Principles of Vaccination

A. Patricia Wodi, MD and Valerie Morelli, BA

Immunology and Vaccine-Preventable Diseases 1

To understand how vaccines work and the foundation of NOTES
recommendations for their use, it is helpful to understand the
basic function of the human immune system. The following
description is simplified; many excellent immunology textbooks
provide additional detail.

Immunity is the ability of the human body to tolerate the

presence of material indigenous to the body and to eliminate
foreign substances. This discriminatory ability to eliminate
foreign substances is performed by a complex system of
interacting cells called the immune system. Since most
organisms (e.g., bacteria, viruses, and fungi) are identified as
foreign, the ability to identify and eliminate these substances
provides protection from infectious diseases. Immunity is
generally specific to a single organism or group of closely
related organisms.

The immune system develops a defense against antigens, which

are substances that can stimulate the immune system. This
defense is known as the immune response and usually involves
the production of:

• Protein molecules (immunoglobulins or antibodies,

the major component of humoral immunity) by
B-lymphocytes (B-cells)

• Specific cells, including T-lymphocytes (also known

as cell-mediated immunity)

The most effective immune responses are generally produced

in response to antigens present in a live organism. However,
an antigen does not necessarily have to be present in a live
organism to produce an immune response. Some antigens,
such as hepatitis B surface antigen, are easily recognized by
the immune system and produce adequate protection even
if they are not carried on the live hepatitis B virus. Other
materials are less effective antigens, and the immune response
they produce may not provide good protection.

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Types of Immunity
1 There are two basic mechanisms for acquiring immunity:
passive and active.
NOTES
Passive Immunity
Passive immunity is protection by antibody or antitoxin
produced by one animal or human and transferred to another.
Passive immunity provides immediate protection against
infection, but that 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 the mother. Antibodies, specifically the
class of antibody referred to as IgG, are transported across the
placenta, primarily during the last 1 to 2 months of pregnancy.
As a result, a full-term infant will have the same type of
antibodies as the mother. These antibodies can protect the
infant from certain diseases within the first few months after
birth. Maternal antibodies provide better protection from some
diseases (e.g., measles, rubella, tetanus) than from others (e.g.,
polio, pertussis).

Passive immunity can also be acquired through the transfusion

of blood products. Some blood products (e.g., washed or
reconstituted red blood cells) contain a relatively small amount
of antibody, while some (e.g., intravenous immune globulin and
plasma products) contain a large amount.

In addition to blood products used for transfusion, there are

three other major sources of antibody used in human
medicine. These are homologous pooled human antibody,
homologous human hyperimmune globulin, and heterologous
hyperimmune serum.

Homologous pooled human antibody, also known as immune

globulin, is produced by combining the antibody fraction,
specifically the class of antibody referred to as IgG, from the
blood of thousands of adult donors. Because it comes from
many different donors, it contains antibody to many
different antigens. It is used primarily for prophylaxis for
hepatitis A and measles, and treatment of certain congenital
immunoglobulin deficiencies.

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Homologous human hyperimmune globulins are antibody
products that contain high titers of antibody targeting more 1
specific antigens. These products are made from donated
human plasma with high levels of the antibody of interest. Since NOTES
hyperimmune globulins are from humans, they are primarily
polyclonal, containing many types of antibodies in lesser
quantities. Hyperimmune globulins are used for postexposure
prophylaxis for several diseases, including hepatitis B, rabies,
tetanus, and varicella.

Heterologous hyperimmune serum, also known as antitoxin, is

produced in animals, usually horses, and contains antibodies
against only one antigen. In the United States, antitoxins are
available for the treatment of botulism and diphtheria. These
products can cause serum sickness, an immune reaction to the
horse protein.

Immune globulin products from human sources are primarily

polyclonal; they contain many kinds of antibodies. 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-Hodgkin lymphoma), prevention of transplant
rejection, and treatment of autoimmune (Crohn’s disease,
rheumatoid arthritis) and infectious diseases.

While certain antibody products, such as immune globulins,

interfere with the immune response to live-virus vaccines,
monoclonal antibody products do not because they are
directed against one antigen or a closely related group of
antigens. A monoclonal antibody product, palivizumab
(Synagis), is available for the prevention of respiratory syncytial
virus (RSV) infection. Since Synagis only contains RSV antibody,
it will not interfere with the response to a live vaccine.

