295

(WHO)
.. 2010/2011 1.7
4,700
9.4 1

38.0
..2537 49.97 .. 2545
63.11 .. 25522

22
3
(multidrug resistant Mycobacterium tuberculosis: MDR-TB)
3.3
MDR-TB
18 - 24
rifampicin

.. 1921
100

26

.. 1921
Calmette Guerin

Mycobacterium bovis
culture medium
2 (passaging) 230 passages
.. 1921

(liquid vaccine)
(lyophilize)

passage passage 1173
.. 1961
passage 230 Calmette

.. 1921 - 1961
943 passages Mycobacterium bovis 4

virulence immunogenicity 5,6

.. 1924
Mycobacterium
bovis

296

1
( 4)

M. bovis .. 1990
phylogenetic tree
molecular fingerprint M .bovis, M. tuberculosis
restriction-fragment-length-polymorphism
(RFLP)
IS6110 MPT64 .. 1921
IS6110 MPT64
IS6110 MPT64
IS6110
.. 1925-1926 MPT64
.. 1927-1931 24
..
1921

Phylogenetic tree
M. bovis BCG
deletions polymorphisms

.. 1961
.. 1921 1 single nucleotide polymorphism
4 deletions
deletions polymorphisms




2 early strain late
strain BCG Pasteur 1173 P2
late strain Tokyo 172-1
early strain genome sequence
[BCG Pasteur 1173 P2 contain
two separate genetic populations with double and triple
tandem duplications in the DU2 region (a protein encoding region with 58 genes) BCG Tokyo 172-1

 26 297

contain two separate genetic population with differ in

the protein encoding RD16 region, one variant having
the full RD16 region the other with a 22 bp deletion in
this region. ] morphology
growth characteristic 7-11

culture medium



2
(lyophilized)

1.
90-95
-
2512 172
30 1
.
12-15 1 .
2
syringe
2.

mycolic acid
M. bovis

.. 1931
methoxymycolic acid M. bovis
methoxymycolic acid
(macrophage)13
3. im-

munogen
immunogen
.. 193114 ESAT-6 CFP-10
M. bovis
MPT64, MPB70, MPB83

.. 1921

vaccine immunogenicity


reactogenicity conversion


protective immunity
lot-to-lot consistency
final lot


biomarker panels mycobacterium growth
inhibition bioassay
molecular biology
(genectic information)
virulent
mycobacterium 15

BCG sub-strain sub-strain

(guinea pig)
early strain
(BCG Tokyo 172-1) late strain (BCG Danish 1331,
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
Regional disease

Description
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
3-7 .
10 . 20
3
28-33 hypertrophic scar
2-4 keloid scars
(infants)

1 21
2 2,500

erythromycin, cloxacillin
( ) isoniazid

isoniazid

22




well baby clinic

2
Complication
Local subcutaneous abscess, regional lymphadenopathy
Musculoskeletal lesions
Multiple lymphadenitis, nonfatal disseminated lesions
Fatal disseminated lesions
( 21)

Incidence per 1 million vaccinations

Age < 1 year
Age 1- 20 years
387
25
0.39 0.89
0.06
0.31 0.39
0.36
0.19 1.56
0.06 0.72

300

3


2

8-9 90 (
10 .) 23

(outbreak)


(Pasteur-1173P2)
Mozambique, Zimbabwe, Zaire
Caribbean


(Pasteur-1173P2) 19
Tokyo Moreau
Copenhagen
Pasteur-1173P2

percutaneous multiple-puncture device

intradermal

3 conversion rate
40
intradermal conversion rate
83 lymphoproliferative response M. tuberculosis
IFN -response
percutaneous
intradermal
subcutaneous
intradermal
intradermal
M. tuberculosis24
(BCG lymphadenitis)
1-4

