National Institute of Allergy and Infectious Diseases

National Institutes of Health

Task Force on

Safer Childhood Vaccines

Final Report and Recommendations
Contents

Contents

January 1998 iii

Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . v

Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . vii

Executive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . ix

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1

Task Force on Safer Childhood Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

The Legal Framework . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

Reporting Requirements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5

The Task Force Approach . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6

Vaccines: Unique Pharmaceuticals . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11

Public Health and Individual Perspectives on Immunization . . . . . . . . . . . . . . . . . . . 11

The Dynamic Nature of the Vaccine Field . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

The Impact of Basic Research and Technological Advances on 

Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

New and Emerging Infectious Diseases: 

Unexpected Challenges to Vaccinology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Vaccine Safety Issues Past and Current . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13

Evolving Recommendations for Use of Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14

Current Capability for Assessing Vaccine Safety—Vaccine 

Evaluation and Licensure . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Existing Structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Procedures for Testing Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15

Advisory Bodies for Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21

The Complexity of Assessing Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23

Gaps in Current Capability for Assessing Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . 27

Current Capability for Promoting Development and Making and 

Ensuring Improvements in Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Contributions of Basic and Clinical Research . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 29

Contributions of Manufacturers . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 31

Contributions of Surveillance, Vaccine Recommendations, 

and Epidemiologic Studies . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 32

Experiences Leading to Development of Improved Vaccines . . . . . . . . . . . . . . . . . . . . . . 35

Reports of Adverse Events That Led to Development of New Vaccines . . . . . . . . . . . 35

Significant Modifications of Manufacturing Processes . . . . . . . . . . . . . . . . . . . . . . . . 36

Gaps in Capability for Promoting Development and Making and

Ensuring Improvements in Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 37
iv January 1998

Contents

Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 39

Appendix 1. 

Examples of Vaccine Safety Issues of Recommended Childhood Vaccines . . . . . . . . . . . 43

Appendix 2. 

National Vaccine Legislation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 47

Appendix 3. 

Impact of Basic Research and Technological Advances on Vaccine Safety . . . . . . . . . . . 49

Appendix 4. 

New and Emerging Infectious Diseases: Unexpected Challenges to Vaccinology . . . . . . 59

Appendix 5. 

Laboratory Evaluation of Vaccine Safety . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 61

Appendix 6. 

Evolving Recommendations for the Use of Vaccines . . . . . . . . . . . . . . . . . . . . . . . . . . 63

Appendix 7. 

Assessing the Causality of Adverse Medical Events Following Vaccination: 

Large Linked Databases . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 67

Appendix 8. 

Summary Tables . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 71

Selected References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 75
Preface

January 1998 v

Preface

This report distills evaluations and discussions by a group of public health

experts on the topic of vaccine safety. The broad scope of the congressionally

mandated charge forced equally broad analysis, congruent with other 

congressionally mandated actions focused on discrete components of the vaccine

safety network in the United States. The Task Force recommendations reflect a

consensus on how to continue and, indeed, improve the diverse activities and

responsibilities related to vaccine safety.

The recommendations clearly acknowledge that vaccine safety depends on a complex network of activities and that the modern tools of immunology, molecular

biology, and epidemiology can prevent additional diseases through the 

development of vaccines as well as the assurance of their safety. This report 

anticipates additional progress in vaccine safety and charts a course to ensure 

continuation of progress to the benefit of the Nation’s children. 

John R. La Montagne, Ph.D.

Chair

Task Force on Safer Childhood Vaccines

Director, Division of Microbiology and Infectious Diseases

National Institute of Allergy and Infectious Diseases

National Institutes of Health
Acknowledgements

January 1998 vii

Acknowledgements

This report is the result of discussions held

by members of the Public Health Service

over the past 4 years. The Task Force wishes to

acknowledge the contributions of all participants in the difficult and complex task of examining the existing U.S. system to ensure the

safety of childhood vaccines at a time of enormous change. 

National Institutes of Health

Dr. John R. La Montagne, Chair

Dr. Regina Rabinovich

Dr. George Curlin

Dr. Chris Breyer

Dr. Bruce Gellin

Centers for Disease Control 

and Prevention

Dr. Walter Orenstein

Dr. Robert Chen

Dr. Stephen Hadler

Dr. Steven Wassilak

Dr. Roger Bernier

Dr. John Glasser

Mr. Stephen Sepe

Food and Drug Administration

Dr. Carolyn Hardegree

Dr. Elaine Esber

Dr. Susan Ellenberg

Mr. William Stevens

Ms. Karen Chaitkin

Dr. Suresh Rastogi

Dr. Jerome Donlon

National Vaccine Injury 

Compensation Program

Dr. Geoffrey Evans

Dr. Marie Mann

Mr. Thomas Balbier

Dr. Robert Weibel

National Vaccine Program Office

Dr. Ken Bart

Dr. Robert Breiman

Dr. Yuth Nimit

Dr. Kimi Lin

Dr. Peter Patriarca

Ms. Cathy Michaelosky

Dr. Anthony Robbins

Dr. Roy Widdus

Office of General Counsel, DHHS

Mr. David Benor

Ms. Gemma Flamberg

The Secretariat wishes to thank Amy Iadarola,

R.O.W. Sciences, and Amrie Otto, Division of

Microbiology and Infectious Diseases, National

Institute of Allergy and Infectious Diseases, for

their editorial support in the creation of this

report.
Executive Summary

January 1998 ix

Executive Summary

As we prepare to enter the 21st century, the

promise of vaccines has never been greater.

If this promise is to be fully realized, vaccines

must not only be effective in the prevention of

diseases—they must also be safe. Recent

reviews by the Institute of Medicine have identified many gaps and limitations, however, in

current knowledge of vaccine safety (Howson

et al., 1991; Stratton et al., 1994). The Task

Force on Safer Childhood Vaccines (TFSCV or

the Task Force) was established by the

Secretary of Health and Human Services at the

direction of Congress, with the sole purpose of

examining vaccine safety and making recommendations to the Secretary to ensure development of safer childhood vaccines and improve

licensing, manufacturing, processing, testing,

labeling, warning, use instructions, distribution,

storage, administration, field surveillance,

adverse reaction reporting, recall of reactogenic

lots or batches, and research on vaccines. This

report summarizes the findings and recommendations of the Task Force. 

The Task Force comprised representatives from

several Public Health Service agencies:

National Institutes of Health; Food and Drug

Administration; Centers for Disease Control

and Prevention; National Vaccine Injury

Compensation Program; Office of the General

Counsel, Department of Health and Human

Services; and National Vaccine Program Office.

As with any committee activity, a number of

individuals have participated in discussions that

resulted in the creation of this report (see

acknowledgements).

There are many reasons why examining the

safety of childhood vaccines is a critical task

and, therefore, mandated by law, but several

reasons were emphasized by the Task Force.

The first is a paradox inherent in the very success of vaccines and immunization programs.

Concerns about vaccine safety become increasingly prominent when effective use of vaccines

in a population reduces the incidence of the target diseases. Yet, since few diseases are eradicable, only immunization programs that maintain

public confidence in vaccines can prevent tragic

recurrence of disease, as demonstrated by outbreaks of pertussis in several countries during

the 1980s. The second reason is that even

under conditions of epidemic or endemic transmission, any given individual in the population

may escape infection and disease. Vaccination is

still essential, however, to protect the population from the spread of disease. Finally, vaccines, unlike therapeutic interventions, are

given to healthy individuals. Consequently, the

risks associated with any vaccine must be minimal, and vaccines must be extraordinarily safe.

Since 1990, the Public Health Service has created much of the infrastructure necessary to

reduce gaps in current knowledge about the

safety of vaccines, as identified by the Institute

of Medicine, but the process is still incomplete.

Safety issues regarding already licensed vaccines

have become of paramount importance to the

success and stability of immunization programs,

vaccine companies, and public support for these

activities. At the same time, advances in basic

biomedical research and the accelerating pace of

the revolution in biotechnology will make a

large array of new vaccines possible. The continued improvement and assurance of vaccine

safety are as much a research priority as the

development of vaccines for the diseases that

continue to affect humankind. 

Although a number of vaccine-preventable diseases, such as poliomyelitis, may be controlled
Executive Summary

x January 1998

and even eliminated globally, others, such as

pertussis, tetanus, or diphtheria, are not candidates for eradication. Therefore, vaccination

against these diseases must be continued to

protect each new cohort of infants, both in the

United States and worldwide. The perception

of risks due to reports of adverse events will

also continue indefinitely. Therefore, systems

required to ensure vaccine safety must be maintained. Given new technologies for the development, production, manufacture, regulation,

and administration of vaccines, the vaccine safety network for the United States must be

enhanced to provide appropriate evaluation of

new candidates. To ensure continued public

acceptance of vaccines, close monitoring of

potential adverse events and adverse reactions,

adequate scientific evaluation of hypothesized

associations, and appropriate responses to newly

identified risks of vaccines, including research

and targeted development of new technologies

and vaccines, are critical. 

The recommendations of the Task Force arise

from broad review and evaluation spanning the

activities and responsible agencies required to

ensure vaccine safety. These recommendations,

developed to address gaps and ensure the continuing safety of vaccines, are summarized below:

1. Assess and address national concerns

about the risks and benefits of vaccines in

order to enhance the education of the

public, families, and health care professionals. 

As development of vaccines to fight diseases

progresses, the assessment of risks and benefits of this intervention has changed, as few

health care providers or parents may have

seen a case of a vaccine-preventable disease.

We need to know more about how to communicate what is known and what is not

known about true and perceived risk (Evans

et al., 1997). Furthermore, it is extraordinarily difficult to obtain spontaneous reporting of adverse events after immunization

without a presumption of potential causality.

Education must appropriately target the

public, families, and health care professionals

in order to assure optimal prevention with

vaccines. The Task Force made the following recommendations:

A) Identify the public’s and health care professionals’ concerns, attitudes, and

knowledge about immunization and the

benefits and risks of vaccination.

B) Develop appropriate interventions to

enhance knowledge of vaccines and their

benefits and risks, reporting of adverse

events, and immunization programs and

their public health impact. 

2. Strengthen the national capability to conduct research and development needed to

promote the licensure of safer vaccines.

Vaccine research and development are driven

both by scientific advances and by the need

to control and prevent disease. Finally, when

an effective and safe vaccine is available, the

perception or association of true adverse

events must be high indeed to support the

costly development (approximately $200 million) of a new vaccine. Technological barriers, however, may confound the process.

For example, recombinant hepatitis B vaccines that did not confer the potential risk of

transmission of other infections were developed less than a decade after the licensure of

serum-derived vaccine. However, the development of safer acellular pertussis vaccines, a

complex task that has required new technologies not available 10 years ago, has been

a much slower process. To promote the

development of safer vaccines, the Task

Force made the following recommendations:

A) Where an association is demonstrated

between an adverse event and vaccination,
Executive Summary

January 1998 xi

ensure that these findings will lead to relevant research and vaccine improvements.

i) Initiate appropriate regulatory

review and action.

ii) Conduct studies of the biologic

basis for vaccine adverse events. 

iii) Develop, where feasible, epidemiologic and biologic markers or tests

that would be useful to evaluate,

predict, or determine risk groups for

adverse events.

iv) Use, wherever possible, vaccines that

have been modified or improved to

avoid adverse events.

B) Consider new assays to detect potential

mediators of adverse events, laboratory

correlates of vaccine safety and efficacy,

and evaluation of the safety of novel

methods to enhance immunogenicity and

vaccine delivery technologies and

improve the thermostability of vaccines.

C) Foster the active participation of industry

and increase public-private collaboration

in development of safer vaccines of public

health priority.

D) Encourage research and development

leading to production of “limited-use

vaccines” of potential public health

importance through public support of

research and development and strengthened interaction with industry. The

development of vaccines for limited populations poses special challenges to the

development of a safety profile.

3. Strengthen the national capability to conduct surveillance of vaccine-preventable

diseases and to evaluate potential adverse

events and vaccine efficacy. 

Safe use of a vaccine to control disease

requires continuous monitoring for the disease as well as for known and potential

adverse events following vaccine administration. This type of monitoring makes it possible to answer the following vital public

health questions: Is the disease effectively

controlled or has something (the vaccine,

the human host, or the environment)

changed? Has the risk/benefit evaluation

altered? Does the use or composition of the

vaccine need to be modified in response to

different conditions? Are changes in national immunization policies regarding mandated childhood vaccines warranted? 

Historically, for both methodological and

logistical reasons, effective surveillance for

adverse events after licensure has been difficult to maintain. Since 1990, the Public

Health Service has initiated major improvements in its ability to conduct both passive

and active surveillance for adverse events.

Continued support for these projects is critical for adequate monitoring of the present

and future safety of vaccines in the United

States. To reduce gaps in vaccine surveillance efforts, the Task Force made the following recommendations: 

A) Integrate government postlicensure surveillance activities to enhance evaluation

of available information, identify gaps,

and reduce duplication of effort, with

emphasis on the following areas: 

i) Develop new methods and approaches for postlicensure evaluation of the

safety and efficacy of vaccines and

vaccine uses and ensure that appropriate studies are conducted.

a) Prospectively evaluate vaccine

safety and efficacy in large populations, including adults, to help

identify the association of
Executive Summary

xii January 1998

vaccination with serious but

uncommon adverse events.

Develop methodology for investigating causality of rare events in

vaccine recipients, especially in

highly immunized populations.

b) Develop novel methods and

approaches for the detection and

evaluation of adverse events associated with new vaccines or new

uses of vaccines to supplement

systems such as Vaccine Adverse

Events Reporting System.

Identify and incorporate into the

current system other U.S. and

international agencies or survey

systems that collect information

relevant to the evaluation of

adverse events.

ii) Identify differences in rates of

adverse events associated with the

simultaneous or combined administration of vaccines. 

B) Ensure the adequacy of clinical data to

support new recommendations for vaccine use, and when appropriate, conduct

studies to address safety considerations.

C) Improve the coordination and sharing of

data concerning standards, adverse event

reports, and analyses with other national

control and epidemiologic authorities,

including the World Health Organization

(regulatory harmonization). The United

States should participate in the development of an international network to monitor vaccine safety, taking advantage of the

differences and similarities in the vaccines

used and in national health care structures.

D) Encourage industry participation in the

collection and analysis of data to address

both prelicensure and postlicensure vaccine safety. 

i) Review industry’s role and responsibilities in collection, receipt, followup, and analysis of received

adverse event reports.

ii) In consultation with vaccine manufacturers, develop procedures to

optimize collection of complete data

and analysis of reports by product

category, product-specific data by

company, and product interaction

with other co-administered vaccines.

4. The Task Force recommends that the

Interagency Vaccine Group (IAVG), composed of representatives from agencies

involved in vaccine research, development, evaluation, regulation, and immunization, be charged with the ongoing

responsibility of ensuring that appropriate vaccine safety activities are carried

out. The IAVG would be expected to

seek routine technical consultation from

an expert external advisory body.

The Task Force identified the roles and

responsibilities of Federal agencies, vaccine

companies, health care providers, the

research community, and parents in ensuring

that vaccines are safe. Experience over the

past century teaches that the activities of

each group are linked to the activities of the

other groups, making both coordination

and communication essential to vaccine safety. Furthermore, the group charged with

this responsibility must be able to focus on

safety. In accordance with the original mandate to integrate the Nation’s vaccine

efforts, the National Vaccine Program

Office could serve as the secretariat for this

group and the entity to ensure action

toward emergent vaccine safety needs. The
Task Force defined the IAVG’s role as 

follows:

A) The IAVG would monitor the vaccine

safety activities of the various agencies

and work to improve interagency communication. It would also facilitate and

monitor progress on the investigation

and evaluation of reports of serious or

frequent adverse events. 

i) Evaluate data relevant to vaccine

safety, which may currently be scattered among various agencies and

manufacturers.

ii) Ensure periodic reviews of the safety

of licensed vaccines and their recommended immunization schedules. If

appropriate, propose studies to

address areas where additional data

may be informative or supportive,

such as in special target groups or

programs.

iii) Ensure effective communication

among existing advisory committees

that focus on vaccines and immunization, including specifically the

Advisory Commission on Childhood

Vaccines, the Advisory Committee

on Immunization Practices, the

National Vaccine Advisory

Committee, and the Vaccines and

Related Biological Products

Advisory Committee.

B) The IAVG would be expected to seek

routine technical consultation from an

expert external advisory body. 

The Task Force is committed to the concept that the public health is best served

by the continued pursuit of safer and

more effective vaccines and by the safe

use of existing vaccines through improvements in the immunization schedule and

delivery of vaccines. The recommendations presented in this report are congruent with the Nation’s immunization and

vaccine goals presented in the U.S.

National Vaccine Plan in 1994.

Executive Summary

January 1998 xiii
Introduction

January 1998 1

Vaccines and immunization programs have

been so remarkably successful in eliminating or controlling many of the more common

infectious diseases of childhood that their use is

often taken for granted. Their impact is evident

every day and everywhere in the United States.

Cases of diphtheria, whooping cough (pertussis), tetanus, measles, mumps, and German

measles (rubella) are so unusual in the United

States that these infections and their consequences are unknown to most Americans. Just

a generation ago, the coming of summer

brought fears of epidemics of polio; now, iron

lungs can be seen only in museums and dusty

hospital storerooms. This has been accomplished through the development and use of safe

and effective vaccines in national immunization

programs around the world. Smallpox was

eradicated from the planet in 1977. Polio eradication was defined as a goal for the year 2000.

