Understanding

Vaccines

National Institutes of Health

National Institute of Allergy 

and Infectious Diseases

U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES

National Institute of Allergy

and Infectious Diseases

NIH Publication No. 98–4219

January 1998
1 Preface

1 Introduction

3 Vaccines

3 Benefits

3 Adult Immunization

4 Evaluating a Vaccine

6 Protection Against Microbes

7 The Immune System

7 Organs of the Immune System

9 How the Immune System Works

14 Naturally Acquired Immunity

15 Artificially Acquired Immunity

15 Different Types of Vaccines

16 Traditional Vaccines

18 New and Second-Generation Vaccines

20 Vaccine Development and Testing

20 Basic Research and Development

22 Clinical Studies

24 Side Effects and Adverse Reactions

25 NIAID’s Role in Basic and Clinical Research

25 The Children’s Vaccine Initiative

26 Vaccines of the Future

29 Glossary

Contents
Understanding Vaccines

This booklet contains information about vaccines

to help you understand how they are made and

tested, as well as why they can prevent disease. You

will not find everything there is to know about

vaccines here, however. In fact, the booklet may

prompt you to think of more questions about

vaccines. After all, vaccines themselves—the

developing, manufacturing and testing of them—are

complex, as are the diseases they are meant to

prevent.

We have tried to anticipate which terms in the booklet

will need further definition and clarification. Those

terms, when they first appear in the text, are in italics.

Italicized words and phrases and basic vaccine

terminology are defined in the Glossary at the end of

the booklet.

You may be able to find more in-depth and detailed

resources at your local library or through your health

care provider. The Internet can be a valuable source

as well. Start with the National Institutes of Health

(NIH) Web site at http://www.nih.gov for

information on the broad range of research conducted

by NIH. For information on vaccine research, go to

http://www.niaid.nih.gov, the Web site for the

National Institute of Allergy and Infectious Diseases.

More than two hundred years ago, Edward Jenner, a

country physician practicing in England, noted that

milkmaids rarely suffered from smallpox, a disease

that was known to kill up to 40 percent of those who

contracted it. The milkmaids often did get cowpox, a

related but far less serious disease, and those who

did, never became ill with smallpox. In an experiment

that was to prove a revelation, Jenner took a few

drops of fluid from a skin sore of a woman who had

cowpox and injected the fluid into the arm of a

healthy young boy who had never had cowpox or

smallpox. Six weeks later, Jenner injected the boy

with fluid from a smallpox sore, but the boy remained

1 Understanding Vaccines

Preface

Introduction
free of the dreaded smallpox. Dr. Jenner had

discovered one of the fundamental principles of

immunization. He had used a relatively harmless

foreign substance to evoke an immune response that

would protect someone from a disease-causing

microbe.

In those days, a million people died from smallpox

each year in Europe alone, most of them children.

Those who survived were often left with grim

reminders of their ordeals: blindness, deep scars,

deformities. When Jenner laid the foundation for

modern vaccines in 1796, he started on a course that

would ease the suffering of people around the world.

By the beginning of this century, vaccines for rabies,

diphtheria, typhoid fever and plague were in use, in

addition to the vaccine for smallpox.

Yet vaccination was not immediately accepted. The

idea of deliberately introducing a potentially harmful

microbe into people was met with suspicion and even

outrage by many in the medical and scientific

communities, and public opinion was bitterly divided

over the merits of vaccination. It took some time to

convince people that the benefits of vaccination

outweigh the few risks. Today’s vaccines are far safer

and more protective than those early vaccines. And as

science advances, we are developing even better

vaccines to protect ourselves from disease.

2 Understanding Vaccines

Edward Jenner

vaccinates a child for

smallpox
Benefits

Disease prevention is the key to public health.

Vaccines benefit in particular the people who receive

them, and in turn, those people cannot spread disease

to others who have not been vaccinated. Infection

cannot spread if it never gains a foothold. Infectious

diseases cause enormous suffering, strain the

capabilities of our health care system, and deplete

financial resources. For the individual, the health care

provider, and in the interest of conserving human and

financial resources, it is always better to prevent a

disease than to treat it.

Veterinary vaccines benefit people, too. Some

diseases, such as rabies, anthrax, certain types of

encephalitis, and Rift Valley fever, are readily

transmissible from animal species to humans. In many

instances, livestock and pets are vaccinated not only

for their own health, but for that of their owners.

In the United States, federal and state public health

programs help assure that children receive vaccines.

Many childhood diseases that were a normal part of

growing up just 50 years ago are now preventable.

Measles, rubella (German measles), mumps, pertussis,

(whooping cough), and chickenpox were almost

unavoidable. Most people did not reach adulthood

without their families or circle of friends being

touched by a serious illness or death caused by an

infectious disease. For the most part, children suffered

through the course of the disease and were left with

naturally acquired immunity, some school work to

catch up on, and perhaps a little pockmark

somewhere on their skin. However, in some cases,

children died, or they were left with permanent loss

of hearing or sight or other tragic effects of serious

infections.

Adult Immunization

Although most of us receive the great majority of our

immunizations during childhood, it is important to

remember that vaccines are not just for young

children. Adolescents and adults should keep up-to3 Understanding Vaccines

Vaccines

Common

VaccinePreventable

Diseases 

Chickenpox

Hepatitis A

Hepatitis B

Hib disease

Influenza

Measles

Mumps

Pertussis

(whooping 

cough)

Pneumococcal 

pneumonia

Polio

Rubella 

(German measles)
date on tetanus and diphtheria immunizations.

Adults who have not had diseases such as measles

or chickenpox during childhood, or the vaccines to

prevent them, should consider being immunized.

