VACCINATION AND IMMUNIZATION

What you need to know:

1. The nature and function of passive and active immunization
2. The role of humoral and cellular immunity in vaccination
3. The types of vaccines currently available and the pros and cons of their use

Introduction: Vaccination, or immunization, is the act of artificially inducing immunity

from disease. Its use dates back to 1796 when Jenner showed that inoculating vesicular
fluid from cowpox lesions into the skin of susceptible individuals could protect them
against smallpox infection. A modified cowpox virus known as vaccinia virus is
currently used to protect against smallpox and it is from this that we get the term
vaccination.

Passive versus Active Immunization:

Passive immunization consists of providing temporary protection from disease through

the administration of exogenously produced antibody. Infants are passively immunized
from their mothers through transplacental transfer of maternal antibodies. These
antibodies protect the infant for 3-6 months after birth and allow the infant’s own
immune system time to develop. Pooled human IgG, known as immunoglobulin, is used
for passive immunization against hepatitis A and measles. Passive immunization against
these diseases is used after a non-immune person has been exposed to the infection but
before they develop the disease in an attempt to avoid serious illness. Pooled
immunoglobulin is also used to prevent infection in individuals with immune deficiencies
such as X-linked agammaglobulinemia. Special preparations of immunoglobulin taken
from donor pools with high levels of antibodies specific to certain infectious agents are
also used to passively protect individuals from infections.

Antibodies provided by passive immunization are generally short-lived and do not give
the long-lasting protection of active immunization strategies.

Active immunization consists of inducing the body to develop defenses against disease.
This usually is accomplished by giving agents that stimulate the body’s immune system
to produce antibodies and/or cell mediated immune responses against a particular
infectious agent. This is the form of immunization that we usually think of when we talk
about vaccination and the various agents of active immunization will be covered in detail
in the following sections.

The immune system in active immunization:

Antibodies react with antigens in the blood stream and extracellular fluid and at
mucosal surfaces. They cannot readily reach intracellular sites of infection. Most
antibodies produced by vaccines are thymus-dependent in that they require activation of
T helper cells to initiate B cell proliferation and antibody production. After an antigen, in
this case a vaccine component enters the body it is presented by mononuclear phagocytes
or dendritic cells which trigger a cascade of cytokines and stimulate the maturation of
naïve T helper cells into T helper type 2 cells (T H2). TH2 cells in turn produce cytokines
that lead to maturation of naïve B cells and release of specific antibody. After the initial
immune response is induced by the vaccine, activated B cells become resting memory
cells ready to respond rapidly when the antigen is encountered again. Protective
antibodies against bacterial infections work in several different ways depending on the
type of pathogen encountered. They can:
1. Inactivate soluble toxic products (anti-toxins, e.g. diphtheria vaccine)
2. Facilitate phagocytosis of bacteria (e.g. pneumococcal vaccine)
3. Interact with serum complement to damage bacterial membranes and
facilitate bacteriolysis (typhoid vaccine) and/or
4. Interfere with the bacterium’s ability to adhere to mucosal surfaces.
Protective antibodies against viral infections can only work when the virus is in
extracellular spaces. These antibodies may bind to viruses preventing their entry into
cells or may interfere with uncoating of virus particles or other steps in the viral lifecycle.

Cell mediated immunity is directed against intracellular antigens and thus is

most effective against organisms that spend at least part of their lifecycle inside cells.
Cytotoxic T cells (CTL) recognize small fragments of antigens presented on the surface
of infected cells in combination with HLA class I molecules. The T cell receptor
molecules of CTL are designed to recognize a specific antigen in combination with a
specific HLA molecule. Like thymus dependent antibody production, the induction of
cellular immunity is dependent upon the activation of T helper cells; however, in order to
stimulate cell mediated immunity, T helper cells mature along the T helper type 1 (T H1)
pathway. TH1 cells release cytokines that cause the maturation of naïve cytotoxic T cells
which can then recognize intracellular antigens using their T cell receptors. When the T
cell receptor of the mature CTL recognizes its antigen combined with its HLA class I
molecule on the surface of an infected cell it releases substances that kill the infected cell.
Like antibody producing B cells, CTL can become resting memory cells ready to become
activated as soon as the host is exposed to the antigen again.