Remarkably, the Americas were declared to be

free of wild-virus poliomyelitis on September

29, 1994, with the last recorded case of wildtype disease registered in South America in

1991. Efforts to eradicate polio in Asia and the

Pacific are well under way.

The global use of vaccines to control childhood

infections has never been broader. The

Expanded Programme of Immunization (EPI)

of the World Health Organization (WHO) now

estimates that 80 percent of the world’s children

are immunized to protect them against pertussis, diphtheria, tuberculosis, polio, tetanus, and

measles. Indeed, vaccines offer solutions to our

most common infectious diseases and have

become part of the background of everyday life. 

Before the development of the vaccines commonly used today, infectious diseases were the

most common cause of death, disability, and disease in the United States. Lives were shortened

or devastated by polio, pertussis, measles, and

diphtheria (table 1). Severe, life-long complications of these infections were commonplace.

Permanent paralysis often followed poliovirus

infection. Deafness and blindness were known

risks of measles infection. Whooping cough left

survivors with permanent brain damage.

However, the control over infectious diseases

that we now enjoy because of the availability of

effective vaccines creates a new and difficult

problem. Simply stated, as disease control is

firmly established and the infections recede in

importance, the adverse events associated with

the use of vaccines become more evident and

gain in importance; their risk-to-benefit relationship is altered. In 1996, for example, the

number of reports to the Vaccine Adverse Event

Reporting System (VAERS) was almost double

the sum of the reported cases of vaccine-preventable diseases. 

Medical interventions and public health measures, including vaccines, are used because they

are expected to produce tangible benefits.

However, benefits are associated with the risk of

adverse reactions (caused by the intervention)

or adverse events (which may or may not be

caused by the intervention), perhaps even lethal

ones. Many vaccines induce short-lived periods

of fever, pain, soreness at the injection site,

malaise, or other systemic manifestations.

Rarely, more serious reactions may occur.

Individuals with unrecognized allergies to eggs,

for example, may develop anaphylactic reactions

to egg proteins that might be present in some

vaccines. Individuals with unrecognized

immunodeficiencies may develop serious and

perhaps fatal complications when they receive

vaccines containing an attenuated living organism (e.g., vaccinia virus in the smallpox vaccine

Introduction
Introduction

2 January 1998

or an attenuated poliovirus in the oral polio vaccine). As disease control is established, adverse

events or reactions increase in importance. All

adverse events must be considered with great

care since they may alter the evaluation of risk

versus benefit. 

Safety is not a condition that can be absolutely

guaranteed. As defined in the biologics regulation, safety is “the relative freedom from harmful effect to the persons affected, directly or

indirectly, by a product when prudently administered, taking into consideration the character

of the product in relation to the condition of

the recipient at the time” (21 CFR 600.3 (p)).

As a result of the process in place for the development, testing, and licensure of new vaccines,

severe adverse events (those requiring hospitalization, causing chronic medical conditions, or

resulting in death) are rare or else would constitute an impediment to vaccine licensure.

Severe adverse events must be considered in

relation to the benefit the vaccines produce for

both the individual and society. This risk-tobenefit relationship is a more complex one

when applied to vaccines than to therapeutic or

surgical interventions for many reasons but primarily because of the following:

♦ Vaccines are given to persons presumed to

be healthy, usually infants and children. 

♦ Vaccines protect the individual from a statistically predictable exposure to the vaccineprevented infection, not a current medical

problem.1

Table 1. 

Maximum and Current Reported Morbidity Due to 

Vaccine-Preventable Diseases in the United States 

Disease Maximum

Reported Cases

Year Maximum

Reported

Reported Cases

1996 Percent Change

Diphtheria

Measles

206,939 1921 4 –100.00

894,134 1941 508 –99.75

Mumps 152,209 1968 751 –99.45

Pertussis 265,269 1934 4,315 –98.37

Polio (wild) 21,269 1952 0 –100.00

Rubella 57,686 1969 238 – 99.96

Congenital

rubella syndrome 20,000 (est) 1964-5 2 –99.99

Tetanus 1,560 1948 36 –97.82

Haemophilus

influenzae type b

invasive disease

20,000 1984 155 –98.65

1 There are exceptions. For example, bacille Calmette-Guérin (BCG) vaccine is now used in bladder cancer therapy.
Introduction

January 1998 3

♦ Vaccines reduce or eliminate the burden of

disease in the general population by reducing the spread of disease. Vaccines are

sometimes given to a large number of individuals to protect the entire population.

♦ Vaccines are often used in campaigns to

control epidemic or endemic public health

problems; thus, the risk-to-benefit ratio is

applied to the general population.

♦ Vaccines are often legally required or mandated by States to protect the health of the

general population.

The dynamic nature of the assessment of the

benefits and risks associated with any vaccine

varies with vaccine coverage, disease incidence,

and specific adverse events (Chen, 1994). A

few discrete stages, illustrated in figure 1, can

be described: 

Stage 1: In the prevaccine era, morbidity and

mortality due to the disease are high, and for

this reason a vaccine is developed.

Stage 2: An effective vaccine results in less disease. With progressive increases in the vaccination levels of the population, immunity in most

of the population is derived from vaccination

rather than disease. A true vaccine adverse

reaction, even if extremely rare, will be

observed more “frequently” as the vaccine is

used in millions of people.

Stage 3: Over time the threat of the disease

will be less urgently perceived, and reports of

adverse events will increase (as the vaccine is

used in larger populations) and receive greater

attention. The public may attribute adverse

events to vaccination even though scientific 

Figure 1. 

Evolution of Immunization Program and Prominence of Vaccine Safety

Disease

Outbreak

Eradication

Adverse

Events

Vaccine

Coverage

INCIDENCE

MATURITY

Vaccinations

Stopped

Prevaccine Increasing

Coverage 

Loss of

Confidence

Resumption of Eradication

Confidence

1 2 3 4 5
evidence of causation other than temporal association may be lacking. Such temporal associations are especially difficult to dissect, especially

medical events for which etiology remains

unknown, such as sudden infant death syndrome (SIDS). This may lead to erosion of

confidence in the vaccine, reduction of vaccine

usage, and a resurgence of disease.

Stage 4: The cyclical resurgence of disease or

the availability of an alternative vaccine may

boost public acceptance of vaccination against

the disease, resulting in high vaccination levels

and reduction of disease. For some vaccinepreventable diseases (e.g., smallpox), epidemiologic characteristics may permit eradication of

the causative organism and hence the disease

from humankind. 

Stage 5: Once eradication is certified, vaccine

use can be stopped, thereby eliminating adverse

reactions. For diseases with lower transmissibility or for which effective therapies exist, routine

vaccinations may be stopped in some areas

before global eradication is confirmed. This

occurred with the use of smallpox vaccine in

the United States (Henderson and Fenner,

1994). Similarly, the use of oral live attenuated

poliovirus vaccine (OPV) has been debated by

advisory bodies in the United States, in the face

of regional elimination of polio in the Americas. 

Although not all of the above stages are applicable to every vaccine (for example, not all diseases are eradicable), this concept of stages

illustrates, in a simple way, the dynamic nature

of the vaccine-risk tradeoffs and was considered

as a framework in the discussions of the Task

Force. 

Introduction

4 January 1998
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 5

The Legal Framework

The Task Force on Safer Childhood Vaccines

(TFSCV) was mandated by Congress in

1986 as part of a set of statutes that have fundamentally affected the national childhood

immunization system of administration, recordkeeping and reporting, compensation for vaccine injuries, labeling, coordination of these

responsibilities, and education. Enacted from

1986 through 1989, these statutes have served

to initiate or accelerate a number of concurrent

activities throughout the Public Health Service

(PHS). Appendix 2 details the vaccine legislation from Public Law 99-660, known as the

National Childhood Vaccine Injury Act

(NCVIA), which enacted Title XXI of the

Public Health Service Act in 1986.

NCVIA established the National Vaccine

Program (NVP), whose goal is “to achieve

optimal prevention of human infectious diseases

through immunization and to achieve optimal

prevention against adverse reactions to vaccines.” Amendments to the Act in 1987 established the National Vaccine Injury

Compensation Program (NVICP) and other

required activities. Among them,

♦ Section 2125, “Recording and Reporting of

Information,” defined the information

required to be recorded for the administration of vaccines by every health care

provider in the United States.

♦ Section 2126 required the Secretary,

Department of Health and Human Services

(DHHS), to develop vaccine information

materials for vaccines subject to the NVICP.

♦ Section 2128, “Manufacturer Recordkeeping

and Reporting.”

♦ Section 2127, “Mandate for Safer Childhood

Vaccines,” became effective on December

22, 1987, and required a report on the

progress of the issues included in Section

2127(a) (development of safer childhood

vaccines; the licensing, manufacturing, processing, testing, warning, use instructions,

distribution, storage, administration, field

surveillance, adverse reaction reporting,

recall of reactogenic lots, and research on

vaccines). Paragraph (b), which calls for the

establishment of the Task Force on Safer

Childhood Vaccines, was not enacted until

December 1989 (Public Law 101-239)

(box 1).

♦ Section 312 required a review of adverse

events associated with pertussis and rubella

vaccines.

♦ Section 313 required a review of adverse

events associated with other childhood vaccines.

♦ Section 314 required a review of labeling for

warnings, use instructions, and precautionary information.

Reporting Requirements

TFSCV is required to prepare a report and recommendations for the Secretary, DHHS, in

consultation with the Advisory Commission on

Childhood Vaccines (ACCV), an external advisory group charged with providing advice to

the Secretary on the operation of the National

Vaccine Injury Compensation Program. The

report of the Task Force must include recommendations on how to “promote the development . . . and make or assure improvements” as

described in Section 2127(a). In developing

the report, the Task Force reviewed the NVICP

and found it compatible with the aims of the

National Vaccine Plan (U.S. Department of

Task Force on Safer Childhood Vaccines
NIAID Task Force Report on Safer Childhood Vaccines

6 January 1998

Health and Human Services, 1994) to ensure

the promotion of vaccine safety and effectiveness. This document constitutes the report of

the Task Force.

The Task Force Approach 

To meet its charge and carry out the reporting

requirements under the Act, the TFSCV 

(1) reviewed and summarized previously identified safety issues regarding vaccines currently in

use; (2) reviewed current policies and procedures to ensure the safety of vaccines; and 

(3) determined options for improving existing

structures to ensure vaccine safety. As a result

of these reviews, the Task Force provided the

Secretary with a series of recommendations

designed to further enhance vaccine safety. 

The Task Force executed this agenda through a

series of meetings during which detailed 

Box 1.

Section 2127(b) of the Public Health Service Act Created the 

Task Force on Safer Childhood Vaccines.

Section 2127 of the Act embodies explicit language regarding safety as well as the specific mandate of the Task Force on Safer Childhood Vaccines. It provides in its entirety as follows:

a. General Rule—In the administration of this subtitle and other pertinent laws under the

jurisdiction of the Secretary, the Secretary shall: 

(1) promote the development of childhood vaccines that result in fewer and less serious

adverse reactions than those vaccines on the market on the effective date of this part and

promote the refinement of such vaccines; and 

(2) make or assure improvements in, and otherwise use the authorities of the Secretary with

respect to, the licensing, manufacturing, processing, testing, labeling, warning, use

instructions, distribution, storage, administration, field surveillance, adverse reaction

reporting, and recall of reactogenic lots or batches of vaccines, and research on vaccines,

in order to reduce the risks of adverse reactions to vaccines. 

b. Task Force:

(1) The Secretary shall establish a task force on safer childhood vaccines which shall consist

of the Director of the National Institutes of Health, the Commissioner of the Food and

Drug Administration, and the Director of the Centers for Disease Control.

(2) The Director of the National Institutes of Health shall serve as chairman of the task

force.

(3) In consultation with the Advisory Commission on Childhood Vaccines, the task force

shall prepare recommendations to the Secretary concerning implementation of the

requirements of subsection (a). 

c. Report—Within two years after the effective date of this part, and periodically thereafter, the

Secretary shall prepare and transmit to the Committee on Energy and Commerce of the

House of Representatives and the Committee on Labor and Human Resources of the

Senate a report describing the actions taken pursuant to subsection (a) during the preceding

two-year period.
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 7

outlines, position papers, and other documents

were used to facilitate discussion. In considering its broad mandate to review vaccine safety

and make recommendations, the Task Force

examined alternative approaches. Because two

comprehensive, congressionally mandated

reviews of safety issues for the childhood vaccines were under way by the Institute of

Medicine (IOM), cofunded by the National

Institute of Allergy and Infectious Diseases

(NIAID); the National Vaccine Program Office,

Office of the Assistant Secretary for Health;

Centers for Disease Control and Prevention

(CDC); and Health Resources and Services

Administration (HRSA), detailed examination

of vaccine safety issues for each of the licensed

vaccines was considered duplicative and not

attempted. 

The Task Force elected to examine the systems

in place to ensure vaccine safety, specifically

because of its fundamental premise that assurance of safety of the vaccine supply depends on

a sequence of diverse activities that crosscut

agency responsibilities as well as the field of

vaccinology (figure 2). This continuum of

activities includes research through development, testing of experimental vaccines, 

Figure 2. 

The Vaccine Safety Continuum

Basic research: 

pathogenesis/immunology/microbiology

R&D: 

New and Improved Vaccines

Vaccine

Usage

Post-License

Evaluation

PLA/ELA 

Licensure

Animal/Clinical

Studies

Production

GMP/GLP

Eradication
NIAID Task Force Report on Safer Childhood Vaccines

8 January 1998

production methodology, regulation, surveillance for infectious diseases, establishment of

routine criteria for the in vitro and animal testing of every lot of vaccine released after licensure (by manufacturers, confirmed by the Food

and Drug Administration [FDA]), reevaluation

of efficacy and safety following licensure, and

the safe use of vaccines in clinical practice. It

presents examples of some activities or systems

required to ensure the safety of a single vial of

vaccine. Furthermore, sites for vaccine safety

activities are immensely diverse and include the

laboratories of basic researchers and clinical

investigators, research laboratories and production suites of vaccine companies, offices of regulatory agencies, and storage facilities for vaccine in each immunization clinic.

It is essential to recognize that a number of

vaccine safety-related activities took place during the deliberations of the Task Force, reflecting a dynamic field driven by both legislated

and programmatic activities resulting from the

rapid development of research technologies and

vaccines. Because the field is relatively small, the

same small group of PHS personnel participated in these activities as necessary. Although not

a full compilation, box 2 highlights associated

and relevant vaccine safety activities from 1990

to 1995.
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 9

Box 2.

Vaccine Safety Activities From 1990 to 1995

♦ As mandated by Section 312, a study sponsored by PHS was conducted by IOM and resulted in publication of the report on the adverse effects of pertussis and rubella vaccines

(Howson et al., 1991).

♦ As required under Section 313, a second study was undertaken on the adverse effects of the

other childhood vaccines (Stratton et al., 1994). Two addenda were requested by PHS to

examine research strategies for evaluating vaccine adverse events. Both addenda were published in 1994 (Stratton et al., 1994).

♦ An indepth evaluation of vaccine labels and package inserts, as well as one public meeting,

was conducted by FDA, as required under Section 314 of the Act. This project continues. 

♦ The Vaccine Adverse Events Reporting System was implemented by FDA and CDC, and a

number of presentations on the design and analysis of this system were presented in 1994 to

the Task Force, as well as to the Advisory Commission on Childhood Vaccines, Vaccines

and Related Biological Products Advisory Committee, and National Vaccine Advisory

Committee. Progress reports to these groups continue.

♦ The Vaccine Safety Datalink project, a large linked database, was established by CDC (see

Appendix 7) to focus on the study of vaccine safety, utilization, and postlicensure efficacy.

♦ Guidelines and reference documents were published by FDA on a variety of safety-related

issues, including combination vaccines and their evaluation, and cell lines used in the manufacture of biological products.

♦ PHS sponsored scientific workshops addressing issues of vaccine safety, such as:

◆ The Protective and Disease-Enhancing Immune Response to RSV—May 1993 (Anderson

and Heilman, 1995) 

◆ Combination Vaccines—July 1993 (Williams et al., 1995)

◆ Harmonization of Adverse Event Reporting—September 1993

◆ Meningococcal Vaccine Candidates—February 1994

◆ DNA Vaccines—February 1996 (Smith et al., 1997)

♦ Research initiatives specifically targeted to address issues of vaccine safety: Respiratory syncytial virus (RSV)—Request for applications entitled “Mechanism of RSV Vaccine

Immunopotentiation” issued by NIAID in FY 1994.

♦ Recognition and evaluation of vaccine safety problems: Mumps (non-U.S. strain) vaccine

and associated encephalitis in other countries.

♦ Investigations of the risk of Guillain-Barré syndrome following influenza immunization by

CDC (Tuttle et al., 1997, in press).
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 11

Anumber of factors serve to differentiate the

development, manufacture, and regulation

of vaccines from those of other pharmaceutical

products. Since vaccines are given to healthy

infants, children, and adults, acceptable risks for

these agents must be minimal indeed to ensure

continued public trust and, therefore, maximum acceptance of immunization. Unlike

many other pharmaceutical agents, most vaccines are used only a few times in an individual’s lifetime, leading to fewer opportunities to

examine their impact as well as a much more

restricted market. In addition, many vaccines

are mandated by the States and are frequently

required for school, day care, or employment

entry. No other drugs or biologic agents have

such widespread mandated use. Vaccination is

an integral part of public health practice and

well-baby care. 