Ironically, childhood diseases such as measles,

mumps, and chickenpox can be far more serious in

adults.

People who travel overseas should determine,

together with their physicians or at international

travel clinics, which vaccines would be appropriate

based on their destinations. Effective vaccines are

available to prevent yellow fever, polio, typhoid

fever, hepatitis A, cholera, and other bacterial and

viral diseases that are more prevalent abroad than

in the United States.

Each year, as we prepare for winter and the flu

season, many adults should consider the benefits of

the flu vaccine. In addition to flu vaccine,

immunizations for pneumococcal pneumonia,

hepatitis A, and hepatitis B are recommended for

people who may be at risk.

Evaluating a Vaccine

Variations in individuals and their immune systems

are many and subtle; thus no vaccine is totally

effective. In the United States, a vaccine is

approved for general use if it fulfills several

stringent requirements.

• The vaccine must be safe. Although it is quite

unlikely that a vaccine will ever be 100 percent

safe, it must produce protective immunity with

only minimal side effects (such as redness and

soreness at the vaccination site) for the

overwhelming majority of those who receive it.

More discomfort in side effects can be

acceptable, however, depending upon the

severity of the disease the vaccine is designed to

prevent. For example, most people would

consider vaccine side effects that mimicked the

symptoms of a bad cold acceptable if the vaccine

protected them from HIV disease.

4 Understanding Vaccines
5 Understanding Vaccines

Vaccines Licensed in the United States

• Adenovirus vaccine

• Anthrax vaccine

• Bacille Calmette-Guérin vaccine

• Cholera vaccine

• Diphtheria toxoid

• Diphtheria and tetanus toxoids

• Diphtheria and tetanus toxoids and acellular pertussis vaccine 

• Diphtheria and tetanus toxoids and whole cell pertussis vaccine

• Diphtheria and tetanus toxoids and pertussis and Haemophilus influenzae

b (Hib) conjugate vaccine

• Hib conjugate vaccine (with diphtheria, meningococcal, and tetanus

conjugates)

• Hepatitis A vaccine

• Hepatitis B vaccine

• Influenza virus vaccine

• Japanese encephalitis virus vaccine

• Measles virus vaccine

• Measles and mumps virus vaccine

• Measles, mumps, and rubella virus vaccine 

• Meningococcal vaccine, Group A

• Meningococcal vaccine, Group C

• Meningococcal vaccine, Groups A and C

• Meningococcal vaccine, Groups A, C, Y, and W-135

• Mumps virus vaccine

• Pertussis vaccine (acellular)

• Pertussis vaccine (whole cell)

• Plague vaccine

• Pneumococcal vaccine

• Poliovirus vaccine—inactivated

• Poliovirus vaccine—live, attenuated

• Rabies vaccine

• Rubella vaccine

• Smallpox vaccine

• Tetanus toxoid

• Typhoid vaccine

• Varicella (chickenpox) virus vaccine

• Yellow fever vaccine
• The vaccine must be immunogenic, that is, it must

cause a strong and measurable immune response.

Vaccines usually contain antigens, bits of material,

sometimes from the disease-causing microbe itself,

that can stimulate the immune system to respond

and fight off a potential infection. When a vaccine is

immunogenic, it primes the recipient’s immune

system to recognize the disease-causing microbe

and launch a counterattack before illness can occur.

In addition, the vaccine must induce the right type

of immunity. When microbes invade, they cause

disease in different ways, and different parts of the

immune system respond to fight them. Vaccines

must stimulate the specific parts of the immune

system that protect against a particular kind of

organism.

• The vaccine must be stable during its shelf life, that

is to say, its potency must remain at the proper level

for the vaccine to evoke an immune response.

Many inactivated vaccines are simple to store, since

they are in powdered form and are reconstituted

with the appropriate fluid before they are given.

Live, attenuated vaccines, however, require

refrigeration from manufacturer to clinic to maintain

stability and potency.

All approaches to vaccine development focus on the

immune system and the body’s natural defenses

against foreign invaders. To understand something of

how vaccines work, it is best to start with the immune

system. Together, your immune system and vaccines

are powerful allies in the fight against disease.

Protection Against Microbes

The body has an arsenal of defenses that it uses to

ward off foreign invaders. Healthy immune systems

recognize as foreign many things that are not self. 

Most of the foreign invaders that confront the human

immune system are microscopic. Fungi, parasites,

bacteria, and viruses populate our planet in far greater

numbers than any other living organisms. Some are

beneficial. We coexist quite happily with certain types

6 Understanding Vaccines

Bacteria: streptococci
of bacteria that live in our gastrointestinal and genital

tracts. These bacteria help prevent infection by

harmful organisms. We are even dependent on some

microorganisms that inhabit our gastrointestinal tracts

for their help in digesting food. Whether beneficial or

harmful, however, all foreign microbes in the human

body display special markers on antigens called

antigenic determinants or epitopes. It is these antigens

and their determinants that the immune system may

recognize as harmful and identify for destruction.

Organs of the Immune System

The immune system is a complex of organs—highly

specialized cells and even a circulatory system

separate from blood vessels—all of which work

together to clear infection from the body.

The organs of the immune system, positioned

throughout the body, are called lymphoid organs. The

word “lymph” in Greek means a pure, clear stream—

an appropriate description considering its appearance

and the purpose of our immune systems. 

Lymphatic vessels and lymph nodes are the parts of the

special circulatory system that carries lymph, a

transparent fluid containing white blood cells, chiefly

lymphocytes. Lymph bathes the tissues of the body,

and the lymphatic vessels collect and move it

eventually back into the blood circulation. Lymph

nodes dot the network of lymphatic vessels and

provide meeting grounds for the immune system cells

that defend against invaders. The spleen, at the upper

left of the abdomen, is also a staging ground and a

place where immune system cells confront foreign

microbes.

