. (Neonatal herpes simplex (focal neurologic)
infection) 3 pleocytosis
(disseminated infection) lymphocytes erythrocytes
trigeminal neuralgia,
Bells palsy, ascending myelitis postinfectious
(central nervous system infections) encephalomyelitis

(skin eyes and mouth, SEM)


3

polymerase chain reaction (PCR)
HSV DNA gold standard

enzyme immunoassay (EIA)
cytopathogenic effect (CPE)
2-4 1-3
5
2. (Children beyond
neonatal period and adolescents) 48
colonization (contamination)
HSV-1 gingivostomatitis Tzank smear
multinucleated giant cells
submandibular
HSV-2 genital herpes
 43 575

HSV
HSV acyclovir, 9-13
valacyclovir, famciclovir valacyclovir L-valyl ester HSV neuron
acyclovir
acyclovir famciclovir penciclovir
(epithelium)
1. HSV neonatal axonal uptake
HSV infection, HSV encephalitis acyclovir HSV (replicate)
nucleoside
inhibitor herpes DNA polymerase 24
60 ././ 3 14 HSV
SEM 21 HSV-1 HSV-2
6 HSV-1
2. HSV HSV
acyclovir
topical acyclovir T-lymphocyte
HSV T-cell (cellular response) B-cell
acyclovir (antibody response)
acyclovir
foscarnet 7
3. HSV HSV
HSV neuron reactivate
neuron reactivate latent
(recurrent infections) infection

acyclovir 6
viral shedding 3-5
acyclovir 2
1 8
(mode of delivery)

lipopeptide needle-free mucosal

HSV vaccine
CD8 CD4 14,15

576

HSV16 DNA vaccines

1. (prophylactic vaccine) recombinant HSV glyco-
(primary infection) protein adjuvant deacylated mono-
genital phosporyl lipid A
tract genital herpes genital herpes11

(symptomatic HSV
infection)
HSV
2. (therapeutic
vaccine)17 Live-attenuated/replication impaired
- R7020 Pasteur Merieux
recurrent genital herpes - ICP10DPK AuRx Inc.
Killed/viral component
viral shedding - HSV-2 GS Merck,
HSV 2 Sharpe & Dohme
live-attenuated viral vaccine, killed vaccine - Biocine Chiron
subunit vaccine purified viral protein (gD2/gB2/MF59)
adjuvant - Herpvac GlaxoSmithKline11
(gD2/MPL-alum)
heterologous viral vector expressing HSV
protein, replication-impaired HSV vaccine HSV ( 2)
DNA vaccine 1. Inactivated or component vaccine
killed viral vaccine,
Inactivated whole virus subunit vaccine purified viral protein
Subunit vaccine (detergent solubilized) derivates recombinant proteins
Live-attenuated vaccine (passaged) live-attenuated vaccine virulent
strain
Recombinant HSV proteins glycoprotein
Synthetic peptides adjuvant
Lived-attenuated vaccines (specific (booster reactivity)
mutations) 18
Replication-impaired vaccines 2. Live-attenuated HSV vaccine
Heterologous viral vectors expressing
HSV antigens inactivated
 43 577

vaccine reactivity interference

recombination specific viral vector
circulating wild-type HSV strain 13
19 6. HSV DNA vaccine
3. Recombinant viral protein vaccine plasmid HSV gene
HSV glycoprotein humoral-mediated cellular-
gB gD recombinant DNA mediated
Escherichia coli 22
Biocin (Chiron) HSV cytokine/chemokine gene
glycoprotein gB gD MF59 adjuvant CCR7 ligands
neutralizing antibody HSV-2
genital herpes 20 gD2 DNA vaccine (GENEVAX, Apollon, USA)23-25
Herpvac (GlaxoSmithKline)
HSV glycoprotein gD alum 2-O-deacylated-
monophosphoryl lipid A (MPL) adjuvant


HSV-2
humoral-mediated cellular-mediated
genital herpes
HSV-1 HSV-2
HSV-1
11 (lifelong immunity)
4. Peptide vaccine
HSV-specific T B cell antigenic protein recombinant
immunodominant epitopes LEAPS vaccine protein vaccine polytopes (genes representing
(ligand epitope antigen presentation system) antigenic epitopes) DNA vaccine
peptide adjuvant vector
21
5. Heterologous viral vectors expressing
HSV antigens
genetic engineering
HSV antigen foreign live recombinant (cross protection) HSV-1 HSV-2
viral vector vaccinia virus, adenovirus, varicella
zoster virus (Oka vaccine strain) CD8 T-lymphocyte natural killer
cell mucosal innate immunity
578

Curr Med Res Opin. 2005;21:1577-82.

4. Cunningham AL, Diefenbach RJ, Miranda-
Saksena M. The cycle of human herpes simplex virus
infection: virus transport and immune control. J Infect
Dis. 2006;194(Suppl 1):S11-8.
5. Whitley R, Arvin A, Prober C, Corey L,
Burchett S, Plotkin S, Starr S, et al. Predictors of
morbidity and mortality in neonates with herpes
simplex virus infections. The National Institute of
Allergy and Infectious Diseases Collaborative Antiviral
Study Group. N Eng J Med. 1991;324:450-4.
1 HSV 6. Kimberlin DW, Lin CY, Jacobs RF, Powell
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76
 581

44

Borrelia burgdorferi4 spirochete

(Lyme Disease)
.. (erythema migrans) menin-
1976 gopolyarthritis acrodermatitis chronica atrophicans
(ACA) 5-7
juvenile rheumatoid arthritis1 B. burg-
dorferi8
erythema migrans
(multisystem disease) (vector-borne)
15 9
2
(Ixodid tick)3
.. 1982 Burgdorfer Barbour
spirochete ixodes dammini ticks ( 1)
582

13

3

(Midwest)
B. burgdorferi sensu lato (s.l.) complex10
13 species ( 2)9,14
3 species B. burgdorferi sensu
stricto (s.s.), B. afzelii, B. garinii 3 species
2 species (B. afzelii B.
garinii) B. burgdorferi (s.s.) 15
B. burgdorferi
spirochete flagella (surveillance)
o u t e r m e m b r a n e ..1982
1-5 Mb 11,12 (Centers for Disease
virulence factor surface protein Control and Prevention)

2
. 2006
 44 583

3-4 extracellular matrix

20,000 / 95 innate adaptive im-
(vector borne disease) mune response macrophage
antibody-mediated killing
5-14 16 B. burgdorferi lipoprotein
50-59 9 adaptive T cell independent
host B cell22 antibody outer surface pro-
(I. scapulris) teins C (OspC)
humoral immune system non-lipidated
20 16 protein
B. burgdorferi-specific T
(Ixodid tick) helper 1 T-cell
(feeding habit) animal hosts dependent B cell

opsoniza-
tion complement fixation16

B. burgdorferi erythema
2 migrans
9


B. burgdorferi
B. burgdorferi


3 ( 1)
human plasminogen, plasminogen activator (localized erythema migrans)
spirochete 17 ( 2)
B. burgdorferi
host integrin,18 matrix glycoaminogly- 3
can19 extracellular matrix protein20 Bor-
relia decorin-binding protein (Dbps) A B
decorin21 glycoaminoglycan collagen 2 323
fibrils 3-32
584

70-80 1
synovial hypertrophy, vascu-
24,25 lar proliferation infiltration mononuclear cell
rheumatiod arthritis

2



(secondary annular
skin lesion) B. burgdorferi chronic menin-
15 goencephalitis spastic paraparesis, cranial neu-
ropathy, cognitive impairment intrathe-
(neuroborreliosis)26,27 cal antibody 5 B.
lymphocytic meningitis afzelii acrodermati-
(subtle encephalitis with difficult tis chronica atrophicans
mentation) 30
cranial nerve 7 facial palsy
1 2 motor sensory 10 6
radiculoneuritis, mononuritismultiplex, cerebellar
ataxia myetitis 5

atrioventicular oligoarthricular arthritis
block myopericarditis 5
(chronic neurologic manifestations)
(fatal pancarditis)28,29 mild encephalopathy 31,32
heart block (antibody production)
33 axonal polyneuropathy
( 3) spinal radicular pain
60 distal paresthesis34,35 electromyogram
2-3 diffuse
involvement proximal distal nerve segment


10 complex
 44 585

liquid media Barbour-Stoenner Kelly Medium8,36

B. burgdorferi VIsE lipoprotein
erythema migrans37
IgG band
38 western blot45
polymerase chain reaction (PCR)
39,40 serologic test 1)
46

2) B. burgdorferi
(endemic area)
B. burgdorferi enzyme link immunosorbent (Smithkline-Beecham
assy (ELISA) western blot41 Lyme Vaccine Trial)
20 asymptomatic IgG seroconversion
(US CDC) 42 western blot 1047 3)
spirochete
immu-
noblot 1qG ELISA48
43

erythema migrans IDSA
1 49
immunoglobulin M (IgM) localized disseminates infection
B. burgdorferi 4 doxycycline 100 . 2
14-21 8 50
IgG 8
95-9944 amoxicillin 500 . 3
IgG blot doxycycline amoxicillin
cefuroxime axetil 500 . 2
5 10 (18, 23, 28, 30, 39, 41, 45, 58, 66 51
93 KDa)42 1 3 erythromycin 250 . 4
IgM 52

1 IgG ceftriaxone 40-50 ././
ELISA peptide invariant region 6 ( 2 ./)32,53,54 2-4
586

cefotaxime penicillin G (SmithklineBeecham) ImuLyme (Pasteur-

Meurieux-Connaught) 2
chronic neuroborreliosis B. burgdorferi outer surface protein A
(OspA)
4 atrioventricular 3 (phase 3 clinical trials)
block 10,000 LYMErix
(intravenous therapy) car-
diac monitoring permanent .. 1998
pacemaker oral intravenous 15-70 3
Lyme arthritis 1 12
phase 3
76 100
PCR
3
arthroscopic synovectomy 3
phase 3
155 Advisory Committee on Immunization Practice
24 . (ACIP)
.. 199957 LYMErix
15-70
.. 1998 - .. 2000
1.4 Vaccine Adverse
Event Reporting System (VAERS) passive sur-
(antibiotic prophylaxis) doxycycline 200 . 1 veillance system
72 .
905 58 7.4

Passive Immunization
10,000 VAERS
56



56 HLA-DR4 major histocompatibility
1990 2 locus
Lyme Disease LYMErix
 44 587

(temporal association)





VAERS

Internet United
States Agency for International Development


.. 56
2002 GlaxoSmithKline ( SmithKline-
Beecham)

59

1)
(

) 2)


3)
ACIP

LYMErix



588

1
()

Doxycycline 100 mg orally twice daily for 14- 21 days
Amoxicllin 500 mg orally 3 times daily for 14-21 days
Alternatives in case of doxycycline of amoxicillin allergy:
Cefuroxime axetil 500 mg orally twice daily for 14- 21 days
Erythromycin 250 mg orally 4 times daily for 14-21 days
(8 )
Amoxicillin 250 mg orally 3 times daily or 50 mg/kg per day in 2 divided doses for 14-21 days
Alternatives in case of penicillin allergy:
Cefuroxime axetil 125 mg orally 3 twice daily or 30 mg/kg per day in 2 divided doses for 14-21 days
Erythromycin 250 mg orally 3 times a day or 30 mg/kg per day in 3 divided doses for 14-21 days


Ceftriaxone 2 g IV once a day for 14-28 days
Cefotaxime 2 g IV once a day 8 h for 14-28 days
Na pencillin G 20 million U IV in 6 divided doses every 4 h for 14-28 days
Alternative in case of ceftriaxone or penicillin allergy:
Doxycycline 100 mg orally 3 times a day for 30 days; this regimen may be ineffective for late
neuroborreliosis
Facial palsy alone:
Oral regimens may be adequate
(< 8 )
Ceftriaxone 75-100 mg/kg per day (maximum, 2g) IV once a day for 14-28 days
Cefotaxione 150 mg/kg per day in 3 or 4 divided doses (maximum, 6g) for 14-28 days
Na penicillin G 200,000-400,000 U/kg per day in 6 divided doses for 14-28 days

Oral regimens listed above for 30-60 days or
IV regimens listed above for 14-28 days

First-degree AV block: oral regimens, as for early infection
High-degree AV block (P-R interval>0.3s): IV regimens and cardiac monitoring; once the patient has
stabilized, the course may be completed with oral therapy

Standard therapy for manifestation of the illness; avoid doxycycline
 44 589

serotype-1 (B. burgdorferi s.s) serotype-2

(B. afzelii) OspA molecule
B.garinii
60 61 B.valaisiana
62 Eurasia63 recombination OspA
atigen 2 B.garinii
(endemic area) neuroborreliosis
combination vaccine
OspA antigen OspA molecule

Livey
protective epitopes

10
56


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76
 595

45

sheep blood agar 3-4
Group B streptococcus (GBS) Strep- .
tococcus agalactiae -hemolysis GBS 9
capsular polysaccharides (Ia, Ib, II III-
GBS 2 VIII) 95
(early onset disease) 6 Ia, Ib, II, III V III
(late onset disease) 10
7 3
2
34-36 10 GBS
30 33 .. 2513 0.7-3.7
1 1,000 11
GBS GBS
.. 2533
1.8 1,000 12
(chorioam- early onset late onset 1.5 0.3
nionitis) (endometritis) 1,000
5.8 .. 2535
GBS
2-9 early onset
.. 2541 0.6
Group B Streptococcus 1,000 late
onset 1
GBS
GBS Strep- (colonization) 4.6
tococci Lancefield group B 40.613-15 GBS colonization
facultative GBS
596

26-28 65
GBS colonization
GBS
816
.. GBS early
2538 GBS onset
early onset 0.27 1,000 GBS colonization
0.1 .. 2544 GBS
late onset .. 2538 0.05 50-65 ( 98)
1,000 17 colonization 1-2
GBS colonization 5.1-6.218-20 30
.. 2547-2548 GBS late onset 50
(rectum)
35-37 GBS
1621 GBS


GBS GBS 2
early onset 122-29 (early onset disease)
GBS early (late onset disease)
onset GBS early onset 6
24
GBS late onset 7 3
1 3
15,16 31,32 ( 2)

1 GBS early onset

1. GBS colonization
2.
3. 18
4. (chorioamnionitis)
5.
6. 38 o .
7. GBS
( 32)
 45 597

GBS early onset 5013

GBS
4-61,2
33,34
33 late onset
80 0.624

24-48 35,36

5-10

GBS late onset

GBS
late onset 38,39 polymerase chain
35 reaction 97
100
37


Penicillin G GBS
early onset MIC Penicillin G Group A strepto-

2 GBS
Early-onset Disease Late-onset Disease
1 1 3








() Ia, III, V III, Ia, V
() 10-15 2-6
( 32)
598

coccus 10 GBS
GBS Penicillin G
32
ampicillin, extended- .. 1975
spectrum penicillins, cephalosporins ( cefoxitin),
carbapenem vancomycin GBS 53
cefotaxime GBS Ia, Ib, II, III,
penicillin V opsonization
140 phagocytosis
erythro-
mycin clindamycin erythromycin GBS
7-20 clindamycin 3-1541-45 54
GBS tetracycline,
trimethoprim-sulfamethoxazole, metronidazole GBS
gentamicin gentamicin 55-59
penicillin ampicillin GBS

10 GBS
14-21 GBS
28 dexamethasone 60



GBS

1. GBS colonization GBS
2. phase 1 GBS
GBS colonization III61
3.
GBS Ia II62,63
4. GBS

GBS
III
( 1) 46-52
 45 599

64 2


GBS GBS

GBS
GBS

III
GBS
GBS 71
III
18-40


65 GBS


GBS

GBS
GBS
Ia, Ib, II V


66-68

GBS GBS
65
GBS V

69
GBS

bivalent II III70

600
Kimberlin DW, Long SS, eds. Red Book: 2009 Report
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al Baker CJ, Rench MA, Fernandez M, Paoletti LC,
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 605

46

trypsin-sensitive surface
exposed M protein trypsin resistant T antigen
1
(Streptococcus pyo-
genes group A -hemolytic streptococcus
GAS) 1
.. 1600 .. 1900 (Scarlet
fever) (Acute rheumatic fever, ARF)


GAS GAS
.. 120 M-protein
1980 GAS ARF serotype M typing 150
streptococcal toxic shock syndrome (STSS) emm typing
emm type
M-protein M type
emm
.. 1880 Pasteur GAS 1, 3, 5, 6, 18, 19
(puerperal 24
fever) .. 1898 Cheadle 49, 55, 57
5 ARF carditis, polyarteri- 59 (pyoder-
tis, chorea, erythema marginatum subcutane- ma) (acute glomerulonephritis,
ous nodules .. 1903 Brown complete AGN) 1, 6 12
() hemolysis blood agar AGN STSS
15 (pyrogenic toxin)
Lancefield (serology) superantigen
-hemolytic streptococcus tumor necrosis factor (TNF)
(group-specific mediator
polysaccharide) 2
606