All these factors have led to the evolution of an

infrastructure for the delivery of immunization

services that focuses primarily on the delivery of

vaccines to infants and children. Immunization

practices have been developed to make vaccines

safe and effective for the child and convenient

for the parent. 

In many countries, immunization programs and

policies are under constant review and revision.

In the United States, immunization policies are

reviewed by established committees that seek

representation from parents, professional societies, State governments, and Federal agencies.

Thus, changes in vaccination schedules, such as

the addition of newly licensed vaccines to the

standard of care, require broad consensus and

are relatively slow and more complex than

changes in other classes of agents within the

pharmaceutical industry. This process has

become increasingly complex with the need to

co-administer newly licensed vaccines, often

produced by different manufacturers, and

ensure their safety and efficacy.

Finally, new vaccines are extensively studied for

safety and are unlikely to proceed through

lengthy development steps to licensure if there

is evidence of severe adverse reactions. After

licensure, pediatric vaccines are given to very

large numbers of infants at a time when neurologic and other medical conditions are developing, so that some clinical syndromes, however

rare and for whatever cause, may occur in temporal association with vaccination. The assessment of safety and of attributable risk is therefore problematic for both new and old vaccines.

These and other factors have helped shape the

special nature of the vaccine industry at a time

of unparalleled growth in the basic sciences and

in the technologies for vaccine development. 

Public Health and Individual

Perspectives on Immunization

In universal immunization programs that aim

vaccines at the entire healthy pediatric population, there is an inherent conflict between the

interests of the individual and the community

(Fine and Clarkson, 1987; Nokes and

Anderson, 1991). The tension between individual risks and public benefits is the classic ethical dilemma for public health. For the individual, the goal of immunization is protection

from disease. Informed adults are able to

weigh benefits derived from this protection

against risks associated with the vaccine, particularly for healthy children. In some cases, such

as the use of rabies vaccine after exposure to a

potentially rabid animal, the risks and benefits

are clear and evident. For other vaccines, they

are not as obvious. This is especially true if the

vaccine to be given protects against a disease

Vaccines: Unique Pharmaceuticals 
NIAID Task Force Report on Safer Childhood Vaccines

12 January 1998

that has become rare due to vaccination or one

that is not perceived as a significant threat. 

In contrast, the public health interest is the

reduction of disease in the community. High

rates of immunization may be required to

achieve this goal, and for some diseases where

there is person-to-person transmission, reducing

the incidence by vaccination results in “herd

immunity,” with reduction of risk for all community members regardless of their individual

immunization status. Where a disease is prevalent and feared, benefits of immunization for

the individual far outweigh the risk of disease,

in the minds of both the public and the medical

community (Freed et al., 1996c). The early

years of polio immunization exemplify this situation. If a vaccine is effective, however, and

high coverage levels for vaccination are sustained over time, the disease, such as polio, will

become rare. In this context, the risks of

immunizations may seem to outweigh the benefits from the perspective of the individual, as

long as everyone else remains immunized and

the risk of transmission of poliovirus remains

low. All documented cases of polio in the

United States since 1980 have been caused by

the live oral polio vaccine. While the numbers

have been very small (four to nine cases per

year), they represent a risk that may increasingly

outweigh the value of oral immunization for

some parents and physicians. The change in

the risk-to-benefit ratio is heightened by an

alternative means of prevention, in this case

enhanced inactivated poliovirus vaccine. This

change and the selection of the optimal polio

immunization policy in the face of elimination

of polio from the Americas were discussed at a

series of meetings hosted by NVP, IOM, and

Advisory Committee on Immunization

Practices (ACIP) in 1995. 

Herd immunity may be maintained only if the

majority of parents accept immunization for their

children. When overall population coverage

falls, the pool of susceptible persons increases in

size. This situation was demonstrated by the

1989-1990 measles epidemic. While national

coverage rates for measles vaccine were acceptable for children to the age of 5, high-risk populations remained unprotected from measles until

school age. The population of susceptible children was sufficient to permit sustained transmission of measles virus, producing the largest outbreak of measles since 1977. In 1990 alone,

27,672 cases of measles were reported in the

United States. Tragically, the largest annual

number of measles deaths (89) since 1971

resulted from this epidemic (NVAC, 1991).

When communities require vaccination for entry

into school, day care, or other public settings,

some parents may feel that they are being

coerced, especially if the procedure is perceived

as potentially dangerous or unnecessary. Such

was the situation in Sweden when public concerns about both the efficacy and safety of

whole-cell pertussis vaccine led to cessation of

routine pertussis immunization in 1979

(Gershon, 1990). As a result, pertussis again

became an epidemic disease of childhood. A

similar situation occurred in Japan, where two

deaths after pertussis immunizations led to widespread refusal of the vaccine. The number of

cases in Japan then rose from fewer than 1,000

per year in 1975 to 13,105 in 1979, with a case

fatality rate of about 1 percent (Gershon, 1990).

In the mid-1980s, the American public’s perception of the risks associated with whole-cell pertussis vaccine caused concern for the viability of

the immunization program in the United States.

In 1985, two manufacturers ceased production

of diphtheria, tetanus, and pertussis (DTP) vaccine because of litigation concerns or manufacturing difficulties, leaving a single U.S. manufacturer of the vaccine to supply the needs of the

Nation. The price of DTP vaccine increased

fivefold in that year and threatened national

immunization efforts by making vaccine unaffordable to many programs.
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 13

The Dynamic Nature of the Vaccine Field

Advances in basic research fields such as

immunology, microbiology, and genetics, together with advances in applied technology, have

opened windows of opportunity for the development of new vaccines and the improvement of

older ones. These advances have also generated

new challenges in vaccine safety as novel classes

of immunogens are investigated and new technologies are applied. At the same time, newly

emerging pathogens, such as the human immunodeficiency virus (HIV), Borrelia burgdorferi (the

cause of Lyme disease), and strains of

Mycobacterium tuberculosis resistant to current

antimicrobial agents, present opportunities for

vaccine development. In addition, there is a consensus that the development of safe and effective

vaccines may be crucial for control of many older

infectious diseases. Examples of such conditions

include malaria and gonorrhea, both of which

continue to be serious public health problems

despite the existence of effective treatment. 

Changes in health care organization and

improvements in computer technology now permit computerized vaccination and medical

records to be linked for large numbers of individuals. Compared with passive surveillance systems, such large linked databases (LLDBs) permit a more accurate assessment of the occurrence of serious vaccine reactions and the rates

and risk factors that have been identified. The

development of regional or even national computerized vaccine registries may one day improve

accessibility of an individual’s record of vaccines

and combinations as well as contraindications to

future doses.

The Impact of Basic Research 

and Technological Advances 

on Vaccine Safety

The Task Force reviewed examples of research

and technological advances in the fields of

microbiology, immunology, and chemistry that

may have important implications for vaccine safety in the future. For example, detailed molecular

analysis of attenuated live vaccine strains may

permit the design of vaccines that are unlikely to

revert to virulence. A number of new antigen

production systems employing recombinant and

chemical conjugation technologies have already

resulted in totally new vaccines of known purity

or enhanced efficacy (Ada, 1990). The need for

easily delivered combination vaccines is fostered

by novel technologies for their creation.

However, the use of new technologies for the

production and delivery of antigens will present

additional challenges to vaccine safety. Some

vaccines produced with these technologies are

still at the basic research stage while others have

been tested in humans. As technologies are

developed, safety must remain a priority. Finally,

enhancement of the specific immune response to

vaccine candidates by immunologic adjuvants is

often necessary for new approaches utilizing

highly purified antigens. The development and

testing of any immunoenhancer are both driven

and limited by concerns about its safety in

humans. 

A summary of the Task Force review of basic

research and technological advances and examples of applications of these new technologies are

presented in Appendix 3. 

New and Emerging Infectious Diseases:

Unexpected Challenges to Vaccinology

In the last decade several new or previously

unidentified infectious diseases have been recognized as important pathogens and are currently

the subject of intensive vaccine research. A brief

summary of the development of vaccines for

three emerging pathogens—HIV, multidrugresistant tuberculosis, and Lyme disease—is presented in Appendix 4. 

Vaccine Safety Issues Past and Current

Vaccine safety has a long history (for different

perspectives, see Freed et al., 1993b; Money

Magazine, 1996b). Some of the currently recommended childhood vaccines have been in use

for decades; they have intensively scrutinized
NIAID Task Force Report on Safer Childhood Vaccines

14 January 1998

safety profiles and detailed descriptions of

adverse events associated with their use. Others

are new agents with which we have relatively few

years of clinical experience. A number of vaccines used in the past are no longer licensed in

the United States because of safety concerns;

appropriately, the memory of these discontinued

agents and the problems associated with them

persists. Appendix 1 lists childhood vaccines,

examples of safety issues associated with their

use, and responses to address them. The most

recent reviews by the Institute of Medicine

(Howson et al., 1991; Stratton et al., 1994),

summarized in Appendix 8, examined many conditions for possible causal relationships to vaccines and concluded that most of the conditions

in question remained in category 2—that is, the

data were insufficient to evaluate. 

Laboratory Evaluation of Vaccine

Safety—New Technologies. New technologies,

including recombinant DNA or plasmid DNA

vaccines and plant vaccines, pose challenges and

offer novel approaches to in vitro evaluation of

safety. Rapid evolution of technologies has dramatically changed the ways in which vaccine

safety can be assessed. Older vaccines, developed

about 40 years ago, are being reevaluated with

these approaches. The new classes of vaccines,

including conjugates, recombinants, combinations, and vectored vaccines, will require use of

novel biotechnologies and evaluation mechanisms. The current situation is changing rapidly

and presents powerful new tools for the evaluation of vaccine safety. A description of these

technologies and their potential application to

vaccine safety is presented in Appendix 5.

Clinical Evaluation of Vaccine Safety—New

Technologies. Tools for the clinical evaluation

of vaccine safety that have developed over the

past 50 years include clinical trial methodology,

biostatistics, and epidemiology, as well as the

recent application of molecular epidemiology

(Chen, 1994). Thus, it was possible to use viral

culture techniques to confirm the hypothesis of

polio-vaccine-associated paralytic poliomyelitis

that was based on epidemiologic data. The successful application of molecular epidemiology to

enhance surveillance and subsequent vaccine

development has been demonstrated in influenza

as well as measles. 

Evolving Recommendations 

for Use of Vaccines

As additional information emerges, adjustments

and revisions are made to recommendations for

the use of vaccines. Examples of new types of

data that have caused a change in immunization

practice are changes in disease epidemiology and

improvements in vaccines that alter target groups

for immunization. The Advisory Committee on

Immunization Practices of CDC monitors the

epidemiology of target diseases and vaccine use

and makes recommendations to the Public

Health Service on immunization strategies that

will ensure public health. Other groups, such as

the Committee on Infectious Diseases (“Red

Book”) of the American Academy of Pediatrics,

the American College of Physicians, and the

American Association of Family Physicians, contribute to the evolution of use recommendations, as well as their implementation. The

effective dissemination of new immunization recommendations is an important factor in a successful immunization program, especially for the

introduction of a new vaccine, and may require

approaches that will reach all target audiences:

pediatricians, family practitioners, nurses,

patients, parents, and policymakers.

Appendix 6 describes examples of immunization

recommendations that have evolved over time.

They demonstrate that assessments of safety and

efficacy are closely linked; that immunization

practices must promote both safety and efficacy

to protect the public health; and that ensuring

both safety and efficacy requires ongoing evaluation of immunization practices. The examples

pertain to three diseases and their respective vaccines, namely, measles, pertussis, and hepatitis B. 
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 15

Existing Structures 

FDA is the agency responsible for ensuring

that only vaccines demonstrated to be safe

and effective are licensed and sold in the

United States. The authority to regulate vaccines and other biologics is based in both the

Public Health Service Act and the Food, Drug

and Cosmetic Act. As a result of this legislation, a variety of safeguards are in place to

ensure and maintain the safety of vaccines.

CDC also plays a major role in developing

appropriate recommendations for vaccine use,

under advice from the ACIP, and conducts

postmarketing surveillance on vaccine safety

and efficacy. Before this framework and its

implications for assessing safety are described, it

is useful to recall that the definition of safety

formally used by FDA is stated in the biologics

regulation as “relative freedom from harmful

effect”—safety cannot be absolutely guaranteed. 

The procedures and processes that are in place

evolve as new knowledge is gained. As defined

by the relevant Code of Federal Regulations,

these procedures include extensive laboratory

testing of experimental materials before use in

human subjects, the use of ethics review committees to evaluate and monitor such experimental use, extensive evaluation in animal

model systems, and rigorous requirements to

report and investigate any adverse events associated with use of a vaccine.

Procedures for Testing Vaccine Safety

Laboratory and Animal Studies. Assessment

of a vaccine’s safety begins long before any testing in humans. A candidate vaccine must first

be tested extensively in animals and in the laboratory. The primary objective of this phase of

the testing is to ascertain whether the candidate

vaccine exhibits any reactogenicity or toxicity.

These studies are also generally used to gain

insight into the product’s immunologic properties. Laboratory assays and animal models have

been developed for many infectious diseases

and have proven to be extremely useful in characterizing the product before experimental use

in human subjects. Modifications in vaccines

are often introduced at this stage of development to improve immunogenicity and reduce

reactogenicity.

Studies in Human Subjects. Clinical studies

in the development of all pharmaceutical products proceed along a logical path that involves

three discrete phases prelicensure (see box 3).

During vaccine development, these three phases

are carefully monitored by FDA using the

Investigational New Drug Application (INDA

or, more commonly, IND) process.

Review of Protocol by Committees and

Regulatory Authorities. After the product

has been evaluated in animals, the sponsor of

the candidate vaccine may apply for permission

to conduct testing in humans. Before testing

begins, an application must be submitted to

FDA. The application will certify that a properly constituted institutional review board (IRB)

has reviewed and approved the proposed study

and has found that all appropriate safeguards

for human subject protection are in place,

including signed informed consent. A summary of the preclinical testing is also submitted. If

the proposed clinical study is the first evaluation

of a vaccine candidate in humans, it is common

practice to restrict the number of subjects to be

studied. Additional studies are permitted only

Current Capability for Assessing Vaccine Safety—

Vaccine Evaluation and Licensure
NIAID Task Force Report on Safer Childhood Vaccines

16 January 1998

after the initial study is completed and the general safety of the candidate vaccine is confirmed.

The test protocol is described in detail and contains the study design and a plan for statistical

analysis. Information is included on the product’s composition, assays of purity and potency,

and method of manufacture. Furthermore, the

investigators must provide a statement of their

qualifications and experience. If, after reviewing the information, FDA determines that test

subjects will not be exposed to any untoward

risk, clinical trials may proceed. To ensure continued safeguards, the investigators are

required, during the course of the trials, to submit annual reports and notify FDA of any

adverse events. FDA has published proposed

rules for reporting adverse events concerning

drugs and biologicals to provide uniformity and

facilitate reporting (Federal Register, October

27, 1994). The proposed rules also cover

amendments to clinical study design and

requirements for IND safety reporting.

The IND system of phased clinical trials has

several advantages for safety assessment. First

of all, the phased entry of subjects allows only

small numbers of people to be exposed to

unknown risk; more individuals are exposed as

more safety data are collected. Should serious

reactions occur, the trial can be suspended until

the problem is resolved. The system also allows

the characterization of adverse events in terms

of dose relationships, age relationships, and

drug interactions. Finally, all phases of testing

are rigorously monitored by FDA. 

Licensure Application. After completion of

the trials, if the data indicate that the product is

safe and effective, the manufacturer may submit

an application to FDA to market the product.

For a biological product, such as a vaccine, two

license applications are required: 

♦ The first, a product license application

(PLA), includes a description of the manufacturing process, results of the clinical trials

that demonstrate the product to be safe and

effective, results of required testing on consistency lots of the product, product specifications, and a copy of the package insert

that will accompany the product.

♦ The second, an establishment license application (ELA), contains information about

the facility used to make the product and

data demonstrating that the facility is in

compliance with the requirements of 21

Box 3.

Phases of Vaccine Clinical Trials

♦ Phase 1 trials involve very small numbers

of healthy subjects (20 to 80). These

studies are used to determine whether

the product has any gross toxicity problems and to acquire safety and immunogenicity data on dose-related immune

responses. 

♦ Phase 2 trials use controls and larger

numbers of subjects (100 to 200). They

are designed to further assess product

safety as well as to obtain preliminary

information on dosing and efficacy.

♦ Phase 3 trials use large numbers of subjects (several hundred to thousands) to

confirm safety and effectiveness, define

risk-benefit relationships, gather information to be incorporated into the package

insert, and support marketing approval.

This phase may also be used to collect

data concerning lot consistency and the

acceptability of manufacturing scale-up

operations. 

♦ Phase 4 trials are conducted postlicensure. They may involve different study

designs and numbers of subjects, e.g.,

case control or large cohort studies.

Data may be gathered over a number of

years. 
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 17

CFR 600 and 211. These regulations cover

the facility’s personnel, quality control,

buildings, equipment, containers, records,

and distribution procedures to ensure a consistent, safe product. 