7 Understanding Vaccines

Parasite: malaria 

The Immune

System 

Virus: herpes simplex virus Fungus: candida
Pockets of lymphoid tissue are in many other

locations throughout the body, such as the bone

marrow and thymus. Tonsils, adenoids, Peyer’s

patches, and the appendix are also lymphoid tissues. 

8 Understanding Vaccines

Lymphatic

Vessel

Lymph

Node

Lymphatic vessels

form a circulatory

system that operates in

close partnership with

blood circulation.

Organs and tissues of

the immune system

dot the body in a

protective network of

barriers to infection.

Tonsils and

adenoids

Lymph

nodes

Lymph

nodes

Lymphatic

vessels

Appendix

Bone

marrow

Thymus

Spleen

Peyer's

patches

Lymph

nodes
Both immune cells and foreign molecules enter the

lymph nodes via blood vessels or lymphatic vessels.

All immune cells exit the lymphatic system and

eventually return to the bloodstream. Once in the

bloodstream, lymphocytes are transported to tissues

throughout the body, where they act as sentries on

the lookout for foreign antigens.

How the Immune System Works

Cells that will grow into the many types of more

specialized cells that circulate throughout the immune

system are produced in the bone marrow. This

nutrient-rich, spongy tissue is found in the center

shafts of certain long, flat bones of the body, such as

the bones of the pelvis. The cells most relevant for

understanding vaccines are the lymphocytes,

numbering close to one trillion. 

The two major classes of lymphocytes are B cells,

which grow to maturity in the bone marrow, and T

cells, which mature in the thymus, high in the chest

behind the breastbone.

B cells produce antibodies that circulate in the blood

and lymph streams and attach to foreign antigens to

mark them for destruction by other immune cells. B

cells are part of what is known as antibody-mediated

or humoral immunity, so called because the

antibodies circulate in blood and lymph, which the

ancient Greeks called, the body’s “humors.” Certain T

cells, which also patrol the blood and lymph for

foreign invaders, can do more than mark the antigens;

they attack and destroy diseased cells they recognize

as foreign. T cell lymphocytes are responsible for cellmediated immunity (or cellular immunity). T cells

also orchestrate, regulate and coordinate the overall

immune response. T cells depend on unique cell

surface molecules called the major histocompatibility

complex (MHC) to help them recognize antigen

fragments.

9 Understanding Vaccines
Antibodies

The antibodies that B cells produce are basic

templates with a special region that is highly specific

to target a given antigen. Much like a car coming off a

production line, the antibody’s frame remains

constant, but through chemical and cellular messages,

the immune system selects a green sedan, a red

convertible or a white truck to combat this particular

invader. However, in contrast to cars, the variety of

antibodies is very large. Different antibodies are

destined for different purposes. Some coat the foreign

invaders to make them attractive to the circulating

scavenger cells, phagocytes, that will engulf an

unwelcome microbe. When some antibodies combine

with antigens, they activate a cascade of nine proteins,

known as complement, that have been circulating in

inactive form in the blood. Complement forms a

partnership with antibodies, once they have reacted

10 Understanding Vaccines

Antibody

Epitope

Antigen

Antibodies produced

by cells of the immune

system recognize

foreign antigens and

mark them for

destruction.
with antigen, to help destroy foreign invaders and

remove them from the body. Still other types of

antibodies block viruses from entering cells.

T Cells

T cells have two major roles in immune defense.

Regulatory T cells are essential for orchestrating the

response of an elaborate system of different types of

immune cells. Helper T cells, for example, also known

as CD4 positive T cells (CD4+ T cells), alert B cells to

start making antibodies; they also can activate other T

cells and immune system scavenger cells called

macrophages and influence which type of antibody is

produced. Certain T cells, called CD8 positive T cells

(CD8+ T cells), can become killer cells that attack and

destroy infected cells. The killer T cells are also called

cytotoxic T cells or CTLs (cytotoxic lymphocytes). 

11 Understanding Vaccines

T lymphocytes become

CD4+ or helper T cells,

or they can become

CD8+ cells, which in

turn can become

killer T cells, also

called cytotoxic T cells.

Activated

helper T cell

Activated

cytotoxic T cell

Resting T cell

B cell

Plasma cell Antibody

B lymphocyte cells

become plasma cells,

which produce

antibodies when a

foreign antigen

triggers the immune

response.
Processed antigen

and Class I MHC

Processed

antigen and 

Class I MHC

Activated cytotoxic

T cell

Cytotoxic T cell 

becomes activated

Resting 

cytotoxic T cell

Cytotoxic T-cell

receptor

recognizes

processed

antigen plus

Class I MHC

Antigen

Antigen (virus)

Processed

antigen

(viral protein)

Macrophage

Class I MHC Antigen is processed

Activated helper T cell

Infected cell

Cell dies

After a macrophage engulfs and processes an antigen, the macrophage displays

the antigen fragments combined with a Class I MHC protein on the macrophage

cell surface. A receptor on a circulating, resting cytotoxic T cell recognizes the

antigen-protein complex and binds to it. The binding process and a helper T cell

activate the cytotoxic T cell so that it can attack and destroy the diseased cell.

Antigen Antigen is processed

Macrophage

Class II

MHC

Processed 

antigen and

Class II MHC

are displayed

Helper T-cell

receptor recognizes 

processed antigen 

plus Class II MHC

Activated helper 

T cell

Resting

helper T cell

Activation of helper T cells

Activation of cytotoxic T cells

After it engulfs and processes an antigen, the macrophage displays the antigen

fragments combined with a Class II MHC protein on the macrophage cell surface.