On first exposure to a vaccine antigen, the primary response requires a latent

period of several days before humoral (antibody) and cell mediated immunity can be
detected. Circulating antibodies do not appear for 7-10 days and initially are of the IgM
class. Two or more weeks after vaccination the titers of IgG antibodies rise. After a
second exposure to the same antigen heightened antibody and cell mediated immune
responses are seen and occur within 4-5 days after exposure. Because antibody responses
are easier to measure, the response to a vaccine is usually measured by the antibody titer
in the serum of the vaccinated host; however, cell mediated immune responses have been
shown to be induced by vaccines and the lack of detectable antibody does not mean that
the individual is necessarily unprotected by the vaccine.

Determinants of the Effectiveness of Active Immunization: The ability of a vaccine to

produce an effective immune response is determined by the vaccine antigen(s), the
genetic background of the vaccinee (e.g. HLA type), the physiologic condition of the
vaccinee, the manner in which the vaccine antigen is presented, dose, use of adjuvants
and route of administration.
HLA (Human leukocyte antigen) types vary widely amongst individuals
and contribute the recognition of different parts of a complex antigen in different
populations. This variation is of particular importance for vaccines that primarily
attempt to elicit cell mediated immunity (e.g. HIV vaccine). These vaccines
must contain antigenic molecules that can be recognized and presented by at least

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 one HLA molecule in every individual vaccinated. Differences in HLA types
may explain why certain people never respond to certain vaccines (hepatitis B
vaccine).
The age, nutritional status, and immune status of a vaccinees may
influence the effectiveness of the response to a vaccine. Young infants often do
not respond to vaccines because of the presence of maternal antibodies. The
elderly often have diminished immune responses to vaccines because of waning
cellular immunity. Severely malnourished individuals have blunted immune
responses and people with immune deficiencies may be unable to respond to
many vaccines.
The type of vaccine used may have significant effects on
immunogenicity. Live attenuated vaccines, in which a weakened strain of live
infectious agent is given to the vaccinee (measles, mumps, rubella), actually
multiply in the recipient until checked by the immune response. Most of these
vaccines can confer life-long immunity after a single dose because they allow for
large amounts of antigen to be presented to the immune system. Killed or
subunit (vaccines containing only part of the infecting organism) vaccines in
contrast usually require more than a single dose and often require booster shots
(tetanus, rabies, diphtheria) throughout life.
The dose and route of administration of the vaccine can also affect
immunogenicity. There is usually a dose-response curve relationship between
antigen dose and peak response; however, this response often plateaus. The route
of administration may determine the nature of the immune response to a vaccine.
Intranasally administered vaccines are more likely to induce local IgA production
than parenterally administered vaccines.
Adjuvants are substances added to vaccines that enhance the
immunogenicity of antigens. They are particularly useful with inactivated
vaccines and toxoids. The mechanism of immune enhancement is not completely
defined but may include mobilization of phagocytes and delayed release of
antigen.

Currently Available Vaccines Recommended for General Use: Currently available

vaccines can be made up of live attenuated organisms, whole killed organisms, fractions
of organisms or toxoids (modified bacterial toxins which are nontoxic but retain
immunogenicity).

Live attenuated vaccines consist of live organisms that have been specially modified to
make them considerably less virulent than wild type pathogens. These vaccines have the
ability to infect the vaccinated host and multiply, but generally do not cause disease. For
the reasons given earlier, they are generally the most effective vaccines available;
however, because they do contain live organisms their use may be problematic in certain
populations (e.g. pregnant women, people with AIDS, etc) and not every organism can be
attenuated enough that it does not cause disease but remains capable of inducing an
immune response (e.g. HIV to date).
Measles vaccine is a live attenuated virus vaccine with an efficacy of over 95%
when administered in a single dose to children over the age of 15 months; however,
because measles can continue to circulate in the 2-5% of the population who do not
respond, 2 doses of vaccine are recommended (second dose generally at school entry).
The introduction of the measles vaccine in the US has resulted in 99.75% decrease in
measles cases; however, vaccination rates may be quite low in developing countries.