ARF
GAS
6
AGN ARF

AGN

2-6 10-157
GAS3
GAS .. 2005 GAS host
10,400 (3.5 ) GAS
1,350 ( 13) herd immunity
4 ARF GAS
(virulence factor) bacteriophage
ARF
20 CovRS
3-4 GAS (
5 )1 host
.. 1992 400,000 ARF RHD
(Rheu- (autoimmune
matic heart disease, RHD) 12 response)
RHD 1 GAS
HLA class II gene
RHD .. 2002 HLA DR7 allele
0.7-14 ( 4
) HLA
RHD class II antigen-presenting
cells (APCs) macrophage, dendritic cell,
B cell
ARF T cell HLA
T cell receptor (TCR) T cell

HLA
T cell
ARF GAS
 46 607

macrophage STSS
HLA class II CD4+ T cell
humoral cell (immune evasion)
ARF/RHD M protein M protein
(molecular mimicry phagocytosis
mechanism) T cell plasma protein
GAS C3b alter-
B cell (autoreactive B cell) native complement pathway
T cell M protein amino terminal
ARF/RHD5 GAS

1 M protein

(inflammation) GAS M protein
(immune evasion)
(tissue invasion) (alpha-helical coiled-coil fibrillar rods)
carboxy (C) terminus LPxTG motif peptido-
GAS host glycan
plasma protein matrix protein fibronectin, 4 ( A - D)
fibrinogen immunoglobulin (Ig) G adhesin 1 A-repeat amino ( N ) terminus
lipotechoic acid, M protein, hyaluronic acid (highly
capsule, C5a peptidase, fibronectin binding protein variable) serotype
( SfbI FBP54) R28 ( GAS M typing ( emm)
C re-
GAS ) peat epitope
pili (extracel- conserved region M type
lular binding protein) adhesin B repeat A C repeat
1 M protein streptococcal pyogenic cross react
exotoxin (SPEs) pro-inflammatory ARF B
SPEs superantigen repeat superantigen
GAS
SpeA streptolysin O, deoxyribonuclease B,
C erythrogenic toxin streptokinase hyaluronidase
bacteriophage-encode GAS
T cell receptor MHC class II SpeA GAS C
608

1 functional domain streptococcal M protein

( 6)

terminus C5a ARF AGN

peptidase SCPA (surface bound C5a peptidase) M protein
chemoattractant cardiac muscle myosin
extracellular matrix ( synovium
glomerular basement membrane)
nonsuppurative post-in- GAS
fectious sequelae GAS
ARF
GAS 3 VCAM-1 adhesin
endemic CD4+ T cell M protein
ARF myosin

ARF ( epitope group A carbohydrate, N-acetylglu-
) ARF cosamine lysoganglioside
M type GM1 Sydenhams
chorea SpeB
GAS AGN
molecular mimicry cross react
 46 609

GAS
2
STSS GAS
nonsuppurative

nonsuppurative 2
1

1, 2 generalized erythematous macular rash
(pharyngitis) 2
(impetigo pyoderma) 2.2 post-infectious immune-mediated1
GAS ARF acute glomerulonephritis (AGN)
GAS 1-3 ARF Jones criteria 2 major 1
(serous rhinitis) major 2 minor criteria
GAS 12
3 2
GAS 2
1. suppurative complication
GAS
peritonsillar
abscess, cervical adenitis, pneumonia, erysipelas, swab
cellulitis, necrotizing fasciitis, lymphangitis, bacter- GAS blood agar
emia, meningitis, septic arthritis, osteomyelitis latex agglutination, fluorescent
postpartum endometritis antibody assay, coagglutination, precipitation
2. nonsuppurative complication GAS beta-hemolytic strepto-
2.1 infection-mediated scarlet fever coccus bacitracin disk GAS
STSS
scarlet fever

1 Jones Criteria Acute rheumatic fever

2 major 1 major 2 minor criteria GAS
Major criteria Minor criteria Supporting evidence
Carditis Clinical findings: Positive throat culture or rapid
Polyarthritis Fever, arthralgia test
Chorea Laboratory findings: OR
Erythema marginatum Elevated acute phase reactants; Elevated or rising
Subcutaneous nodules prolonged PR interval streptococcal antibody test
610

10 GAS
GAS
rapid test
nitrous acid group A carbohydrate
antigen

GAS
GAS vaccine
rapid test optical immunoassay
chemiluminescent DNA probe


1 2 GAS vaccine
ARF 2
90 9 1. M protein vaccines
2. non-M protein vaccines
30 RHD
GAS 1. M protein vaccines1,8
M protein
4
GAS
A-repeat C-repeat M protein vaccines
AGN 2
GAS 1.1 N-terminal GAS vaccines A-re-
peat
() (highly variable)

STSS opsonization, bactericidal, protective, M type-specific
long-lasting .. 1970
ARF partially purified M3 pro-
GAS tein
ARF GAS
GAS ARF

Dale
 46 611

2 Group A streptococcal vaccines 8

..
1923 21 strain heat-killed GAS
1930 Heat-killed GAS
1931 Heat-killed GAS
1932 Heat-killed GAS
1933-1943 GAS toxin and GAS tannic acid precipitated toxin
1937-1941 GAS tannic acid precipitated toxin
1946 Heat-killed or ultraviolet-inactivated M17 and M19 GAS
1949 Heat-killed M3 and M17 GAS
1960 Partially purified M19 GAS
1962 Cell wall of M5 and M12 GAS
1963 Cell wall of M14 GAS
1968 Partially purified M protein M3 GAS
1969 Highly purified M protein M12 GAS
1973 Highly purified M protein M1 GAS
1975 Highly purified M protein M1 GAS
1978 Highly purified M protein M3 and M12 GAS
1979 Polypeptide fragment M protein M24 GAS
2004 Six-valent N-terminal M protein fragment M1, M3, M5, M6, M19, M24
2005 Recombinant 26-valent M protein vaccine along with Spa

recombinant fusion Spa, M28, M3, M1.2, M18, M1.0), Septa C.2 (M2,
protein N-terminus fragments 6 M protein M43, M13, M22, M11, M59, M33, M2) Septa D.1
M1, M3, M5, M6, (M89, M101, M77, M114, M75, M76, M92, M89)
M19 M24 epitope cross
react ARF
M type
57/60 ( 95) 26 valent
recombinant 26-valent M 6
protein vaccine6 valent adjuvant 1
1.2 Conserved region M protein vaccines8
C-repeat conserved region
85-90 Streptococcal protective
antigen (Spa) 1. C-terminal region M6
2. Selected B and T-cell epitopes C-
4 component fusion protein Hexa A.1 (M24, repeat region M5 (PepVac StreptInCor vaccine)
M5, M6, M19, M29, M14, M24), Septa B.2 (M1.0, M12, 3. 12-amino acid minimal B-cell epitope
612

C-repeat region (J8)

conserved region M type

2.3 Streptococcal fibronectin-binding
proteins serum opacity factor (SOF),
fibronectin-binding protein 54 (FBP54), FbaA,
(IgA) streptococcal fibronectin-binding protein 1 (Sfb1)

C-repeat
IgG
2. Non-M protein vaccines8

M-protein 2.4 Cysteine protease and streptococcal
cross-react pyrogenic exotoxins
type-specific - Streptococcal pyrogenic exotoxin A (SpeA)
non-M protein SpeC superantigen toxin STSS
2 - extracellular cysteine protease
(extracellular virulence factors) streptococcal pyrogenic exotoxin B (SpeB) (
streptococcal C5a peptidase (SCPA), GAS carbo- pyrogenic
hydrate, streptococcal fibronectin-binding proteins exotoxin ) GAS
cysteine protease
proteomic reverse SpeA SpeB
vaccinology non-M protein STSS
2.1 Streptococcal C5a peptidase
SCPA 2.5 Streptococcal pili ( T antigen)
Pili GAS, GBS, S.pneumoniae
A, B, C G
chemokine C5a highly conserved 12
phagocyte pili variants 90
colonization SCPA 2.6 New antigens identified by proteomics
IgG mucosal IgA and/or genomics reverse vac-
opsonization cinology
M type Pro-
B teomics
2.2 Group A streptococcus carbohydrate
 46 613

streptococcal asymptomatic colonization

serine esterase (Sse), 2 heme-binding proteins (shp emm type
and HtsA), Streptococcal cell envelope proteinase non-vaccine serotype
(Spy0416 SpyCEP or ScpC) Lipo-
proteins



GAS

(predisposed) ARF, AGN STSS
GAS GAS

M protein
GAS

non-M protein
1

phase I
26-valent M protein vaccine Dale 6
conserved region M protein vaccine 1. Kotloff KL. Streptococcus group A vac-
phase I cines. In: Plotkin S, Orenstein W, Offit P, editors.
J8 vaccine8 GAS 120 M serotype Vaccines. 5th ed. Philadelphia: Saunders; 2008.
150 emm types p.1317-25.
aminoterminus M type 2. American Academy of Pediatrics. Group
A Streptococcal infections. In: Pickering LK, Baker
CJ, Kimberlin DW, Long SS, editors. Red Book: 2009
preclinic Report of the Committee on Infectious Diseases. 28th
ARF ed. Elk Grove Village, IL: American Academy of Pedi-
B T cell epitopes cross atrics; 2009. p.616-28.
react host 3. Glezen WP, Clyde WA Jr, Senior RJ,
superantigen Sheaffer CI, Denny FW. Group A streptococci, myco-
plasma, and viruses associated with acute pharyngitis.
phase III JAMA. 1967;202:455-60.
herd immunity 4. Centers of Disease Control and Preven-
614

tion (CDC)[Internet]. Active bacterial core surveillance

report, Emerging infections program network, Group A
streptococcus; 2005. Available from: http://www.cdc.
gov/ncidod/dbmd/abcs/survreports/gas05.pdf
5. Guilherme L, Fae KC, Higa F, Chaves
L, Oshiro SE, Freschi de Barros S, et al. Towards a
vaccine against rheumatic fever. Clin Dev Immunol.
2006;13:125-32.
6. Dale JB. Current status of group A strep-
tococcal vaccine development. Adv Exp Med Biol.
2008;609:53-63.
7. Anthony BF, Kaplan EL, Wannamaker
LW, Briese FW, Chapman SS. Attack rates of acute
nephritis after type 49 streptococcal infection of the
skin and of the respiratory tract. J Clin Invest. 1969;
48:1697-704.
8. Steer AC, Batzloff M, Mulholland K, Cara-
petis JR. Group A streptococcal vaccines: facts versus
fantasy. Curr Opin Infect Dis. 2009;22:544-52.
 615

47

Vancomycin-resistance S. au-
reus VRSA S. aureus
Staphylococcus aureus


S. aureus 300,000

S. aureus
3
5 1 S. aureus
S. aureus (Invasive S. aureus genus Staphylococci
infection) 19-341
Staphy-
S. aureus lococcus S. aureus
262
44-483,4 Staphylococci S. aureus
coagulase clumping factor
S. aureus
cloxa- adhesin toxin 20
cillin methicillin (Methicillin-resistance S. aureus 30 Coagulase-negative staphylococci
MRSA) adhesin 10
72-73 toxin1
S. aureus 5 ( 1)10
MRSA 23-423,4,6,7 1. Cell wall peptidoglycan
( 1) peptidoglycan
glycopeptides vancomycin endotoxin
(Vancomycin-intermediate resistance S. Cytokines Dis-
aureus - VISA) 8,9 seminated intravascular clotting (DIC)
616

1 S. aureus
( 10)

S. aureus capsular Hemolysin

polysaccharide (CP) S. aureus
S. aureus Leukocidin Panton-Valentine
12 CP5 CP8 leukocidin (PVL)
85 S. aureus PVL
CP5 CP8
10 PVL
2. Surface protein 3.3 S. aureus
Protein A (Anti- Coagulase, Hyaluronidase
phagocytic) S. aureus ( 1)
(Adhesin) S. aureus
Microbial Surface Components Recognizing (Colonization) 30 50
Adhesive Matrix Molecules (MSCRAMM) S. aureus 11


passive
immunization S. aureus 10
3. (Extracellular MRSA1,11
products) ( 1) 1,10
3.1 Superantigens Enterotoxins
Epidemiolytic toxins (Exfoliatin S. aureus
A B) Scalded skin syndrome Toxic
shock toxin-1
3.2 Cytotoxin Hemolysin
 47 617

1 (Extracellular Factors) S. aureus 1

Surface proteins
Protein A Anti-immune, anti-PMN
Collagen BP Collagen binding
Fibronectin BPA and B Fibronectin binding
Clumping factor A and B Fibrinogen binding
Capsular polysaccharides
Polysaccharide capsule type 5 Anti-phagocytosis?
Polysaccharide capsule type 8 Anti-phagocytosis?
Cytotoxins
, , , and -hemolysin Hemolysin, cytotoxin
Panton-Valentine leukocidin (PVL) Leucolysin
Superantigens
Enterotoxin A-D Food poisoning, Toxic shock syndrome
Exfoliatin A, B Scaled skin syndrome
Toxic shock syndrome toxin-1 (TSST-1) Toxic shock syndrome
Enzymes
V8 protease, Hyaluronidase, Coagulase, Spreading factor, Clotting, Clot digestion, Plasminogen
Staphylokinase, etc. activator, etc.

S. aureus
28-35 12,13 S. aureus
1 65 12
hemodialysis Hemophilus influenzae type
peritoneal dialysis B Streptococcus pneumoniae
16-18

COPD Rhumotoid S. aureus
arthritis12,13 3

S. aureus 38 26

60 MRSA
20 14 S. (Health-
aureus sterile site care-associated infection) MRSA
( 19 2-4
15 )15 S. aureus MRSA
618

MRSA

MRSA .. 1997-1999
MRSA 1,10,11
Western-Pacific 46 1. Exfoliative toxin A B
34 26
MRSA MRSA epidermis Scalded skin syndrome
5 .. 2000 Bullous impetigo
(Nosoco- 2. Toxic shock syndrome toxin -1 (TSST-1)
mial) (Healthcare- Superantigen
associated) (Community- T-lymphocyte
acquired) MRSA 61, 52 14 cytokines

19 endotoxin

MRSA hemodynamic
(CA-MRSA HA-MRSA)
MRSA 3. Enterotoxin S. aureus enterotoxin
MRSA 26 67
S. aureus

MRSA 2-6
CA-MRSA HA-MRSA20
CA-MRSA S. aureus


MRSA
2,7,21


S. aureus toxin-mediated (Liquefaction necrosis)
virulence S. aureus
toxin-mediated
S. aureus

 47 619

1,10,11

S. aureus

1.





cellulitis pyomyositis
S. aureus
S. aureus
necrotizing fasciitis
2 Oslers node Janeway lesion S. aureus
septicemia with acute IE

1 septic emboli ( 2)
2. hemiplegia
S. aureus septic emboli 1,22
2.2 (Purulent peri-
carditis) precordial
friction rub
systemic
inflammatory response cardiac tamponade pericardiocen-
thesis
DIC surgical drainage1,22
S. aureus 2.3
2.1 (Infective endocarditis-IE) S. aureus pneu-
S. aureus (Acute IE) monia
(Necrotizing pneumonia)
pulmonary
emboli 1
cardiac murmur 2.4 S. aureus
620

23


2.5
(Acute or Chronic osteomyelitis)

S. aureus systemic 3 Bullous impetigo
epidermolytic toxin S. aureus
( )

2-3
systemic

fistula tract
S. aureus
brain abscess, epidural
abscess, discitis cavernous sinus thrombosis

venticuloperitoneum shunt11
3.
3.1 Staphylococcal scalded skin syndrome
(SSSS) epidermolytic toxin S. aureus



anti-toxin
antibody
Bullous impetigo 4 SSSS S. aureus

( 3, 4) ( )
3.2 Staphylococcal toxic shock syndrome
TSST-1
1-2
S. aureus 1
 47 621

S. aureus 65 MSSA MRSA

47 18 23

1,11 Agar diffusion Kirby-Bauer E-test1

(Molecular diagnosis)

1
Staphylococcal Cassette Chromosome mec
(SCCmec) mecA
S. mecA Penicillin-Binding
aureus blood agar liquid media Protein 2 (PBP2) PBP2a PBP2
Mueller-Hinton broth 18-24 1

SCCmec MRSA 8 24
S. aureus MRSA
Pulsed Field Gel Electrophoresis
11 (PFGE), Multi-locus Sequence Typing (MLST)
SCCmec Typing MLST
(Phenotypic tests) sequencing
Coagulase Agglutination http://www.mlst.net
test surface MRSA
proteins agglutination ST30-MRSA-IV (ST30 Sequencing
S. aureus Staphylococci 1 type 30) Southwest Pacific clone ST30-MSSA
S. aureus 80/81 SCCmec type IV 24
2
2
IE HA-MRSA
aminoglycosides,
50 erythromycin, clindamycin, fluoroquinolone tetra-
1,10 cycline Glycopeptides
vancomycin CA-MRSA
.. 2539-2549
80 MRSA 2
44 vancomycin MRSA
622

2 HA-MRSA CA-MRSA25

HA-MRSA CA-MRSA

()



PVL PVL
SCCmec I-III SCCmec IV-V

CA-MRSA
HA-MRSA CA-MRSA S. aureus
225
MRSA HA-MRSA
Minimal Inhibitory CA-MRSA
Concentration (MIC) S. aureus cloxacillin
MIC 4 ./. MRSA (Skin
CA-MRSA clindamycin and soft tissue infection, SSTIs)
erythromycin clindamycin
Clindamycin-inducible resistance


D-zone test erythromycin
clindamycin
clindamycin
erythromycin zone D ( 5)10
MRSA S. aureus
vancomycin MRSA MIC
vancomycin 4 ./.