Using an internal panel of scientific experts,

FDA reviews and evaluates the data submitted

in these applications, resolves any manufacturing deficiencies, conducts its own testing of the

consistency lots, permits its own analysis of the

clinical and laboratory data submitted, consults

with outside panels of experts as appropriate

(the Vaccines and Related Biological Products

Advisory Committee [VRBPAC]), reviews the

labeling (including the sections containing the

precautions, warnings, and contraindications),

revises the labeling as needed, and obtains commitments from the manufacturer for certain

postapproval safety-related actions. In addition,

a prelicensing inspection of the production

facility is performed to verify the data submitted in the establishment and product license

applications. When FDA is assured that the

data are complete and adequate and demonstrate that the product is safe and effective, the

product and establishment licenses are issued

and the manufacturer may begin distributing

the product.

Concurrent with license approval, FDA may

seek a manufacturer’s agreement to conduct

certain postmarketing studies (phase 4) to

obtain additional information on the product’s

risks, benefits, and optimal use. These studies

include, but are not limited to, studies assessing

schedule of administration, use with other

products, and adverse event associations. Phase

4 studies conducted by the manufacturer are

reportable to FDA for review.

Assessment of Postlicensure Vaccine Safety.

The primary assessment of vaccine safety occurs

during investigative clinical trials. Information

from these trials serves as the basis for the initial package insert and label statements.

However, even large phase 3 clinical trials (see

box 3) involve a relatively limited number of

subjects, are brief, and thus will probably detect

only the more common acute adverse reactions.

These trials may also be conducted among a

healthier and more homogeneous population

than the one that ultimately uses the vaccine.

Information about rare, delayed, or populationspecific adverse reactions can be gathered only

after vaccine licensure in a variety of phase 4

studies when the vaccine is used more widely.

Assessment of vaccine safety continues after

licensure through a variety of activities, including a passive reporting system (VAERS), active

surveillance in controlled studies, phase 4 studies, lot release tests, and facility inspections.

Postlicensure monitoring of product safety continues at several levels. 

1. Lot Release Tests. Each lot of product is routinely tested by the manufacturer, usually for

general safety, potency, sterility, purity, and

identity. Currently, the manufacturer tests

each lot of vaccine with a battery of assays

appropriate for each specific vaccine as

described in 21 CFR (Parts 600-639) and in

relation to other criteria addressed in the relevant document of Points To Consider Test

results and sends samples from each lot to

FDA. FDA reviews the test results and performs confirmatory testing on the samples as

needed. If the data are satisfactory, the manufacturer is authorized to distribute the lot. 

2. Facility Inspections. All facilities used in the

manufacture of vaccines are inspected at

least biannually. During these inspections,

experts in good manufacturing practices

(GMP) and vaccine research from FDA

headquarters and regional offices carefully

examine and evaluate compliance with FDA

regulations of the physical plant, its production records, behavior of plant personnel,

adverse event reports, and any other documents or matters that may indicate the quality of operations at that site. 
NIAID Task Force Report on Safer Childhood Vaccines

18 January 1998

Any observed violations of regulations are

recorded in a formal memo (called an

FD483 by FDA). At the end of the inspection each violation is discussed with the management to determine the cause of the

infraction and remedial action to be taken

and to prevent recurrence of each violation.

The United States is blessed with a vaccine

industry that has a long history of producing

safe and effective vaccines in this highly

monitored environment. Although violations are occasionally observed, most are

minor (e.g., failure to initial the production

log for every step of the manufacturing

process) and do not present immediate safety

concerns. However, should a potential safety hazard be discovered, FDA can halt production and distribution almost immediately.

In addition, in such a circumstance FDA can

request a recall, a return of all suspected

products to the manufacturer.

3. Approval for Changes. Another mechanism

used by FDA to maintain control over product safety after licensure is the requirement

that all changes in indication or usage for

the product, labeling, production methods,

key personnel, testing, or quality assurance

be submitted to FDA for approval before

implementation. Each change is thoroughly

evaluated. FDA may require additional testing or validation to satisfy safety concerns

before approval is granted.

Examples of major actions in which FDA has

participated to ensure product safety are listed in box 4.

Phase 4 Studies. Active and passive surveillance methods, as well as targeted studies, are

used to monitor postlicensure product safety.

These studies are extremely valuable because a

rare reaction (i.e., one that occurs only once in

thousands of doses) may not be detected even

in large clinical trials performed before licensure. Both active and passive surveillance are

needed, however, for early detection if a potential vaccine safety problem occurs. This is a

responsibility traditionally shared by CDC and

FDA. Historically, CDC has focused primarily

on the public sector and safety concerns relevant to ACIP recommendations—serving as the

point of contact for health departments and the

public—while FDA has focused on the private

sector, manufacturers, and regulatory issues.

Examples of investigations of vaccine safety

conducted by the CDC are listed in box 5.

a) Passive Reporting Systems. Historically,

passive reporting has been the major (and

in most countries, the only) postlicensure

surveillance conducted for vaccine adverse

events. The main goals of such systems are

to detect new, previously unreported reactions or changes in rates of known reactions. Because of their national scope, passive reporting systems are frequently the

only means available to monitor extremely

rare adverse events. Passive reporting systems, such as VAERS, act primarily as signal-generating systems. Trends and clusters

can be detected through continuous statistical monitoring of the database. 

Examples of vaccine-related safety hazards

detected in the past by passive surveillance

systems are inadequate inactivation of

poliomyelitis vaccine (the Cutter incident)

and severe reactions to rabies vaccine produced in human diploid cells. The VAERS

is a merger of the CDC Monitoring System

for Adverse Events Following

Immunization (MSAEFI) and the vaccine

reports contained in the FDA Spontaneous

Reporting System (SRS) programs, for

monitoring adverse events associated with

vaccination, implemented by the CDC and

the FDA on November 1, 1990. The

VAERS provides a central focus for reporting (1) specific adverse events associated

with vaccines listed in the Vaccine Injury

Table required by Section 2125 of the
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 19

Public Health Service Act and (2) any

other vaccine adverse events occurring after

licensure. VAERS’ preaddressed, postagepaid forms are widely distributed via annual

mailout to physicians likely to administer

vaccines. The system has been useful in

identifying new vaccine reactions, such as

alopecia after hepatitis B vaccine, and

changes in known vaccine-related adverse

events. After 5 million doses of DTaP

(diphtheria, tetanus, and acellular pertussis)

were distributed for use as fourth and fifth

doses, rates of adverse events reported to

VAERS were about one-third those of

DTP, confirming the greater safety of

DTaP found in prelicensure clinical trials.

Between January 1, 1991, and December

31, 1994, the VAERS program received

more than 45,000 reports. About 40 percent of reports came from manufacturers,

24 percent from private health care

providers, and 35 percent from State health

departments. Approximately 17 percent of

all reports concern serious events resulting

Box 4.

FDA Reports of Vaccine Safety Problems Recognized 

Through FDA Review and Testing Procedures

1971 The diphtheria component of a lot of DTP failed its detoxification test. The 

vaccine lot was recalled. No injuries reported.

1974 A lot of DTP was recalled because of a failure to resuspend after mixture 

(flocculent present). No injuries reported.

1980 Through reporting, the manufacturer learned that its DTP vaccine was producing sterile abscesses. FDA was prepared to halt further release of the vaccine, 

but no action was necessary because the manufacturer voluntarily withdrew the 

vaccine from the market.

1989 Equine influenza vaccine was inadvertently placed in vials labeled DTP. The 

DTP vaccine lot was recalled. No vials containing mislabeled vaccine were 

believed to have left the manufacturer’s facilities. No injuries were reported.

1992 An FDA investigation of a key clinical study being conducted to support the 

licensure of an acellular pertussis vaccine showed that the primary investigator 

had failed to obtain proper consent, maintain adequate records, or appropriately

monitor the study. Under FDA directive, the problems were corrected, and the 

investigator was required to sign a consent agreement. FDA maintained strict 

surveillance over the investigator, and the vaccine licensure process was not 

undermined.

1992 A manufacturer made manufacturing and facilities changes without submitting a

supplement to its product licenses. An FDA inspection of the new, unlicensed 

facility was conducted. Before any action could be taken, the company 

voluntarily withdrew its license to manufacture vaccines. There were no 

imminent safety problems.
in life-threatening illness, hospitalization,

permanent disability, or death. Regulations

requiring that vaccine manufacturers report

all known adverse events to FDA were published in 1994 in the Federal Register.

Should a threat to safety be identified,

FDA has the authority to recall any product from the marketplace. 

As in most passive reporting systems,

underreporting of events occurs (Rosenthal

and Chen, 1995). Even if full reporting

were to take place, passive surveillance systems would be limited by reporting bias

and the lack of accurate data for the population at large. The greatest shortcoming

of passive surveillance is its limitation for

drawing conclusions of causal association.

Passive surveillance systems lack laboratories for evaluating clinical syndromes and

obtain only limited relevant information,

making epidemiologic assessment of vaccine causality difficult.

b) Active Surveillance Studies. Active surveillance studies can be controlled, targeted,

and prospective. They can be used to

detect rare, serious events not detected in

the limited prelicensure clinical trials or to

validate the signal of a potential adverse

event detected by passive reporting.

Compared with passive reports, they offer

the advantage of rigorous scientific design

and allow meaningful conclusions to be

drawn from the data. For rare adverse

events, which may lack unique laboratory

or clinical features, active surveillance studies are the best scientific approach to

answering questions of causality. Because

they are often large, long term, and costly,

relatively few such studies have been done

of vaccine safety. In recent years, FDA has

obtained commitments from manufacturers

to continue surveillance of the use of new

products to gain additional safety data.

One attractive approach to active 

20 January 1998

Box 5. 

Examples of Vaccine Safety Studies 

Conducted or Funded by CDC

1. Associations between poliomyelitis and

inactivated (Nathanson and Langmuir,

1963) and oral polio vaccine (Henderson

et al., 1964; Schonberger et al., 1976;

Strebel et al., 1992) 

2. A cluster of infants with SIDS following

DTP vaccination (Bernier et al., 1982;

Griffin et al., 1988; Chen et al., 1993)

3. Possible association of Guillain-Barré syndrome (GBS) and influenza vaccine

(Schonberger et al., 1979; Safranek et al.,

1991; Chen et al., 1992; Terracciano et

al., 1997) or tetanus toxoid (Tuttle et al.,

1997)

4. A cluster of abscesses following DTP vaccination (Stetler et al., 1985; Simon et al.,

1993)

5. Risk of neurologic illness following DTP

(Gale et al., 1994; Walker et al., 1988;

Griffin et al., 1990) or measles, mumps,

and rubella (MMR) vaccine (Griffin et al.,

1991; Chen et al., 1991; Black et al.,

1997; Davis et al., 1997)

6. Risk of invasive bacterial disease after

DTP vaccine (Griffin et al., 1992)

7. Risk of chronic arthropathy after rubella

vaccination (Ray et al., 1997)

8. Safety of acellular pertussis vaccine

(Rosenthal et al., 1996)

9. Methodology/new surveillance systems

for vaccine safety (Fine and Chen, 1992;

Chen et al., 1994, 1997)

NIAID Task Force Report on Safer Childhood Vaccines
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 21

surveillance is the use of large linked database systems (LLDBs), in which computer

linkages join immunization data to outpatient and inpatient records in large health

maintenance organizations (HMOs) or

other patient databases. This approach may

provide appropriate control groups and

facilitate analysis by speeding data collection. CDC explored the use of such LLDBs

for smaller studies beginning in the mid1980s. In 1990, CDC contracted with

four HMOs with a total population representing 2 percent of the U.S. population

for active surveillance studies of vaccine

safety (Appendix 7). Preliminary results

indicate that this project will help fill many

of the gaps and limitations in knowledge of

vaccine safety found by IOM.

c) Targeted Studies. Ad hoc epidemiologic

studies are designed and conducted to

answer specific questions of vaccine safety,

especially very rare outcomes, such as

Guillain-Barré syndrome, that cannot be

studied effectively using LLDBs. This was

done for GBS after the 1990-91 and

1993-94 influenza seasons (Lasky et al.,

1997).

Continued Research. Active research programs are the foundation for ongoing vaccine safety assessment. As new products

and new processes are developed, basic

research programs on immunologic mechanisms must be in place to assess potential

safety issues. In the event of an alleged

cluster of adverse events, it is essential that

investigators, support services, and

resources be readily available to conduct a

timely product evaluation and epidemiologic study. Public concern about vaccineassociated deaths presents a difficult challenge to public health officials and epidemiologists and clearly requires significant

attention.

Advisory Bodies for Vaccine Safety 

Vaccine safety oversight resides among a broad

group of advisory committees and government

groups. Most notable are the DHHS immunization-related advisory committees including

the Advisory Commission on Childhood

Vaccines, the Immunization Practices Advisory

Committee, the Microbiology and Infectious

Diseases Review Advisory Committee

(MIDRAC) of NIAID, the National Vaccine

Advisory Committee (NVAC), and the Vaccines

and Related Biological Products Advisory

Committee. The Department of Defense

(DoD) is advised on vaccine and other issues by

the Armed Forces Epidemiological Board

(AFEB). Overall coordination of programs

involving both broad vaccine issues and vaccine

safety is the responsibility of the Vaccine

Interagency Group of the National Vaccine

Program Office. Although safety is not the

main or only focus of these groups, aspects of

vaccine safety coordination and oversight exist

within all of them. 

ACCV advises the Secretary of DHHS on the

National Vaccine Injury Compensation

Program, which provides compensation for certain vaccine-related injuries or deaths and recommends research related to vaccine injuries.

This body advises the Secretary regarding the

need for childhood vaccine products that result

in fewer significant adverse reactions.

ACIP provides advice to the Secretary, the

Assistant Secretary for Health, and the

Director, CDC, concerning their responsibilities

to assist States and localities in the prevention

and control of communicable diseases. In addition, the committee reviews and reports on

immunization practices and recommends

improvements in the national immunization

effort. Most recently, Congress added the

selection of vaccines for the Vaccines for

Children program to the ACIP mandate.
NIAID Task Force Report on Safer Childhood Vaccines

22 January 1998

MIDRAC provides the scientific review of contract proposals and grant applications in microbiology and infectious diseases for NIAID. In

this capacity the committee advises on policy,

planning, and operational matters related to

research, development, and evaluation of programs and projects in these fields.

NVAC advises the Secretary, DHHS, and NVP

on a broad spectrum of issues relating to vaccine development, licensure, testing, distribution, and use. Several aspects of its work directly involving safety issues include recommending

research priorities and other measures to be

taken to enhance the safety and efficacy of vaccines, monitoring research and development

activities with regard to new or improved vaccines, and coordinating public and professional

information and education activities, including

those associated with adverse events and contraindications.

VRBPAC reviews and evaluates for FDA data

relating to the safety, effectiveness, and appropriate use of vaccines and related biological

products requiring licensure by FDA that are

intended for use in the prevention, treatment,

or diagnosis of human diseases. The committee

also considers the quality and relevance of

FDA’s research program.

AFEB, DoD’s advisory body, advises the

Assistant Secretary of Defense and the surgeons

general of the military departments on operational programs, policy development, and

research programs and on requirements for the

prevention of disease and injury and promotion

of health. The Subcommittee on Disease

Control is tasked to provide the latest scientific

evaluations and recommendations concerning

immunizations, chemoprophylaxis, and therapy,

as well as disease surveillance, prevention, and

control.

Overall Federal responsibility for implementation of the NVP and coordination of Federal

immunization activities falls to the IAVG, created in the early 1980s. The need for such interagency cooperation in solving national vaccine

problems was first defined during the swine flu

epidemic, with the formation of an influenza

work group. Early efforts to coordinate Federal

vaccine responsibilities led to the formation of

the Interagency Group to Monitor Vaccine

Development, Production, and Usage in 1980.

Upon the formation of the NVP, this group was

chaired by the NVP. Representatives of each of

the vaccine agencies (Agency for International

Development, CDC, DoD, FDA, and the

National Institutes of Health [NIH]) make recommendations about vaccine policy and operational issues. Specific responsibilities related to

vaccine safety oversight involve monitoring

research and development activities for new or

improved vaccines and coordinating public and

professional information and education activities

involving vaccine recommendations, adverse

events, and contraindications. 

The Committee on Infectious Diseases of the

American Academy of Pediatrics formulates and

revises guidelines for the prevention and control of infectious diseases in children, published

in the Red Book (AAP, 1994). These guidelines

represent consensus developed by the committee in conjunction with liaison representatives

(from CDC, FDA, NIH, Canadian Paediatric

Society, and NVP as well as ACIP and others)

based on review of the published literature and

presentations of additional data from experts.

Inevitably, overlap of vaccine safety responsibilities occurs among these various committees and

groups. One such area of perceived overlap is

in recommendations for vaccine use. ACIP

advises CDC in development of use recommendations for vaccines. The Red Book Committee

provides use recommendations to pediatricians.

VRBPAC makes recommendations that are

reflected in licensure decisions and labeling of

vaccine products. The various recommendations have at times been inconsistent, creating
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 23

confusion for the agencies and health care

providers. 

The need for harmonization of use recommendations within the United States has intensified.

The recent licensure of acellular pertussis vaccine for the fourth and fifth doses highlighted

the need to ensure closer coordination of vaccine licensure with the development of vaccine

use recommendations and the availability of an

adequate supply of the newly available vaccine.