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Travelers should be adequately vaccinated as a recent outbreak of measles in Queens in
US born infants who had traveled to India before being vaccinated illustrates.
Mumps vaccine is also a highly effective live attenuated vaccine recommended
for all children over the age of one who do not have specific contraindications
(immunocompromise). Protection is lifelong after a single dose although most people
receive two doses as part of the MMR vaccine. The mumps vaccine has led to a 98.3%
decline in mumps cases in the US since 1968.
Rubella vaccine is a live attenuated vaccine which makes up the third component
of the MMR vaccine. Its purpose is to prevent the congenital rubella syndrome by
ensuring that all women of childbearing age are protected against infection. A single
dose confers lifelong protection in 95% of vaccinees. Because the live attenuated rubella
virus can cross the placenta this vaccine is contraindicated in all pregnant women and
within three months of a planned conception. However, data on 226 women who
received rubella vaccine during pregnancy or within three months of conception showed
no evidence of congenital rubella syndrome.
Oral polio vaccine is a live attenuated vaccine given in three doses to children at
2, 4, and 6 months of age. It is highly effective and easy to administer; however, because
live polio virus is secreted from the intestines of vaccinated individuals for a short time
after vaccination and because vaccine polio virus can cause paralytic disease this form is
no longer used in this country where polio has been eradicated. Oral polio vaccine is still
the vaccine of choice of the World Health Organization’s effort to eradicate polio from
the world.
Varicella zoster vaccine was approved in 1995 for use in the United States. It is
given at 12-18 months of age and is highly effective in preventing severe varicella
infections. Its use is also recommended for adults who may be exposed to VZV and who
are not immune (health care workers, daycare attendants, etc). This vaccine was
originally developed for immunocompromised children; however, because it can cause
chickenpox-like symptoms it is currently contraindicated in individuals with severe
immunodeficiency. The vaccine can cause a mild chickenpox rash in immunocompetent
hosts and has been shown to go latent in dorsal ganglion cells with subsequent
reactivation zoster; however, it is felt that the risk of zoster in vaccinated individuals is
less than that in naturally infected individuals.

Whole killed vaccines consist of organisms that have been inactivated so that they are
no longer capable of infecting a host or of multiplying within the vaccinated host. These
vaccines do not cause disease but can elicit an immune response. However, because they
do not replicate in the vaccinee they provide less antigenic stimulus than live attenuated
vaccines and often require multiple doses to ensure protection. For the most part, these
vaccines are safe and can be used in immunocompromised individuals. Adverse
reactions to whole killed vaccines are often seen in children.
Hepatitis A vaccine is derived from formalin inactivation of hepatitis A virus and
is recommended for travelers to areas of the world where hepatitis A is endemic and for
children in communities with high rates of hepatitis A (and there are a lot!). The vaccine
is very effective at least in the short term. Two doses given 6-12 months apart appear to
be protective for at least 10 years. Longer term protection may require further boosting.
Influenza virus vaccine is composed of whole or disrupted (split) influenza
viruses. The viruses chosen change from flu season to flu season depending upon which
strains are likely to circulate. Revaccination is recommended yearly as strains change
and antibody levels decline over a 6-9 month period after vaccination. Efficacy of this
vaccine is 60-80% in healthy adults. It is less in elderly and immunocompromised
individuals; however, the vaccine is still effective in this group at preventing serious

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illness, hospitalization and death. A live attenuated nasal influenza vaccine (Flumist)
recently received FDA approval for healthy individuals aged 5-49.
Pertussis vaccines come in two different preparations in this country. The first to
be introduced was the whole cell vaccine which consists of whole killed Bordetella
pertussis. More recently an acellular preparation has become available which consists of
combinations of purified components of the organism and detoxified pertussis toxin.
Whole cell pertussis vaccines are associated with a higher rate of adverse events after
vaccination than are most other vaccines in common use. In a large prospective study
more than 60% of vaccinees had local reactions or fever after receiving the vaccine.
Febrile convulsions (without sequelae) were seen in 1/1750 vaccinees. Acellular
pertussis vaccine causes fewer local and systemic reactions than the whole virus vaccine
and for this reason is now the favored form of vaccination. Pertussis vaccine is usually
combined with diphtheria and tetanus vaccines to produce the DTP (now DTaP as the
acellular preparation is used) given to infants at 2, 4, 6, and 15-18 months with a booster
at school entry age.
Inactivated polio vaccine is currently the polio vaccine of choice in the United
States. It is prepared by formalin inactivation of poliovirus strains and has been
formulated to contain antigens recognized by 99% of the population (enhanced potency
IPV). This vaccine is more immunogenic than OPV but must be administered
parenterally (subcutaneously). It is given on the same schedule as OPV (2, 4, 6-18
months) and has an excellent safety record. Vaccination against polio has resulted in the
eradication of wild-type polio infection from the Western hemisphere and from Europe.