The antigen-protein combination attracts a helper T cell, and promotes its

activation.
Antigen

Antigen-specific

B-cell receptor

Class II MHC

Antigen is

processed

Plasma cell

Antibodies

B cell

Class II MHC and

processed antigen

are displayed

Activated

helper T cell

Activation of B cells to make antibody

A B cell uses one of its receptors to bind to its matching antigen, which the B cell

engulfs and processes. The B cell then displays a piece of the antigen, bound to a

Class II MHC protein, on the cell surface. This whole complex then binds to an

activated helper T cell. This binding process stimulates the transformation of the

B cell into an antibody-secreting plasma cell.
Naturally Acquired Immunity

As early as 2500 years ago in Greece, some people

understood enough about contagion to know that a

person who had recovered from plague would not

get it again. Later, physicians recognized that a person

acquires immunity to many diseases in this way.

This protection comes from another special cell of the

immune system. Whenever B cells and T cells are

summoned, they transform some of their numbers

into memory cells. Although the army of antibodies

necessary to destroy an infectious agent does not

remain, the memory cells do. If the memory cells

recognize the invader again, the immune system

quickly mounts a defense and defeats the interlopers

before illness can occur. This type of immunity is

naturally acquired. Most of us benefit from naturally

acquired immunity from our earliest days. Certain

types of immune cells are passed from mother to fetus

during pregnancy. Thus, most newborns, though

vulnerable in many ways, have a head start in fighting

disease.

14 Understanding Vaccines

Naturally acquired

Active Immunity Passive Immunity

Naturally acquired

Artificially acquired Artificially acquired

SERUM

We become immune

through artificial and

natural means.

Vaccines give us

artificially acquired

active immunity to

disease.
Artificially Acquired Immunity

Artificially acquired immunity can be either passive or

active. Artificially acquired passive immunity results

when antibodies produced by another animal or

human are given to someone to prevent or treat

disease. For example, administering tetanus antitoxin

or rabies immune globulin to someone is a way of

conferring passive immunity. This type of

immunization is effective very quickly, but since it

lasts only a short time, it is used to protect people

when they are particularly vulnerable, such as

immediately after exposure to a serious disease.

Artificially acquired active immunity, the type

obtained from vaccines, is essentially the subject of

this booklet. 

Artificially acquired active immunity is achieved

through safe and effective vaccines. Traditional

vaccines are preparations of killed or weakened

bacteria or viruses, or parts of these microbes, or

inactivated toxins from the disease-causing agent.

Recently, innovative vaccine technologies have

revealed many more ways to give people active

immunity to a disease. These include subunit

vaccines, conjugate vaccines and naked DNA

vaccines.

When a new disease emerges or a familiar one

becomes a more significant health threat than it has

been in the past, scientists, physicians and public

health workers recognize the need for a new way to

prevent the disease. Once scientists have identified

the organism or toxin that causes the illness, they

pursue a number of approaches to develop a vaccine. 

Vaccine development has its early roots in the work of

Edward Jenner, who discovered how to protect

people from smallpox, and Louis Pasteur, who

developed a vaccine to protect from rabies. Those

pioneering efforts subsequently led to vaccines for

diseases that had once claimed millions of lives

worldwide.

15 Understanding Vaccines

Different Types of

Vaccines 
16 Understanding Vaccines

The purpose of a vaccine is to bring about active

immunity by provoking a response from a person’s

immune system—marshaling B and T cells to swing

into action—and creating a memory within the

immune system so that exposure to the active disease

agent will stimulate an already primed immune

system to fight the disease. Some vaccines are

combinations that protect against several diseases.

Most of us are familiar with the DTP (diphtheria,

tetanus, pertussis) and MMR (measles, mumps,

rubella) vaccines that children in the United States

receive. Scientists extensively test these combination

vaccines to make sure that none of the antigens

detracts from the immune priming effect of the others.

Thus the vaccines can provide triple protection, the

recipients are spared extra needle sticks, and the

public health costs are reduced.

Based on the biological and chemical characteristics

of the disease-causing agent and on what type of

immunity is desired, researchers begin to develop one

of the following types of vaccines. Vaccines can be

produced from 1) inactivated (killed), 2) live,

attenuated (weakened), or 3) synthetic (laboratorymade) microbial materials. 

Traditional Vaccines

Inactivated Vaccines

Inactivated vaccines are produced by killing the

disease-causing microorganism with chemicals or

heat. Such vaccines are stable and safe; they cannot

revert to the virulent (disease-causing) form. They

often do not require refrigeration, a quality that makes

them accessible to the people of many developing

countries, as well as practical for vaccinating people

who are highly mobile, such as members of the

armed forces. However, most inactivated vaccines

stimulate a relatively weak immune response and

must be given more than once. A vaccine that

requires several doses (boosters) has a limited

usefulness, especially in areas where people have less

access to regular health care.
The flu shot is an inactivated vaccine, as are the

vaccines for cholera, plague, and hepatitis A.

Live, Attenuated Vaccines

To make a live, attenuated vaccine, the diseasecausing organism is grown under special laboratory

conditions that cause it to lose its virulence, or

disease-causing properties. Although live vaccines

require special handling and storage in order to

maintain their potency, they produce both antibodymediated and cell-mediated immunity and generally

require only one boost, or additional dose. Most live

vaccines are injected; some, however, such as the

polio vaccine, are given orally. In addition, intranasal

vaccines, administered in the nose, show promise in

preventing flu. 

