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CHAPTER 22
VACCINATION
VACCINATION has had a huge impact on increasing human life expectancy.
ACTIVE IMMUNIZATION confers long-lasting immunity by inoculation with killed or
attenuated organisms, toxoids or purified antigens. PASSIVE IMMUNIZATION by
transfer of antibodies has the advantage of more rapidly establishing protection, but it is
short-lived and may carry a risk of inducing serum sickness. The route and schedule of
immunization, physical nature of the vaccine antigen, and immune status of the host all
contribute to the relative effectiveness of any vaccination protocol, in ways which are still
not fully understood.
HISTORY
Awareness of acquired resistance to infectious diseases has existed since ancient times. This
knowledge led to the development in China, several centuries ago, of the technique of
variolation, the deliberate inoculation of small amounts of material from smallpox pustules
into healthy individuals. Having recovered from the disease induced by this treatment, which
generally was milder and less dangerous than the naturally acquired disease, the inoculated
individuals had a life-long immunity to smallpox. Variolation was brought from China to the
West, and was increasingly widely used in Europe and the New World through the eighteenth
century. It remained, however, a dangerous procedure with an appreciable risk of death, and
provided a source of infection for spread to others.
This technique was replaced almost overnight following Jenner's publication of the results of
his technique of vaccination. He had learned of the fact that milkmaids who had handled
cows which were suffering from cowpox developed a high degree of resistance to the related
human disease, smallpox. He then was able to show that inoculation of cowpox material into
humans, while not causing serious disease, was in fact capable of producing resistance to
smallpox.
The distinction between variolation and vaccination is an important one. In vaccination, the
fact that the inoculated material is not a virulent human pathogen makes this technique much
safer than variolation, and it derives its name from the species which originally provided this
material (vaccus = cow).
MODES OF IMMUNIZATION
A)
ACTIVE IMMUNIZATION
Active immunization, of which Jenner's original vaccination is an example, involves the
inoculation of immunogenic material to induce an immune response (and therefore
immunological memory) in the recipient. Active immunity takes longer to develop than
passive (see below), but also lasts much longer, and may often be life-long.
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Various forms of antigenic material may serve as a vaccine:
i) Killed organisms. The viruses which cause rabies, influenza and polio (the latter
in the case of the Salk vaccine) can be collected, killed by treatment with heat or
chemicals, and used as effective vaccinating agents. The bacteria responsible for
cholera, whooping cough (pertussis) and typhoid fever can be used in the same
manner.
ii) Attenuated organisms. Live viruses, but in a weakened or "attenuated" form,
provide effective vaccination for measles, mumps and polio (Sabin vaccine), and
more recently for influenza (in a form administered by nasal mist). Attenuated
bacterial vaccines also exist, typified by those for anthrax and for tuberculosis
(BCG, “Bacille de Calmette-Guerin”, an attenuated form of the organism which
causes bovine turberculosis). The advantage of attenuated organism over killed
ones is that they can set up active (although hopefully harmless) infections and
provide more effective stimulation of protective immune responses.
Attenuation of viruses may be achieved by growth in vitro in the laboratory and
selection of genetic variants with limited pathogenic potential. While the use of
vaccinia (cowpox virus) also falls into the category of "attenuated viruses", it actually
represents the fortuitous existence in nature of a cross-reactive but non-pathogenic
organism. Similarly, attenuation of bacteria may be achieved by allowing bacterial
cultures to "age" during laboratory culture with or without deliberate selection of
variants.
A key factor in producing any viral vaccine is the development of a cell culture system
which allows the growth of the virus in the laboratory. The development of the Salk
vaccine in the 1950's, for example, followed hard on the heels of the discovery that
monkey kidney cells in culture could be used to grow the virus.
iii) Toxoids. In the case of diphtheria and tetanus infections, the real danger in the
disease comes not from the presence of the organisms themselves but from the
potent toxins which they produce. Effective immunity can be induced by
immunization with chemically modified toxins, or toxoids, which are no longer
toxic but still highly immunogenic (and, of course, cross-reactive with the native
toxins).
iv) Purified antigens ("subunit vaccines"). Vaccines for meningococcus (Neisseria
meningitidis), pneumococcus (Streptococcus pneumoniae) and the Hepatitis B
virus each consist of purified antigens from these organisms, polysaccharide for
the first two and protein for the last. In those cases where effective antigens can
be identified and purified they have an advantage over attenuated vaccines in not
posing any risk of infection, and over killed organism vaccines in being less likely
to cause severe inflammatory reactions.