Subunit vaccines consist of immunogenic parts of whole organisms and are used when
attenuation of the organism is difficult and whole killed vaccines are either not
immunogenic enough or too toxic. Many subunit vaccines are conjugated, that is
attached to protein carriers which greatly enhance their immunogenicity. Subunit
vaccines, like killed vaccines, cannot cause disease. In general, adverse events are rare
with subunit vaccines.
Haemophilus b vaccine consists of purified high molecular weight haemophilus b
polysaccharide (PRP) which is covalently linked to a carrier protein. The linkage of the
polysaccharide to the carrier protein greatly enhances the immunogenicity of the vaccine
and allows for its use in young infants (the group most at risk of serious Hib infection).
There are currently 4 licensed formulations of the vaccine which differ in their carrier
protein. PRP-D, which consists of the PRP linked to diphtheria toxoid, is the least
immunogenic of the 4 and is not recommended for use in infants. PRP-OMC, which
consists of the PRP linked to the outer membrane protein complex derived from N.
meningitidis, is the most immunogenic formulation. PRP-T (PRP linked to tetanus
toxoid) and HbOC (oligosaccharide linked to mutant diphtheria toxin protein) are as
effective as PRP-OMC but require an extra dose of vaccine at 6 months. Hib vaccine is
generally given at 2 and 4 months of age with a boost at 12-15 months if using the PRP-
OMC preparation. If using PRP-T or HbOC a third dose at 6 months followed by a boost
at 12-15 months is recommended. All preparations of the vaccine are quite safe and have
resulted in a dramatic decrease in serious Hib infections in vaccinated populations.
Hepatitis B vaccine consists of purified, inactivated hepatitis B surface antigen
particles derived, nowadays, from recombinant DNA technology. In some other
countries HBV vaccine is still made from HBsAg particles derived from the plasma of
chronic carriers of HBV. The vaccine is safe, well-tolerated and generally highly
effective although a small number of vaccinated individuals never seroconvert.
Vaccination is currently recommended for all adults with potential blood/ body fluid

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exposure (that includes all of you) and is given to all infants in the United States (usually
in combination with a Hib vaccine).
Meningococccal polysaccharide vaccine contains purified meningococcal
polysaccharides of groups A, C, Y, and W135. A single IM dose induces protective
antibody levels in over 90% of vaccinees over the age of 2. Adverse events are rare. The
vaccine is recommended for high risk groups including those with complement
deficiency, asplenia, and travelers to countries with endemic disease. It is recommended
by some for college students, particularly freshmen living in dormitory accommodation.
It should be noted that the vaccine does not confer protection against group B
meningococcus infection -- an important cause of meningitis.
Both pneumococcal polysaccharide vaccine and conjugated pneumococcal
polysaccharide vaccine are currently available in the United States. The unconjugated
vaccine consists of 23 different serotypes of pneumococcal capsular polysaccharide
covering the strains responsible for 85% of all bacteremic pneumococcal disease in the
US. This vaccine is recommended for people over the age of 65 and in adults and
children over the age of 2 with high risk for pneumococcal disease. The conjugated
pneumococcal polysaccharide vaccine consists of polysaccharide from 7 serotypes of
pneumococcus linked to protein carriers. It is recommended for all children aged 2-23
months and is generally given at 2,4,6, and 12-15 months.

Toxoids are modified bacterial toxins that have been rendered non-toxic but retain the
ability to stimulate the formation of antibodies (antitoxins). Toxoids are generally safe
and well-tolerated but most do not produce life-long immunity and require booster doses.
Diphtheria toxoid is a purified preparation of inactivated diphtheria toxin. It is
highly effective in inducing antibodies that will prevent disease although it has little
effect on acquisition or carriage of the actual organism, Corynebacterium diphtheriae,
that makes the toxin. Local reactions to the toxoid are frequent especially with booster
doses. A high dose of toxoid is given in combination with pertussis vaccine and tetanus
toxoid to young children (DTaP) and in a lower dose in combination with tetanus toxoid
(Td) to older children and adults. After the initial 3 doses of toxoid, booster doses need
to be given every 10 years to ensure continued protection against diphtheria. The use of
the diphtheria toxoid has resulted in a 99.99% decrease in cases of diphtheria in the
United States from 1921 to 1992.
Tetanus toxoid is a purified preparation of inactivated tetanus toxin precipitated
with alum and is one of the most effective immunizing agents known. A course of 3
doses induces protective antibodies in over 95% of recipients. It is given to young
children as part of the DTaP vaccine and to older children and adults as the Td vaccine.
After the initial series of vaccinations boosters are recommended every 10 years (given as
Td to ensure both tetanus and diphtheria protection is given). The most common side
effects are fever and local reactions. As the local reactions can be quite severe, boosters
are recommended only every 10 years unless a particularly tetanus-prone wound has
occurred in which case a booster should be given if it is more than 5 years since the last
booster. Tetanus cases have decreased over 97% since the introduction of tetanus toxoid.