0.013 2325-27



22
AFB
M. bovis
Staphylococcus aureus, Streptococcus group A M. bovis

M. bovis

20

 26 301

Russian BCG-osteitis
35 : 1,000,000
BCG-osteitis19
.. 1960-1970
Gothenburg
BCG osteitis 7.3 : 100,000 ..
1971-1978 Gothenburg
Copenhagen
BCG-osteitis 36.9 : 100,000
29 BCG-osteitis



BCG osteitis 222
.. 1960-1988 30,31
96 0-1
1.5 ( 0.25-5.7)
1
2.5 ( 1.7-3.6)
1.5-2
14
24 arthritis


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
3.8
( 1-6 ) 2-4 .
10 15 . 9
10-15 . 1 10 .
17 ( 85)
9.1 ( 2.5-19 )
3 20
11.8 (
5-23 )28 spontaneous
regression 20-85

M. bovis

isoniazid, rifampicin

sinus tract

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)


(disseminated BCG) 2
1,000,000 18

severe
combined immunodeficiency (SCID), chronic granulomatous disease (CGD)
.. 1921-1982 60
.. 1980-1995 27
5,000
84 immunocompromised
71 2

(failure to thrive)
disseminated BCG
3 418
M. bovis firstline pyrazinamide
disseminated BCG
isoniazid, rifampin, ethambutol, streptomycin
70

pyrazinamide

drug interaction

4 Disseminated BCG
3
1.
2.
2.1
2.2 2

3. systemic

( 18)

 26 303

outbreak BCG
adenitis

(lot number)








Pasteur-1173 P2

intradermal


syringe
Zimbabwe outbreak

19
.. 2553
(Serum Institute of India) (Russian 1)

( Tokyo 172)
0.05 .
(0.1 .)

(potency)
PPD

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

immunogenicity hypersensitivity
induration
0-4, 5-9, 10-14 15
. 32

15
(BCG scar)


50-6033
5334

20-5035,36

304

50 37

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

5 38

1 -2



intradermal
T-cell 1-2
1-2

(induration)







1

1-2

 26 305

5
_________________

________________________ .
induration
induration
(abscess)

(hypopigmented patch)

(keloid)

1-2

2


53

(miliary TB) (TB
meningitis) 37

1

(environmental mycobacterium)

1. (induration)

2. 15 .


(active disease)

(LTBI) isoniazid 6-9

3. 1-9 .
( 6-12
10 .31,39)

4. 10-14 .

Kagina BM .. 2009

306

10

BCG-specific CD4
T cells 40 ( polyfunctional T cells coexpression IFN-gamma, TNF-alpha IL2)
immunity mature

BCG-specific
T cells
disseminated
BCG disease 41

2 7

1 7-14
42

.. 1921

9043



(sanatoria)


(endemic area)

44

(endemic area)

( : wane)

( ..
1931)


(over-attenuated vaccine)
45



10-20
46-48

Wuchereria bancrofti, Schistosoma haematobium

49
cytokines

 26 307

Th2-type immune activation Th1

albendazole
(Ascaris lumbricoides)
(live oral cholera vaccine)
IFN-
50,51
Ferreira AP52
Ascaris lumbricoides, Entamoeba histolytica, Strongyloides stercoralis
IFN- IL-10
IL-10
type-2 cytokines response
IFN-

(CMI)

( 3)

43
Blocking hypothesis
(environmental mycobacterium)

(vaccine strain) (CMI)
(block)


(M. tuberculosis)

3 Blocking hypothesis Masking hypothesis

( 43)

308
(nave recipient)

(BCG dissemination)

Masking hypothesis


(
blocking hypothesis)

(nave recipient)

Blocking hypothesis Masking hypothesis
Blocking hypothesis

(tropical regions)
(skin test conversion rate)
(wane)


Malawi
2-3
waning

waning
53 T-cell

responses

waning 54 30
(latitude) (equator)


30 (higher latitudes)
55

Blocking hypothesis

(nave recipient)
Masking hypothesis

10-20


/
(boost existing immunity: Late

 26 309

booster vaccine)