VRSA (MIC 16
./.) VRSA vanA 5 Clindamycin-inducible resistance
Enterococci D-zone test
10,11 ( 10)
 47 623

MSSA cloxacillin
11,26
S. aureus
cellulitis vancomycin clindamycin11

S. aureus



(septic
phlebitis)

clindamycin, trimethoprim-
sulfamethoxazole (TMP/SMX), doxycycline
Passive immunization
7 linezolid
Streptococcus group A clindamycin S. aureus
linezolid TMP/SMX doxy-
cycline amoxicillin ()
impetigo Passive immunization
2% mupirocin ointment26 Passive immunization 2 7
cloxacillin
1. Veronate (INH-A21)
SSTIs
CA-MRSA Clumping factor A (Clf A) surface protein
vancomycin, linezolid clindamycin S. aureus fibrinogen Clf A
clindamycin
1026 clot
2 Veronate
311 3
late-onset sepsis
/ S. aureus 28
S. aureus 11,26
2. AltaStaph
CA-MRSA cloxacillin Capsular Polysaccharide
5 8
624

3 S. aureus11

Susceptibility Antimicrobial Agents Comments

1. Initial empiric therapy (unknown susceptibility)
Vancomycin + Life-threatening infections
Cloxacillin + Gentamicin
Cloxacillin Nonlife-threatening infection when rate of MRSA are low
Clindamycin Nonlife-threatening infection when rate of MRSA are substantial AND
prevalence of clindamycin resistance is low
Vancomycin Nonlife-threatening infection when rate of MRSA are substantial AND
prevalence of clindamycin resistance is high
2. Methicillin-susceptible S. aureus
Cloxacillin
Cefazolin
Clindamycin Serious penicillin allergy AND clindamycin susceptible strain AND
nonlife-threatening infection
Vancomycin Serious penicillin allergy AND clindamycin resistant strain
3. MRSA (Oxacillin MIC 4 ./. )
HA-MRSA Vancomycin
Alternatives TMP/SMX, Linezolid
Fluoroquinolone
(If susceptible)
CA-MRSA Vancomycin Life-threatening infections
Clindamycin Pneumonia, septic arthritis, osteomyelitis, SSTIs
(If susceptible)
4. VISA (MIC 4-16 ./.)
Choices Linezolid, daptomycin Optimal therapy is not known, depend on susceptibility test results
Tigecycline

S. aureus
S. aureus adjunctive adjunctive therapy
therapy 27 Passive immunization
S. aureus 30
3. Paglibaximab
Lipoteichoic acid 27
( 1)
1/2
S. aureus sepsis

27,29
2/3
Surface proteins
S. aureus
Tefibazumab MSCRAMM ( 1)
 47 625

S. aureus
29,31 S. aureus
( Heteropolymers, Lipoteichoic acid (LTA) conjugated
1, 2 3) Autoinducing peptides (AIPs) Accessory
3 ( 4)27,29,31,32 gene regulator (agr) 27,29
colonization
Component
proteins
Conjugated capsular polysaccharide S. aureus S. aureus
(CP) 5 8 (StaphyVAX) 2
S. aureus
3 Opsonization
3,600
S. aureus


5 components CP5, CP8, Teichoic acid,
Non-toxic mutants -toxin PVL
PentaStaph 27
Component proteins 27

4 27,29,31,32

Live whole-cell -
Killed whole-cell Staphypen
Component Protein or Capsule
Conjugated CP5 and CP8 StaphyVAX (Nabi) 3
IsdB V710 (Merck) 2
(Iron surface determinant B)
Multi-components -
(IsdA, IsdB, SdrE, SdrD)
Exotoxin
Mutant of -hemolysin -

Mutant of TSST-1 -
626

Dis. 2006;6:70-1.
S. aureus 4. Nickerson EK, Hongsuwan M, Limmathu-

rosakul D, Wuthiekanun V, Shah KR, Srisomang P,
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 629

48

4 (adenovirus serotype 4; Ad4) 7

(Ad 7) (military recruits)

(adenovirus) 11

12-14
Rowe ..19531 ..1999
Ad7
Fort Leonard Wood Missouri Ad7d2 Ad7h
2 15,16
..2006-2007 Ad14

38
(pharyngitis) (conjunctivitis) 517
(pneumonia)

(immunocompromised
patients)
3-7 double-
stranded, nonenveloped DNA virus genus
hemorrhagic cystitis Mastadenovirus, family Adenoviridae
4,7
10
15 56. 30
8-10 0.25% sodium dodecyl sulfate
..1971 0.5 ./.

(live, oral enteric-coated adenovirus vaccine)
630

antiserum non-enveloped alcohol

51 chlorhexidine
biochemical, biologic, immunologic immersion in
A F4 1% solution of sodium hypochlorite 10
autoclaving25,26


23,24
(tracheostomy tube)
(gown) (mask) 27

(prevalence)
50
28,29
C (Ad1, Ad2, Ad5, Ad6)
pharyngoconjunctival fever (endemic)
(summer camps) 2
(childcare centers) Ad4, Ad7,
Ad14 Ad21
-18
A C
6 5
Ad1 7
Ad4 Ad7
epidemic keratoconjunctivitis
Ad8 Ad37
Ad3, Ad7, Ad32, Ad40 Ad41
(disseminated disease)
Ad3, Ad7 Ad23

4,19-21 2 8



22-24
 48 631

(common cold) (pharyngitis)

(exudative tonsillitis)
(latent state) (cervicaladenopathy)
30 (bronchitis) (bronchiolitis)
(reactivation) (pneumonia)

Ad1, Ad2, Ad3, Ad5
Ad736,37
secretory IgA Ad3, Ad4, Ad7 Ad21
serum-neutralizing, Ad3 Ad7
hemagglutination-inhibiting complement-fixing
antibodies 7 31 necrotizing pneumonia 38-41 Ad7
IgA IgG
(genotype) 7h40,41
neutralizing antibody
Pharyngoconjunctival fever
Ad2, Ad3, Ad4, Ad7 Ad14
32 follicular conjunctivitis

tumor necrosis Epidemic keratoconjunctivitis
factor-, interleukin-1 interleukin-6 2-3 Ad3, Ad8, Ad19 Ad37
cytotoxic T-cells
33,34

interleukin-1 tumor necrosis factor- (subconjunctival hemorrhage)23
35
periorbital
bacterial cellulitis

Ad3, Ad5, Ad7, Ad31, Ad40 Ad41
(gastroenteritis)
2
2-5 Ad1, Ad2, Ad3, Ad5 Ad7
mesenteric lymphadenitis
(intussusception)42,43
632

Ad1, Ad2, Ad3, Ad5 Ad7 35 1

(hepatitis)
44-47
(colitis)
Acute hemorrhagic cystitis




Ad11 Ad7
Ad21 cytopathic
adenovirus-associated hemorrhagic effect cell culture
cystitis cluster of grapes 3-5
neutralization
100 hemagglutination-inhibition
48
direct fluorescence assay (DFA)
nephritis, orchitis, hemolytic uremic syndrome
PCR

(myocarditis) (pericarditis) (serology)
acute
Ad7 Ad2149,50 convalescent serum complement
fixation enzyme immunoassay
50
(meningitis) 53
(encephalitis)
(transverse myelitis)51 7




4,21,52
1, 2, 4, 5, 6, 7, 11, 29, 31, 32, 34 trifluridine,
ribavirin cidofovir54-56
 48 633

52 66
ribavirin SV-40
67
..1960

20,47,55,57 cidofovir 5 Ad7
./.
1-1.5 ./. 3 68
probenecid
Ad4 Ad7

58-62 69,70
Intravenous Immunoglobulin (IVIG) Ad4
5071,72
Ad4
60-64 Ad7
Ad7
Ad473
Passive immunization
Ad4 Ad7

immunoglobulin Ad7 9573-75

Ad21
Ad21
76-79
Ad21

Ad4 Ad7 11
(inactivated) ..1971-1996
..1957 (Wyeth Laboratories Incorporated)

90 (enteric-coated) 2
11,65 Ad4 () Ad7 ()
3 Ad3 104.5 TCID50
human-diploid fibroblast cells (
634

WI-38) Minimal Essential Medium, Eagles

solution, (neomycin sulfate, gentamicin 2
sulfate amphotericin B), fetal bovine serum Ad4 1
sodium bicarbonate Ad7 1
cellulose acetate, phthalate, alcohol, ac-
etone, castor oil, magnesium stearate amberlite
Ad4 Ad7


2
4
..1996 ..1999 neutralizing humoral antibody (IgG,
IgM IgA)78
secretory IgA

25 .. 2001 Barr Labo- 80
ratories, Incorporated of Pomona
Ad4 Ad7
50
9081 Ad4
16 .. 2011 Barr Labo- Ad7
ratories Ad4 74,75,82
Ad7
(multicenter, double-
(WI-38) blind, randomized, placebo-controlled study)
4,040
Ad4
Ad7 FD&C yellow dye #5 (tartrazine) Ad4 (vaccine efficacy)
FD&C yellow dye #6 99.3
Ad7
Ad7
Ad7

2-8 . 93.8 neutralizing antibody
2 1:8
neutralizing
 48 635

antibody 1:8 5.3

Ad4
83
Ad7
17-50 ..1971
67


..1983
Ad4 Ad7
(double-blind, randomized, placebo- 11
controlled study) 3,031
1,009 6
63 37

17-42
21 gentamicin sulfate, neomy-
cin sulfate amphotericin B FD&C
35 ( 1.2) Yellow 5 (tartrazine)
Ad7 bronchial asthma
56
(hematuria) (gastroenteritis)

12 ( 1.2) 4
1 56

36-40





28 7

28
636

28


1. Rowe WP, Huebner RJ, Gilmore LK, Par-
rott RH, Ward TG. Isolation of a cytopathogenic agent
from human adenoids undergoing spontaneous de-

generation in tissue culture. Proc Soc Exp Biol Med.
Ad4 Ad7 1953;84:570-3.
..1971 2. Hilleman MR, Werner JH. Recovery of new
agent from patients with acute respiratory illness. Proc
11,84-86 Soc Exp Biol Med. 1954;85:183-8.
3. Johansson ME, Brown M, Hierholzer JC,
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76
 643

49

8
0-6 6-12 1-5
(Epstein-Barr virus, EBV) 5-15 15 48, 30, 83, 90
human herpesvirus-4 (HHV-4) 93
human herpesvirus
1 3
memory B cell
(reactivated)

2
infectious
mononucleosis (IM), lymphoproliferative disease
hyperplasia
lymphocytic interstitial pneumonitis (LIP) lymphocyte
oral hairly leukoplakia (OHL) reticuloendothelium
3
hyperplasia
granuloma


(droplet transmission)


EBV
0-15 1.
68.4-72.74,5 (acute primary EBV infection)
4-6
55.6-99.54-7 infectious mononucleosis (IM)
644

40 4. Viral associated hemophagocytic syndrome

IM (VAHS)

(Hoaglands sign)

pancytopenia, coagulopathy histiocytic erythro-
lymphocyte atypical lymphocyte phagocytosis 13
atypical lymphocyte 5. Fatal infectious mononucleosis
atypical
lymphocyte 10
IM
80 hemophagocytic 14
6. Fulminant EBV+ T-cell lymphoproliferative
disorder

aplastic anemia 3,9 chronic active EBV 15
2. X-linked lymphoproliferative disease (XLP) pancytopenia
monoclonal proliferation
activated cytotoxic T cell (TIA-1+) CD4
signaling lymphocyte activation molecule CD8 phenotype15 fatal IM uncontrolled
(SLAM)-associated protein10 T cell polyclonal B cell proliferation
T, B natural killer cell 7. EBV-associated malignancies16
IM 30 acquired
hypogammaglobulinemia 25 malig- 7.1 Burkitts lymphoma African type
nant lymphoma11 submandibular area
3. Chronic active EBV infection (CAEBV) American type
6 abdominal lymphoma 20
EBV genome
7.2 Posttransplant lymphoproliferative
basal ganglia12 disease AIDS-related
T cell (CD4 ) NK cell13 lymphoma primary CNS lymphoma
EBV peripheral
monoclonality 80 non-Hodgkin lymphoma EBV genome
malignant lymphoma 12 30-50
oral
 49 645

hairy leukoplakia lymphoid interstitial pneumonitis 80

4
7.3Hodgkins disease EBV DNA 17 heterophile
Hodgkins Reedsternberg cell antibody
40-60 viral genome
monoclonal guinea pig kidney cell
mononucleosis CMV, toxoplasmo-
sis, HHV-6
7.4 Nasopharyngeal carcinoma epithelial heterophile antibody 18
malignancy
EBV antigens19,20
viral capsid antigen (anti-
7.5 VCA IgM IgG) early antigen (EA)
EBV Epstein-Barr nuclear antigen (EBNA)
genome 1


polymerase chain reaction (PCR), EBV-encoded RNA
in situ hybridization, Immunohistochemistry
viral load PBMC

1


heterophile antibody, monospot, monocheck
EBV-associated mononucleosis (IM)
heterophile antibody 20-30

1
VCA IgG VCA IgM EA (D) EBNA
- - - -
+ + +/- -
+ +/- +/- +/-
+ - +/- +
( 20)
646

(reactiva-
tion) oropharyngeal
epithelium B cell oropharyngeal epithelium
hemophagocytic lymphohistiocytosis lytic cycle
prednisolone 1 ././ ( 20
./) 7 20
acyclovir
cell fusion receptor glycoprotein
IM EBV lymphopro- CR2 (complement receptor) B lym-
liferative syndromes 20 phocyte CR2
EBV lymphoproliferative disease glycoprotein gp350
21

B lymphocyte
EBV-specific immortalized continuous B-lymphoblastoid cell
cytotoxic T lymphocyte line (LCL)
lytic cycle

(solid organ transplant)
cytotoxic T cells (CTL) CD4 CD8 T cell

B cell
acyclovir
(la- post-
tency)16,20 interferontransplant lymphoproliferative disease (PTLD)
alpha, monoclonal antibody CD21 CD24 EBV gene expression
rituximab monoclonal antibody (EBV-associated diseases)
CD20 B cell antigen adoptive transfer (lytic cycle latent
autologous EBV-specific cytotoxic T lymphocyte proteins)

11 B lymphocyte
episome / integrate
pheno-
type EBV latency 3 21
IM 1. Latency I (lytic)
Burkitts lymphoma (BL) EBV
 49 647

EBNA1 latency
2. Latency II CTL
nasopharyngeal carcinoma (NPC) Hodgkins
lymphoma (HL)
EBNA1 latent membrane proteins (LMP)
1 2
3. Latency III IM, PTLD XLP
latent-
infection protein EBNA1, 2, 3A, 3B, 3C LMP 1. A whole virus vaccine
1 2
(cell-mediated immu-
nity)
CTL EBV proteins
CTL lytic cycle DNA
EBNA3A, 3B, 3C
epitopes LMP 1 LMP2 (whole-killed virus vaccine)
CD4 T cell
EBNA1
EBNA1
HLA class II CD4 T cell 21 16

2. Synthetic peptide vaccines
IM (Vaccines associated
with primary EBV infection) lipid carriers ISCOMS
EBV se- (immunostimulating complexes) (de-
ronegative PTLD livery systems) miscles, liposomes, solid matrix-
XLP EBV seronegative antibody antigen (SMAA)
CTL
membrane antigen (MA)
NPC HL MA neutralizing
21 antibodies neutralize
plasma membrane
3 glycopro-
teins 350,000, 220,000 85,000
(gp350, gp220 gp85)
648

2 EBV seroconversion (acquired EBV)

22 IM 4 4 EBV
lytic protein seroconversion IM25
gp350
cotton-top tamarins high titred EBV 3. Recombinant vector vaccines
poxviruses re-
phase I subunit vaccine combinant expressing EBV antigen
gp350/220 with a single adjuvanted surface
glycoprotein randomized, double-blind
67
23 recombinant vaccinia virus expressing major EBV
phase II randomized, membrane antigen BNLF-1 MA (gp350/220)
double-blind recombinant EBV subu- 9
nit glycoprotein 350/aluminum hydroxide and 3-O- membrane antigen
desacyl-4-monophosphoryl lipid A (ASO4) neutralize 3 9
181 EBV
seronegative 3 16 10
IM 26
78
1
seroconversion gp350