Active Immunity
Active immunity is protection produced by a person’s own
immune system. The immune system is stimulated by an
antigen to produce antibody-mediated and cell-mediated
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 survive infection with

the disease-causing form of the organism. In general, once
persons recover from infectious diseases, they will have lifelong
immunity to that disease (there are exceptions, e.g., malaria).
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 memory B-cells continue
to circulate in the blood and reside in the bone marrow for
many years. Upon re-exposure to the antigen, these memory

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cells begin to replicate and produce antibody rapidly to
1 NOTES reestablish protection.

Another way to produce active immunity is by vaccination.

Vaccines contain antigens that stimulate the immune
system to produce an immune response that is often similar
to that produced by the natural infection. With vaccination,
however, the recipient is not subjected to the disease and its
potential complications.

Many factors may influence the immune response to

vaccination. These include the presence of maternal antibody,
the nature and dose of antigen, the route of administration,
and the presence of an adjuvant (e.g., aluminum-containing
material added to improve immunogenicity of the vaccine).
Host factors, such as age, nutrition, genetics, and coexisting
disease, may also affect the immune response. The more
similar a vaccine is to the disease-causing form of the
organism, the better the immune response to the vaccine.

Classification of Vaccines
There are two basic types of vaccines. Their characteristics
are different and determine how each type is used.
1. Live, attenuated, and
2. Inactivated.

Live, Attenuated Vaccines

Live vaccines are derived from “wild” viruses or bacteria.
These wild viruses or bacteria are attenuated (weakened) in
a laboratory, usually by repeated culturing. For example, the
measles virus used as a vaccine today was isolated from a child
with measles disease in 1954. Almost 10 years of serial passage
using tissue culture media were required to transform the wild
virus into the attenuated vaccine virus.

To produce an immune response, live, attenuated vaccines must

replicate in the vaccinated person. A relatively small dose of
administered virus or bacteria replicates in the body and creates
enough of the organism to stimulate an immune response.

Although live, attenuated vaccines replicate, they usually do

not cause disease such as that caused by the wild form of the
organism. When a live, attenuated vaccine does cause disease,
it is usually much milder than the natural disease and is
considered an adverse reaction to the vaccine.

The immune response to a live, attenuated vaccine is virtually

identical to that produced by a natural infection because the
immune system does not differentiate between an infection
with a weakened vaccine virus and an infection with a wild

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virus. Injected live, attenuated vaccines produce immunity in
most recipients with one dose. However, a small percentage NOTES 1
of recipients do not respond to the first dose of an injected
live, attenuated vaccine (such as measles, mumps, and rubella
[MMR]) and a second dose is recommended to provide an
extremely high level of immunity in the population. Orally
administered live, attenuated vaccines require more than one
dose to produce immunity.

A live, attenuated vaccine may cause severe or fatal infections

as a result of uncontrolled replication of the vaccine virus or
bacteria. However, this only occurs in persons with a weakened
immune system (e.g., from leukemia, treatment with certain
drugs, or human immunodeficiency virus [HIV] infection).

A live, attenuated vaccine virus could theoretically revert to its

original pathogenic form. This is known to happen only with
live (oral) polio vaccine, which is no longer available in the
United States.

Active immunity from a live, attenuated vaccine may not

develop because of interference with the vaccine virus
by circulating antibody. Antibody from any source (e.g.,
transplacental transfer to infants, transfusion of blood products)
can interfere with replication of the vaccine organism and lead
to poor response or no response to the vaccine (also known as
vaccine failure).

Live, attenuated vaccines are fragile and can be damaged

or destroyed by heat and light. They must be stored and
handled carefully. The live, attenuated viral vaccines currently
available and routinely recommended in the United States
are MMR, varicella, rotavirus, and influenza (intranasal). Other
non-routinely recommended live vaccines include adenovirus
vaccine (used by the military), typhoid vaccine (Ty21a), and
Bacille Calmette-Guerin (BCG). BCG is not used as a vaccine in
the United States, but as a treatment for bladder cancer.

Inactivated Vaccines
Inactivated vaccines are not live and cannot replicate. These
vaccines cannot cause disease, even in an immunodeficient
person. Inactivated antigens are less affected by circulating
antibody than are live antigens, so they may be given when
antibody is present in the blood (e.g., in infancy or following
receipt of antibody-containing blood products).