(postexposure
vaccine)

6
Type
rBCG30
rBCG::D
ureC-llo+

Description
Live, recombinant BCGTice, over-expressing
Ag85B from M.tb
Live, recombinant BCG,
urease-deficient mutant that
express lysteriolysin O gene
from Listeria monocytogenes

Developer

Improvement over
available vaccines

University of
Stimulates a stronger,
California, LA, USA longer-lasting response
than conventional BCG

Max Planck Institute Promotes leakage of

of Infectious Biology, antigens from phagosome to
Berlin, Germany
improve CD8 responses
via cross-priming
MVA-85A
Live, recombinant,
Oxford University, Stimulates strong primary
replication-deficient vaccinia Oxford, UK
immune response, but
virus, expressing Ag85A\
intended primarily as a
from M.tb
booster vaccine for individuals
previously vaccinated with
BCG
Ag85B-ESAT6 Recombinant protein,
Statens Serum
Stimulates strong primary
composed of a fusion of
Institue,
immune response, but
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
composed of a fusion of
Biologicals,
immune response, but
Rv1196 and Rv0125 from Rixensart, Belgium intended primarily as a
M.tb and delivered in oil-inbooster vaccine for individuals
water emulsion, containing
previously vaccinated with
immunostimulant 3BCG
decacylated-monophosphoryl
lipid A and a purified fraction
of Quillaria saponaria
SRL172
Autoclaved M vaccae
SR Pharma, London, Enhances Th1 response to
UK. Current trial led shared mycobacterial
by Dartmountantigens, but also drives
Hitchcock Medical regulatory T cells that
Center, Lebanon, inhibit Th2
NH, USA
( 57)

Stage of development
Phase I trials
completed
Clinical trial
scheduled for 2006
Completed phase I
trials in UK and in
clinical trials in The
Gambia
In phase I trials in
Leiden, Netherlands

Completed phase I
trials in USA and
recruiting for phase II
trials in Lausanne,
Switzerland

Phase I completed.
Phase II running in
Tanzania (DarDar
project) in patients
infected with HIV

310

6

(acute phase)
( 4 - A)


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 - C)
DNA vaccine

MHC class I MHC class II
cytotoxic T lymphocytes, helper T cells
primary immune response

HSP65, Ag85, 38 kDa, PstS-3, (ESAT-6, KatG,

( 56)

 26 311

MPT63, MPT64, MPT83), (Mtb39a, HSP65, MPT70,

IL-12), (65 kDa, Ag85), 35 kDa
58 DNA vaccine
HSP65 MPT70
DNA
59



prime subunit
booster vaccine
60-62

(Replacing BCG)




rBCG30 vaccine, rBCG::ureC-llo+ vaccine

M. tuberculosis

M. tuberculosis
(virulent
form)
rBCG30 vaccine63
M. tuberculosis: 30-kDa major secretory protein gene
recombinant vaccine phase I
(guinea pig)

rBCG::ureC-llo+ vaccine64
Kaplan G.

T-cell immunity
B-cell
(M.tuberculosis)
CD4+ T-cells CD8+ T
cells MHC class II
molecules ( CD4+ T cells) MHC class
I molecules ( CD8+ T cells)

phagosome
acid-dependent enzymes phagosome

mycobacterial urease pH phagosome

cytoplasm

MHC class II molecules

MHC class I molecules
cytoplasm
MHC class I molecules

Kaplan G.
MHC class I molecules
MHC class II molecules
cytoplasm phagosome

lysine gene
Listeria monocytogenes
phagosome
MHC class I
molecules MHC class II molecules

64

312

(booster vaccine)

Th1response
MVA-85A, Ag85B-ESAT6,
Mtb72f

primary immune response
recombinant protein vaccine Th1-response
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
preexposure vaccine
response)
(multiphase
vaccination)
immunological memory

Mycobacterium vaccae (heat recombinant killed) (therapeutic

 26 313

vaccine)
1
65

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