A relatively recent development in subunit vaccines can overcome the limitations
of immune responses to carbohydrates, which are typically restricted to IgM.
Carbohydrates can be chemically coupled to immunogenic protein carriers, and the
resulting conjugate vaccines have been developed for pneumococcus and
meningococcus (among others) which can stimulate stronger responses showing
class switching and greater memory, and are effective in younger children.
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v) “Naked” DNA. This relatively recent development in vaccination comes from the
surprising finding that direct inoculation of DNA encoding a protein results in a
strong and long-lived immune response to that protein, both humoral and cellmediated. It is thought that the DNA transfects local APCs resulting in expression
of the encoded protein in the context of both MHC Class I and Class II. One
attractive feature of such a protocol is that it can yield a strong cell-mediated
response without having to resort to the use of live virus vaccines. However,
DNA vaccination in humans has not yet progressed past the clinical trial stage.
B)
PASSIVE IMMUNIZATION
Injection of antibody to a pathogen can provide very rapid, although short-lived, resistance to
infection, and is referred to as passive immunization. Passive immunization is generally
used when there is no time to wait for the development of active immunity (see below), or
when no effective active vaccine exists.
i) Human antibodies. Normal human IgG, prepared from pools of many
individual donors, contains significant levels of antibody to measles and
hepatitis viruses. High levels of protective antibody for tetanus can be obtained
from immunized donors, and anti-Zoster antibodies from the serum of patients
collected during recovery from an infection. In each case, these antibodies can
be administered to recipients who are at high risk for acquiring the disease.
ii) Heterologous antibodies. Horse antibodies to diphtheria toxin or to the toxins
of snake and spider venoms have been very effective in neutralizing the effect of
these dangerous molecules. The use of heterologous serum, of course,
introduces a substantial risk of inducing serum sickness or an allergic reaction.
C)
ADOPTIVE IMMUNITY
We have already discussed adoptive immunity in experimental systems, illustrated by the
transfer of immune reactivity to non-immune (and/or irradiated) recipients using
immunocompetent cells, typically spleen cells. Obviously, such adoptive transfer of reactivity
cannot be carried out in humans due to histocompatibility barriers, and adoptive immunity
essentially does not exist in human medicine. This term is sometimes applied in a somewhat
different context, i.e. describing the hematopoietic restoration/replacement which results
from bone marrow transplantation, as, for example, in the case of Severe Combined
Immunodeficiency (see Chapter 20).
SOME FACTORS AFFECTING IMMUNIZATION
i) Adjuvants (see also Chapter 2). The most effective experimental adjuvant known,
Freund's Adjuvant, cannot be used in clinical medicine because of its severe side
effects (inflammation, pain, and fever). Some human vaccines can be rendered more
effective, however, by precipitating the antigen together with an aluminum
hydroxide salt, a procedure known as alum precipitation; diphtheria toxoid is used
in this form. Synthetic adjuvants usable in humans are currently being developed,
some involving synthetic versions of the biologically active molecules of Freund's
(including muramyl dipeptide).
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In some cases one can take advantage of the natural adjuvant properties of certain
vaccines, notably pertussis. The so-called triple vaccine, (DPT), consists of alumprecipitated diphtheria toxoid, killed pertussis organisms and tetanus toxoid. In this
case, the pertussis organisms act as an adjuvant (much as Mycobacterium does in
Freund's), which increases the immune response to the two purified protein antigens.
ii) Route of immunization. While most vaccinations are introduced through the skin,
either by scarification (e.g. smallpox) or by injection (e.g. Salk polio vaccine and
many others), the Sabin polio vaccine is one notable exception. The attenuated viral
organisms are administered orally, and they set up a chronic infection in the gut,
stimulating a local IgA response. Since the normal mode of entry of polio virus is
through the gut, this antibody response is precisely in the place where it should do
the most good. (It should be noted, however, that the Sabin vaccine is no longer
recommended for use in the U.S.) Similarly, one form of the influenza vaccine
(Flumist) is administered as an intranasal mist, mimicking the normal route of entry
of the infectious organism.
iii) Dose of antigen. The dose and time course of human vaccinations is largely
determined empirically; whatever works is used.
iv) State of the host. The effectiveness of active immunization naturally depends on
the ability of the host to mount a normal immune response. It can be dangerous,
however, to introduce any live vaccine into a host with a T-cell deficiency, since
even an attenuated organism can give rise to a lethal infection in such an
environment.
