IMMUNOLOGY AND VACCINE-PREVENTABLE DISEASE
Immunology is a complicated subject, and a detailed discussion of
it is beyond the scope of this text. However, an understanding of
the basic function of the immune system is useful in order to
understand both how vaccines work and the basis of recommendations
for their use. The description that follows is simplified.
Many excellent immunology textbooks are available to provide
additional detail.
Immunity is the ability of the human body to tolerate the presence
of material indigenous to the body (“self”), and to eliminate
foreign (“non-self”) material. This discriminatory ability provides
protection from infectious disease, since most microbes are identified
as foreign by the immune system. Immunity to a microbe is
usually indicated by the presence of antibody to that organism.
Immunity is generally very specific to a single organism or group of
closely related organisms. There are two basic mechanisms for
acquiring immunity - active and passive.
Active immunity is protection that is produced by the person’s
own immune system. This type of immunity is usually permanent.
Passive immunity is protection by products produced by an
animal or human, and transferred to another human, usually by
injection. Passive immunity often provides effective protection, but
this protection wanes (disappears) with time, usually a few weeks or
months.
The immune system is a complex system of interacting cells
whose primary purpose is to identify foreign (“non-self”) substances
referred to as antigens. Antigens can be either live (such
as viruses and bacteria) or inactivated. The immune system develops
a defense against the antigen. This defense is known as the
immune response and usually involves the production of protein
molecules, called antibodies (or immunoglobulins), and of specific
cells (also known as cell-mediated immunity) whose purpose is
to facilitate the elimination of foreign substances.
The most effective immune responses are generally produced in
response to a live antigen. However, an antigen does not necessarily
have to be alive, as in a natural infection with a virus or bacteria,
to produce an immune response. Some proteins, such as hepatitis
B surface antigen, are easily recognized by the immune system.
Other material, such as polysaccharide (long chains of sugar molecules
that make up the cell wall of certain bacteria) are less effective
antigens, and the immune response may not provide as good
protection.

PASSIVE IMMUNITY
Passive immunity is the transfer of antibody produced by one
human or other animal to another. Passive immunity provides pro-
tection against some infections, but this protection is temporary. The
antibodies will degrade during a period of weeks to months and the
recipient will no longer be protected.
The most common form of passive immunity is that which an
infant receives from its mother. Antibodies are transported across
the placenta during the last 1-2 months of pregnancy. As a result,
a full-term infant will have the same antibody “profile” as its mother.
These antibodies will protect the infant from certain diseases
for up to a year. Protection is better against some diseases (e.g.,
measles, rubella, tetanus) than others (e.g., polio, pertussis).
Virtually all types of blood products contain antibody. Some
products (e.g., washed or reconstituted red blood cells) contain a
relatively small amount of antibody, and some (e.g., intravenous
immune globulin and plasma products) contain very large
amounts.
Besides blood products used for transfusion (e.g., whole blood, red
cells, and platelets) there are three major sources of antibody used
in human medicine. These are homologous pooled human antibody
(immune globulin), homologous human hyperimmune globulin,
and heterologous hyperimmune serum (antitoxin).
Homologous pooled human antibody is also known as
immune globulin. It is produced by combining (pooling) the
IgG antibody fraction from thousands of adult donors in the U.S.
Because it comes from many different donors, it contains antibody
to many different antigens. It is used primarily for postexposure
prophylaxis for hepatitis A and measles.
Homologous human hyperimmune globulins are antibody
products that contain high titers of specific antibody. These products
are made from the donated plasma of humans with high levels
of the antibody of interest. However, since hyperimmune globulins
are from humans, they also contain other antibodies in lesser quantities.
Hyperimmune globulins are used for postexposure prophylaxis
for several diseases, including hepatitis B, rabies, tetanus, and
varicella.
Heterologous hyperimmune serum is also known as antitoxin.
This product is produced in animals, usually horses (equine), and
contains antibodies against only one antigen. In the U.S., antitoxin
is available for treatment of botulism and diphtheria. A problem
with this product is serum sickness, a reaction to the horse protein.
Immune globulin from human sources is polyclonal - it contains
many different kinds of antibodies. In the 1970s, techniques were
developed to isolate and "immortalize" (cause to grow indefinitely)
single B cells, which led to the development of monoclonal antibody
products. Monoclonal antibody is produced from a single
clone of B cell, so these products contain antibody to only one
antigen or closely related group of antigens. Monoclonal antibody
products have many applications, including the diagnosis of certain
types of cancer (colorectal, prostate, ovarian, breast), treatment of
cancer (B-cell chronic lymphocytic leukemia, non-Hodgkins lymphoma),
prevention of transplant rejection, and treatment of
autoimmune diseases (Crohns disease, rheumatoid arthritis) and
infectious disease.
Two globulin products are available for the prevention or treatment
of respiratory synctial virus (RSV) infection - RSV-IGIV and
palivizumab (Synagis). RSV-IGIV is a hyperimmune globulin from
human donors. It contains antibody other than RSV, like other
hyperimmune globulin products. Palivizumab is a humanized
monoclonal antibody specific for RSV. It does not contain any
other antibody except anti-RSV antibody.