The immunity provided by inactivated vaccines is generally not

as long-lasting as that obtained from live, attenuated vaccines.
Multiple doses over time are needed to obtain ongoing
immunity. In general, the first dose does not produce protective
immunity, but “primes” the immune system. A protective

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immune response develops after the second or third dose.
1 NOTES Unlike live vaccines, which produce an immune response that
closely resembles natural infection, the immune response to
an inactivated vaccine is mostly antibody production. Little or
no cellular immunity results. Antibody titers against inactivated
antigens diminish with time. As a result, some inactivated
vaccines may require periodic supplemental doses to increase,
or “boost,” antibody titers.

Inactivated vaccines include whole-cell inactivated vaccines

(e.g., polio, hepatitis A, and rabies vaccines), subunit vaccines
(e.g., influenza and pneumococcal vaccines), toxoids (e.g.,
diphtheria and tetanus toxoid), and recombinant vaccines
(e.g., hepatitis B, human papillomavirus [HPV], and influenza
[Flublok brand]).

Whole-cell inactivated vaccines contain bacteria or viruses

that have been killed through a physical or chemical process.
Whole-cell inactivated viral vaccines against polio, hepatitis A,
and rabies are available in the United States. A vaccine made
from whole killed pertussis (whooping cough) bacteria is
available outside the United States.

Subunit vaccines contain a portion of the bacteria or virus. The

portion of the organism selected is the part needed to produce
a protective immune response. Antigens in subunit vaccines can
be protein, polysaccharide, or a combination of polysaccharide
and protein molecule (i.e., conjugate vaccine).

Conjugate subunit vaccines (e.g., Haemophilus influenzae

type b and pneumococcal conjugate vaccines) are produced
by chemically attaching a polysaccharide from the surface
of bacteria to a protein molecule through a process called
conjugation. Conjugating a polysaccharide antigen to a protein
molecule produces long-lasting protective immunity to the
polysaccharide antigen.

The immune response to a pure polysaccharide vaccine is

typically T-cell-independent, which means these vaccines
can stimulate B-cells without the assistance of T-helper cells.
T-cell-independent antigens, including polysaccharide vaccines,
are not consistently immunogenic in children younger than
age 2 years, probably because of immaturity of the immune
system. Attaching the polysaccharide antigen to a protein
makes it possible to prevent bacterial infections in populations
where a polysaccharide vaccine is not effective or provides only
temporary protection.

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Toxoid vaccines are made using inactivated toxins produced
by bacteria. These protein-based toxins are inactivated using NOTES 1
heat, chemicals, or other methods. Some bacteria (e.g., tetanus,
diphtheria) cause disease by producing toxins. The ability of
the immune system to recognize and eliminate these toxins
provides protection from the disease.

Recombinant vaccines are produced by recombinant DNA

technology. Recombinant DNA technology enables the
combination of DNA from two or more sources. Hepatitis B,
human papillomavirus (HPV), and influenza (Flublok brand)
vaccines are produced by insertion of a segment of the
respective viral gene into the gene of a yeast cell or virus. The
modified yeast cell or virus produces pure hepatitis B surface
antigen, HPV capsid protein, or influenza hemagglutinin when
it grows. Serogroup B meningococcal vaccines are proteins and
outer membrane vesicles generated by recombinant technology.

Acknowledgements
The editors would like to acknowledge Jennifer Hamborsky,
Andrew Kroger, Ginger Redmon, and Skip Wolfe for their
contributions to this chapter.

Selected References
American Academy of Pediatrics. Active and passive
immunization. In: Kimberlin D, Brady M, Jackson M, et al., eds.
Red Book: 2018 Report of the Committee on Infectious Diseases.
31st ed. Itasca, IL: American Academy of Pediatrics;2018:13–64.

Plotkin S. Correlates of vaccine-induced immunity.

Clin Infect Dis 2008;47:401–9.

Plotkin S. Vaccines, vaccination, and vaccinology.

J Infect Dis 2003;187:1347–59.

Siegrist C. Vaccine immunology. In: Plotkin S, Orenstein W, Offit

P, et al., eds. Plotkin’s Vaccines. 7th ed. Elsevier;2018:16–34.

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1 NOTES