In the case of an immunologically healthy host, the degree of urgency may determine
if passive or active immunization is appropriate. For tetanus, active immunization
with the toxoid is generally used and is effective for ten years or more. However, in
the case of a very severe wound, or a tetanus-prone wound which is several days old
before being presented to the physician, passive immunization may be administered
for immediate protection, together with active immunization for longer-lasting
immunity. Similarly for rabies, passive immunization may be added to the standard
active immunization in the case of a particularly severe rabies-prone wound, or one
close to the head (since the brain is a major target of the virus).
OTHER ISSUES ASSOCIATED WITH IMMUNIZATION
A) Antigenic variation. Influenza virus, for example, can rapidly alter its antigenic
structure by mutation, so that it is no longer recognized by antibodies made against the
original virus. Influenza can therefore give rise to repeated infection with variants of
the same organism.
B) Antigenic competition. Two antigens given at the same site can sometimes each
interfere with the immune response to the other. In general, therefore, different
immunizations are given at different times and/or at different sites. But remember that
DPT is a notable exception to this rule, and other routine multiple vaccination protocols
exist (such as MMR).
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C) Maternal immunoglobulin. The presence of specific antibodies at the time of
vaccination may interfere with its success. Measles vaccine, for example, should not be
given before 15 months of age, since the presence of maternal IgG antibodies may
prevent active immunization (remember RhoGAM, discussed in Chapter 10).
ACTIVE IMMUNIZATIONS
Diseases
Vaccine Type
Disease Organism
General
*Poliomyelitis
Measles
Mumps
Rubella
"MMR"
(German Measles)
*Diphtheria
*Pertussis
(whooping cough) “DPT”
*Tetanus
*Hepatitis B
Pneumococcal (PCV)
Meningitis
Hib
*Influenza
Varicella (chicken pox)
killed virus (Salk)
Polio virus
attenuated virus (Sabin) [not currently recommended]
attenuated virus
Measles virus (Rubeola)
attenuated virus
Mumps virus
attenuated virus
toxoid
Rubella virus
Corynebacterium diphtheriae
killed bacteria
toxoid
purified protein (recombinant )
conjugated carbohydrate
conjugated carbohydrate
conjugated carbohydrate
killed virus (injected)
attenuated virus (nasal mist)
attenuated virus
Bordatella pertussis
Clostridium tetani
Hepatitis B virus
Streptococcus pneumoniae
Neisseria meningitidis
Hemophilus influenzae type b
Influenza virus
live virus (Vaccinia)
killed virus
attenuated virus
killed organisms
killed or attenuated bacteria
killed bacteria
killed bacteria
killed bacteria
attenuated bacteria (BCG)
killed bacteria
Smallpox virus (Variola)
Rabies virus
Yellow fever virus
Rickettsia typhi
Salmonella typhi
Salmonella paratyphi
Vibrio cholera
Yersinia pestis
Mycobacterium tuberculosis
Rickettsia rickettsii
attenuated virus
Varicella-zoster virus
Varicella-zoster virus
Special
*Smallpox
Rabies
Yellow fever
Typhus
Typhoid fever
Paratyphoid
Cholera
Plague
Tuberculosis
Rocky Mountain
Spotted Fever
Shingles
*Key examples
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CHAPTER 22, STUDY QUESTIONS:
1.
Describe at least one example each of clinical vaccination by (a) live organisms,
(b) killed organisms, or (c) purified antigen. What are the advantages and
disadvantages of each?
2.
What are the benefits and risks of active versus passive immunization?
examples.
3.
How might one account for the phenomenon of antigenic competition?
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Give