While there are advantages to live vaccines, there is

one caution. It is the nature of living things to change,

to mutate, and the organisms used in live vaccines are

no different. There is a remote possibility that the

organism may revert to a virulent form and cause

disease. It is for this reason that live vaccines continue

to be carefully tested and monitored.

For their own protection, people with compromised

immune systems—such as people who are taking

immunosuppressive drugs, people who have cancer or

people living with HIV—are usually not given live

vaccines.

The vaccines for yellow fever, measles, rubella, and

mumps are all produced from live, attenuated

organisms.

Toxoids

A toxoid is an inactivated toxin, the harmful substance

produced by a microbe. Many of the microbes that

infect people are not themselves harmful. It is the

powerful toxins they produce that can cause illness.

For example, the bacterium that causes tetanus is

found everywhere in nature, and in an environment

with plenty of oxygen, it is harmless. If that same

organism is put into an environment without oxygen,

17 Understanding Vaccines
however, the organism starts to change and produce

tetanus toxin, a substance far more potent than the

well-known poison sodium cyanide. To inactivate

such powerful toxins, vaccine manufacturers treat

them with materials known to completely cripple any

disease-causing ability. Formalin, a solution of

formaldehyde and sterile water, is most often used to

inactivate toxins and produce toxoids.

Toxoids are used to immunize people against tetanus

and diphtheria.

New and Second-Generation Vaccines

Scientists are using new technologies to improve

traditional vaccines. These new second-generation

vaccines, as well as vaccines for diseases that had not

been preventable very long ago, are made using

powerful techniques such as recombinant genetic

engineering (also called recombinant DNA

technology).

Conjugate Vaccines

The bacteria that cause some diseases, such as

pneumococcal pneumonia and certain types of

meningitis, have special outer coats. These coats

disguise antigens so that the immature immune

systems of infants and younger children are unable to

recognize these harmful bacteria. In a conjugate

vaccine, proteins or toxins from a second type of

organism, one that an immature immune system can

recognize, are linked to the outer coats of the diseasecausing bacteria. This enables a young immune

system to respond and defend against the disease

agent.

Currently, conjugate vaccines are available to protect

against a type of bacterial meningitis caused by

Haemophilus influenzae type b (Hib). Meningitis, an

inflammation of the fluid-filled membranes that

protect the brain and spinal cord, can be fatal, or it

can cause severe, life-long disabilities such as

deafness and mental retardation. Since Hib vaccines

18 Understanding Vaccines
have been in widespread use in the United States, Hib

meningitis has nearly disappeared among babies and

young children. 

Subunit Vaccines

Sometimes vaccines developed from antigenic

fragments are able to evoke an immune response,

often with fewer side effects than might be caused by

a vaccine made from the whole organism. Subunit

vaccines can be made by taking apart the actual

microbe, or they can be made in the laboratory using

genetic engineering techniques.

Today, subunit vaccines are used to protect against

pneumonia caused by Streptococcus pneumoniae and

against a type of meningitis.

A recombinant subunit vaccine for hepatitis B virus

infection is now licensed for use in the United States.

The recombinant vaccine is made by inserting a tiny

portion of the hepatitis B virus’ genetic material into

common baker’s yeast. This process induces the yeast

19 Understanding Vaccines

Incidence rate of invasive Haemophilus influenzae type b (Hib)

disease among children aged <5 years, United States, 1989-1994

40

30

20

10

0

1989 1990 1991 1992 1993 1994

Rate (per 100,000 children

aged <5 years)

Hib-caused diseases

among children have

plummeted since

1989, when Hib

vaccines became

widely used.

Source: Summary of Notifiable

Diseases, United States, 1995.

CDC Morbidity and Mortality

Weekly Report
to produce an antigen, which is then purified. The

purified antigen, when combined with an adjuvant, a

substance that stimulates the immune system, results

in a safe and very effective vaccine. 

Recombinant Vector Vaccines

A vaccine vector, or carrier, is a weakened virus or

bacterium into which harmless genetic material from

another disease-causing organism can be inserted. 

The vaccinia virus, the virus that causes cowpox, is

now used to make recombinant vector vaccines. In

the submicroscopic world of viruses, vaccinia is

relatively large and has ample room to accept

additional genetic fragments. A vaccinia virus with

several genes from the human immunodeficiency

virus (HIV) is currently being tested as a vaccine for

acquired immune deficiency syndrome (AIDS). In

addition, a close relative of vaccinia, canarypox virus,

engineered with harmless fragments of HIV, is being

tested in human volunteers as a vaccine for AIDS.

Similarly, scientists are testing a weakened

bacterium—salmonella—to carry portions of such

microbes as the hepatitis B virus. Currently no

recombinant vector vaccines are licensed for general

use in the United States.

To be approved for general use, a candidate vaccine

must go through a long period of testing and

validation. The time between discovery of a disease

agent and production of a widely available vaccine

has been as long as 50 years. Today, with biological

synthesis and recombinant vaccine development

techniques, the length of time from basic research to

availability of a licensed product can sometimes be

greatly reduced.

Basic Research and Development

Basic research focuses on biochemistry and

physiology and on mechanisms that disease-causing

microbes use to cause damage. Such research also

takes into account the biophysical characteristics of

20 Understanding Vaccines

Vaccine

Development 

and Testing
21 Understanding Vaccines

Vaccinia

virus

Mammalian

cell

Progeny

virus

(wild-type

and recombinants

with foreign

gene)

Wild-type and

recombinant

virus plaques

Recombinant

plaques are selected for

development as candidate

vaccines

Foreign

gene

inserted into

transfer

vector

Vaccinia virus is recombined in a mammalian cell with a foreign gene. The

vaccinia viruses produced are both wild-type viruses and new, recombinant

viruses. These recombinant viruses are isolated and used to develop a safe,

effective vaccine.
the organisms that might be used in vaccines or drugs

to prevent or interrupt the disease process.