ACTIVE IMMUNITY
Active immunity is stimulation of the immune system to produce
antigen-specific humoral (antibody) and cellular immunity. Unlike
passive immunity which is temporary, active immunity usually lasts
for many years, often for a lifetime.
One way to acquire active immunity is to have the natural disease.
In general, once persons recover from infectious diseases, they will
be immune to those diseases for the rest of their lives. The persistence
of protection for many years after the infection is known as
immunologic memory. Following exposure of the immune system
to an antigen, certain cells (memory B-cells) continue to circulate
in the blood (and also reside in the bone marrow) for many
years. Upon reexposure to the antigen, these memory cells begin
to replicate and produce antibody very rapidly to reestablish protection.
Another way to produce active immunity is by vaccination.
Vaccines interact with the immune system and often produce an
immune response similar to that produced by the natural infection,
but do not subject the recipient to the disease and its potential
complications. Vaccines produce immunologic memory similar to
that acquired by having the natural disease.
Many factors may influence the immune response to vaccination.
These include the presence of maternal antibody, nature and dose
of antigen, route of administration, and the presence of adjuvants
(e.g., aluminum-containing materials added to improve the
immunogenicity of the vaccine). Host factors such as age, nutritional
factors, genetics, and coexisting disease, may also affect the
response.

CLASSIFICATION OF VACCINES
There are two basic types of vaccines: live attenuated and inactivated.
The characteristics of live and inactivated vaccines are different,
and these characteristics determine how the vaccine is used.
Live attenuated vaccines are produced by modifying a disease-
producing (“wild”) virus or bacteria in a laboratory. The resulting
vaccine organism retains the ability to replicate (grow) and produce
immunity, but usually does not cause illness. Live attenuated
vaccines available in the U.S. include live viruses and live bacteria.
Inactivated vaccines can be composed of either whole viruses or
bacteria, or fractions of either. Fractional vaccines are either protein-
based or polysaccharide-based. Protein-based vaccines
include toxoids (inactivated bacterial toxin), and subunit or subvirion
products. Most polysaccharide-based vaccines are composed
of pure cell-wall polysaccharide from bacteria. Conjugate
polysaccharide vaccines are those in which the polysaccharide is
chemically linked to a protein. This linkage makes the polysaccharide
a more potent vaccine.
General Rule
The more similar a vaccine is to the natural disease, the
better the immune response to the vaccine.

LIVE ATTENUATED VACCINES
Live vaccines are derived from “wild,” or disease-causing, virus or
bacteria. These wild viruses or bacteria are attenuated, or weakened,
in a laboratory, usually by repeated culturing. For example,
the measles vaccine used today was isolated from a child with
measles disease in 1954. Almost 10 years of serial passage on tissue
culture media was required to transform the wild virus into
vaccine virus.
In order to produce an immune response, live attenuated
vaccines must replicate (grow) in the vaccinated person. A
relatively small dose of virus or bacteria is given, which replicates
in the body and creates enough virus to stimulate an immune
response. Anything that either damages the live organism in the vial
(e.g., heat, light), or interferes with replication of the organism in
the body (circulating antibody) can cause the vaccine to be ineffective.
Although live attenuated vaccines replicate, they usually do not
cause disease, such as may occur with the natural (“wild”) organism.
When a live attenuated vaccine does cause “disease,” it is usually
much milder than the natural disease, and is referred to as an
adverse reaction.
The immune response to a live attenuated vaccine is virtually identical
to that produced by a natural infection. The immune system
does not differentiate between an infection with a weakened vaccine
virus and an infection with a wild virus. Live attenuated vaccines
are generally effective with one dose, except those administered
orally. s of Vaccination
Live attenuated vaccines may cause severe or fatal reactions as a
result of uncontrolled replication (growth) of the vaccine virus.
This only occurs in persons with immunodeficiency (e.g., from
leukemia, treatment with certain drugs, or HIV infection).
A live attenuated vaccine virus could theoretically revert back to its
original pathogenic (disease-causing) form. This is known to happen
only with live (oral) polio vaccine.
Active immunity from a live attenuated vaccine may not develop
due to interference from circulating antibody to the vaccine virus.
Antibody from any source (e.g., transplacental, transfusion)
can interfere with growth of the vaccine organism and lead to
a poor response or no response to the vaccine (also known as
vaccine failure). Measles vaccine virus seems to be most sensitive
to circulating antibody. Polio and rotavirus vaccine viruses are
least affected.
Live attenuated vaccines are labile, and can be damaged or
destroyed by heat and light. They must be handled and stored
carefully.
Currently available live attenuated viral vaccines include measles,
mumps, rubella, vaccinia, varicella, yellow fever, and influenza
(intranasal). Oral polio vaccine is a live viral vaccine but is no
longer available in the United States. Live recombinant rotavirus
vaccine is still licensed in the U.S. but is no longer distributed
because of its association with intussusception. Live attenuated
bacterial vaccines include BCG and oral typhoid vaccine.