Other Vaccines to Know About: A number of other vaccines are available and
recommended for use under certain circumstances. It is worthwhile knowing about these
vaccines especially if you work with travelers and immigrants, plan to travel yourself, or
have an interest in potential agents of bioterrorism.
Anthrax vaccine is a cell-free filtrate prepared from microaerophilic cultures of
an avirulent strain of Bacillus anthracis. The vaccine is indicated only for those at high
risk of anthrax infection (this definition may change over time but currently consists of

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people coming into contact with animal hides from endemic areas, laboratory personnel
working with anthrax, and the military). Its efficacy is not known but it does induce
antibodies in over 90% of individuals who receive the primary course of 6 subcutaneous
injections. Annual boosting is required to sustain antibody levels. Mild local reactions
are quite common however system reactions are very rare.
BCG vaccine contains living Calmette-Guerin bacillus, an attenuated strain of
Mycobacterium bovis. Although widely used throughout the world it is not
recommended for general use in the United States because it can affect the PPD test and
is of controversial efficacy. It appears to be most effective in preventing complications
of disseminated TB in young children and it is therefore recommended primarily for
infants and young children at high risk of exposure to TB in the US. Because BCG
vaccine contains live organisms, it can disseminate in immunocompromised individuals
and therefore it should not be used in this population. BCG produces a vigorous local
immune response and has been instilled into the bladder to produce an immune response
in people with bladder cancer.
Rabies vaccine is an inactivated virus vaccine prepared in human or fetal rhesus
lung diploid cell culture. The human diploid cell preparation (HDCV) can be used either
intramuscularly or intradermally, while the rhesus lung preparation (RVA) can only be
used IM. Rabies vaccine is used in people likely to be exposed to rabies (veterinarians,
certain travelers, etc) or in people who have been exposed to potentially rabid animals.
Preexposure prophylaxis is given as three doses either IM or intradermally at 0, 7, 21-28
days with follow-up boosting every 2 years or when a potential exposure has occurred.
Postexposure prophylaxis is given as 5 IM shots on days 0, 3, 7, 14, and 28 along with
rabies immune globulin on day 0. Rabies immune globulin is not needed in persons who
have received pre-exposure prophylaxis. Local reactions are common (30-74% of
vaccinees) and systemic complaints are also frequently seen with rabies vaccine but no
contraindication exists for its administration to at risk or exposed individuals (remember
the alternative is certain death).
Yellow fever vaccine is a live attenuated virus preparation. It is highly effective
and very well tolerated and excellent immunity is achieved after a single dose of vaccine.
It is recommended for travelers to areas of endemnicity and is required by some countries
for entry. As it is a live attenuated virus its use is contraindicated in
immunocompromised individuals; although pregnancy is not an absolute contraindication
for its use.
Smallpox vaccine has resulted in the eradication of naturally occurring smallpox
infection on earth. Smallpox vaccines are derivatives of cowpox (vaccinia) virus and are
the derivatives of one of three strains: Elstree (Lister, France) strain, EM63 (Moscow)
strain, and the New York City Board of Health strain. Smallpox vaccines are produced
from a seed virus propagated on the skin of calves and then processed to eliminate
bacterial contamination. Vaccinations are given over the deltoid region of the upper arm
using a bifurcated needle dipped in the vaccine. The needle is held perpendicular to the
skin and pressed in and out 5 times in unvaccinated individuals, 15 times in previously
vaccinated individuals. A successful vaccination is defined as a pustular lesion or an area
of definite induration or congestion surrounding a central lesion 6-8 days after
vaccination. Although smallpox vaccine is highly effective, it does have a number of
serious adverse consequences which preclude its general use at the current time.

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