There currently exists an informal practice to

coordinate impending actions on new and

improved vaccines. For example, a

CDC/ACIP representative attends VRBPAC

meetings, and the FDA is represented at ACIP

meetings. Further measures to ensure coordination of impending actions on new and

improved vaccines have been discussed and

recently reviewed (Halsey and Hall, 1995).

Determination of the need for further vaccine

safety research also falls to several committees

and groups. MIDRAC evaluates the NIAID

research agenda from the broadest perspective,

ACCV advises the Secretary regarding the need

for safer childhood vaccines, and NVAC monitors research activities related to new or

improved vaccines. IAVG identifies gaps in

research involving vaccine safety. Where possible, the vaccine agencies address these gaps or

devise strategies to do so.

The Complexity of Assessing 

Vaccine Safety 

The development of sensitive and specific methods to assess the safety of existing and new vaccines has proven to be a challenge. Although

relatively small-scale, phase 2 and phase 3 studies have been useful in estimating the incidence

of minor, common adverse reactions (e.g., local

erythema, fever, etc.), the medical community

and consumers are most concerned about

severe, life-threatening events. While such

events are believed to occur at a frequency of

less than one per million doses administered,

universal application of these vaccines, particularly during childhood, dictates both the need

and obligation to develop better means of

detection. Practical barriers exist and will continue to be a challenge, as illustrated by the following examples: 

OPV and Reversion to Neurovirulence.

Paralysis following administration of oral

poliovirus vaccine is believed to occur at a frequency of approximately 1 case per 2.5 million

doses distributed and has constituted the sole

form of paralytic poliomyelitis acquired in the

United States for the past 15 years (Nkowane et

al., 1987). Rapid advances in molecular biology

have provided opportunities to learn more

about the gene segments of the Sabin strains

that may be associated with reversion to neurovirulence. Scientists and public health officials

are currently evaluating a molecular biologic

assay to replace the current test for neurovirulence. The exclusive use of enhanced potency,

inactivated vaccine could theoretically eliminate

vaccine-associated paralytic polio (VAPP). Both

the ACIP and the AAP recommend an immunization schedule that will increase the use of

inactivated poliovirus vaccine.

Difficulty of Conducting Safety Evaluations.

Nearly all childhood vaccines are administered

on multiple occasions during the first year of

life, a time when rare neurological, immunological, and other disorders may manifest themselves. Vaccination is a nearly universal practice

so that controlled evaluations to compare the

incidence of such events in vaccinated and

unvaccinated children have become increasingly

difficult to conduct. Large-scale studies involving thousands or millions of children could theoretically provide large enough comparison

groups based on differences in the timing of

vaccination in relation to these extremely rare

clinical disorders. However, lack of definitive

case definitions for some of these events, combined with difficulties in controlling for myriad

confounding variables, has made these studies
virtually impossible to carry out. The cost of

such studies has also been considered prohibitive, particularly in the environment of efforts

to reduce spiraling health care costs.

Table 2 illustrates a simplistic approach to

determining sample sizes required to answer a

question of association or causality for a rare

adverse event that occurs in children, with the

following assumptions: The condition is

assumed to be severe and easily recognized, and

the condition may be caused by vaccines as well

as other stimuli. If we were to conduct a clinical trial to detect a difference of twice the rate

between vaccinated and unvaccinated individuals (power = .80 and α = 0.025), then the sample size needed for a simple, randomized clinical trial to demonstrate the difference between

vaccinated and unvaccinated when the condition occurred in 1 per 100,000 vaccinated

would be approximately 9.5 million subjects. 

The potential rare and serious adverse events of

greatest concern would occur less frequently

than 1 per 1,000 children. Furthermore, the

assumptions of an ideal clinical trial are rarely

met in real life, especially in the setting of

postlicensure surveillance because (1) conditions are not fully diagnosed or similarly

expressed in every child, (2) symptoms may not

always develop within days or hours of immunization, and (3) children are not randomly

assigned to vaccination or nonvaccination

groups. For these reasons, other study designs,

such as case-control studies, are also used to

study very rare outcomes. 

Combination Vaccines. Vaccine innovation

has been successful when directed toward

development of products that include a number

of antigens. The most recent examples are the

combined DTP-Hib (Haemophilus influenzae

type b) vaccines. Although simultaneous

administration of multiple antigens in a combination vaccine reduces the number of injections

and simplifies the immunization schedule, the

incidence of common and serious adverse

events associated with each antigen becomes

extremely difficult to estimate. This problem

will become even more evident within the next

few years, when combination products containing DTaP, Hib, hepatitis B, and inactivated

poliovirus vaccines are likely to become available. Combinations are carefully tested as new

products prior to licensure (Arbeter et al.,

1986; Brunell et al., 1988). Combination vaccines will simplify the immunization schedule

and assure that vaccine components are successfully administered.

Conjugate Vaccines. Prelicensure data available for an entirely new vaccine are based on

studies in hundreds or thousands but not hundreds of thousands of children. The existence

of an elevated risk for very rare adverse events

cannot be ruled out solely with experience in a

clinical trial population and before experience in

the population at large. The evaluation of safety for a new vaccine administered in infancy can

be further complicated by co-administration of

a vaccine with other childhood vaccines that

NIAID Task Force Report on Safer Childhood Vaccines

24 January 1998

Table 2.

Sample Sizes Required for Determining

Causality by Frequency of Condition

Rate of

Condition 

in the

Vaccinated

(1:1 Control

and

Vaccinated)

Rate of

Condition in 

the Controls

Total 

Sample Size

Required

1/100

1/1,000

0.5/100 9,348

0.5/1,000 94,000

1/10,000 0.5/10,000 942,071

1/100,000 0.5/100,000 9,421,372
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 25

may themselves be reactogenic. The clinical

evaluation of co-administered vaccines made by

two different manufacturers (e.g., hepatitis B

and DTP) may require testing at sites acceptable to both manufacturers. 
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 27

The IOM reviews, summarized in Appendix

8, examine 76 medical conditions and the

scientific data available to assess possible causal

relationships to vaccines (Howson et al., 1991,

1992; Stratton et al., 1994). IOM found that

for about two-thirds of these conditions, there

was either no evidence bearing on the association, or the evidence was insufficient for acceptance or rejection of a causal relationship. Both

IOM reports identified gaps and limitations in

current knowledge on vaccine safety and made

suggestions on research needs. 

The Task Force recognized the following areas

and addressed them in their recommendations

concerning vaccine information, safe practices

for using vaccines, and requirements for scientific and technological improvements. Many of

the gaps noted in the IOM report, as well as by

the review of the Task Force, were due to

intrinsic methodological difficulties in conducting vaccine safety evaluations. Other gaps have

been addressed through activities undertaken

over the past 4 years. 

Vaccine Information 

♦ Assess effectiveness of the vaccine package

inserts.

♦ Assess and improve health provider knowledge and patient awareness of immunization

risks and benefits.

♦ Develop or, where possible, improve educational standards on immunization within

curricula of health care professionals.

♦ Design vaccine information materials that

clearly and effectively communicate instructions on use, precautions, and contraindications so that vaccines will be administered in

the safest and most effective manner.

(These are already available as second-generation documents following exhaustive

review and revision by CDC.)

♦ Improve communication with families and

persons affected by vaccine adverse events. 

♦ Develop programs to enhance the reporting

and accuracy of reporting by health care

providers of potential adverse events in both

public and private health sectors.

Safe Use of Vaccines 

♦ Assure availability of data on complex schedules, including studies of simultaneous

administration and combination vaccines, to

ensure development of safe recommendations and immunization practices.

♦ Ensure consistency and harmonization of

use recommendations among advisory

groups in the United States. 

Improved Surveillance 

♦ Develop standardized analyses of VAERS

data emphasizing evaluation of data for new

vaccines and co-administration of vaccines. 

♦ Enhance analyses of serious events, specifically deaths reported to VAERS, by exploring its use as a registry of potential rare serious adverse events.

♦ Incorporate adverse event recording into

developing State or regional immunization

tracking systems to permit the rapid and

detailed evaluation of adverse events.

Intrinsic Improvements in Vaccines

♦ Apply emerging technologies to development of improved safety evaluation tests and

new laboratory standards. 

Gaps in Current Capability for Assessing Vaccine Safety
♦ Conduct review of scientific advances in the

field of vaccine adverse event methodology

(noting reviews published by IOM [Stratton

et al., 1994]).

♦ Conduct phase 4 studies using LLDBs and

other approaches to monitor and assess vaccine safety, efficacy, and effectiveness postlicensure.

28 January 1998

NIAID Task Force Report on Safer Childhood Vaccines
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 29

Several branches of the Public Health Service

have responsibilities and capabilities in the

field of vaccine research and development. The

FDA Center for Biologics Evaluation and

Research (CBER) has played a pivotal role in

vaccine research for many years. As their principal mandate, NIH and its member institutes

support research, both basic and clinical, that

will lead to improvement of the Nation’s health.

CDC and its National Center for Infectious

Diseases and National Immunization Program

are also actively involved.

Contributions of Basic 

and Clinical Research

The NIH is the lead PHS agency for vaccine

research, focused on basic and clinical research

on candidate vaccines. A number of institutes

within NIH, including the National Institute of

Allergy and Infectious Diseases, the National

Cancer Institute, and the National Institute of

Child Health and Human Development

(NICHD), support vaccine research. Nationally,

other research institutions, vaccine companies,

FDA, CDC, DoD, and biotechnology firms conduct or support basic, developmental, and clinical research on vaccines. Participating Federal

agencies play a central role in research interactions with vaccine companies, international agencies, private organizations, and academic institutions. In 1981, NIAID founded its Program for

the Accelerated Development of Vaccines to

focus and enhance research activities leading to

new vaccines for important diseases, and to

improve existing vaccines. Since the program’s

inception, 12 new or improved vaccines have

become available, and 4 have been added to the

recommended childhood immunization schedule. In 1990, NIH intensified efforts to evaluate

acellular pertussis vaccines. NIH works closely

with other PHS agencies involved in the

Nation’s research efforts to improve vaccines and

prevent disease.

Definition of Disease Pathogenesis. To develop effective vaccines, it is essential to understand

the pathogenic mechanisms by which infectious

organisms cause disease in humans. For example, basic research on microbial virulence factors

of Staphylococcus aureus has identified polysaccharides as key components in the disease mechanisms of this important bacterial pathogen.

Expected Immunologic Response to Natural

Disease. Generation of effective vaccines

requires understanding of human immune

responses to disease-causing agents. Vaccines

seek to replicate protective immune responses of

natural diseases without producing symptoms or

pathology. For new generations of vaccines,

especially those relying on mucosal immunity,

basic research on immune responses is a priority.

An NIH-funded research group began preclinical testing in 1991, focusing on the systematic

exploration of the mucosal immune responses

generated by a variety of vaccines. NIH also

sponsors research on mucosal immunity aimed at

creating vaccines for sexually transmitted diseases

and on the enteric mucosal response that will be

critically important to the development of oral

vaccines. 

Determination of Serological Correlates of

Immunity. Evaluation of the immunogenicity

of new vaccines hinges on the ability to identify

protective immune responses. Serological correlates of immunity remain unclear for a number

of targeted diseases and are a research priority.

Current Capability for Promoting Development and

Making and Ensuring Improvements in Vaccine Safety
NIAID Task Force Report on Safer Childhood Vaccines

30 January 1998

NIAID is currently sponsoring an intensive

investigation of the serological correlates of

immunity against Bordetella pertussis as part of

the acellular pertussis vaccine initiative.

Identification of Candidate Immunogens.

The evolution of basic sciences and biotechnology has allowed for new classes of vaccines

made up of immunogenic proteins and polysaccharides of infectious agents. The first of these

to be licensed, the Haemophilus influenzae

type b conjugate vaccines, have demonstrated

the safety and practicality of this approach.

Investigators are currently attempting to identify candidate immunogens of a number of

organisms, including group B streptococcus

and pneumococcus.

Intramural Research Laboratories. In addition to supporting research by awarding grants

and contracts, NIH supports intramural

research laboratories that focus on vaccine

development and play an important role in

improving vaccine safety and efficacy. The glycoconjugate technology that allowed the development of the Hib conjugate vaccines was the

product of intramural research at NICHD.

Intramural scientists have active programs in a

number of disease and vaccine areas, including

respiratory syncytial virus, rotavirus, malaria,

and dengue. Other agencies, such as FDA,

DoD, and CDC, also support internal laboratory research.

Workshops To Enhance Communication and

Peer Review. The workshop mechanism allows

PHS to convene focused scientific meetings on

issues relating to vaccine improvement and

development. When a number of new acellular

vaccines against pertussis were under development, NIH convened a workshop involving

principal investigators and sponsors of each of

these vaccines to discuss safety issues of these

acellular agents. Such gatherings provide an

opportunity for researchers to meet, share

results, and have their work informally reviewed

by peers.

Extramural Process and Peer Review. NIH

stimulates and supports research on vaccine

improvement and development through a number of mechanisms. NIH operates extensive

extramural programs, including the award of

research grants, training grants, and extramural

research contracts. 

Both solicited and unsolicited proposals are

funded through support for investigator-initiated research grants in the areas of immunology,

microbiology, and pathogenesis essential to the

development of safe and effective vaccines. All

extramural grant proposals are peer reviewed by

expert panels to ensure the highest standards of

science. 

NIH training grants help ensure the manpower

resources necessary for the Nation’s vaccine

research agenda. These grants typically support

junior investigators for 3 to 5 years. Training

grants are also used to sustain and develop

research infrastructure and capacity in institutions outside PHS. Training grants, like

research grants, are peer reviewed.

Research contracts allow the NIH to target

research to answer questions, e.g., the development of animal model systems needed for 

vaccine research and contracts to evaluate the 

safety of candidate vaccines in humans. These

contracts, because they involve research protocols of candidate vaccines with human subjects,

are closely coordinated with FDA and vaccine

companies.

The vaccine industry, comprising the major vaccine manufacturers as well as biotechnology

companies, sponsors or conducts a significant

amount of vaccine research. However, because

its results are not always published and its

financial records are confidential, the extent of
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 31

this commitment can only be estimated.

Clearly, it contributes significantly to the development and licensure of new vaccines.

Standards for Human Testing. A number of

standards have been developed to guide testing

of medical intervention in humans. In the

United States, conduct of federally supported

or FDA-regulated clinical studies is regulated

via legislation that includes, among other safeguards, institutional review boards (IRB),

whose mandate is the protection of human subjects from research risks, and the informed consent process. In the United States, an IRB

must have at least five members and may be

established by the institution or independently.

An IRB must review and approve an investigator’s protocol and informed consent form

before a study may be initiated. In addition, an

IRB reviews periodic reports from investigators,

including reports of any serious adverse reactions and changes in the clinical trial; investigates aspects of the clinical trial to ensure

patient safety; terminates the trial if appropriate;

and maintains appropriate records of all correspondence regarding the clinical trial.

Phase 1 and 2 Clinical Trials:

Immunogenicity and Safety. The phases of

clinical vaccine research in humans have been

described earlier (see box 3). In the 1960s,

NIAID established the Vaccine and Treatment

Evaluation Units (VTEUs) with the capability

of conducting clinical trials of candidate vaccines. Currently, NIAID supports seven nonAIDS VTEUs at university-based medical

research institutions around the country to

accelerate the testing of new and improved vaccines in early human trials of safety, immunogenicity, and protective efficacy. Their experience with vaccine trials, combined with their

access to population groups for relevant studies,

makes the VTEUs a national resource for early

evaluation of vaccines. A number of other clinical centers conduct phase 1 and 2 trials directly

sponsored by industry.

Phase 3 Clinical Trials: Efficacy and Safety.

Phase 3 clinical trials are safety and efficacy

evaluations that are usually done with large

numbers of subjects drawn from the population

at risk. PHS has sponsored a number of phase

3 trials of improved or new vaccines, such as

the NIH-sponsored acellular pertussis trials performed in Sweden and Italy. Most often, these

trials are sponsored directly by industry. 

Communication With the Vaccine Research

Community. Communication and coordination among a number of related agencies are

essential for an effective immunization and vaccine research and development program. The

NIH, individual research groups, IAVG, vaccine

companies, international organizations, and

government agencies in other countries are

important participants in this process. The

NIH-sponsored acellular pertussis trial in Italy

was a coordinated effort involving the NIH, the

Italian Ministry of Health, the Italian Public

Health Service, and four private vaccine manufacturers. In addition, the FDA had considerable input in the protocol for the study, the

CDC was involved in epidemiologic training of

the staff, WHO held an important meeting to

discuss the pertussis clinical case definition that

would be used in this and other trials, and a

number of universities and medical centers in

the United States were involved in the phase 1

and 2 trials in which vaccines for the Italian trial

were evaluated and selected. Such communication and coordination help ensure that research

is based on a true consensus within the world

vaccine community and that the results of such

a large and expensive trial will be of high order

and validity.

Contributions of Manufacturers 

In the United States, vaccine companies, in

addition to manufacturing the final product,

conduct a significant amount of research and

vaccine development, provide most of the

national expertise in process development for

pilot lot production of vaccines, and conduct or
NIAID Task Force Report on Safer Childhood Vaccines

32 January 1998

support clinical studies leading to licensure.

They are an integral part of the vaccine research

and immunization system. Federal agencies,

whether regulatory, immunization program, or

research-based, work with the vaccine companies to achieve development and safety goals. 