98.7 18 24
1. . .
EBNA3 : , , -
CTL , , .
IM . :
phase I ; 2550. .275-86.
immunogenicity HLA 2.Babcock GJ, Decker LL, Volk M, Thorley-
B*0801-restricted peptide epitope FLRGRAYGL and Lawson DA. EBV persistence in memory B cells in
tetanus toxoid formulated in a water-in-oil adjuvant, vivo. Immunity. 1998;9:395-404.
Montanide ISA 720 HLA B8 3. .
EBV seronegative (Infectious mononucleosis). : ,
23 , . .
: ; 2536. .119-25.
2-12 1 2 4.Pancharoen C, Bhatrarakosol P, Thisyakorn
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characteristics of chronic active Epstein-Barr virus 20.American Academy of Pediatrics. Epstein-
650

Barr virus infections (Infectious mononucleosis). In:

Pickering LK, Baker CJ, Kimberlin DW, Long SS,
editors. Red Book 2009 Report of the Committee on
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meulen C, Moutschen M, Lonard P, Moreels A, et al.
Recombinant gp350 vaccine for infectious mononucle-
osis: a phase 2, randomized, double-blind, placebo-
controlled trial to evaluate the safety, immunogenicity,
and efficacy of an Epstein-Barr virus vaccine in healthy
young adults. J Infect Dis. 2007; 196:1749-53.
25.Elliott SL, Suhrbier A, Miles JJ, Lawrence
G, Pye SJ, Le TT, et al. Phase I trial of a CD8+ T-cell
peptide epitope-based vaccine for infectious mononu-
cleosis. J Virol. 2008; 82:1448-57.
26.Chu CM, Gu SY, Huang TM, Ruan L, Miao
YH, Lu H, et al. First EBV vaccine trial in humans us-
ing recombinant vaccinia virus expressing the major
membrane antigen. Dev Biol Stand. 1995; 84:171-7.
 651

50

(Ebola hemorrhagic family Filoviridae Filo
fever)
Marburg family Filoviridae


.. 2519 U 6
.. 2551
25-90 Marburg4
RNA
biosafety (non-segmented, negative-sense single stand RNA)
level 4 19
7 nucleoprotein
1 (NP), virion protein (VP) 24, VP30, glycoprotein (GP),
VP35, VP40 RNA-dependent RNA polymerase4
5
(amino acid sequence)
Ebola-Zaire, Ebola-Sudan,
2 3 Ebola-Reston, Ebola-Cte dIvoire Ebola-Bun-
dibugyo Ebola-Zaire, Ebola-Sudan
Ebola-Bundibugyo
Ebola-Zaire
60-90 Ebola-Sudan
Ebola-Bundibugyo 40-60
25 5-7 Ebola-Cte dIvoire
1 8
652

Ebola-Reston 4
2, 7 2
.. 2537
5 Ebola-Cote dIvoire Cote dIvoire
1
8
( .. 2538 Ebola-Zaire
) .. 2519 315
.. 2551 819
2,100 10.. 2537-2540
1,500 Ebola-Zaire 3 Gabon
30-60
60-70
.. 2543-2544
Uganda Ebola-Sudan 425
53
.. 2544-2546
Ebola-Zaire Gabon
5 302
.. 2519 84
( .. 2547 Ebola-Sudan
) 17
284 151 ( 53) 20 41 25
.. 2550
318 280 Bundibugyo Bundibugyo
( 88) Uganda 149
256
.. 2550-2551 Ebola-Zaire
2
Ebola-Sudan Ebola-Zaire 187 32
.. 2522 88 47
34 22 5
.. 2532-2533 (zoonotic virus)
Ebola-Reston
Reston
 50 653

/ 42 ()

5,10



proinflammatory cytokine
91 11 coagulation factors dis-
seminated intravascular coagulopathy (DIC)
Cote dIvoire Gabon5, 8 7,12

1.

macrophage dendritic cells
1,5

1.
12
2. Systemic inflammatory response
60o . cytokine, che-
30 mokine proinflammatory cytokine
2. tumor necrosis factor (TNF)-alpha, interleukin (IL)-
1beta, IL-6, macrophage chemotactic protein nitric
oxide13
universal precaution
contact precaution vascular permeability
14
3. (Coagulation
defect)
ma-
3. crophage tissue factor (TF)15
3 extrinsic coagulation pathway
2 38.3o . coagulation factor proinflam-
matory cytokines macrophage
654

TF 6-11
21,22
D-dimer 24
coagulation factor 1 5
15,16 11
4. adaptive immunity
dendritic 7
lymphocyte
(apoptosis) dendritic
(maturation)
lymphocyte

17 VP24 1. hypovolemic
VP35 interferon shock adrenal insufficiency4
18,19 2.

7 3.
2-21 4-10
4.
(septic shock)

5.
hepatocellular necrosis


2-3
4
1. Complete blood count (CBC)
1,000 /..

(multiple organ failure) 6-8 21
50 2.
7,20
6-16 (multifocal hepatic necrosis)
aspartate
2 (AST) alanine (ALT) aminotransferase
 50 655

AST ALT
23
3. (coagulogram)
DIC 1. Antisense oligonucleotides RNA
prothrombin time, partial thrombo- interference positively charged phosphorodi-
plastin times D-dimer amidatemorpholino oligomer (PMO plus)
translation VP24
PMO plus 30-60
biosafety level 4 60 PMO
1. nucleic acid plus 24
2. Anticoagulation
7,11 2.1 Recombinant nematode anticoagulant
- protein c2 (rNAPc2)
enzyme-linked immunosorbent assay rNAPc2 tissue factor coagula-
(ELISA) tion pathway Ebola-Zaire
- reverse tran- rNAPc2 10 24
scription-polymerase chain reaction (RT-PCR) rNAPc2 33
- - 25
Marburg 2.2 Recombinant human activated protein
c(rhAPC) anticoagulant
2. Ebola-Zaire rhAPC
rNAPc226
3. recombinant
3. vesicular stomatitis virus (rVSV) expressing
IgM 2 Multivalent Ebola vaccine
30-168 3 (Ebola-Zaire, Ebola-Sudan
IgG 6-18 Ebola-Cte dIvoire) rVSV
11 3
IgM IgG (four- 27
fold) 30
Ebola-Sudan 100
Ebola-Zaire 5028,29

656

Passive immunization 1 plaque
pas- forming unit (PFU) passive im-
sive immunization munization neutralized
passive immunization 34 passive
.. immunization
2519
inter- neutralized
feron 1 2
Ebola-Zaire (convalescent
serum) 450 . 6
Ebola-Sudan 330

. 10 30
.. 2538 Ebola-Zaire (conventional vac-
cine)
8
7 (
12.5) live attenuated vaccine
80


31
10

10
32 passive
immunization 33

1. Conventional vaccines
replication-deficiency Ebola virus lacking
VP30 VP30
(replication-deficient)
passive monoclonal immunization 35

34 2. Vector-Based vaccines
passive immunization (vector)
 50 657

(replication competent/defective) HPIV-343

2.3 Vesicular stomatitis virus (VSV)
VSV
VSV
2.1 Adenovirus adenovirus Human
adenovirus parainfluenza virus rVSV
rVSV
innate adaptive 44
adenovirus adenovirus rVSV expressing Ebola-Zaire GP 1
5 (Ad5) E1 adenovirus Ebola-Zaire
Ad5 (replication-defective adeno- 45 27
virus) E3 E4
3. DNA-based vaccines
Ad5 36 DNA-based vaccines
recombinant (r) Ad 5expressing Ebola-Zaire DNA DNA
glycoprotein (GP)
Ebola-Zaire cytotoxic T-cells 46
1 37
DNA-based vaccines
autoimmune disease
rAd5 expressing Ebola- integration host genome
Zaire, Ebola-Sudan [multivalent vaccine (EBO7)] DNA-based vaccines
2 DNA-
38 based vaccines vector-based
rAd5-based vac- vaccines
cine 3.1 DNA prime/ rAd5 Ebola-Zaire GP
Ad5 DNA-prime DNA vac-
Ad5 60- cine GP Ebola-Zaire, Ebola-Sudan,
8539,40 Ebola-Cte dIvoire NP Ebola-Zaire
2.2 Human parainfluenza virus 3 (HPIV-3) 3 rAd5 expressing Ebola-
rHPIV-3 expressing Ebola-Zaire Zaire GP DNA prime/ rAd5
GP + NP Ebola-ZaireGP Ebola-Zaire
Ebola-Zaire 41,42 47
rHPIV-3-based vaccine 3.2 DNA prime/rAd5 expressing Ebola-Zaire,
rAd5-based vaccine Ebola-Sudan GP
658

2.
GP
Ebola-Sudan Ebola-Zaire GP
Ebola-Bun-
dibugyo .. 2551 406
DNA prime/rAd5 expressing Ebola-Zaire,
Ebola-Sudan GP
(cross protective heterogenus species)48

1.
2.
4. Virus-like particles (VLPs) vaccine
3.
VP40, NP GP
4.
VLPs

live
attenuated vaccine
Ebola-ZaireVLPs
3 6
Ebola-Zaire 1000 PFU 1. Center for Disease Control and Prevention
4 [Internet]. Bioterrorism agents/diseases. [cited 2011
Ebola-Zaire VLPs March 1]. Available from: http://www.bt.cdc.gov/agent/
3 agentlist-category.asp#a
2. Jahrling PB, Geisbert TW, Dalgard DW,
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325:204-6.

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76
 663

51

1




Enterotoxigenic E. coli
enteric adenoviruses, astroviruses, human calciviruses
E. coli, Shigella
Campylobacter E. coli facul-
antigenic tative anaerobe
diversity E. coli 6
diarrheagenic E. coli2 E.
(gastrointestinal coli virulent
mucosal immunity) factor 13

1 Diarrheagenic E. coli virulent factor

Adhesins Toxins
ETEC CFA LT, STa, STb probe LT
ST toxins
EAEC AAFI, EAST1 Adherence assay probe
AAFII AAF1
EPEC EAF probe EAF adherence

STEC (EHEC) EAF Shiga-toxins HUS probe shiga toxins
EIEC EAF probe invasin

: AAF = adherence fimbriae, CFA = colonizing fimbriae, EAEC = enteroaggregrative E. coli
EAF = EPEC adherence factor, EAST = E. coli aggregrative secretory toxin, EHEC = enterohemorrhagic E. coli, EIEC =
enteroinvasive E. coli , EPEC = enteropathogenic E. coli , ETEC= enterotoxigenic E. coli, HUS = hemolytic uremic syndrome,
LT = heat-labile toxin, ST = heat-stable toxin, STEC = shiga-toxin producing E. coli
( 3)
664

cross protection 5 CFAs receptor

Enterotoxigenic E. coli ( ETEC) enterocyte enterotoxin 2
heat labile toxin (LT) heat stable toxin ( ST)
5 LT cholera toxin (CT)
70-80 1 A subunit 5 B subunit LT
ETEC 280-400 adenylate cyclase intracellular cyclic AMP
2 ETEC secretory diarrhea LT
( 20-70) ST peptide toxin
(traveler diarrhea) ETEC 18-19 amino acid ST immuno-
genic candidate immunogen
(foodborne outbreak)3

ETEC
ETEC (natural history)
(fecal-oral route) ETEC
108 109 ETEC

cholerae ETEC ETEC
fimbriae colonization
factor antigens (CFAs) coli surface antigens
(CSs) CFAs ETEC ETEC candidate vaccine
20 7 (inactivated ETEC vaccine)
CFA/I CS1 CS64 (live candidate vaccine)
fimbriae ETEC
1. ETEC
fimbirae 26

2 ETEC
ETEC
Toxoids (CTB, LT, mutant LT, LTB, CTB/LTB hybrid) transcutaneous
Inactivated CF-expressing whole bacterial cell + toxoid
Purified CFs CF tip proteins transcutaneous
Heat-stable enterotoxin toxoids transcutaneous
: ETEC= enterotoxigenic Escherichia coli, CF = colonization factor, LT = heat labile toxin,
CTB = cholera toxin subunit B, LTB = heat-labile toxin subunit B
( 6)
 51 665

6-18 350
- Cholera-ETEC vaccine whole cell 1
killed vaccines rCTB-killed
Goteborg formalin- ETEC vaccine
killed ETEC 5 strains express fimbriae 6 protective antigen CFA
CFA/I CS1-CS6 recombinant technology10,11 LT
recombinant cholera toxin B subunit (rCTB) toxoid hybrid LTB/CTB toxoid (
2-12 cholera ETEC) mucosal
7 adjuvant LTR192G/L211A strong
intestinal lavage antibody secreting cells (ASC) adjuvant activity
sublingual
rCTB fimbrial
endemic area (mucosal vac-
cine)12
rCTB-killed ETEC vaccine
2. ETEC
ETEC
828 placebo-controlled phase III 36
trial - Live attenuated ETEC vaccine
genetically attenuated ETEC vector
ETEC 779 ETEC immunogenic ETEC

3 ETEC
Vaccine approach prototype
Attenuated nontoxigenic ETEC bacteria ACE Biosciences
expressing colonization factor
Hybrid Shigella/ETEC live vector vaccine Center for Vaccine Development ( CVD)

Vibrio cholerae Peru 15 expressing Avant Immunotherapeutics
cholera toxin subunit B
Salmonella expressing heat-labile toxin Emergent Biosolutions
subunit B
Vibrio cholerae CVD 103-HgR expressing Berna Biotech/Crucell
CS3
: ETEC= enterotoxigenic Escherichia coli, CS = coli surface antigen
( 6)
666

deletion mutation aroC, ompC, ompF ex- 17,18

press CS2 CS3 CS1+CS2+CS3 cholera
phase I mucosal immunity vaccine 6-18
CF 13,14 3 3
strain ACM2023, ACM2025, ACM2027 3
express LTB CS4-CS6, CFA/1 CS1-CS3 19

immunogenicity
Shigella species
- Multivalent Shigella/ETEC vaccine
attenuated Shigella 5 Shi-
gella dysenteriae 1, S. flexneri 2a, S. flexneri 3a, Shigella family Entero-
S. flexneri 6 S. sonnei live vector bacteriaceae, non-motile, nonencapsulated Shigella
express ETEC CFA/I, CS1-6 4 A (S. dysenteriae), B
LT ETEC (S. flexneri), C (S. boydii) D (S. son-
nei) serotype O
systemic IgG mucosal IgA 47 O
ETEC Shigella 15,16 lipopolysaccharide
outer membrane protein lipopoly-
saccharide core oligosaccharide
lipid A
ETEC Shigella

Shigella
- Attenuated Vibrio cholerae Sal-
monella strain vector ETEC
attenuated Shi- 6
gella attenuated Salmonella serovar 10
Typhi V. cholera O1 strain express CTB/
LT B subunit CFs ETEC
S flexneri
S. sonnei 20 (
4) Shigella


Shigella
 51 667

4
Shigella

160 100,000
1.1 10,000





5
()

Serogroup (%)
S. flexneri 60 18
S. sonnei 23 72
S. dysenteriae 10 2
S. boydii 6 1
( 20)

epithelium cell transcy-
tosis M cells lymphoid follicles
1. Live attenuated Shigella vaccine
- S. flexneri 2a, SC602
S. dysenteriae Shiga toxin 88 79 8-10
hemolytic uremic syndrome5 1

LPS
Shigella 21
- FS bivalent vaccine
S. sonnei
O Shigella invasion plasmid S. Flexneri 2a22
Shigella vac-
cine Shigella 65-75
5 LPS Shigella vaccine 1-3

668

17,500 response)

(passive surveillance) 5-6
S. flexneri, S. sonnei multivalent vaccine S. flexneri 2a,
Shigella 61-65, 50-72 S. sonnei S. dysenteriae126
48-52

Shiga-toxin producing
E. coli (STEC)5
2. (killed whole cell) subunit vaccine

- Shigella LPS conjugate vaccine E. coli lysogenized phage encode
3 1,5 Shiga toxin Shiga-toxin producing E. coli
S. dysenteriae type 1 LPS conjugate (STEC) enterohemorrhagic E. coli (EHEC)
tetanus toxioid
S. flexneri 2a LPS conjugate recom-
binant Pseudomonas exoprotein A STEC serotype O157:H7
S.sonnei LPS conjugate exopro- (endemic)
tein A
3 STEC serotype O157:H7
100


- invasin
invasin extracellular protein
23 inva- 27
sion complex vaccine S. flexneri
S. sonnei
STEC colonize
challenge homologous strain STEC STEC
(bivalent vaccine) serotype O157:H7
2 24,25 hemorrhagic colitis Shiga toxin
S. flexneri 2a Invaplex50 32
3 2 hemolytic uremic syndrome (HUS)
20
(systemic and mucosal immune intestinal
 51 669

perforation cerebro-vascular accident28 microaerophilic spiral

s
flagella genus Campylobacter 14 species 7
STEC
subspecies C. jejuni
STEC serotype O157:H7 C. coli C. upsaliensis, C.
O157 lari C. fetus
polysaccharide capsular type O

Campylobacter

5
- E. coli O157:H7 Type III secreted protein
vaccine
type III-secreted supernatant protein
entero-hemorrhagic E. coli
29 3 4
3 2
36.5 ETEC
32
9930 Bioniche Life
Science Inc.