INACTIVATED VACCINES
These vaccines are produced by growing the bacteria or virus in
culture media, then inactivating it with heat and/or chemicals (usually
formalin). In the case of fractional vaccines, the organism is
further treated to purify only those components to be included in
the vaccine (e.g., the polysaccharide capsule of pneumococcus).
Inactivated vaccines are not alive and cannot replicate. The
entire dose of antigen is administered in the injection. These vaccines
cannot cause disease from infection, even in an immunodeficient
person. Unlike live antigens, inactivated antigens are usually
not affected by circulating antibody. Inactivated vaccines may be
given when antibody is present in the blood (e.g., in infancy, or following
receipt of antibody-containing blood products). Inactivated
vaccines always require multiple doses. In general, the first dose
does not produce protective immunity, but only “primes” the
immune system. A protective immune response develops after the
second or third dose. In contrast to live vaccines, in which the
immune response closely resembles natural infection, the immune
response to an inactivated vaccine is mostly humoral. Little or no
cellular immunity results. Antibody titers against inactivated antigens
fall diminish with time. As a result, some inactivated vaccines
may require periodic supplemental doses to increase, or “boost,”
antibody titers.
Currently available inactivated vaccines are limited to inactivated
whole viral vaccines (influenza, polio, rabies, and hepatitis A).
Whole inactivated bacterial vaccines (pertussis, typhoid, cholera,
and plague) are no longer available in the United States.
“Fractional” vaccines include subunits (hepatitis B, influenza, acellular
pertussis), and toxoids (diphtheria, tetanus). A subunit vaccine
for Lyme disease is no longer available in the U.S.

POLYSACCHARIDE VACCINES
Polysaccharide vaccines are a unique type of inactivated subunit
vaccine composed of long chains of sugar molecules that make up
the surface capsule of certain bacteria. Pure polysaccharide vaccines
are available for three diseases: pneumococcal disease,
meningococcal disease, and Salmonella typhi. A pure polysaccharide
vaccine for Haemophilus influenzae type b is no longer available in
the U.S.
The immune response to a pure polysaccharide vaccine is typically
T-cell independent, which means that these vaccines are able to
stimulate B-cells without the assistance of T-helper cells. T-cell
independent antigens, including polysaccharide vaccines, are not
consistently immunogenic in children <2 years of age. Young children
do not respond consistently to polysaccharide antigens, probably
because of immaturity of the immune system.
Repeated doses of most inactivated protein vaccines cause the antibody
titer to go progressively higher, or “boost.” Repeat doses of
polysaccharide vaccines do not cause a booster response. This is
not seen with polysaccharide antigens. Antibody induced with
polysaccharide vaccines has less functional activity than that
induced by protein antigens. This is because the predominant antibody
produced in response to most polysaccharide vaccines is
IgM, and little IgG is produced.
In the late 1980s, it was discovered that the problems noted above
could be overcome through a process called conjugation.
Conjugation changes the immune response from T-cell independent
to T-cell dependent, leading to increased immunogenicity in
infants and antibody booster response to multiple doses of vaccine.
The first conjugated polysaccharide vaccine was for Haemophilus
influenzae type b (Hib). A conjugate vaccine for pneumococcal disease
was licensed in 2000. A meningococcal conjugate vaccine
may be available in the future.

RECOMBINANT VACCINES
Vaccine antigens may also be produced by genetic engineering
technology. These products are sometimes referred to as recombinant
vaccines. Three genetically-engineered vaccines are currently
available in the United States. Hepatitis B vaccines are pro-
duced by insertion of a segment of the hepatitis B virus gene into
the gene of a yeast cell. The modified yeast cell produces pure
hepatitis B surface antigen when it grows. Live typhoid vaccine
(Ty21a) is Salmonella typhi bacteria that has been genetically modified
to not cause illness. Live attenuated influenza vaccine (LAIV)
has been engineered to replicate effectively in the mucosa of the
nasopharynx but not in the lungs.

SELECTED REFERENCES
Ada G. The immunology of vaccination. In: Plotkin SA, Orenstein
WA. Vaccines. 4th ed. Philadelphia, PA: Saunders, 2003:31-45.