Improvements in vaccine safety are enhanced by

the regulatory framework used by FDA to

ensure vaccine safety and efficacy. Field-developed current good manufacturing practices

(cGMP) are standards that ensure that manufacturers use the best available technology for

vaccine production. In FDA’s interpretation,

the word “current” means that without amendment of the regulations manufacturers will use

state-of-the-art technology and procedures. If

a health hazard is imminent, FDA has demonstrated capability to recall from the market any

questionable vaccine and prevent it from being

marketed until the problem is resolved (see box

4). In addition, FDA can require that a manufacturer revise the warnings, precautions, and

contraindications in its product literature if a

new type of adverse reaction is detected. 

Contributions of Surveillance, 

Vaccine Recommendations, 

and Epidemiologic Studies

Epidemiology of Disease and Risk Factors.

Understanding the epidemiology and risk factors for any disease is important to its control

and prevention and is thus a priority for CDC.

This is especially true for a vaccine-preventable

disease in order to (1) monitor the impact of

vaccines on reducing the target diseases (e.g.,

Hib) and (2) monitor any changes in disease

epidemiology that may require changes in vaccine recommendations (e.g., a two-dose measles

vaccination schedule). Such information on

disease incidence and risk is critical to overall

risk-benefit analysis and to public announcement of recommendations for vaccine use. 

Provision of Vaccine to the Public Sector.

As the Nation’s largest single purchaser and

provider of vaccines, and because vaccines are

critical to its duties in disease prevention, CDC

has maintained a major interest in vaccine safety

since its founding. A separate Vaccine Safety

Activity was created at CDC in 1990 to provide

a focus for this important area. Vaccinations

not only provide substantial benefit to the individual but also indirectly benefit nonimmune

individuals. It is therefore important to ensure

that all persons have access to certain vaccinations. Through immunization grants administered by CDC, the public sector has historically

been estimated to provide approximately half

the childhood vaccines for each birth cohort.

This may increase under the Vaccines for

Children Program. For special vaccination programs like the National Influenza Program of

1976, the public sector may provide almost all

the vaccine. 

Risk/Benefit Assessment. ACIP is an advisory group composed of independent experts on

immunization and public health. It meets three

times annually to weigh the risks and benefits of

vaccinations and formulate recommendations

for their use by the American public. Accurate

and timely information on vaccine safety is critical to ACIP in its deliberations and recommendations.

Warnings/Use Instructions. There is a need

for concise and accurate summaries of the risks

and benefits of individual vaccines that are

understandable to the general public. CDC

first developed one-page Important

Information Sheets (IIS) for use by all administrators of publicly purchased vaccines in the

1970s. These were updated periodically and

aimed at a fifth-grade reading level. The IISs

also instructed vaccinees how to report adverse

events. In 1988, development of the Vaccine

Information Pamphlets mandated by the PHS

Act was undertaken by CDC. Simpler sets of

Vaccine Information Materials (VIM) were

developed, pretested, and released in 1994.

VIMs for childhood vaccines are now available.
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 33

Distribution/Storage/Stockpile. To ensure

the Nation’s supply of needed vaccines, CDC

negotiates contracts annually with vaccine manufacturers; they agree to store and distribute

the vaccine directly to eligible vaccine administrators. Because of the small number of vaccine

manufacturers and the need to minimize the risk

of vaccine shortages, a system of rotating vaccine

stockpiles for the public sector has been established. Safety is served in two ways: The immunization program keeps a stable supply of vaccine, and the required standards (dating, storage,

etc.) for maintaining the stockpile are enforced.

Field Surveillance/Adverse Reaction

Reporting. CDC implemented adverse events

surveillance in conjunction with the 1976

National Influenza Program. Subsequently, the

MSAEFI system was established for the public

sector in 1978. Major improvements in

MSAEFI were implemented in 1985.

Following the passage of NCVIA, CDC has

worked closely with FDA to develop and implement VAERS, a merger of the CDC MSAEFI

and FDA SRS databases. CDC serves as the

contracting office for VAERS.

Special Ad Hoc Epidemiologic Studies.

Because of its expertise in conducting disease

surveillance and epidemiologic studies and its

close contact with local health departments that

may be the first to learn of potential vaccine

safety concerns, CDC has conducted or funded

a number of epidemiologic studies to assess

potential vaccine safety problems through the

years. Examples of such ad hoc studies are listed in box 5. Creation of the LLDB in 1990

has been important in permitting more timely

assessment of potential signals generated by

VAERS and other sources. CDC has also

developed several new methodologies to

improve PHS’s ability to examine vaccine safety

issues, e.g., safety profiles and linkage of

MSAEFI reports with pre-vaccine-release lab

tests. Other sources of such studies include

NIH (the NIH-sponsored epidemiologic study

of SIDS and DTP vaccine) and the U.K.

Medical Research Council (National Childhood

Encephalopathy Study).

Monitor Vaccine Use. To monitor the national immunization program, CDC compiles a

number of types of data on the use of vaccines

as indicators of program effectiveness. Such

data also generate estimate denominators for

VAERS reports used to derive approximate

rates for vaccine adverse events. The information includes doses purchased and distributed

via the public sector contract, doses administered by age and antigen data, and estimated

vaccine coverage via a variety of surveys (e.g.,

the National Health Information Survey and

retrospective school-entry surveys). FDA maintains confidential data on numbers of doses in

each vaccine lot distributed for use in the

United States.

In the future, State vaccination registries may

provide accurate and timely data for use in vaccine safety studies.

Interaction With Global Immunization

Programs. PHS agencies participate in and

contribute to global immunization, research,

and regulatory programs, by both consultation

and collaboration with individual countries as

well as participation in multilateral projects.

For example, CDC provides substantial technical assistance to various national immunization

programs and the WHO Expanded Programme

of Immunization. In vaccine safety, CDC staff

has assisted WHO and the Pan American

Health Organization to develop draft guidelines

on vaccine adverse event surveillance. Because

an infrastructure for disease surveillance has

been developed via the national EPIs, it has

been possible to build vaccine adverse event

surveillance on an existing framework. CDC

staff has also consulted closely with other

national EPIs as ad hoc vaccine safety concerns

arose (e.g., mumps vaccine aseptic meningitis,

allergies to Japanese encephalitis vaccine, and a
cluster of deaths following DTP vaccine).

Similarly, FDA is participating in the plans and

discussions of international harmonization of

adverse event reporting systems so that eventually a database of all safety experience with 

vaccines can be easily consulted. NIH has supported trials in high-risk endemic areas and

provides scientific expertise and collaborates

with the newly formed Global Programme on

Vaccines and Immunization.

34 January 1998

NIAID Task Force Report on Safer Childhood Vaccines
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 35

Reports of Adverse Events That Led to

Development of New Vaccines

During the past several decades, reports

from a number of widely divergent

sources have served as the principal driving

force behind the development of alternative

preparations for existing vaccines. Previously

cited examples include the development of acellular pertussis vaccines. Several other examples

follow:

Measles—Killed or Live. Although both live

attenuated and inactivated measles virus vaccines were licensed in 1963, many providers

preferred the inactivated preparation because of

the reduced incidence of acute side effects.

Within a few years, however, it became apparent that prior receipt of the inactivated vaccine

was associated with a relatively severe atypical

clinical syndrome when recipients were exposed

to natural measles virus infection. Once this

problem was recognized, inactivated measles

vaccines were no longer recommended.

Attention was directed toward development of

live vaccines that were further attenuated.

Inactivated measles vaccines have not been used

since that time, and atypical measles is no

longer reported.

Rubella. The early rubella vaccines, first

licensed in 1969, included some vaccines produced in dog kidney cells that were associated

with a relatively high incidence of arthralgia.

The occurrence of these and other systemic

reactions (e.g., fever) prompted the development of alternative products grown in duck

embryo and later in human diploid cells. This

field was recently reviewed, and emphasis was

placed on the development of an animal model

for arthritis caused by rubella (Frey, 1994).

Influenza. Although inactivated influenza vaccines have been widely used for a number of

decades, severe adverse reactions other than

anaphylaxis were not described until 1976. At

that time, the development and mass application of the so-called “swine” influenza vaccine

led to an increasing number of reports of

Guillain-Barré syndrome (GBS) within the 30-

day period following vaccination. Subsequent

investigation confirmed the association of this

influenza vaccine with GBS. However, largescale studies of GBS during the subsequent 

3-year period showed no association with

influenza antigens other than the swine-like

strain. Epidemiologic vigilance continues.

Hepatitis B. The development and licensure

of plasma-derived hepatitis B vaccine was heralded as an important event in the prevention

of hepatitis B and hepatocellular carcinoma.

Unfortunately, plasma donors for vaccine production were often populations at high risk for

HIV/AIDS, causing concern about the potential for HIV transmission through vaccination,

even though HIV, if present in the plasma,

would have been destroyed in the manufacturing process. Nevertheless, the perception of a

risk probably reduced hepatitis B immunization

rates. An effective, genetically engineered vaccine produced in yeast was subsequently

licensed in the United States. As a consequence, the plasma-derived product is no

longer available in this country. Although considered to be safe and effective, the plasmaderived product is only used in certain developing countries.

Rabies. Before 1988, the use of preexposure

booster doses of human diploid cell rabies 

vaccine (HDCV) was limited because 

Experiences Leading to Development of Improved Vaccines
approximately 6 percent of recipients who

received both primary and booster vaccinations

with HDCV developed serum sickness-like

reactions. These reactions were believed to be

due to the presence of a small amount of

human serum albumin that was rendered allergenic by the beta-propiolactone used in making

HDCV. To counteract this problem, the

Michigan Department of Public Health developed an adsorbed rabies vaccine (licensed in

1988) that did not use human serum albumin

as a component in the cell culture medium;

consequently, albumin is not present when

beta-propiolactone is added to inactivate the

virus. Other recombinant approaches are being

pursued.

Significant Modifications of

Manufacturing Processes 

Over the years, FDA has become aware of circumstances that cast doubts on the safety of

specific vaccines. In these situations FDA and

its predecessor, the Division of Biological

Standards (DBS), concentrated their efforts to

solve the problems quickly. One example

occurred when the work of Sweet and Hilleman

indicated that simian virus 40 (SV40) was commonly present in tissue cultures prepared from

rhesus monkey kidney cells. This newly recognized agent produced no cytopathologenic

changes, which made it very difficult to detect

by the safety testing in place at the time.

The publication in March 1961 of the finding

that SV40 was relatively resistant to the formalin used to inactivate viruses during manufacture caused great concern. DBS scientists

investigated vaccines that were produced in

these cultures and discovered several lots containing infectious SV40. Although the virus

produced no discernible disease, other DBS

personnel demonstrated that volunteers inoculated with a massive dose of the virus developed

antibodies and sometimes shed virus in their

nasopharyngeal secretions. DBS felt that this

evidence, while not extremely alarming, called

for action. Taking advantage of the observation

that while the virus causes no change in rhesus

cells, it regularly did so in the cytoplasm of tissue culture cells prepared from the African

green monkey kidney, on May 5, 1961, DBS

required that safety testing in green monkey

kidney cells be included as part of the battery of

regulatory assays. Quick action on DBS’s part

minimized the number of Americans who

might have been exposed to this agent (Meyer

et al., 1962). Long-term studies of the potential effects of such exposure are ongoing.

NIAID Task Force Report on Safer Childhood Vaccines

36 January 1998
NIAID Task Force Report on Safer Childhood Vaccines

January 1998 37

Based on this review, the Task Force recognized the following gaps in the U.S. capability to promote development and ensure

improvements in vaccine safety.

General Needs

♦ Conduct a detailed review of Section 312

and Section 313 congressionally mandated

reports conducted and published by IOM,

and ensure appropriate response by PHS.

Results of these reports are summarized in

Appendix 8. The review of the IOM

reports is ongoing. 

♦ Understand host factors associated with

adverse reactions to vaccines. 

♦ Identify microbial properties and mechanisms for adverse events. 

♦ Determine factors associated with the use of

vaccines (licensed as well as IND) in the face

of national emergencies (Pandemic

Influenza Preparedness Plan, in progress).

Gaps in Capability for Promoting Development and

Making and Ensuring Improvements in Vaccine Safety
Glossary

January 1998 39

AAFP American Academy of Family Practitioners

AAP American Academy of Pediatrics

ACCV Advisory Commission on Childhood Vaccines

ACIP Advisory Committee on Immunization Practices

Adverse Negative sequelae of variable severity that occur after an 

Event intervention but may or may not be caused by it

Adverse Negative sequelae caused by an intervention: minor (pain, swelling,

Reaction or low-grade fever), severe (requiring hospitalization), or lethal 

(causing death)

AFEB Armed Forces Epidemiological Board

AIDS Acquired immunodeficiency syndrome

BCG Bacille Calmette-Guérin (vaccine for tuberculosis)

CBER Center for Biologics Evaluation and Research

CDC Centers for Disease Control and Prevention

cGMP Current good manufacturing practices

CVI Children’s Vaccine Initiative

DBS Division of Biological Standards

DHHS Department of Health and Human Services

DoD Department of Defense

DTaP Diphtheria, tetanus, acellular pertussis (vaccine)

DTP Diphtheria, tetanus, pertussis (vaccine)

eIPV Enhanced inactivated poliovirus vaccine

ELA Establishment license application

EPI Expanded Programme of Immunization, WHO

FDA Food and Drug Administration

GBS Guillain-Barré syndrome

GLP Good laboratory practices

GMP Good manufacturing practices

HbPV Hib polysaccharide vaccine

Glossary 
Glossary

40 January 1998

HBsAg Hepatitis B surface antigen

HBV Hepatitis B virus

HDCV Human diploid cell (rabies) vaccine

HepB Hepatitis B vaccine

HHE Hypotonicity, hyporesponsive episode

Hib Haemophilus influenzae type b

HIV Human immunodeficiency virus

HMO Health maintenance organization

HRSA Health Resources and Services Administration

IAVG Interagency Vaccine Group of the National Vaccine Program Office

IIS Important Information Sheet

IL Interleukin

IND Investigational new drug

IOM Institute of Medicine

IPV Inactivated poliovirus vaccine

IRB Institutional review board

ISCOM Immunostimulatory complex

LLDB Large linked database

MAPS Multiple-Antigen Peptide Systems

MIDRAC Microbiology and Infectious Diseases Review Advisory Committee

MMR Measles, mumps, rubella (vaccine)

MSAEFI Monitoring System for Adverse Events Following Immunization

NCVIA National Childhood Vaccine Injury Act

NIAID National Institute of Allergy and Infectious Diseases

NICHD National Institute of Child Health and Human Development

NIH National Institutes of Health

NVAC National Vaccine Advisory Committee

NVICP National Vaccine Injury Compensation Program

NVP National Vaccine Program

NVPO National Vaccine Program Office

OPV Oral poliovirus vaccine
PCR Polymerase chain reaction

PHS Public Health Service

PLA Product license application

PRP Polyribosylribose phosphate

rDNA Recombinant DNA

RSV Respiratory syncytial virus

Safety “the relative freedom from harmful effect to the persons affected, 

directly or indirectly, by a product when prudently administered, 

taking into consideration the character of the product in relation to 

the condition of the recipient at the time” (21 CFR 600.3 (p))

SIDS Sudden infant death syndrome

SRS Spontaneous Reporting System

SSPE Subacute sclerosing panencephalitis

SV40 Simian virus 40

TB Tuberculosis

Td Tetanus and diphtheria toxoid, adult type vaccine

Th Thymus-derived helper lymphocyte

TFSCV Task Force on Safer Childhood Vaccines (the Task Force)

Vaccine A preparation that is administered to produce or artificially increase 

immunity to a particular disease

Vaccine “that quantity of uniform material identified by the manufacturer as 

Lot having been thoroughly mixed in a single vessel” (21 CFR 600-639)

VAERS Vaccine Adverse Events Reporting System

VAPP Vaccine-associated paralytic polio

VERO Cell line derived from monkey kidney cells

VIM Vaccine Information Material

VRBPAC Vaccines and Related Biological Products Advisory Committee to 

the FDA

VSD Vaccine Safety Datalink

VTEU Vaccine and Treatment Evaluation Unit

VZV Varicella-zoster vaccine

WHO World Health Organization

Glossary

January 1998 41
January 1998 43

Appendix 1.

Examples of Vaccine Safety Issues of Recommended Childhood Vaccines

Vaccine Status Evidence and 

Risk Groups

Safety Issue

Oral poliovirus 

vaccine (OPV)

Vaccine-associated

paralytic polio

(VAPP)

Basic research ongoing to define

and detect determinants of neurovirulence (FDA, NIH). 

OPV not to be used in immunocompromised patients or in

infants or children who are

household contacts of persons

with altered immunity.

National recommendations to

increase use of enhanced inactivated poliovirus vaccine (elPV) in

schedules to decrease risk of

VAPP (ACIP, AAP).

Four to 8 cases/year in

the United States or less

than one per million

doses. Risk is higher

after first dose of OPV (1

per 500,000) than for

subsequent doses (1 per

2,000,000) (Strebel et

al., 1992). More significant in immunocompromised. Mechanism is

purported to be reversion

of live attenuated vaccine

strain to neurovirulence.