coloniza-
tion Campylobacter
terminal
STEC31 ileum enterotoxin
noninflammatory diarrhea
epithelium
Campylobacter dysentery inflammatory diarrhea
epithelium lamina propria
Campylobacter mesenteric lymph node
Campylobacterales 2 families mesenteric lymphadenitis
Helicobacteraceae, Campylo bacteraceae
genera Campylobacter, Arcobacter Campylobacter
Sulfurospirillum Campylobacter Guillain Barr syndrome
670

5,33

1. Girard MA, Steele D, Chaignat CL, Kieny
MP. A review of vaccine research and development:
Campylobacter
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LT 4. Peltola H, Siitonen A, Kyrnsepp H, Simula
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Med. 2000;7:27-9.
9. Sack DA, Shimko J, Torres O, Bourgeois
AL, Francia DS, Gustafsson B, et al. Randomised,
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cherichia coli and Vibrio cholera strains expressing
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11. Tobias J, Holmgren J, Hellman M, Nygren
E, Lebens M, Svennerholm AM. Over-expression
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of Escherichia coli O157:H7 by cattle following
vaccination with type III secreted proteins. Vaccine.
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30. Peterson RE, Klopfenstein TJ, Moxley
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Effect of a vaccine product containing type III secreted
proteins on the probability of Escherichia coli O157:H7
fecal shedding and mucosal colonization in feedlot
cattle. J Food Prot. 2007;70:2568-77.
31. Alfredo GT. Intestinal pathogenic Es-
cherichia coli. In: Barrett ADT, Stanberry LR, editors.
Vaccines for Biodefense and Emerging and Neglected
 673

52

(prophylactic vaccine)

/ (therapeutic
.. 2524 vaccine)
25
60



.. 2527


(envelope)






(virologic and immunologic challenges)
20


674

trimer N-linked glycosylation

conserved epitope
highly immunogenic variable
1 loop
reverse transcriptase conserved region
chemokine receptor binding site
CD4
HIV-1 receptor 3
M N-linked glycans
9 clades circulating recombinant forms NAb
(envelope, broadly reactive
Env) clade NAb activity
20 envelop clade conserve region Env glycoprotein
351,2 CD4 binding site4

NAb
conserved
region membrane proximal external region (MPER)
gp41 epitope lipid
membrane viral entry


nonhuman primate (immunogen)

immunogen broadly
reactive NAbs broadly reactive
monoclonal antibodies
HIV-1 specific humoral immunity nonhuman primate
broadly
virus-specific neutralizing antibody reactive NAbs immunogen
(NAb) titers HIV-1 Env
subunit immunogens (engineered antigens)
Env Env trimers Env immunogen
broadly reactive
NAbs HIV-1 Env glycoprotein immunogen
 52 675

CD4 binding site, MPER structurally macaque

conserved element V3 loop Simian immunodeficiency virus (SIV)
non-neutralizing antibodies chimeric SHIV
antibody-dependent cell-mediated virus neutralizing antibody
inhibition, complement activation phagocytosis 7
macaque
HIV-1 specific cellular immunity (homologous
T lymphocyte virus challenge) 8

9
virus-specific CD8+T lymphocyte (CTL) SIV

5
long-term nonprogressors6
specific HLA alleles Gag- 2 10
specific T-lymphocye response 1. Traditional strategies
live attenuated virus, whole killed
cellular immune response virus protein subunits

CTL
epitopes T lymphocyte
epitope live attenuated virus11,12
T lymphocyte (breadth) whole killed
virus13 protein subunits14
neutralizing antibodies
T lymphocyte CD8+ T lymphocyte response
Toll-like
receptor adjuvants protein subunit
15
2. Novel strategies
plasmid DNA vaccine lived recombinant vector
HIV-1 antigen

(animal model) 2.1 DNA vaccine

676

16
(adjuvant) 4.
DNA vaccine
in vivo electroporation
2.2 recombinant vectors attenuated
replication-incompetent viruses 5.
Adenoviruses poxviruses virus
vectors heterologous DNA prime,
vector boost


virus vectors 18
vesicular stomatitis virus (VSV),
adeno-associated virus (AAV), Venezuelan equine
encephalitis (VEE) virus, cytomegalovirus (CMV), 1 .. 2530
herpes simplex virus (HSV) measles virus NAbs recombinant
bacterial vectors Samonella, soluble monomeric gp120 gp16019
Listeria BCG broad NAbs
17 DNA
1. viral vector CD8+ CTL
STEP study20 rAd5 vector
CTL
( IFN
)



2. broadly neutralizing
humoral immunity broadly reactive effective cell-
mediated immunity RV144


3.
(whole-killed) 160
(attenuated) (www.iavireport.org/trials) 4
 52 677

2b 3
AIDSVAX B/E (VAX003)
3 .. 2546 14 AIDSVAX B/B adenovirus serotype 5 (Ad5)
(VAX004) 3 4 20
21
18
gp120 clade B E AIDSVAX B/E epitopes
NAbs long-term
AIDSVAX B/B nonprogressor elite controller
STEP study
T-cell-based vaccine
CTL
IFN HIV antigen
22
NAbs IFN
in vitro HIV inhibition assay24

2b STEP (HVTN 502)
macaque nonhuman primate (NHP)
Phambili (HVTN 503)

CTL MRKAd5 gag/pol/nef
homologous prime-boost regimen (STEP study)
.. 2550

Ad5 vectors
Phambili study
STEP 3
study T lymphocyte IFN
enzyme-linked immunosorbent spot (ELISPOT) RV144 vaccine study25
77 23
31.2
1 2 community-based, randomized, multicenter,
double-blind, placebo controlled efficacy study
prime-boost
678

strategy recombinant canarypox vector somatic hypermutation

vaccine, ALVAC-HIV (vCP1521) 4 3-4 NAbs
recombinant glycoprotein
120 subunit vaccine (AIDSVAX B/E) 2 immunogen
NAbs
16,402

HIV-1 immunobiology

40.4 47.6 1)

3.7 2) vector
3)
CD4+ T cells

T-cell-receptor cytokine
NAb immunogen
NAb
(heterogenous strains)


antibody-
dependent cell-mediated cytotoxicity (ADCC)
1. Gaschen B, Taylor J, Yusim K, Foley B,
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chimpanzees from infection by HIV-1 after vaccination
with recombinant glycoprotein gp120 but not gp160.
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9. Connor RI, Korber BT, Graham BS, Hahn
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2008;372:1881-93.
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identifies broadly neutralizing human monoclonal
antibodies to HIV-1. Science. 2010;329:856-61.
 681

53

(intramuscular, IM)
(subcutaneous, SC)


1
1
Immunization route Advantages Disadvantages
Parenteral Powerful systemic immune Invasive
response Limited mucosal immune
Accurate dosing response
Nasal Non-invasive Mucociliary clearance
Mucosal and systemic immune Inefficient uptake of soluble
response antigens
Easily accessible Application device needed
Little degradation (compared to
oral)
Oral Non-invasive Vaccine digestion in stomach
Mucosal and systemic immune and gut
response Inefficient uptake of soluble
Large surface area antigens
Mucosal tolerance
Pulmonary Non-invasive Delivery of antigen highly variable
Mucosal and systemic immune from
response person to person
Little degradation (compared to Dry powder inhaler or nebulizer
oral) needed
Clearance from lungs
Dermal Non or minimally invasive May require (minimally) invasive
Large, easily accessible technology
application area (e.g. tattooing, microneedles)
High density of immune cells in Patch or application device
skin needed
Mucosal immune response Less established technology
possible
( 13)
682

Langerhans cell (LC) (epidermal

(Transcutaneous vaccination) langerhans cell)
immature LC kerati-
nocyte epidermis process
epidermis, dermis antigen immature LC
subcutaneous tissue 1 epidermis mature LC
stratified squamous epithelium MHC class II mature
barrier stratum corneum LC T cell
keratinocyte1
epidermis dermis
1.5-3 . fibroblast skin
organelles
dermis nitroglycerin
subcutaneous tissue

(abrading,
scraping) vibrating permeability


keratinocyte pro-inflammatory 22
cytokine interleukin 1
antigen presenting 1. Stripping and abrading
cell (APC) MHC
class II ICAM-13

1 epidermis, dermis subcutaneous tissue barrier

stratum corneum ( 2)
 53 683

2
(transcutaneous vaccination)
( 2)

2. Electromagnetic energy

ultrasonic
(Respiratory vaccination)
(keratinocyte)4-6
3. Kinetic deposition mucosal
immunity mucosal
Jet injection (JI) immunity
systemic immunity
7
mass vaccination mucosal
8,9 8 immunity
JI
10,11 (herd
immunity)
(adjuvant)
alum
JI
delayed local reaction 8,12

track epithelial cell, intraepithelial DC, macrophage
microfold (M) cells
M cell specialized epithelial cell

684

endocytosis DC lym- intraepithelial DC alveolar macrophage

phocyte process antigen APC
Lymphoid organ
B cell plasma cell IgA
M cells 14
deposition
posterior nasal passage immune response immune tole-
rance15 immune tolerance
(nasal
vaccine delivery) 313 (state of unresponsiveness)

tolerance
(mucosa)
(mucosal vaccine)

unresponsiveness


16


3

(nasal vaccine delivery)
(1) (mucoadhesion) 17
(2) uptake M-cell DC
(3) activation maturation DC
(4) B-cell T-cell

( 13) AccuSprayTM (Becton Dickinson
and Company, US) syringe



3
powder device inactivated
mutant diphtheria toxoid CRM197 Norwalk
virus liquid delivery device
 53 685

diphtheria and influenza18 7. Hingson RA, Figge FH. A survey of the

development of jet injection in parenteral therapy. Curr
Res Anesth Analg. 1952;31:361-6.

8. Ruben FL, Smith EA, Foster SO, Casey HL,

Pifer JM, Wallace RB, et al. Simultaneous administra-
tion of smallpox, measles, yellow fever, and diphtheria-
pertussis-tetanus antigens to Nigerian children. Bull
World Health Organ. 1973;48:175-81.
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Carrasco PA, da Silveira CM. Measles eradication:
experience in the Americas. Bull World Health Organ.
1998;76(Suppl 2):47-52.
10. Reis EC, Jacobson RM, Tarbell S, Weniger
BG. Taking the sting out of shots: control of vaccina-
tion-associated pain and adverse reactions. Pediatr
Ann. 1998;276:375-86.
11. Mitragotri S. Current status and future
prospects of needle-free liquid jet injectors. Nat Rev
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Pharm. 2001;224:1-18. 12. Parent du Chatelet I, Lang J, Schlumberger
2. Bal SM, Ding Z, van Riet E, Jiskoot W, M, Vidor E, Soula G, Genet A, et al. Clinical immu-
Bouwstra JA. Advances in transcutaneous vaccine nogenicity and tolerance studies of liquid vaccines
delivery: do all ways lead to Rome? J Control Release. delivered by jet-injector and a new single-use cartridge
2010;148:266-82. (Imule): comparison with standard syringe injection.
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in epidermal immune responses. Curr Opin Allergy Clin 13. Slutter B, Hagenaars N, Jiskoot W.
Immunol. 2001;1:469-76. Rational design of nasal vaccines. J Drug Target.
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Ultrasound-mediated transdermal protein delivery. 14. Neutra MR, Kozlowski PA. Mucosal vac-
Science. 1995;269:850-3. cines: the promise and the challenge. Nat Rev Im-
5. Mitragotri S, Kost J. Low-frequency sono- munol. 2006;6:148-58.
phoresis: a review. Adv Drug Deliv Rev. 2004;56:589- 15. Mestecky J, Moldoveanu Z, Elson CO. Im-
601. mune response versus mucosal tolerance to mucosally
6. Lavon I, Kost J. Ultrasound and transdermal administered antigens. Vaccine. 2005;23:1800-3.
drug delivery. Drug Discov Today. 2004;9:670-6. 16. Borges O, Lebre F, Bento D, Borchard
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G, Junginger HE. Mucosal vaccines: recent progress

in understanding the natural barriers. Pharm Res.
2010;27:211-23.
17. Sharma S, Mukkur TK, Benson HA, Chen
Y. Pharmaceutical aspects of intranasal delivery of
vaccines using particulate systems. J Pharm Sci.
2009;98:812-43.
18. Jabbal-Gill I. Nasal vaccine innovation. J
Drug Target. 2010;18:771-86.
 687

gene-based vectors

54
1



regulatory sequences
native conformation
inactivated virus recombinant
gene-based vectors (DNA protein
vaccine)


CD4 CD8
(preclinical disease models)

live-attenuated viruses

3




gene-based vectors




(DNA vaccine)

12
688
1
(innate immunity)
helper T cells, cytolytic T lymphocytes
(CTLs)


(viral vectors)
attenuated viruses
(mucosal delivery)




(prime-boost)

( 2)

3
envelope (Env)
(antigen processing)
Cytolytic T lymphocytes (CTLs)
major histocompatibility complex (MHC) class I
(cellular immunity)


4

CTLs (humoral response) (cellular
CTLs response)

CTLs MHC
class I CTLs
helper T cells (Th) 5



 54 gene-based vectors 689

(adaptive immunity) CTLs, helper T cells expression vectors
(innate immunity)
(adjuvants)

(preclinical enhancer/promoter
study)
6
DNA plasmids DNA 2
plasmids gene-based
vectors







(potency) CTLs

2 gene-based vectors

cellular
humoral
vectors packaging cell lines
viral vectors
vectors
viral vectors

vectors
prime-boost

(prime-boost)
690

DNA
plasmids
(lymphoma) plasmids
T-helper cells plasmids

formulation Vaxfectin
adjuvant
7
Th1 T helper cells8 DNA plasmids
microparticles 1-10
32 antigen-presenting cells (APCs)
DNA plasmids
(Delivery of DNA 9
vaccine)

plasmids Salmonella Shigella10,11
(formulations)
transfection (viral vectors)
(bacterial vectors) APCs

3

Viruses Bacteria
HIV Influenza B. Burgdorferi
Rabies Hepatitis B, C C. Tetani
Ebola Herpes simplex S. Typhi

Parasites Cancer
Malaria Breast (Her2/neu) Myeloma
Leishmania Colon Lymphoma
Schistosoma Prostate Fibrosarcoma

Allergy Autoimmune diseases

House dust mite Diabetes
Peanut

( 2)
 54 gene-based vectors 691

19
12
13 Mycobacterium tuberculosis
14 SIV/HIV
15 Bacil-
lus of Calmette and Gerin (BCG)
gene gun BCG
gold beads DNA plasmids 20 BCG
BCG
CTLs, Th cells
DNA plasmids
hepatitis B surface antigen (HBsAg) polyvalent booster BCG
16
mycobacteria
recombinant HBsAg hepatitis 15 18 BCG21
DNA vaccine gene gun
17 (booster) BCG
gold beads
3

gold beads infectious hematopoietic necrosis virus (IHNV)
Biojector plasmids 22 West Nile virus 23
APCs 18 4




Rabies virus, Filovirus, Flavivirus, Togavirus,
Bunyavirus
anthrax


nucleoprotein
(prime) recombinant adenovirus
(boost) (host genome)
692

4

West Nile-Innovator West Nile virus 2005
Apex-IHN Infectious
haematopoietic 2005
necrosis virus
Oncept Melanoma 2010

( 2)

tolerance
24





prime-boost


viral vectors

HIV adenovectors25 modified
vaccinia Ankara (MVA) 26


MVA27

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 54 gene-based vectors 693
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694

served nucleoprotein. Vaccine. 2005;23:5404-10. V. PTEN c.511C>T nonsense mutation in a BRRS

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tana J, Sinthuwiwat T, Tongkobpetch S, Shotelersuk
 695

55

(adjuvant)

(Live vaccine)







(attenuation of virulence)

()

(vector)
696

cell-mediated immune response vaccinia

vaccinia






(reversion) (Serial passage in cell culture)



(attenuation) ()
(overattenuated)
(serial passage)
(underattenuated)
(unnatural cell
substrate)












(oral poliovirus vaccine) Albert Sabin
 55 697

(yellow fever vac- 8,9
cine) 17D
58
(Japanese encephalitis (over attenuation)
vaccine) SA14-14-2
100
(primary hamster kidney cell)
1 SA14-14-2 1
(measles vaccine)
(mumps vaccine) -
(varicella-zoster vaccine)
89-12 2
SV40
porcine circovirus 10

(Reassortment)



(segmented RNA genome)

3

Sabin
10-56
480, 481 472
5
1, 2 3 4-7
2 16681
primary dog kidney 53

53
5
NS1 NS3
698

PR8 17
(RRV-TV)
4
rhesus hemagglutinin neuraminidase
RRV
18
G1, G2 G4
G3
11-13 (RV5 PRV)
WC3
-
5 (Temperature-selected mutant)
G1, G2, G3,
G4, P(8) 13-15 (cold-adapted
strain)
(temperature-sensitive mutant)
RRV-TV cold-adapted strain
(intussusception)

cold-adapted strain
(rubella virus vaccine)
MMR
RA27/3 WI-38
MRC-5 30.19

16

reassortment segmented genome
20,21

25.
25.