To develop a candidate vaccine, scientists test vaccine

preparations in cell-culture, and often eventually in

animals such as mice, guinea pigs, or even monkeys.

In some cases, computers can help researchers

visualize the vaccine candidates in three dimensions

to predict how vaccine antigens will interact with the

immune system. If the vaccine candidate is shown to

be promising throughout the preclinical evaluations, it

can become an investigational vaccine.

An investigational vaccine is one that successfully has

gone through basic research and developmental

processes, often including preclinical trials in animals,

and has been approved by the U.S. Food and Drug

Administration (FDA) for use in human volunteers in

clinical trials. 

Clinical Studies

Clinical studies rely entirely upon the participation of

volunteers, people who contribute their time and

energy for the advancement of science and improved

health care for all. Thousands of volunteers of all ages

and from all walks of life have participated in these

studies. A typical volunteer in a vaccine study agrees

to be given the vaccine, makes frequent visits to a

clinic for evaluation, participates in medical testing,

and provides blood or tissue samples that will be

used in assessing the vaccine’s safety and potential

effectiveness. Unlike the boy vaccinated by Dr. Jenner

200 years ago, volunteers today must sign an

informed consent document indicating their

understanding of the study, its risks, and their

willingness to participate.

A candidate vaccine undergoes three phases of

clinical trials before it can be licensed for public use.

Phase I trials, to determine the safety of various doses

of the vaccine, usually begin with small numbers of

volunteers, and then expand to include more

volunteers if the vaccine appears to be safe.

22 Understanding Vaccines

Phase I

Phase II

Phase III

Before a vaccine is

licensed, researchers

carefully evaluate its

safety and

effectiveness in many

volunteers.
23 Understanding Vaccines

Steps in Vaccine Development

Understanding the disease

• Recognition of disease

• Diagnosis

• Location and identification of disease agent in nature

• Studies of extent of human disease

• Studies on how the agent damages the body and how the body’s defenses

react

• Studies of naturally acquired immunity

Understanding the disease agent

• Biochemical and biophysical description and characterization

• Growth in cell culture

• Analysis of antigens and genetic properties

• Studies of infection in animals

Developing a vaccine candidate

• Inactivating or weakening the disease agent

• Selection and purification of an appropriate antigen to stimulate the

immune response

• Selection of adjuvants

• Demonstration of stability and lack of harmful properties in animals

• Stimulating a protective immune response in animals

• Production of pilot lots

Testing vaccines in volunteers

• Phase I studies: safety

• Phase II studies: safety and immunogenicity

• Phase III studies: safety, immunogenicity and effectiveness

Production of vaccine for public and 

commercial use

Licensing of the vaccine

Professional and 

public acceptance
Phase II trials, to determine whether the vaccine is

safe and immunogenic, are open to hundreds of

volunteers. The vaccine is tested for safety, for its

ability to evoke an immune response, and for its

potential to prevent disease.

Phase III trials are large-scale efficacy studies, often in

thousands of individuals, to confirm that the vaccine

safely prevents disease. A vaccine is considered

successful if its overall effect is beneficial; it should

prevent disease, and any side effects should be

minimal. If the disease the vaccine is designed to

prevent is rare in the United States, Phase III trials

may be conducted in a country where the disease is

prevalent. In the cases of such international

cooperation, each government signs an agreement

and expects its citizens to benefit from the study. 

Side Effects and Adverse Reactions

The most common side effects of vaccines include

low-grade fever, soreness and redness at the site of

the injection, or sometimes body aches for up to 24

hours after vaccination. These minor side effects of a

vaccine are far preferable to having the disease.

The extensive testing that a vaccine undergoes before

it is licensed for public use is conducted, in part, to

assure safety as much as possible by closely observing

large numbers of volunteers for harmful side effects.

But no matter how thorough the testing, it is

impossible to allow completely for the extensive

variation among individuals, their immune systems,

and their reactions to the introduction of new

substances into their bodies. Serious systemic

reactions to vaccines can occur, although they are

very rare. The FDA and the Centers for Disease

Control and Prevention monitor vaccine distribution

and use. Information about adverse reactions to a

vaccine is collected even after the vaccine is licensed

for general use. Both organizations record any

incident of a serious reaction and follow up on any

re-evaluation of the vaccine that is necessary.

24 Understanding Vaccines
Basic research conducted and supported by the

National Institute of Allergy and Infectious Diseases is

helping scientists understand more about infectious

microbes and human immune responses. From this

understanding has come the development of vaccines

and other tools needed to prevent many infectious

diseases and immune system disorders. The goal of

these efforts is not only to protect individuals from

serious infections; but eventually to eradicate diseases,

as we have seen with smallpox.

In clinical research, NIAID revolutionized the classical

but cumbersome, piecemeal approach to clinical

vaccine studies by designing a network of vaccine

and treatment evaluation units, and more recently, an

international network for testing vaccines to prevent

infection with HIV. Testing sites are based at leading

university medical research centers, public health

departments, and community clinics. Investigators

working within these networks and other NIAIDsupported researchers played major roles in the

clinical studies required for licensing of vaccines for

Hib meningitis and of new acellular pertussis

vaccines.

The Children’s Vaccine Initiative

NIAID has been recognized by Congress as the lead

agency to provide the scientific and programmatic

direction for the Children’s Vaccine Initiative (CVI).