Adventitious

agents—simian

virus 40 (SV40)

SV40, a viral contaminant of OPV vaccine

grown in monkey kidney

cell culture, was found to

be carcinogenic in hamsters (Eddy, 1961).

Surveillance of population

showed no increased incidence of

cancer due to SV40 (Mortimer et

al., 1981).

Long-term studies ongoing.

New technologies developed

(polymerase chain reaction) to

detect adventitious agents. 

New cell culture production systems developed (OPV grown in

VERO cells lines) to obviate need

for primary monkey cells.

Strict control over manufacturing

standards, consistency, purity, and

inactivation. Current regulations

include additional filtration systems.

Cutter incident (1955)—

204 vaccine-related cases

of polio due to improper

production (Nathanson

and Langmuir, 1963).

In recent history IPV has

an excellent safety profile

(Stratton et al., 1994).

Incomplete inactivation

Anaphylaxis Neomycin and streptomycin used in manufacture to prevent bacterial

contamination.

Local reactions in allergic

individuals. Theoretical

risk.

Surveillance is ongoing.

Inactivated

poliovirus vaccine

(IPV)

Appendix 1
Appendix 1. continued...

Vaccine Status Evidence and 

Risk Groups Safety Issue

Diphtheria,

tetanus toxoid,

pertussis (DTP)

Protracted, inconsolable

crying

Seven large-scale acellular pertussis (DTaP) clinical trials in

Sweden, Italy, Germany, and

Senegal (three sponsored by

NIH) showed improved safety

profile of acellular vaccines. 

Causal relation ascribed to cellular pertussis component.

Rate is estimated at 0.1 to 6

percent of vaccinated infants

(Howson et al., 1991).

Typically resolves in under 24

hours.

Acute 

encephalopathy

IOM found evidence “consistent

with a causal relation.” Studies

contradictory: meta-analysis

suggests that risk is between 0.0

and 10.5 cases per million doses

(Howson et al., 1991).

Acellular pertussis vaccines

licensed for infants. Evaluation

of VAERS system for reporting

adverse neurologic events.

Comparison of VAERS and

LLDB efficiency of reporting of

ongoing febrile seizures

(CDC).

Comparisons of DTP and DTaP

in clinical trials show that HHE

is reported more often after

whole cell, but can occur after

DT and DTaP vaccines. 

IOM found evidence consistent

with a causal relation.

Evidence contradictory and

rates vary from 3.5 to 291 cases

per 100,000 injections. 

Shock and "unusual

shock-like state"—

hypotonicity, hyporesponsive episodes

Sudden infant death

syndrome (SIDS)

All studies reviewed by IOM

have suggested either no relationship between SIDS and

DTP immunization or a

decrease in SIDS risk for DTP

recipients.

SIDS surveillance and VAERS

surveillance continue. National

incidence decreases after “Back

to Sleep” campaign.

Anaphylaxis Causation is not ascribed to any

one component. Rate is estimated at 2 per 100,000 doses

(Howson et al., 1991).

Basic research in 

immunopathology. 

Acute arthropathy and

arthritis

IOM found evidence consistent

with a causal relation attributed

to rubella component. Rate is

13 to 15 percent of adult

women and much lower among

men, children, and infants.

Epidemiologic studies under

way.

Chronic arthritis IOM found evidence consistent

with a causal relation attributed

to rubella component. Not

enough data to determine a

rate.

Epidemiologic studies to evaluate risks and risk factors are conducted through LLDB with

negative findings.

Measles, mumps, 

rubella (MMR)

Anaphylaxis MMR vaccine is contraindicated

by a history of allergy or anaphylaxis due to neomycin. Egg

allergy is a relative contraindication. Recent studies of safe

administration (James et al.,

1995) in spite of allergy history.

Has occurred with MMR. The

vaccine contains both trace

neomycin and trace egg antigens, which are known allergens and immunogens.

44 January 1998
Measles,

mumps,

rubella

(MMR)

Aseptic meningitis Urabe vaccine mumps

strain only: not used in

United States.

Vaccine removed from European

and other markets. Strain not available in United States.

Passive surveillance for SSPE is

ongoing. 

SSPE incidence rates have fallen with

widespread use of MMR.

1993 IOM study (Stratton et al.,

1994) concluded that evidence was

inadequate to accept or reject a

causal relation.

Rare, severe complication

of measles disease, questionably of measles vaccine

strain. Rates estimated at

0.7 per million doses of

vaccine versus 8.5 per million cases of measles

(Johnson et al., 1984).

Subacute sclerosing

panencephalitis

(SSPE)

Unknown; few

serious AEs

described 

Safety profile for very rare

reactions (less than 1 per

100,000 doses) not yet

established.

Anaphylaxis Has been reported in both

United States and Finland

(1 per 100,000 doses in

the Finnish Hib titer trial).

Not enough data to determine rate.

Postlicensure surveillance by

FDA.

Unknown; few

serious adverse

reactions described

IOM study (Howson et al., 1991)

includes evaluation of safety profile

of this vaccine.

Anaphylaxis Potential for this reaction. IOM report 

(Stratton et al., 1994).

Hib

Conjugate

Hepatitis B 

vaccine

Potential for

change in efficacy

or safety profile in

some combination

vaccines

Altered immunogenicity

has been demonstrated

with live attenuated vaccines (MMR-varicella

zoster virus). 

DTP-Hib safety profile.

Development of safe, effective combinations continues.

Evaluated by FDA Advisory

Committee before licensure.

Combination

vaccines

Anaphylaxis Local reactions are known

to occur. Allergic reactions have been reported,

data suggest that serious

allergic reactions to Td are

rare. Anaphylaxis rate in

1985 and 1986 was 6.4

cases per million doses

(Plotkin and Mortimer,

1994).

Vaccine is contraindicated in patients

with a history of allergic reaction.

Surveillance for adverse events is

ongoing. 

Tetanus and

diphtheria,

adult type

(Td)

January 1998 45

IOM study included evaluation of

safety of this vaccine.

Appendix 1. continued...

Vaccine Status Evidence and 

Risk Groups Safety Issue
Appendix 2

January 1998 47

The Department of Health and Human

Services (DHHS) is responsible for a variety

of activities related to vaccines. They include

supporting, conducting, and promoting research

on vaccines; regulating the manufacture and distribution of vaccines; promoting and administering vaccination services; and monitoring impact

of immunization programs on disease rates.

Most of these activities have been part of the

Department’s mission for decades, but others

have been assigned since the enactment of the

National Childhood Vaccine Injury Act of 1986

(Public Law 99-660). 

The issue of safety is and has been inherent in

the Department’s administration of its varied

authority related to vaccines. Indeed, safety is

one of the statutory requirements for licensure

of vaccines, whether under the authority of section 351 of the Public Health Service Act or

under other authorities of the Food and Drug

Administration. These include the Food, Drug

and Cosmetic Act, expanded by the DurhamHumphrey Amendments of 1951, the

Kefauver-Harris Amendments of 1962, and the

Drug Regulation Reform Act of 1979.

Nevertheless, Public Law 99-660 gave additional emphasis to this issue in the context of

childhood vaccines.

On March 13, 1985, the House Energy and

Commerce Committee convened an oversight

hearing on biotechnology and its role in vaccine

development. The Congress recognized that

vaccines and immunization were critical to public health. They also concluded that progress in

research was providing important opportunities

to develop new vaccines against many infectious

diseases. The previous decade of disease prevention through immunization had been

labeled a global revolution in public health.

However, vaccines and immunization were

troubled by the liability crisis and perceived disarticulation of the vaccine efforts. In 1986, in

response to concerns from parent groups, vaccine companies, and the medical and public

health communities, Congress established the

National Vaccine Program (NVP) and the

National Vaccine Injury Compensation

Program (NVICP) under Public Law 99-660. 

NVICP is a no-fault system to compensate children and their families presumed to have suffered serious adverse reactions to mandated vaccines. By establishing this program, Congress

also aimed to reduce the threat of tort liability

for vaccine manufacturers and thereby stabilize

vaccine supply, and to improve the climate for

new vaccine research and development. The

program is funded through an excise tax

imposed on each dose of vaccine sold in the

United States and by an appropriation from

general funds to cover injuries that had

occurred prior to the enactment of the law. 

While some of these goals have been met, others have proved more elusive. The supply of

vaccines was stabilized following implementation of the NVICP, albeit at a higher price due

in part to the surcharge placed on vaccines to

pay for the compensation fund. Hundreds of

petitioners have received awards from the trust

fund, and lawsuits filed against domestic diphtheria, tetanus, and pertussis (DTP) vaccine

manufacturers dropped from a peak of 255

claims in 1986 to fewer than 20 in 1993 (CDC

data). Investigational new drug applications for

vaccines have more than doubled from 1986 to

Appendix 2. 

National Vaccine Legislation
48 January 1998

Appendix 2

1993, possibly reflecting a more attractive commercial outlook for development of new vaccines. In the research arena there has been a

very real increase in vaccine development in

both public and private sectors, particularly in

the development of acellular pertussis vaccines

(Jordan Report, 1995). 

NVPO was created to coordinate government

and nongovernment activities related to immunization and to allocate funds appropriated

under the Act to supplement otherwise unavailable resources. The law requires that the

Director, NVPO, ensure procurement of safe

and effective vaccines. The effective date of the

Act was October 1988.

The National Vaccine Advisory Committee

(NVAC) was established under Title XXI to

serve as a technical advisory group to NVP.

NVAC has as its mission those activities that

will promote the use of vaccines, improve vaccines already in use, and enhance the development of new vaccines. 

Vaccine safety and availability are of concern to

families, manufacturers, and physicians, and the

vaccines agencies of the Public Health

Service—the Food and Drug Administration,

the National Institutes of Health, and the

Centers for Disease Control and

Prevention—are each involved in different

aspects of the regulation, development, evaluation, and delivery of safe vaccines. Certain

aspects of vaccine supply and availability, however, are outside the current scope of the Public

Health Service. If the number of manufacturers falls, for any reason, the possibility of a vaccine shortage can become a threat to the public

health. In 1985, this became a very real possibility when the number of domestic DTP manufacturers fell to one. 
Appendix 3

January 1998 49

The Task Force reviewed a number of examples of basic research and technology

advances that have important implications for

vaccine safety. These advances offer not only

challenges to the assurance of safety and a significantly expanded scope for vaccine development, but also the potential for production of

purer, better characterized, more consistent

components and better understood mechanisms

of action than the older generation of biologically active, albeit effective, mixtures.

Host Responses to Infection. New information in the field of immunology about host

responses to infection and host responses to

immunization has raised important questions

with regard to vaccine safety. It is now clear,

for example, that recipients of the discontinued

killed measles vaccine (given in the United

States from 1963 to 1967) can suffer from a

potentially severe atypical measles syndrome

after exposure to wild-type virus or after revaccination with live attenuated virus. This syndrome is thought to be due to a delayed hypersensitivity reaction and may be related to failure

of the killed vaccine to induce antibody to the

F protein of the measles virus, a recently characterized virulence factor. Monkeys immunized

with killed vaccine, then challenged with live

measles developed a striking eosinophilia. This

research suggests that the killed vaccine

enhanced production of type 2 cytokine during

atypical measles.

Another recently appreciated host response is

immune enhancement. This response may have

played a key role in the complications associated

with an early vaccine for respiratory syncytial

virus (RSV). In this situation an inactivated RSV

preparation appeared to have been safe on

administration but caused severe complications in

some vaccinated children when they encountered

the wild virus. The pathogenesis of immune

enhancement is currently under investigation.

Determinants of Virulence. Attenuation, the

process by which organisms lose the ability to

cause disease, either through serial passage in

organisms or cultures, mutagenesis, and selection of auxotrophs, or by cloning of strains with

virulence factor genes deleted or inactivated by

mutation, is the basis of live attenuated vaccines. Until very recently, the biological basis

of attenuation remained a mystery; it was solely

an empirical process. Moreover, because attenuation was not fully understood, the biology of

reversion to pathogenicity was also unclear.

This ambiguity had important implications for

safety, because the genetic changes that differentiated the oral poliovirus vaccine (OPV)

strain from the wild virus, for example, had not

been identified and could only be tested empirically in monkeys. This situation changed with

the advent of monoclonal antibodies to viral

antigens, oligonucleotide fingerprinting, and

genetic sequencing technology, which can measure genetic homology among isolates and

detect subtle strain variations in genetic composition. Genetic mechanisms for virulence and

attenuation have now been identified for a

number of pathogens (Strebel et al., 1992).

The genetic basis for the reversion to neurovirulence of some type 3 polio vaccine strains is

currently being elucidated. Genetic sequencing

Appendix 3. 

Impact of Basic Research and Technological 

Advances on Vaccine Safety
of mutant type 3 vaccine strains has enabled

identification of transcription loci essential for

viral protein synthesis (Svitkin et al., 1990).

Research of this kind may lead to vaccine strains

incapable of reversion that could greatly reduce

the incidence of vaccine-associated paralytic

polio, the only form of polio seen in the United

States since 1980. 

Antigen Production Systems. New technologies for the production of antigens have had

important effects on vaccine safety. Two vaccines most recently added to the recommended

immunization schedule for all children—the

hepatitis B and Hib vaccines—are both products

of the new technologies. The first hepatitis B

vaccine was made from pooled hyperimmune

human sera, and, while efficacious and considered safe, it was an expensive product with

potential supply problems for mass use. In

addition, there was public concern about the

possibility of adventitious agents, particularly the

AIDS virus. There are currently two licensed

recombinant (rDNA) hepatitis B vaccines grown

in yeast, the first such recombinant vaccines

licensed for use in humans. Recombinant technology eliminates the need for human donors

and has produced safe vaccines with a potentially unlimited supply. Because the hepatitis antigen is produced in yeast and is dead, there is no

potential for hepatitis B infection associated with

immunization. 

The licensed Hib vaccines are also the product

of new production technology. These are conjugate vaccines, utilizing capsular polysaccharide

antigens of Haemophilus influenzae type b

bound to immunogenic proteins such as the

outer membrane protein of Neisseria meningitidis or diphtheria toxoids. These conjugates

are entirely acellular, have no microbial genetic

material, and have thus far had very few reports

of minor adverse events. Conjugate vaccines

are currently under development for a number

of other diseases, notably pneumococcal and

meningococcal infections, and also offer potentially promising safety profiles. 

Combination Vaccines. One of the goals of

the global Children’s Vaccine Initiative (CVI) is

the development of vaccines that will protect

the world’s children from a maximum number

of diseases with a minimum number of vaccinations. This is not simply a goal for developing

countries. While combination vaccines such as

MMR and DTP have long been in use, the

recent development of new vaccines and the

potential for more vaccines in the future have

created intense interest in combining antigens.

New vaccines have been added to the U.S. universal childhood immunization schedule (Hib

and hepatitis B, second varicella), and the

incorporation of IPV in lieu of OPV replaces an

oral vaccine with an extra injection. There is a

consensus among providers that we cannot add

many more visits, or many more vaccinations

per visit, without overburdening patients, parents, clinics, and the vaccine delivery system.

The appeal of combination strategies becomes

apparent as we consider the likely future incorporation of vaccines against rotavirus, RSV, and

others. Two formulations of a DTP-Hib combination, one combined in the syringe, have

been licensed (Watemberg et al., 1991). There

is considerable interest in DTaP-based combinations and an MMR-varicella vaccine (MMRV) (Brunell et al., 1988).

Combination vaccines will raise important challenges for assurance of safety in addition to efficacy. There are, first, safety concerns over

unsuspected adverse reactions to each of the

components of the new combination vaccines.

Both hepatitis B and Hib vaccines, for example,

have been given to many thousands of individuals without serious adverse effects, but they

were not given to millions prior to licensure,

and very rare adverse reactions were a possibility. Potential cross-reactions of antigens, either

in the vial or in terms of the immunologic

50 January 1998

Appendix 3
Appendix 3

January 1998 51

response, must also be evaluated. There

remains a theoretical possibility of altered

immune responses to multiple antigens given

simultaneously. This was a problem 

documented early in the development of 

trivalent oral polio vaccine but subsequently

resolved. 

From an epidemiologic standpoint, the evaluation of adverse reactions to combination vaccines is complex. The methodology currently

available to assess adverse events related to vaccination will need development and refinement.

It may prove particularly difficult to link an

event to a specific component of a combination

vaccine. The same difficulty is likely to complicate the liability issues surrounding vaccine 

safety as well.

Microcarrier Cultures. Microcarrier cultures

are continuous cell line culture systems that

allow for the production of recombinant antigens on a large scale. They have been used to

produce antigens of the AIDS virus (the gp160

antigen, which is under evaluation as a potential

HIV vaccine) in VERO cell lines, and to produce enhanced inactivated polio vaccine, OPV,

and rabies vaccine in France (Barrett et al.,

1989; Montagnon, 1989). Microcarriers have

the potential to greatly simplify production of

vaccines. The safety issues raised by this new

technology are essentially the same as for vaccines produced in continuous cell lines without

microcarrier technology (explained in the section below on cell lines and vaccines).

Vector Delivery Systems. For many diseases

the ideal vaccine is a live attenuated derivative of

the disease-producing organism that induces

strong, long-lasting immune responses without

causing disease. Developing such a vaccine is

not always possible, however, either because the

organisms cannot be cultured in the laboratory

or because reliable attenuation cannot be

obtained. One strategy to overcome these

obstacles is to use recombinant DNA technology

to insert one or more of the pathogen’s genes

into another organism, which then serves as a

vector for expression of these genes in the host.