 55 699

23
hemagglutinin neuraminidase
18






8,9
respiratory syncytial virus
22


(Generation of recombinant virus) 8

messenger RNA
point mutation

24,25











1 4
(deletion) 3
30
700

hemagglutinin
30
furin
chimeric virus


26,27

(mosaic virus)

Japanese encephalitis virus herpes simplex
(chimeric virus) 1 2
herpes
Flaviviridae28 simplex 31
17D single cycle virus
prM E
Japanese encephalitis
virus
Japanese encephalitis virus
8

28

Japanese encephalitis virus
(trans-complement)
recombination (
)
West Nile virus
29


4



 55 701

(
) poxvirus vaccinia

receptor vaccinia
33,34

fowlpox canarypox

single cycle virus adenovirus herpes
virus
capsid poxvirus
Vesicular stomatitis virus
capsid alphavirus Sindbis

32
35

(Recombinant viral vector)


()
adenovirus vector pox virus vector
(vector) prime-boost strategy
36,37

HIV-1




ALVAC HIV-1 (vCP1521)
canarypox
gp160 gag pro HIV-1
702

(booster) gp120
(Mutagenesis)

cell-mediated immune response
gamma interfer-
on
HIV-1 Salmonella typhi Ty21a
38 galactose
adenovirus serotype 5 gag, pol,
nef 39 HIV-1 45
46,47
ovine atadenovirus40

(Generation of recombinant bacteria)
(Serial passage)








BCG
Mycobacterium bovis Vibrio cholerae
231 13 BCG Inaba 569B subunit A
cholera toxin CVD 103-HgR
BCG 48
49
41
BCG 50
BCG
42,43
44
Peru-15 Vibrio cholerae O1 El Tor Inaba
 55 703

ctxA, rtxA, zot ace (Inactivated bacteria)

toxin recA
cholera toxin B subunit
recombination
flagella51,52
thimerosal phenol
(whole cell)
innate
immunity
(Recombinant bacterial vector)
WC
Vibrio cholerae biotype
Salmonella typhi, Vibrio cholerae, classical El Tor serotype Inaba
Salmonella flexneri, Listeria monocytogenes, Ogawa formaldehyde
BCG Streptococcus gordonii WC-BS Vibrio
Salmonella typhi, cholerae cholera toxin B
Vibrio cholerae, Salmonella flexneri subunit
BCG 53,54
WC-BS WC
cholera toxin B subunit toxin
(Inactivated vaccine) enterotoxigenic E. coli WC-BS

enterotoxigenic E. coli

(Inactivated virus)



adjuvant


cell-mediated formaldehyde
immune response adjuvant


704

1. (Protein-based)








Bordetella
Japanese encephalitis virus pertussis
SA 14-14-255
formaldehyde glutaraldehyde
(Subunit vaccine)












(genetic inactivation) 56

Haemophilus
influenzae57 cholera toxin
B subunit
B subunit
WC-BS

A subunit
 55 705

53,54



circumsporozoite
Plasmodium falciparum
HBsAg Saccharomyces
cerevisiae HBsAg RTS,S
22 61
(virus-like particle)
58 adjuvant conformational epitope



papillomavirus L1 adjuvant
RTS,S
59,60 circumsporozoite fusion protein
HBsAg
papilloma adjuvant 62
3. (Carbo-
hydrate-based)

fusion protein

(antiphagocytosis)





2. (Peptide-based)



T-independent
706

2

T-dependent response CpG innate
immunity codon
(codon optimization)

T-dependent
tetanus toxoid, diphtheria toxoid,
diphtheria toxoid CRM197
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 715

56

1,2

(primary congenital immunodefi- 1.
ciency diseases) x-linked agammaglobulinemia,
chronic granulomatous disease
(secondary
immunodeficiency disease) Pneumococcal vaccine
Inactivated influenza vaccine
Hib vaccine
2.
inactivated vaccine



3.
2

4. BCG,
OPV, MMR, Varicella, MMRV, live JEV, Rota virus,
(inactivated vaccines) live attenuated influenza vaccine (LAIV), Zoster, yel-
low fever, Ty21a typhoid
(
(live attenuated vaccine) 1,2
)
5.



716

(cocooning strategy) cell-mediated im-
munodeficiency severe combined
OPV Small pox immunodeficiency (SCID)


MMR, varicella rotavirus
vaccine
phagocyte
chronic granulomatous disease
rotavirus vaccine (live attenuated
virus vaccine)
(live attenuated bacterial vaccine) BCG
Ty21a typhoid vaccine
6. passive immunization im- complement deficiency
mune globulin
S.
3 pneumoniae N. meningitidis
1 meningococ-
cal vaccine

serogroup B
4


(Pri-
mary immunodeficiency)


11 -
humoral immunodeficiency 2 ././ 20 ./
10 .
14
(intravenous
immunoglobulin; IVIG)
1,2
IGIV 1.
 56 717

1 1


B-lymphocyte BCG, OPV, live Pneumococcal vaccine
(humoral) ( x-linked typhoid vaccine, ( measles/
agammaglobulinemia yellow fever vaccine, MMR varicella IVIG
common variable smallpox live- vaccine)
immunodeficiency) attenuated influenza measles
vaccine varicella vaccine
( selective OPV, BCG Pneumococcal vaccine
IgA deficiency IgG yellow fever vaccine
subclass deficiency)

T-lymphocyte (cell- Pneumococcal vaccine
mediated and humoral) ( severe *
combined immune
deficiency
complete DiGeorge Pneumococcal vaccine
syndrome) *

(
DiGeorge syndrome
Wiskott-Aldrich
syndrome, ataxia-
telangiextasia)
Complement Complement, Pneumococcal vaccine
properdin meningococcal
factor B vaccine
Phagocytic function Chronic granulomatous Pneumococcal vaccine
disease, leukocyte *
adhesion deficit
myeloperoxidase
deficiency
* 1. : BCG, oral typhoid vaccine 2. : OPV, MMR, MMRV,
live-attenuated influenza vaccine, yellow fever vaccine, rotavirus vaccine, varicella vaccine, zoster vaccine, smallpox vaccine

therapy) physiologic maintenance

3.
( 2 ././
20 ./
1
2. (replacement 10 .)
718

(anatomical asplenia)
4.
( 2 ././ (functional asplenia)
20 (encapsulated
./ bacteria) S. pneumoniae, Hib
10 .) N. meningtidis 5-9
14 S. pneumoniae Hib1,2,9,10
2 3
Meningococcal vaccine
2


5.
( 2 ././
20 ./
10 .) 10

1 (elective splenectomy)
6. S.pneumonia Hib
14 1,10

1







10

14
2 14


3

 56 719

2 Pneumococcal vaccine
5,6

Pneumococcal vaccine
2-6 3 PCV13 2 1 12-15
7-11 2 PCV13 2 1 12-15
(PCV 13 2 2 )
12-23 2 PCV13 2
23-71 PCV PS-23 2 PCV13 8
PS-23 1 PCV13 8 PS-23
1 5 PS-23
PCV 1-3 1 PCV13
PS-23 1 PCV13 8 PS-23 1 5
PS-23
* < 2 PCV13 24-71 PCV PCV13 2
8 6-18 PCV13 1 PCV7 PS-23

3 Hib vaccine
7,11

2-6 3 2 12-15
7-12 2 2 12-15 2 2
12-14 2 2
15-59 1
5 * 1 Hib vaccine
* Hib vaccine Hib vaccine
1 Hib vaccine 2

1,10 4
haemagglutination inhibition (HI) titer > 32
(Inactivated Influenza vaccine) 25-52
2
12 50-86
Cochrane reviews 200913 71-81


708

720

1 15 Esposito 14


1 13 4

2,14
3-4
neutrophil lymphocyte 1000 /
..32
14


3-6 2,14
2
3 (remission) hematopoietic
1 lymphocyte > 700 ablative therapy
/.. > 100,000 /..14 graft versus host disease (GVHD)
16,17

18 19 S.pneumoniae20
21
1-10
autologous al-
Centers for Disease Control and Prevention logenic 22-25




immune memory 2

acute lymphoblastic leukemia 26-29
 56 721

4 14


MMR 2 3 1
3-6 3-6
VZV 2 3 1 (remission)
(remission) 1 1
lymphocyte > 700/.. lymphocyte > 700/..
> 100,000/..; > 100,000/..;
maintenance 1 maintenance
1
RV
OPV IPV IPV
DTP, < 7 primary series (3 1
DTaP-IPV, 1 ) 2 3
Tdap-IPV 6 3
> 7 primary series (0, 1, 6 )
3
Tdap dT 2
3
Hib primary series 1
3 3
Pneumococcal primary series PCV PS-23 1
vaccine (PCV 8 > 2 3
PS-23) 3
Inactivated 2 1 1
influenza < 9 1
vaccine
HAV 2 6 1

HBV 3 (0,1, 6 ) 2 3

Inactivated 3 (0,1,12 ) Live JEV
JEV 3

3-12
polymorphonuclear cells, monocytes natural killer rituximab B-cell
cells 2-3 lymphocyte 6 31
T-cell B-cell 30 B-cell B-cell
1-3
722

T-cell B-cell
1-3 (CD4 (Solid Organ Transplantation; SOT
< 200/..) T-cell candidates and recipients)
CD4+ T cell 18
CD4 35
200/.. 6-9 71
GVHD
GVHD 2 36,37
CD4 >200/.. T-cell
memory T-cell


nave T-cell
6-12 1
16
immunoglobulin 35,38
32

38
(autologous, allogenic, umbilical cord transplantation)
6

516
(inactivated 6
vaccine) 6 graft dysfunction rejection

6
24 1,2,33 32,39
GVHD
6

GVHD
6
GVHD34 35,39
GVHD 12-15
12 32 39
 56 723

5 16,33



Pneumococcal vaccine1 3-6 3-4 PCV13 0, 2, 4 PS-23
8 PCV 3
Diphtheria, tetanus 6-12 3 < 7 DTP/DTaP 0,
Pertussis2 2,12 > 7 DTaP 0,
2,12
Hib3 6-12 3 0, 2,12
IPV 6-12 3 0, 2,12
HBV4 6-12 3 0, 2,12
Inactivated influenza 4-6 1-2
vaccine5
MMR6 24 1-2 0, 1
HAV 2 2 0, 6-12
Inactivated JEV 12 3 0,1-2,12
Varicella vaccine7 24
BCG
OPV
Rotavirus vaccine
1
PCV 3 3-6 8 (
4 ) PS-23 1 8 PCV 3
GVHD PCV 4 PS-23 16
2

DTaP DTP 3 > 7 DTaP
Tdap
autologous allogenic Tdap16
3
Hib 3 1 6
4
(Anti-HBS Antibody) 1 HBV 3
HBV 3 16
5
(inactivated influenza vaccine) 6

4 6 2
6 9 2
1 2,16
6
MMR 2 1 16
7
Varicella vaccine
24 16,17
724

6
(Solid Organ Transplantation; SOT candidates and recipients)38

SOT SOT
6 1 2 4
(DTP/DTaP) 1 2 3 4
3 4 6
4 5 6
(HAV) 2 6 1 2 4
(HBV) 1 2 4
2 3 8
(Hib) 6 1 2 4
2 3 4
3 4 8
(Influenza)3 6 1 2 4
(PCV7)4 6 1 2 4
2 3 4
3 4 8
(PS-23) 2 -
(IPV)5 6 1 2 4
2 3 4
3 4 6
(BCG) -
6 1 2 4

(MMR)
(VZV) 6 1 2 4
1
Td 10 38
2

6
38
3
9
2 4 1 38
4
PCV PS-23 1 2
PCV 8 PS-23 1 3-5
38
5
OPV 1

 56 725

1. National Center for Immunization and

39 Respiratory Diseases. General recommendations on
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 729

HIV-exposed babies 57

2


1.

2.

3.

4. (BCG)

1




1:

( 1)



DNA Polymerase Chain Reaction (PCR)
1-2
4-6

730

1a :
17

1 2 4 6 9 12 18 2-2 4-6 11-12
Tuberculosis(1) BCG
Hepatitis B(2) HBV1 HBV2 (HBV) HBV3
Diphtheria, tetanus,
pertussis(3) DTwP1 DTwP2 DTwP3 DTwP4 DTwP5 dT
Polio(4) OPV1 OPV2 OPV3 OPV4 OPV5
or IPV1 or IPV2 or IPV3 or IPV4
Measles, mumps,
rubella(5) MMR1, (MMR2) MMR2
Japanese JE1, JE2
encephalitis(6) 4 JE3

Diphtheria, tetanus,
pertussis
( 4 ; DTaP, DTaP1 DTaP2 DTaP3 DTaP4 DTaP5 Tdap
4 ; Tdap)(3)
Japanese B JE4
(4-5
encephalitis(6) JE3)
Haemophilus influenza Hib3
Hib
(
type B(7) Hib1 Hib2 PRP-T)
Hepatitis A(8) HAV1, HAV2 6-12
Varicella(9) VAR 2 3
Influenza(10) Influenza vaccine 6
Pneumococcal (11) PCV4
(PCV PS23) PCV1 PCV2 PCV3 12-15 PS23 2 3-5
Human papilloma HPV 3
0,1-2,6
virus(12)

9-26

DNA PCR 1-2 2:

( 1)

2



1-5

 57 HIV-exposed babies 731

1b : Hib 17

PRP-T, HbOC PRP-OMP
2 - 6 0, 2, 4, Booster 0, 2, Booster
7 - 11 0, 2, Booster 0, 2, Booster
>12 - 59
Booster 12-18 2

1c : PCV 17

2-6 3 6-8 12-15
7-11 2 6-8 12-15
12-23 2 6-8
24-59
1
2 6-8

(1) BCG

(2) HBV DTP-HBV 2, 4, 6
(3) DTP DTwP DTaP (Tdap) 1
(4) Polio vaccine IPV OPV IPV

(5) MMR (clinical stage C CD4 15)
MMR2 1 MMR1 4-6

(6) JE 1 3 4-5
(7) Hib 2 1 12-18
2 1b
(8) HAV 1 2 6-12
(9) VAR 1 CD4 15 2 3
(10) Influenza vaccine
9 2 1
(11) PCV 2 3 2 12-15
( 1a 1c) PS23 2 PCV
2 PS23 1 5
(12) HPV 3 0, 1-2, 6 9 26

732

14
(VAR) %CD4
15 2 3
8215
-- (MMR)

(CDC stage C WHO stage IV) CD4 (PCV) polysaccharide 23
156 valent (PS23) 2
BCG
16
BCG


BCG (systemic disseminated
BCG disease) 407-1,300 100,000
7


3:
1
14
(IPV/
OPV)8-10

IPV 1
OPV
OPV
(Vaccine associ-
ated polio paralysis, VAPP)11, 12

13
( 2a 2b)


6
 57 HIV-exposed babies 733

2a : 1-6
18

1 0 dT1, OPV/IPV1, MMR, BCG
2 1 HBV1, JE1
3 2 dT2, JE2, OPV/IPV2, HBV2
4 7 HBV3
6 12 dT3, OPV/IPV3, JE3

2b : 7-18
18

1 0 dT1, OPV/IPV1, MMR, BCG
2 1 HBV1, JE1
3 2 dT2, JE2, OPV/IPV2, HBV2
4 7 HBV3
6 12 dT3, OPV/IPV3, JE3
2 1

CD4 15
19-26

27

4: 4:







14
14

CD4 15

CD4 25
CD4 350 /.. ( > 5 )
6 19-24 CD4 15
viral suppression 400 copies/. 1
T cell B cell 3


CD4 CD4
734

3
CD4 1514

1 2 6

HBV vaccine HBV1 HBV2 HBV3 3
JE vaccine* JE1 JE2 2
Measles vaccine** MMR1 1
dT vaccine
>7 10
*

** MMR

2. Chokephaibulkit K, Plipat N, Yoksan S,

CD4 15 Phongsamart W, Lappra K, Chearskul P, et al. A com-
parative study of the serological response to Japanese
encephalitis vaccine in HIV-infected and uninfected
Thai children. Vaccine;28:3563-6. Epub 2010 Mar 11.
3. Abzug MJ, Warshaw M, Rosenblatt HM,

Levin MJ, Nachman SA, Pelton SI, et al. Immunogeni-
city and immunologic memory after hepatitis B virus
booster vaccination in HIV-infected children receiving
28 highly active antiretroviral therapy. J Infect Dis. 2009;
(TIG) (RIG)
200:935-46.
4. Madhi SA, Klugman KP, Kuwanda L,
Cutland C, Kayhty H, Adrian P. Quantitative and
qualitative anamnestic immune responses to pneu-
mococcal conjugate vaccine in HIV-infected and HIV-
uninfected children 5 years after vaccination. J Infect
1. Machado AA, Machado CM, Boas LS, Dis. 2009;199:1168-76.
Lopes MC, de Fatima Barbosa Gouvea A, de Menezes 5. Tejiokem MC, Njamkepo E, Gouandjika
Succi RC, et al. Immunogenicity of an Inactivated I, Rousset D, Beniguel L, Bilong C, et al. Whole-cell
Influenza Vaccine and Postvaccination Influenza Sur- pertussis vaccine induces low antibody levels in hu-
veillance in HIV-Infected and Noninfected Children man immunodeficiency virus-infected children living
and Adolescents. AIDS Res Hum Retroviruses. Epub in sub-Saharan Africa. Clin Vaccine Immunol. 2009;
2011 Mar 1. 16:479-83.
 57 HIV-exposed babies 735