The CVI, a worldwide public health effort, combines

the efforts of many international scientists and

representatives of the United Nations International

Children’s Emergency Fund, the World Health

Organization, the World Bank, The United Nations

Development Program, the Rockefeller Foundation

and vaccine manufacturers, biotechnology firms, and

national research agencies. The CVI has made

impressive strides towards its goal of universal

immunization. Already 80 percent of all children in

the United States receive their initial immunizations by

their first birthdays. NIAID is making progress toward

achievable goals, such as making existing vaccines

safer and more effective and improving vaccines so

that fewer doses will be needed.

25 Understanding Vaccines

NIAID’s Role in

Basic and Clinical

Research
Currently scientists are pursuing many promising new

strategies in vaccine development and exploring novel

ways to administer vaccines. The following

descriptions of just a few of these innovative ideas

provide a preview of safer, more effective ways to

fight disease.

Exposing mucosal membranes to vaccines is a strategy

that can produce an immune response in a lessstressful and better targeted manner. Mucosal

membranes are located throughout our bodies, but

are most accessible in the lungs, nose, mouth, throat,

gastrointestinal tract, rectum and vagina. The oral

polio vaccine, in use since the 1950s, is an early

example of the effectiveness of this strategy. Another

possible mucosal route of administration is through

the nose, and flu vaccines may soon be widely

available in a nasal spray. Researchers have shown

that the route of entry a disease-causing organism

takes is often an effective vaccine route as well. 

Many vaccine improvements may result from progress

in designing better adjuvants. At present, only an

26 Understanding Vaccines

Vaccines of the

Future

Mucosal membranes,

located throughout the

body and

concentrated at

entryways, can

produce a protective

immune response

when stimulated by a

vaccine.
aluminum salt called alum is approved as an adjuvant

by the FDA, but scientists are studying many new

natural and synthetic compounds.

Scientists are also looking at new ways of presenting

the vaccine to the immune system. Microspheres, tiny

spheres containing bits of antigenic material, show

promise in that they can release small doses of

vaccine over extended periods of time as the

microspheres gradually dissolve in the body. This

means that someone may be able to receive two or

three doses in just one administration of vaccine.

Perhaps the most exciting new vaccine technique is

introducing pure genetic material directly into the

body. This genetic material, called “naked DNA,”

encodes a few proteins from a disease-causing

organism. The DNA is then incorporated into the

body’s own cells, which make the proteins encoded

by the new DNA. It is these proteins that are

recognized as foreign and stimulate the immune

system. In this way, the DNA will have an effect

similar to that of a live, attenuated vaccine. In effect,

the DNA will produce antigens for years and induce

strong, long-lasting immunity. At the same time, the

exclusion of genes that are critical to the diseasecausing organism’s survival will assure that the

vaccines are safe and do not actually cause disease.

Researchers are also exploring ways to create edible

vaccines. By genetically engineering plants to

incorporate synthetic antigens, scientists may be able

to develop a banana or potato, for example, that will

produce protective immunity when eaten. Obviously,

such a vaccine technique would greatly simplify

immunization for many people of the world.

Vaccines remain among the most powerful tools we

have for disease prevention, and advances in

biotechnology have ushered in a new era in vaccine

development that holds even more promise for

improving public health. NIAID remains a leader in

the discovery and testing of new and improved

vaccines and will continue to nourish this exciting

renaissance in vaccine development.

27 Understanding Vaccines

acellular vaccine—devoid of whole cells. Acellular

vaccines contain only portions of cellular material.

active immunity—immunity produced by the body in

response to stimulation by a disease-causing organism

(naturally acquired active immunity) or by a vaccine

(artificially acquired active immunity).

adjuvant—a substance sometimes included in a

vaccine formulation to enhance the immunestimulating properties of a vaccine.

antibody—soluble protein molecule produced and

secreted by B cells in response to an antigen and

capable of binding to that specific antigen.

antibody-mediated immunity (humoral immunity)—

immune protection provided by B cells which secrete

antibodies in response to antigen (as distinct from that

provided by the direct action of immune cells, or

cellular immunity).

antigen—a substance that provokes an immune

response.

B cells—small white blood cells crucial to the immune

defenses. Also known as B lymphocytes, they are

derived from bone marrow and develop into plasma

cells, which produce antibodies.

bone marrow—soft tissue located in the cavities of

the bones. The bone marrow is the source of all

blood cells.

29 Understanding Vaccines

Glossary
cell-mediated immunity (cellular immunity)—

immune protection provided by the direct action of

immune cells (as distinct from that provided by

soluble molecules such as antibodies).

complement—a complex series of blood proteins

whose action “complements” the work of antibodies.

Complement destroys antibody-coated cells, produces

inflammation, and regulates immune reactions.

conjugate vaccine—a vaccine in which proteins that

are easily recognizable to the immune system are

linked to the outer coat of the disease-causing

organism to promote an immune response.

cytotoxic T cells—a subset of T lymphocytes that can

kill other cells infected by viruses, fungi or certain

bacteria, or cells transformed by cancer.

efficacy—in vaccine research, the ability of a vaccine

to produce a desired clinical effect, such as protection

against a specific disease, at the optimal dosage and

schedule in a given population. A vaccine may be

tested for efficacy in Phase III studies if it appears to

be safe and shows promise in smaller Phase I and II

studies.

epitope—a unique shape or marker carried on an

antigen’s surface, which triggers a corresponding

antibody response.

formalin—a solution of water and formaldehyde,

used as an antiseptic, disinfectant or fixative.

genetic material—deoxyribonucleic acid (DNA) that

carries the directions a cell uses to perform a specific

function, such as making a given protein.