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children. American Academy of Pediatrics. Committee 2553.
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Sirisanthana T, Sirisanthana V. Prevalence of protec-
tive antibody against measles in HIV-infected children
with immune recovery after highly active antiretroviral
therapy. HIV Med. 2006;7:467-70.
23. Aurpibul L, Puthanakit T, Sirisanthana T,
Sirisanthana V. Response to measles, mumps, and
rubella revaccination in HIV-infected children with im-
mune recovery after highly active antiretroviral therapy.
Clin Infect Dis. 2007;45:637-42.
24. Melvin AJ, Mohan KM. Response to im-
munization with measles, tetanus, and Haemophilus
influenzae type b vaccines in children who have human
immunodeficiency virus type 1 infection and are treated
with highly active antiretroviral therapy. Pediatrics.
2003;111:e641-4.
25. Tejiokem MC, Gouandjika I, Beniguel
L, Zanga MC, Tene G, Gody JC, et al. HIV-infected
children living in Central Africa have low persistence of
antibodies to vaccines used in the Expanded Program
on Immunization. PLoS One. 2007;2:e1260.
26. Rainwater-Lovett K, Moss WJ. The urgent
need for recommendations on revaccination of HIV-
infected children after successful antiretroviral therapy.
Clin Infect Dis. 2010;51:634-5.
27. Weinberg A, Huang S, Fenton T, Patter-
son-Bartlett J, Gona P, Read JS, et al. Virologic and
immunologic correlates with the magnitude of antibody
responses to the hepatitis A vaccine in HIV-infected
 737

58

1-51





4,5
( 1)

40
2-3
active immunization
(antibody)

10

severe
immunocompromised host



4
738

1
Category Elements
Assessing the health of Assessment of underlying medical conditions such as
the traveler pregnancy, immunocompromised condition,
medication, and allergies
Assessment of immunization history
Assessing the health risk of Season of travel
travel Itinerary Duration
Reason for travel
Style of travel, rural or urban
Planned activities
Risks of exposure
Preventive advice Vaccine-preventable illness
Travelers diarrhea prevention and self-treatment
Malaria prevention
Insect avoidance measures
Other vector-borne and water-borne illness
Personal safety, behavior, and sexual health
Educate on sexual transmitted diseases, bloodborne diseases
Environmental illness (related to altitude, heat, cold, swimming, and diving)
Motion sickness and jet lag
Animal bites and rabies avoidance
Long-term travelers, expatriates, and business travelers
Special needs travelers (e.g., pregnant women, patients with diabetes,
immunocompromised patients, and transplant recipients)
Travel health resources (e.g., traveler-oriented Web sites)
Travel medical kits
Travel health and medical evacuation insurance
Access to medical care overseas
Vaccination Update routine vaccine profile
Routine, required and recommended vaccines
Post-travel assessment Access illnesses after trevelling (such as returning fever)

(last minute travelers)

 58 739

1.


(risk-benefit)



2. (destination)



3
3. ( 2)
1.
(mandatory or required vaccines for
certain destination)

website (yellow fever vaccine)
4. (meningococ-
( / ) cal vaccine)

2 2
Routine vaccines Mandatory or required vaccines Recommended vaccines
for certain destinations for persons with
before entering risks of exposure
Tetanus-diphtheria Yellow fever Hepatitis A
Pertussis Meningococcal* Typhoid
Varicella-zoster Rabies
Polio Meningococcal
Influenza Japanese B encephalitis
Pneumococcus Tick-borne encephalitis
Hepatitis B Cholera
Haemophilus influenzae type B
Measles, mumps, Rubella
*The tetravalent vaccine (A, C, Y, W-135) is required by Saudi Arabia for Hajj and Umrah pilgrims
740

6

6-12


(
15 ) (
www.cdc.gov/
travel/index.htm)


Aedes () Culex Haemagogus ()
(endemic hyperendemic area)

subsahara


(-)

quadrivalent vaccine Neisseria meningitidis
A, C, Y W-135 (
1:300-1:2,000 serogroup B)




70 meningococcal serogroup
live-attenuated B meningococcal
vaccine vaccine 8-10
9 10
95 2. (routine vaccines)
10 10 6,7
the Official International Certificate of Vaccination
against Yellow Fever (yel-
low book)
 58 741

Knowledge, Attitudes and Practices among foreign

(national program backpackers towards malaria risk in Southeast Asia.
for immunization) J Travel Med. 2009;16:101-6.
4. Boapimp P, Comarmond C. Assessment
and counseling of international travelers: A guide for
practicing physicians. J Infect Dis Antimicrob Agent.
dT 2005;22:133-49.
10 5. World Health Organization. International
travel and health 2009. WHO Press, Geneva,
polysaccharide pneumococcal Swtizerland; 2007. p.193-218.
vaccine 6. Barnath ED. Yellow Fever: Epidemiology
and Prevention. Clin Infect Dis 2007;44:850-6.
3. 7. Centers for Disease Control and Prevention.
(recommended vaccines for person with risks of ex- Yellow fever vaccine. Recommendations of the Advisory
posure) Committee on Immunization Practices (ACIP). MMWR.
2002;51:1-10.
8. Prevention and control of meningococcal
disease. Recommendations of the Advisory Com-
mittee on Immunization Practices (ACIP). MMWR
Recomm Rep. 2000;49:1-10.
9. Recommendation of the Advisory Com-
mittee on Immunization Practices (ACIP). Revised
recommendations of the Advisory Committee on Im-
munization Practices to vaccinate all persons aged
1118 years with meningococcal conjugate vaccine.
MMWR. 2007; 56:765-6.
1. Steffen R. Epidemiology: Morbidity and 10. Harrison LH. Prospective for vaccine
mortality in travelers. In: Keystone JS, Kozarsky PE, prevention of meningococcal infection. Clin Microbiol
Freedman DO, et al. Travel Medicine 2nd Edition. Rev. 2006;19:142-64.
Mosby an imprint of Elsevier Limited; 2008. p.1-11.
2. Hamer DH, Conner BA. Travel health knowl-
edge, attitudes and practices among United States
travelers. J Travel Med. 2004;11:23-6.
3. Piyaphanee W, Wattanagoon Y, Silacham-
roon U, Meansanguan C, Wichianprasat P, Walker E.
742
 743

59

( )1,2


3-5

1.

2.


3.

4.



5.



1




(Pre-exposure prophylaxis)
(
)
744

1

2 0.5 . SC
2 1 SC


2 0.5 . SC
1 SC
1 0.5 . SC SC
2 0.5 . SC
4-8 13
2 SC


3 1.0 . 0, 1 IM
serology 6 IM

1 0.5 . IM IM
(LAIV)

(Tdap) 1 0.5 . IM IM
2 1 . 6-12 IM IM
: IM = intramuscular; SC = subcutaneous

3 0, 1 (Post-exposure prophylaxis)
6 anti-HBs
1-2 36
anti-HBs anti-HBs ( 10 mlU/.)
10 mlU/. HBIG 0.06 ./.
1
HBIG
anti-HBs 10 mlU/. 2 3
(known nonresponder) HBIG
3 (0, 1, 6 ) anti-HBs 1-2 2 1 2
3 anti-HBs
10 mlU/.

hepatitis B immunoglobulin (HBIG)

 59 745

2 HBsAg

(anti-HBs) HBsAg HBsAg

HBIG 1 HepB 3 HepB 3

HepB 3 a

HBIG 2
1 HBIG
1
3 b HBsAg
anti-HBs anti-HBs

- 10 mIU/. - < 10 mIU/.
- < 10 mIU/. HepB
HBIG 1 - 10 mIU/.
HepB c
: HBIG = hepatitis B immune globulin; HepB= hepatitis b
a HBIG 0.06 ./. 3 0, 1-2, 6
b HepB 2 (6 ) (nonresponder) HBIG (0.06 ./.)
2 1
c anti-HBs HepB 1-2 HBIG
HBIG 4-6 anti-HBs (< 10 mIU/.) 2 3
( 7)

8-10 .. 2552-
2553
(H1N1) 2009
11

(H1N1) 2009
746

0.5 .


2-49 13
0.5 .
2 4-8
7
2
99

( Pre-exposure prophylaxis )
(Post-exposure prophylaxis)

2 MMR
0.5 . 2 4 12 negative
pressure airborne
(Post-exposure prophylaxis) precaution contact precaution14

MMR 72


varicella lgG varicella lgG


()

1.

3
(Pre-exposure prophylaxis) 5 15-17
2.

2
VZIG 96 VZIG
IVIG acyclovir 7-10
 59 747

7 VZIG
125 /10 . ( 625 ) 0.02 ./.
3. acyclovir
10 ./. ( 400 .) 4
7 7

19-21
10-21 18



22-26
CDC

Tdap 1 27
Td
10
(Pre-exposure prophylaxis)



1 .
2 6-12

(Post-exposure prophylaxis)

2
40

1
748

vaccine acceptance: a survey of health care workers.

Am J Infect Control. 1991;19:177-84.
3. Centers for Disease Control. Immunization of
Health Care Workers: recommendations of the Advisory
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Hospital Infection Control Practices Advisory Committee
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on Adult Immunization and Infectious Disease Society
of America. Guide for Adult Immunization, 3rd ed.
American College of Physicians, Philadelphia; 1994.
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Salmonella typhi on Infectious Diseases, 28th ed, Pickering, LK (Ed), American
Academy of Pediatrics, Elk Grove Vil age, IL; 2009. p.94-97.
6. Lemon SM, Thomas DL. Vaccines to prevent
viral hepatitis. N Engl J Med. 1997;336:196-204.
7. , ,
, , ,
. 2010-2011.
Tdap 1 ; 2553.
8. Balkovic ES, Goodman RA, Rose FB, Borel
CO. Nosocomial influenza A (H1N1) infection. Am J Med
Technol. 1980;46:318-20.
9. Van Voris LP, Belshe RB, Shaffer JL.
Nosocomial influenza B virus infection in the elderly.
Ann Intern Med. 1982;96:153-8.
10. Centers for Disease Control (CDC).
Suspected nosocomial influenza cases in an intensive
care unit. MMWR Morb Mortal Wkly Rep. 1988;37:3-4.
11. , ,
1. Nichol KL, Hauge M. Influenza vaccination , , ,
of healthcare workers. Infect Control Hosp Epidemiol. .
1997;18:189-94. (H1N1)
2. Christian MA. Influenza and hepatitis B 2553.
 59 749
. 2553;41:409-15. adults during the 1993 outbreak in Chicago. J Infect
12. Bolyard EA, Tablan OC, Williams WW,
Pearson ML, Shapiro CN, Deitchmann SD. Guideline
for infection control in healthcare personnel, 1998.
Hospital Infection Control Practices Advisory Committee.
Infect Control Hosp Epidemiol. 1998;19:407-63.
13. Nettleman MD, Schmid M. Controlling
varicella in the healthcare setting: the cost effectiveness
of using varicella vaccine in healthcare workers. Infect
Control Hosp Epidemiol. 1997;18:504-8.
14. Garner JS. Guideline for isolation
precautions in hospitals. The Hospital Infection Control
Practices Advisory Committee. Infect Control Hosp
Epidemiol. 1996;17:53-8.
15. Asano Y, Nakayama H, Yazaki T, Kato R,
Hirose S. Protection against varicella in family contacts by
immediate inoculation with live varicella vaccine.
Pediatrics. 1977; 59:3-7.
16. Arbeter AM, Starr SE, Plotkin SA. Varicella
vaccine studies in healthy children and adults.
Pediatrics. 1986;78:748-56.
17. Salzman MB, Garcia C. Postexposure
varicella vaccination in siblings of children with active
varicella. Pediatr Infect Dis J. 1998;17:256-7.
18. American Academy of Pediatrics. Varicella
zoster infections. In: Red Book: 2009 Report of the
Committee on Infectious Diseases, 28th ed, Pickering,
LK (Ed), American Academy of Pediatrics, Elk Grove
Village, IL; 2009. p.714-27.
19. Mink CM, Cherry JD, Christenson P, Lewis
K, Pineda E, Shlian D, et al. A search for Bordetella
pertussis infection in university students. Clin Infect Dis.
1992;14:464-71.
20. RosenthalS,StrebelP,CassidayP, SandenG,
Brusuelas K, Wharton M. Pertussis infection among
Dis. 1995;171:1650-2.
21. Wright SW, Edwards KM, Decker MD,
Zeldin MH. Pertussis infection in adults with persistent
cough. JAMA. 1995;273:1044-6.
22. Steketee RW, Wassilak SG, Adkins WN Jr,
Burstyn DG, Manclark CR, Berg J, et al. Evidence for a high
attack rate and efficacy of erythromycin prophylaxis in a
pertussis outbreak in a facility for the developmentally
disabled. J Infect Dis. 1988; 157:434-40.
23. Fisher MC, Long SS, McGowan KL, Kaselis E,
Smith DG. Outbreak of pertussis in a residential facility
for handicapped people. J Pediatr .1989;114:934-9.
24. Addiss DG, Davis JP, Meade BD, Burstyn DG,
Meissner M, Zastrow JA. A pertussis outbreak in a
Wisconsin nursing home. J Infect Dis. 1991;164:704-10.
25. Christie CD, Glover AM, Willke MJ, Marx ML,
Reising SF, Hutchinson NM. Containment of pertussis in th,
e regional pediatric hospital during the Greater Cincinnati
epidemic of 1993. Infect Control Hosp Epidemiol.
1995;16:556-63.
26. Calugar A, Ortega-Snchez IR, Tiwari T,
Oakes L, Jahre JA, Murphy TV. Nosocomial pertussis:
costs of an outbreak and benefits of vaccinating health
care workers. Clin Infect Dis .2006;42:981-8.
27. Mast EE, Weinbaum CM, Fiore AE, Alter MJ,
Bell BP, Finelli L, et al; Advisory Committee on Immunization
Practices (ACIP) Centers for Disease Control and Prevention
(CDC). A comprehensive immunization strategy to eliminate
transmission of hepatitis B virus infection in the United
States: recommendations of the Advisory Committee on
Immunization Practices (ACIP) Part II: immunization of
adults. MMWR Recomm Rep. 2006;55:1-33.
750
 751

60

1 2







(Tetanus vaccine)

1
752

10




.. 2541-25422 88-98
anti-tetanus toxin
antibody 0.15 IU/.

3
10 15-30
()

3 tetanus toxoids
(TT)
1
30-60 diphtheria-tetanus toxoids (dT) tetanus toxoid
(TT) 10
 60 753

3 (primary immuniza- TT dT 1
tion) 3 0,
4-8 6-12 1 ( 81-94
) TIG
1
1 dT 2
1 2
dT 1
(Diphtheria vaccine)
3 5 dT
1
5 (epi-
demic)
1 4 4 100,000 0.1
1 100,000
5-14
tetanus immune globulin 15 ( 21.7 ..
(TIG) 2533-2542)
TIG 3 .. 2533-2537
3
Tetanus immune globulin (TIG) 10-100
TT dT 40-49

1 (TIG)
(completed primary immunization) 7
- dT TT 11-16 10
/
- dT TT 2 4-8 1 6-12
- dT TT 3 10

- /
(clean wounds) - dT TT 2 4-8
1 6-12
(contaminated wounds) - dT TT 2 4-8
1 6-12 TIG
- ( tetanus toxoid 3 )
(clean wounds) - dT TT 1 10
(contaminated wounds) - dT TT 1
5
754

TT
10
dT TT

3 92 dT 1
72
81-90
7,8

4,5
(Acellular pertussis
vaccine)

( 20-60
)6 2-3
7 .. 2537
17 (classic pertussis)
5-14
15 15

3





2
85 9-12
(anti-diphtheria toxin antibody 0.1 --
IU/.) .. 2520

7.25 3.52
.. 2520 .. 2529
0.02 ..
dT 2549
TT dT
 60 755

6
5
90 2

5-8
2

3
serologic tests
10-25 ( PCR 2-10)
80 13,14

2-3 acellular pertussis vaccine
50
6 effectiveness 70-90
whooping cough
8-40 Tdap (diphtheria-tetanus-
( 22) acellular pertussis vaccine)
Tdap 1
Tdap
dT 1




Tdap

Streptococcus
pneumoniae (23-valent polysaccharide
pneumococcal vaccine; PS-23)

CDC S.pneumoniae
756

(invasive pneumococcal infection)
( 70 ) 65
2
PS-23 influenza vaccine


15,18-20
5
( 65 ) 90 S.pneumoniae
(pandemic influenza)
PS-23 ( S.pneumoniae
1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A,
12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F (pandemic influenza
33F) S. pneumoniae H1N1:1918-19)
PS-23
1, 3, 19F, 6B, 19A, 5, 23F
PS-2315 215,17
S. pneumoniae (revaccination) 2
PS-23

( 65-74 )
5
71 75-84
67 non-
bacteremic pneumococcal pneumonia
S.pneumoniae primary vaccination


( 65 ) PS-23
( 30-
50)
16 1-3
(cost-effectiveness)
 60 757

2 23-valent polysaccharide pneumococcal vaccine15,17

(revaccination)

65 5
65
2 - 65
- (asplenia) 3-5
-
cardiomyopathy (COPD)
- (CSF)
19 - 64 ()
-
-

2 - 65
- HIV
-
- 5
- (chronic renal failure)
-

7-valent 2
pneumococcal conjugated vaccine 13-valent (inactivated vaccine) split
pneumococcal conjugated vaccine virion vaccine

surface antigen exter-
nal antigen (H N) internal antigen
subunit vaccine external
antigen
(Influenza vaccine)
live-
attenuated vaccine
()
3-5
2-49
antigenic drift
(COPD, asthma, cystic
fibrosis)

(seasonal influenza) inactivated influ-
758

enza vaccine ( 1)
( 3.
)






(Rabies vaccination for pre-exposure

prophylaxis)




21-25 (bite prevention)
1.
20 (
65 300,000 )
(COPD) (pre-exposure prophylaxis)





2 ()
3
(6 - 18 )
(
Reyes syndrome

2.
(rabies
immune globulin)

 60 759

Nab titer 1-2

Nab titer 0.5 IU/.