30 Understanding Vaccines
Haemophilus influenzae type b (Hib)—a bacterium

found in the respiratory tract that causes acute

respiratory infections, including pneumonia, and other

diseases such as meningitis.

helper T cells—a subset of T cells that typically carry

the CD4 marker and are essential for turning antibody

production on, activating cytotoxic T cells, and

initiating many other immune responses.

humoral immunity—immune protection provided by

soluble factors such as antibodies, which circulate in

the body’s fluids, primarily serum and lymph. (See

antibody-mediated immunity.)

immunogenic—capable of stimulating an immune

response (immunogenicity).

immunosuppressive—capable of reducing immune

responses. For instance, drugs given to prevent

transplant rejection are immunosuppressive.

inactivated toxins—organic toxins, such as those

produced by bacteria and viruses, that have been

killed by chemical means, heat, or irradiation, and are

no longer capable of causing disease.

inactivated vaccine—(killed vaccine) a vaccine made

from a whole virus or bacterium whose biological

ability to grow or reproduce is ended. 

investigational vaccine—a vaccine that has been

approved by the Food and Drug Administration for

testing in humans, but that has not yet completed

evaluation and been accepted for licensure and public

use.

31 Understanding Vaccines
killer T cells (cytotoxic T cells, cytotoxic lymphocytes,

CTLs)—a subset of T cells that can kill cancer cells

and cells infected with viruses, fungi or certain

bacteria.

live, attenuated vaccine—a vaccine whose biological

activity has not been inactivated, but whose ability to

cause disease has been weakened.

lymph—a transparent, slightly yellow fluid that carries

lymphocytes, bathes the body tissues, and drains into

the lymphatic vessels.

lymph nodes—small bean-shaped organs of the

immune system, distributed widely throughout the

body and linked by lymphatic vessels. Lymph nodes

are gathering sites of B, T, and other immune cells.

lymphatic vessels—a bodywide network of channels,

similar to the blood vessels, that transport lymph to

the immune organs and into the bloodstream.

lymphocytes—small white blood cells produced in the

bone marrow and thymus that are essential in

immune defense.

lymphoid organs—organs of the immune system,

where lymphocytes develop and congregate. They

include the bone marrow, thymus, lymph nodes,

spleen, and various other clusters of lymphoid tissue,

such as the appendix. The blood vessels and

lymphatic vessels also can be considered lymphoid

organs.

32 Understanding Vaccines
major histocompatibility complex (MHC)—a large set

of cell surface molecules in each individual, encoded

by genes. MHCs serve as unique biochemical markers

of individual identity.

macrophage—a large and versatile immune cell that

acts as a microbe-devouring phagocyte, an antigenpresenting cell, or an important source of immune

secretions.

memory cell—a subset of T cells and B cells that have

been exposed to specific antigens and can then

respond more readily when the immune system

encounters the same antigens again.

microbe—a minute living organism, such as a

bacterium or virus.

microspheres—tiny, microscopic spheres that can

carry vaccines or drugs and can pass easily through

the body’s tissues. 

mucosal membranes—the moist tissues lining body

cavities or passages that have an opening to the

external world, such as the mouth, nose, rectum or

vagina. Mucosal immunity depends on immune cells

and antibodies being present in the linings of the

reproductive, respiratory, gastrointestinal tracts, and

other mucosal membranes.

mutate—to change a gene or unit of hereditary

material that results in a new inheritable characteristic.

naked DNA vaccine—vaccine made up of

deoxyribonucleic acid that is not encased or

encapsulated. In naked DNA vaccines, genetic

material is injected directly into the vaccine recipient.

naturally acquired immunity—immunity produced

by immune cells passed from mother to fetus or by

the body in response to exposure to a disease-causing

organism.

33 Understanding Vaccines
passive immunity—immunity resulting from the

transfer of cells or antibodies or antiserum produced

by another individual.

Peyer’s patches—a collection of lymphoid tissues in

the intestinal tract.

phagocyte—an immune cell that is able to ingest and

destroy microbes and other foreign matter.

potency—the strength of a substance. In vaccines, one

of the qualities that makes a vaccine protective. 

preclinical—a phase of study of a vaccine or drug

that is completed before clinical studies are carried

out in people. Preclinical studies may be conducted in

cells or in animals.

protective immunity—complete resistance to disease,

whether long-lasting or temporary. 

recombinant DNA technology—the technique by

which genetic material from one organism is inserted

into a foreign cell or another organism in order to

mass-produce the protein encoded by the inserted

genes. (Also called recombinant genetic engineering.)

recombinant genetic engineering—See recombinant

DNA technology.

recombinant subunit vaccine—a subunit vaccine

made using recombinant DNA technology. (See

subunit vaccine.)

recombinant vector vaccine—a vaccine that combines

a vector—a harmless bacterium or virus used to

transport an antigen into the body to stimulate

protective immunity—and an antigen or immunogen

from an organism other than the vector.

34 Understanding Vaccines
spleen—a lymphoid organ in the abdominal cavity

that is an important center for immune system

activities.

Streptococcus pneumoniae—a bacterium found in the

respiratory tract that is a common cause of

pneumonia.

subunit vaccine—a vaccine that uses one or more

components of a disease-causing organism, rather

than the whole, to stimulate an immune response.

T cells—small white blood cells that orchestrate or

directly participate in immune defenses. Also known

as T lymphocytes, they mature in the thymus.

thymus—a primary lymphoid organ, high in the chest,

where T lymphocytes proliferate and mature.

toxoid—an inactivated or killed organic toxin used to

immunize against specific bacteria.

vector—in vaccine technology, a bacterium or virus

that does not cause disease in humans and is used in

genetically engineered vaccines to transport genes

coding for antigens into the body to induce an

immune response.

virulent—toxic, causing disease.

35 Understanding Vaccines