1 (
( )
)
Nab titer



25,26 WHO
category 2 3
27

27-30
(Measles-mumps-rubella vaccine)

1
( 0.1 .) 31
0, 7 21 28 ( 32,33
)25 12 15
95 98
16 34

(neutralizing antibody; Nab) 0.5 97
IU/.
Nab titer
6 Nab titer 0.5 75-93 30
IU/. 1 35
0.1 . 1 98
1 12 12
16 36
--
9-12
760

85-95 63-95 -
96-9937,38 - 1 41



(Varicella and zoster vaccine)
(primary vaccine failure)

(secondary vaccine failure)

39
2
2 4-6 40
70- 90 95
42,43
.. 2500 13
78-82 2
9944,45 breakthrough
.. 2500 1-4

46 breakthrough
-- 1
1 4

1.

2. .. 2506-2510

3. 47
4.
5.

.. 2500



 60 761

Zostavax
48 Oka
0.65
2 4 . 1
zoster vac-
cine
1-3 3

51.3
anaphylaxis PHN 66.5

(post-
exposure varicella immunization)
90 3

5 60-69 50,51

49

(Human papillomavirus vaccine)

1

6,300 17
50

post-herpetic neuralgia (PHN) (persistent infection) 0.5
10-15
PNH
10-20 52-55
16
18, 45, 31 33
762

70 16 18 34.9
CIN2 CIN2+
HPV 16 18 98.1
L1-VLP CIN2 CIN2+
HPV 31, 33, 45 58
2 67.4, 49.8, 100
1) HPV 4 (quadrivalent) 6, 49.6
11, 16 18 amorphous aluminium 58,59
hydroxyphosphate sulfate
L1 L1
MSD (HPV 16, 18)
(HPV 6, 11)
0, 2, 6 2) HPV 2 (bivalent) 11-26
16 18 L1
L1 11-12
ASO4 ( aluminium hydroxide
3-deacylated monophosphoryl lipid A)
GSK 0, 1, 6
2
5-7


(persistent
infection) 90-96 CIN 2 3 adenocarcinoma in situ (AIS)
(
31, 45)
2 26
HPV
3 quadrivalent
16-24 (
CIN2 CIN3 AIS HPV 16 )
18 98 3
56,57 3 bivalent
15-25 18,644 14
1,852
 60
9. Senzilet LD, Halperin SA, Spika JS, Ala-
1. Wassilak SGF, Murphy TV, Roper MH,
Orenstein WA. Tetanus toxoid. In Plotkin SA, Oren-
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763
garatnam M, Morris A, Smith B et al. Pertussis is a
frequent cause of prolonged cough illness in adults
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brile nonproductive cough illness in American soldiers
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tussis and chronic cough in adults. Clin Infect Dis.
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12. Jackson LA, Cherry JD, Wang SP,
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13. Turnbull FM, Heath TC, Jalaludin BB,
Burgess MA, Ramalho AC. A randomized trial of
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a licensed diphtheria-tetanus vaccine (DT) in adults.
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14. Halperin SA, Smith B, Russell M, Scheifele
D, Mills E, Hasselback P, et al. Adult formulation of a
five component acellular pertussis vaccine combined
with diphtheria and tetanus toxoids and inactivated
poliovirus vaccine is safe and immunogenic in adoles-
cents and adults. Pediatr Infect Dis J. 2000;19:276-83.
15. Prevention of pneumococcal disease:
Recommendations of the Advisory Committee on Im-
munization Practices (ACIP). MMWR. 1997;46:1-24.
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Rethinking recommendations for use of pneumococcal
vaccines in adults. Clin Infect Dis. 2001;33:662-75.
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764

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19. Jackson LA, Neuzil KM, Yu O, Benson . . 2543;187:445-52.
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21. Recommendations of Advisory Commit- ..2520-2537 : ; 2538.
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gies for the 2005-2006. Influenza season. MMWR. ; 2544. .292-5.
2005;54:307. 33.
22. Influenza vaccine supply and recommen- :
dation for prioritization during 2005-2006. MMWR. ; 2544. .219-26.
2005;54:850. 34. -
23. Monto AS. The risk of seasonal and - :
pandemic influenza. Clin Infect Dis. 2009;48:s20-5.
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26. Immunization Practice Advisory Commit- rmann KL, Greenspan JR, Henderson AK, et al.
tee (ACIP). Human Rabies Prevention-United States Rubella antibody persistence after immunization.
2008. MMWR. 2008;57(RR-3):1-21. Sixteen-year follow-up in the Hawaiian Islands. JAMA.
 60 765

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37. , , (ACIP). MMWR Morb Mortal Wkly Rep. 1996;45:1-36.
, , , 45. American Academy of Pediatrics. Vari-
Comparative study of antibody response of two dif- cella-zoster infections. In: Peter G, editor. 2000 Red
ferent combinations of measles, Mumps, Rubella Book: Report of the Committee on Infectious Diseases.
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Thai Congress of Pediatrics November 12-13, 1993. Village, Illinois: American Academy of Pediatrics; 2000.
38. , . p.624-38.
2 46. Clements DA. Modified varicella-like
9-12 . . 2539;48:595-600. syndrome. Infect Dis Clin North Am. 1996;10:617-29.
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Measle vaccine in Plotkin SA, Orenstrein WA. Vaccines. CA, Shefer A. Impact of varicella vaccination on health
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40. Centers for Disease Control and 48. Breuer J. Varicella vaccination for health-
Prevention(CDC) Recommendations of the Advisory care workers: is beneficial to patients and staff. BMJ.
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for elimination of measles, rubella, and congenital of postexposure immunization with live attenuated
rubella syndrome and control of mumps. MMWR. varicella vaccine in the household setting-a pilot study.
1995:47:1-57. Vaccine. 2004;23:325-8.
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(CDC). Recommended adult immunization schedule- Schmader KE, Straus SE, Gelb LD, et al. A vaccine
United States, October 2005-September 2006. MMWR to prevent Herpes Zoster and postherpetic neuralgia
Morb Motal Wkly Rep. 2005;54:Q1-4. in older adults. N Engl J Med. 2005;352:2271-84.
42. Chu SY, Bernier RH, Stewart JA, Herrmann 51. Recommendation of the Advisory Com-
KL, Greenspan JR, Henderson AK, et al. Oka/Merck mittee on Immunization Practices (ACIP). Prevention
varicella vaccine in healthy children: final report of a of herpes zoster. MMWR. 2008;57:1-21.
2-year efficacy study and 7-year follow-up studies. 52. Walboomers JM, Jacobs MV, Manos MM,
Vaccine. 1991;9:643-7. Bosch FX, Kummer JA, Shah KV, et al Human papil-
43. Weibel RE, Neff BJ, Kuter BJ, Guess HA, lomavirus is a necessary cause of invasive cervical
Rothenberger CA, Fitzgerald AJ, et al. Live attenuated cancer worldwide. J Pathol. 1999;189:12-9.
varicella vaccine: efficacy trial in healthy children. N 53. Clifford GM, Smith JS, Plummer M, Mu-
Engl J Med. 1984;310:1409-15. noz N, Franceschi S. Human papillomavirus types in
44. Centers for Disease Control and Preven- invasive cervical cancer worldwide a meta-analysis. Br
tion (CDC). Prevention of varicella: recommendations J Cancer. 2003;88:63-73.
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Stevens CE, Paavonen J, Beckmann AM, et al. A co-
hort study of the risk of cervical intraepithelial neoplasia
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55. Stanley MA. HPV vaccines. Best Prac-
tice & Research Clinical Obstetrics and Gynecology.
2006;20:1-15.
56. Garland SM, Hernandez-Avila M, Wheeler
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lent vaccine against human papillomavirus to prevent
anogenital diseases. N Engl J Med. 2007;356:1928-43.
57. The FUTURE II Study group Quadriva-
lent vaccine against human papillomavirus to prevent
high-grade cervical lesions. N Engl J Med. 2007;356:
1915-27.
58. Harper DM. Sustained immunogenicity
and high efficacy against HPV 16/18 related cervical
neoplasia:long-term follow up through 6.4 years in
women vaccinated with Cervarix (GSKs HPV 16/18
AS04 candidate vaccine). Presented at the Annual
Meeting on Womens Cancer of the Society for Gyne-
cologic Oncology, Tampa, Florida, USA, 9-12 March,
2008. Abstract in Gynecologic Oncology. 2008;109:58.
59. Paavonen J, Naud P, Salmern J, Wheeler
CM, Chow SN, Apter D, et al. Efficacy of human
papillomavirus (HPV)-16/18 AS04-adjuvanted
vaccine against cervical infection and precancer
caused by oncogenic HPV types (PATRICIA): final
analysis of a double-blind, randomised study in young
women. Lancet. 2009;374:301-14.
 767

61

6 - 12











( 1)






(Congenital
(killed vaccine) rubella syndrome, CRS)
(live attenuated vaccine)
85
1 16

,,
768
1 Vaccination in pregnancy : Live attenuated vaccines
Vaccines Recommendation Comments
Bacteria BCG Contraindicated
Oral typhoid vaccine Contraindicated Inactivated typhoid Vi polysaccharide
vaccine is preferred.
Virus Influenza Contraindicated Should receive inactivated influenza vaccine
MMR Contraindicated
Smallpox Contraindicated Has been reported to cause fetal infection
Varicella Contraindicated
Yellow fever Contraindicated Unless travelling to yellow fever endemic area
Zoster Contraindicated
( 15)

progressive encephalopathy
CRS

.. 2010 .. anti-Rho (D)
20151

CRS






1 28 198
16 3

.. 1971-1989 1 cerebral
1-2 cortical atrophy, mental retardation
CRS 321 4
(RA 2713) 5
2 2
 61 769

17-30 315


1 304
2
4-8 1
7



362 .. 1995-2000
6

3

( 2, 3)



varicella zoster immunoglobulin 96 8,9
125 10
( 625 )


4 10
1
(
)

252
26.1 11,12
4



770

2 Vaccination in pregnancy : Inactivated vaccines

Vaccines Recommendation Comments
Bacteria Cholera (oral) Not recommended Inadequate safety information
Meningococcal Recommended for No documented adverse events in either pregnant
polysaccharide women at increased women or their newborns, but the number
vaccine (MPSV4) risk of vaccinees reported is small.

Pneumococcal Recommended for Data are limited to clinical trials and deferral
polysaccharide women at increased of vaccine unless there is an increased
vaccine (23 v PPV) risk risk of IPD.
Tdap Recommended for If not given before pregnancy, it should be
women who work in given as soon as possible after delivery.
close contact with
infants
Typhoid Vi Travelling to No evidence of risk to the fetus
polysaccharide endemic countries
vaccine
Virus Hepatitis A Recommended for
susceptible pregnant
women
Hepatitis B Recommended for
susceptible pregnant
women
Human papilloma Not recommended
virus (HPV)
Influenza Recommended No evidence of congenital defects on
the fetus.
Japanese Recommended for No adverse effects on pregnancy, whereas
encephalitis (JE) women at risk JE infection is associated with miscarriage.
Polio (IPV) Recommended for Vaccination of pregnant women should be
women at risk avoided on theoretical grounds
Rabies Recommended
( 15)
3 Vaccination in pregnancy : Toxoids and Immumoglobulins
Toxoids and Immumoglobulins Recommendation Comments
Tetanus/diphtheria Recommended Toxoids are safe in pregnancy
Hyperimmune globulins Recommended for No known risk to the fetus from passive
susceptible pregnant immunization of pregnant women with
women exposure to immune globulins.
measles, hepatitis A,
hepatitis B, rabies,
varicella and tetanus
( 15)
 61 771

13


(Td) 6
Td
10 1

3
Td 2
Td 2
4 Tdap 1 Td 12
6


2

Tdap Td
Catch-up


<12

772

1.

2.
3.
4.

5.
6.
7.

40.
8. anaphylaxis neomy-
cin streptomycin
14 9.

10.

2






 61 773

1. Centers for Disease Control and
1
Prevention(CDC). Progress Toward Control of Rubella
1. and Prevention of Congenital Rubella Syndrome--
-Worldwide, 2009. MMWR Morb Mortal Wkly Rep.
2. 2010;59:1307-10.
2. Watson JC, Hadler SC, Dykewicz CA,
3. Reef S, Phillips L. Centers for Disease Control and
Prevention. Measles, mumps and rubella vaccine
use and strategies for elimination of measles,
4. rubella, and congenital rubella syndrome and
control of mumps: recommendations for the advisory
committee on immunization practices (ACIP). MMWR
5. Recomm Rep.1998;47(RR-8):1-57.
3. Gershon AA. Chicken pox, measles and
4 mumps. In: Remington JS, Klein JO, eds. Infectious
6. diseases of the fetus and newborn infant. Philadelphia:
WB Saunders; 2001. p. 683.
7. 4. Hargar JH, Ernest JM, Thurnau GR,
Moawad A, Thom E, Landon MB, et al. Frequency
8. of congenital varicella syndrome in a prospective
cohort of 347 pregnant women. Obstet Gynecol.
2002;100:260-5.
5. Denicola LK, Hanshaw JB. Congenital and
neonatal varicella. J Pediatr .1979;94:175-6.
6. Shields KE, Galil K, Seward J, Sharrar
RG, Cordero JE, Slater E. Varicella vaccine exposure
- during pregnancy: data from the first 5 years of the
pregnancy registry. Obstet Gynecol. 2001;98:14-9.
7. Cavalcanti DP, Salomo MA, Jopez-
Camelo J, Pessoto MA. Campinas Group of Yellow
774

Fever Immunization During Pregnancy. Early exposure

to yellow fever vaccine during pregnancy. Trop Med
Int Health. 2007;12:833-7.
8. Harris JW. Influenza occurring in pregnant
women: a statistical study of thirteen hundred and fifty
case. JAMA. 1919;72:978-80.
9. Freeman DW, Barno A. Deaths from Asian
influenza associated with pregnancy. Am J Obstet
Gynecol. 1959;78:1172-5.
10. Neuzil KM, Reed GW, Mitchel EF,
Simonsen L, Griffen MR. Impact of influenza on acute
cardiopulmonary hospitalizations in pregnant women.
Am J Epidemiol. 1998;148:1094-102.
11. Munoz FM, Greisinger AJ, Wehmanane
OA, Mouzoon ME, Hoyle JC, Smith FA, et al. Safety of
influenza vaccination during pregnancy. Am J Obstet
Gynecol. 2005;192:1098-106.
12. Fiore AE, Uyeki TM, Broder K, Finelli L,
Euler GL, Singleton JA, et al. Prevention and control of
influenza with vaccines: recommendations of the
Advisory Committee on Immunization Practices (ACIP),
MMWR Recomm Rep. 2010;59(RR-8):1-62.
13. Centers for Disease Control and
Prevention. Seasonal Influenza and 2009 H1N1
Influenza Vaccination Coverage Among Pregnant
Women---10 States, 2009--10 Influenza Season.
MMWR Morb Mortal Wkly Rep.;59(47):1541-5.
14. Rotz LD, Dotson DA, Damon IK, Becher
JA; Advisory Committee on Immunization Practices.
Vaccinia (smallpox) vaccine: recommendations of
the Advisory Committee on Immunization Practices
(ACIP). MMWR Recomm Rep. 2001;50(RR-10):1-25.
15. Gruslin A, Steben M, Halperin S, Money
DM, Yudin MH. Immunization in pregnancy. J Obstet
Gynaecol Can. 2008;30:1149-54.
 775

Community immunity 62

1.
Community immunity
3
- community (herd)
6 immunity ..1923 Topley
smallpox inocula- Wilson The spread of bacterial infec-
tions variolation tion: the problem of herd immunity4

Lady Mary, Wortley Montagu 5

Edward Jenner (..1749-1823)


Bacillus enteritidis
..1853

..1980
(World Health Organization: WHO) Wilson
herd immunity Greenwood
polio Epidemics and Crowd Diseases
1,2 ..19355,6
..1807-1883 William Farr


20
3 smallpox
(disea