Several vectors have been tested and are in various stages of development as vaccines. Safety

issues may well arise with the vector vaccines,

principally from the potential for reactogenicity

and pathogenicity in the vector organisms.

♦ Vaccinia. Vaccinia virus, effectively used as

the vaccine to prevent smallpox, has been

extensively studied as a vector for other antigens. Because it has a large genome of

approximately 200,000 base pairs and many

DNA integration sites, it has the potential

for expressing multiple antigens. Antigens

from influenza virus, hepatitis B, RSV, footand-mouth disease, malaria, rabies virus,

dengue virus, HIV, and human proteins

have been integrated into vaccinia.

However, a number of safety issues may

complicate the use of vaccinia as a vector.

The vaccinia strain used to eradicate smallpox had a serious adverse reaction rate of

about 1 in 50,000 doses, a rate that would

be unacceptable by current standards.

Adverse reactions to vaccinia included

eczema vaccinatum, progressive vaccinia,

generalized vaccinia, postvaccinal encephalitis, and skin lesions at the vaccination site

(Henderson and Fenner, 1994). The vaccine was contraindicated for patients with

immune dysfunction and infants with

eczema (Moss, 1991). Vaccinia has the

potential to produce disseminated disease in

immunocompromised individuals, and a case

of vaccine-related disease in a patient with

HIV infection has been reported (Redfield

et al., 1987). Research is now under way to

develop strategies to reduce the virulence of

vaccinia and other vector viruses through

recombinant technology. A recombinant

vaccinia strain has been developed that

expresses the human lymphokine interleukin-2 (IL-2). It had a protective effect in

immunodeficient animals and may be an
Appendix 3

52 January 1998

important safety advance for vectored vaccines (Andrew et al., 1991). Other 

lymphokine genes may also be candidates for

inclusion in recombinants. Finally, other

promising viral vectors lacking the problems

inherent in vaccinia, such as canary pox

virus, are being pursued. 

♦ Salmonella. Various Salmonella species have

been studied for their potential as vaccine

vectors. The rationale for this approach

stems from the extensive literature on the

value of attenuated salmonellae as vaccines.

One currently licensed typhoid fever vaccine,

Ty21a, is an attenuated strain of Salmonella

typhi. Because these strains can be administered orally and interact with the gut-associated lymphoid tissue—where they stimulate

high levels of immunoglobulin A production

as well as cellular immune responses—they

have been most actively studied for use as

vaccine vectors for diseases requiring strong

mucosal immune responses. Salmonella

recombinant vectors expressing the Shigella

O antigen, a subunit of the enterotoxin of

Escherichia coli, and the colonization factor

antigen of Vibrio cholerae have been tested

in humans. These would be potentially

bivalent vaccines, offering protection against

S. typhi as well as the recombinant antigen.

Potential safety concerns with these vaccines

include the possibility of reversion to virulence of the Salmonella strains in the gut

and the well-described reactogenicity of the

old killed, whole-cell S. typhi vaccines. As

with vaccinia, recombinant technology may

allow for multiple attenuating mutations to

be included in vector strains, and this could

increase safety and markedly decrease the

potential for reversion to virulence.

♦ Bacille Calmette-Guérin (BCG). The only

vaccine currently in use to prevent tuberculosis is an attenuated Mycobacterium bovis.

It is the most widely used vaccine in the

world and, along with HBV, is routinely

given to infants at birth. A number of BCG

strains exist, and while most are similar “sister” strains, others appear to differ. BCG

has also been studied as a potential vaccine

vector. Antigens of HIV and of leishmania

have been successfully expressed on BCG.

The safety of BCG in immunocompromised

individuals remains uncertain, however, and

cases of disseminated BCG disease in children with leukemia have been reported

(Coppes et al., 1992). BCG is currently

contraindicated in the United States for children with HIV infection (AAP, 1994). The

safety profile of BCG in healthy recipients is

also problematic, given the current demand

for vaccines with very low incidence of such

effects. Estimates of side effects with BCG

range from 1 to 10 percent of recipients and

include severe or prolonged ulceration at the

vaccination site, regional lymphadenitis, and

rarely, lupus vulgaris and BCG osteomyelitis.

Clearly, recombinant vector vaccines using

BCG strains as carriers will have to develop

further attenuated lines of these organisms.

♦ Adenoviruses. Adenoviruses have also been

used as potential vaccine vectors. Vaccine

strains currently used in the military to prevent respiratory disease have been genetically

engineered to express foreign DNA from

respiratory syncytial virus, hepatitis B virus,

and HIV. Studies in rats suggest that adenoviruses may be useful for delivering therapeutic gene products to patients suffering

from inherited lung disorders such as alpha1 antitrypsin deficiency and cystic fibrosis. 

Continuous Cell Lines To Produce

Antigens. Advances in biotechnology have

allowed for the creation of continuous cell lines

for the production of vaccine antigens. The

VERO cell line, derived from monkey kidney

cells, has been extensively studied in this light

and is the basis for an inactivated rabies vaccine

grown on these cells and currently licensed in

France (the purified VERO rabies vaccine

[Merieux]). This vaccine is considerably simpler and cheaper to produce than HDCV, the

human diploid cell vaccine, and it has demonstrated that VERO cells can produce large

amounts of consistent and pure antigen. 
Appendix 3

January 1998 53

Monoclonal Antibodies and Antigenic

Purification. The development of monoclonal

antibodies has revolutionized the fields of

immunology and microbiology. Monoclonal

technology allows for the production of highly

specific antibodies to an almost limitless array of

substances. In terms of antigen purification for

vaccines, monoclonal antibodies can be used to

detect minute amounts of undesirable protein,

genetic material, and adventitious agents, thus

offering the potential for major advances in vaccine safety. Monoclonal technology has been

developed for use in viral protein purification,

in the development of new vaccines for cholera

(Sanchez et al., 1990), leprosy (Clark-Curtis et

al., 1990), respiratory syncytial virus (Baker et

al., 1992), herpes simplex (Erturk et al., 1991),

tuberculosis (Rumschlag et al., 1990), malaria

(Tolbert and Rupp, 1989), Chagas disease

(Segura et al., 1989), H. influenzae type b

(Green et al., 1991), and certain types of

Hodgkin’s lymphoma (Pohl et al., 1992).

Recombinant DNA (rDNA) Techniques To

Produce or Express Antigens. The application of recombinant DNA technology to vaccine development has led to a new generation

of vaccines. The first licensed vaccine based on

rDNA technology was the vaccine for hepatitis

B, a yeast recombinant. Recombinant technology allows genes from one organism to be

inserted into the genome of another. In the

case of hepatitis B vaccine, the gene for the

hepatitis B surface antigen (HBsAg) is inserted

into yeast, which then expresses the gene product, HBsAG, on its surfaces. This antigen, after

extraction and purification, serves as the active

agent in the vaccine. Many more recombinant

vaccines are under development and are used

for recombinant “overexpression” systems in

which amplification genes are included in the

recombinant organisms to facilitate antigen production (Sanchez et al., 1990). Recombinant

vaccines have the potential for marked advances

in vaccine safety over either whole-cell or live

attenuated vaccines because of greatly increased

purity of antigens.

Other Delivery Systems and Routes

Mucosal Vaccination. Immunization by either

an inhaled or intranasal route has been investigated for a number of respiratory infections and

has been shown to be effective and safe for children to prevent influenza. There is a scientific

basis for the concept of stimulating respiratory

mucosal immunity to prevent these infections.

Using mucosally delivered vaccines, it also has

been shown that these vaccines can stimulate

systemic immunity, expanding their potential

application. Mucosal vaccines are being developed, with particular attention to immune

response, safety, consistency of dosing, patient

compliance, and costs.

Microencapsulation. Microencapsulation

holds promise for the development of slowrelease, single-dose immunizations that could

be a major advance toward simplifying immunization schedules. However, this technology

raises some important safety issues. They

include adverse reactions to antigens that might

not be removable from the body, sustained

inclusion of solvents whose safety in encapsulated forms needs to be demonstrated, and the

potential for microencapsulation to lead to

immune tolerance of antigens.

The World Health Organization and CVI are

evaluating microencapsulated tetanus toxoid vaccines in animal systems. These are single-dose

vaccines of microencapsulated antigen formulated

such that antigen is released over a period of

weeks to months. The tetanus toxoid is encapsulated in microspheres composed of lactic and glycolic acids. A single dose of such a vaccine could

potentially provide long-lasting immunity to

Clostridium tetani. Theoretically, however, if an

allergic or anaphylactic reaction occurred in 
Appendix 3

54 January 1998

association with one of these vaccines, and the 

antigen or solvent could not be removed, sustained or pulse release could potentially lead to 

prolonged adverse reactions.

Immune tolerance is a theoretical safety issue

with microencapsulated antigens and is being

studied carefully. If an antigen is released

under the correct conditions (release of small

amounts over time), the immune system may

become tolerant of an antigen rather than 

resistant to it. Immune tolerance, rather than

protecting against disease, could make an individual more susceptible. 

A number of microencapsulation systems have

been tested in animals, and some have been

shown to be safe and immunogenic

(Moldoveanu et al., 1989). A phase 1 safety

and immunogenicity trial of a liposome-based

microencapsulated vaccine against malaria evidenced both safety and impressive immunogenicity in humans (Fries et al., 1992a). It

remains to be seen how large a role microencapsulation will play in future vaccine development.

Devices. The administration of vaccines, particularly multicomponent vaccines, may sometimes

be best accomplished by special devices, such as

multichamber syringes and jet injectors. These

devices are often used for the multiple inoculation of individuals during an immunization campaign. FDA requires that the device and the

biologic product, both as individual components

and in combination, be safe and effective prior

to approval. This may complicate and slow the

evaluation of products using these devices. For

example, issues of safety peculiar to multichamber syringes include consistency in mixing the

components of the vaccine and consistency in

volume delivered. Jet injectors, previously associated with the transmission of infection from

patient to patient, have been made safer with

modification of the device itself.

Application of Robotic Technologies to

Vaccine Production. After years of use and

refinement in the auto and semiconductor industries, robotic technology has recently been

applied to vaccine production. Robotic technology offers manufacturers the advantages of

increased productivity (there are reports of doubled output), consistent technique (i.e., one

manufacturer is claiming more than 700,000

consecutive fillings with no break in sterility),

and the ability to simultaneously process batches

of several products. To ensure safety and efficacy, utilization of such technology by a manufacturer requires extensive validation of the hardware and software.

Enhancement of Immunity: 

The Development of New 

Antigens and Approaches

It has been known for many years that the polysaccharide capsules of certain bacteria are

important virulence factors in the pathogenesis

of disease. Examples of these virulence factors

include the Vi antigen of typhoid, the PRP

polysaccharide of H. influenzae, and the capsular antigens of pneumococcus and meningococcus. It was also known that these antigens,

while important in the disease process, were

often poor immunogens and evoked especially

weak immune responses in children under 24

months of age. A vaccine composed entirely of

one such antigen, the PRP polysaccharide of H.

influenzae type b, though licensed in Finland,

proved to be incompletely protective in

American trials (Shapiro, 1990). 

The immunologic basis for the response to capsular polysaccharide has begun to be understood. These antigens appear to be T cell independent; i.e., they fail to elicit T cell-mediated

immunity and thus stimulate immunologic

memory. The development of glycoconjugate

technology allowed for the linkage of these

polysaccharide antigens to more immunogenic

proteins. According to the concept of antigen
Appendix 3

January 1998 55

“conjugates,” by linking protein and polysaccharide antigens, T cell-mediated as well as

humoral responses can be elicited. The first

generation of these vaccines has now been

licensed; all three are conjugate vaccines of the

Hib capsular polysaccharide, PRP, with

immunogenic proteins such as the diphtheria

toxoid or the outer membrane protein of N.

meningitidis. These vaccines have proven to be

remarkably safe and effective and to elicit good

immune responses from infants as young as 6

weeks of age. Recent studies indicate that the

different Hib conjugate vaccines can be safely

and effectively administered in mixed sequential

schedules, eliminating one safety concern. 

The glycoconjugate approach should be valuable for other bacterial diseases, such as pneumococcal, streptococcal, and meningococcal

diseases. A Pseudomonas aeruginosa conjugate

vaccine has been tested in humans. This vaccine links a polysaccharide antigen and the

toxin A antigen of the same organism to create

a novel conjugate (Schad et al., 1991). Clinical

evaluations have been done on a malaria conjugate vaccine linking an outer membrane antigen

of Plasmodium falciparum to the Pseudomonas

toxin A (Fries et al., 1992b), and on an E. coli

conjugate vaccine consisting of the O polysaccharide of E. coli bound to the O-PS toxin of

Cholera vibrio (Cryz et al., 1991).

In addition to enhancing immunity through

stimulation of both humoral- and cell-mediated

immune responses, conjugate vaccines may have

another advantage in disease prevention. There

is evidence that antibody to polysaccharides

alone may not cross the placenta and protect

the neonate. Glycoconjugates may stimulate

production of immunoglobulins that do cross

the placenta, presenting the possibility of

maternal immunization against such important

neonatal pathogens as group B streptococcus

(Baker et al., 1988). 

Approaches to Enhancing

Immunogenicity—Adjuvants

The advent of recombinant DNA technology

has stimulated the production and testing of

new subunit vaccines designed to be safer and

more efficient. Unfortunately, the limited

immunogenicity of many of these peptide or

subunit candidates has hindered their development as potential vaccines, making critical various strategies to enhance their capacity to elicit

a protective immune response while avoiding

the production of harmful effects. Ideally, both

improved understanding of the mechanisms of

immunoenhancement and the increasing number of available experimental approaches should

be integral components of rational vaccine

design. The process of development of new

vaccines, however, is still highly empirical. 

Adjuvants are agents that make it easier for an

antigen to elicit an immune response. Depottype adjuvants, such as alum, were originally

thought to increase the immunological half-life

of the antigen, but their effects may be mediated by cytokine release (Allison, 1992). Novel

adjuvants may function by one of the following

mechanisms: (1) changing the conformation of

the antigen, thereby enhancing the antigen presentation; (2) preventing proteolytic destruction in the stomach, thus allowing the antigen

to pass into the intestines intact for presentation to the gut-associated lymphoid system; 

(3) targeting antigen directly to M cells of the

gut to induce mucosal immune responses; 

(4) targeting macrophages (particulate adjuvants); and (5) inducing the production of various immunomodulatory cytokines, which act

directly on thymus-derived helper (Th) lymphocytes to selectively promote specific arms of the

immune system. 

The traditional approach to vaccine development assumes that a vaccine will stimulate an

immune response that is qualitatively and quantitatively similar to that produced by natural
Appendix 3

56 January 1998

infection and that this will prevent disease when

a person is subsequently exposed to the

pathogen. Often, however, the immune

response after vaccination is far weaker than

that measured after disease, and protection can

be variable. Adjuvants are substances that can

amplify the cell-mediated and humoral immune

response to an antigen. The only adjuvant

approved for human use in the United States is

aluminum salt (aluminum hydroxide or aluminum phosphate), which, when adsorbed to

antigen, augments antibody responses to

diphtheria and tetanus toxoids and the hepatitis

B vaccines. Vaccines containing alum adjuvants, however, cannot be lyophilized or frozen

and are not effective with all antigens, particularly subunit vaccines.

The development of alternative conventional

vaccine adjuvants is approached empirically by

mixing an antigen with the potential adjuvant,

which must then be tested in an animal or

human to determine effectiveness and safety.

Research in this area is focused on a variety of

oil-based emulsions that contain biodegradable

materials. Candidates include the Syntex formulation, SAF-1 (containing squalene oil, an

amino acid derivative of muramyl dipeptide

[threonyl-MDP], and nonionic block polymers),

the Ciba-Geigy formulations (containing squalene, surfactants, and a fatty acid derivative of

muramyl tripeptide [MTPPE]), the Ribi formulation (containing monophosphoryl lipid A and

mycobacterial cell walls), and the saponin derivatives, such as the Cambridge Biotech QS21. 

The development of new adjuvants has been

dominated by concerns regarding safety

(Goldenthal et al., 1993). Some adjuvants are

in early trials in humans while others are being

developed for veterinary vaccines. Some empirically developed adjuvants have been too toxic

for use in humans, causing tissue damage at the

site of injection and later granulomatous reactions, pyrogenicity, arthritis, and anterior uveitis

in animal models. While effective adjuvants can

reduce the amount of foreign proteins introduced in the vaccinee by achieving protection

with fewer doses, extensive experience with

adverse reactions caused by candidate adjuvants

prompts FDA to demand an approach to testing

for safety that is even more careful and systematic than that required for a new antigen.

Prudently, the preclinical animal safety studies

will use the exact antigen-adjuvant combination,

routes of administration, injection volume, and

formulation intended for clinical use to best

demonstrate freedom from untoward events.

Approaches to Enhancing

Immunogenicity—

Epitope-Based Strategies

Strategies for immunization with only the relevant epitopes have developed as a result of

enhanced understanding of the mechanisms for

antigen recognition by B and T cells.

Theoretically, these strategies result in an

immune response only to the relevant target

and offer the potential for avoiding the toxicity

associated with the presence of an immune

response to other components of the pathogen.

The simplest approach is to link B cell and T

cell (helper and cytotoxic) epitopes and use

these linear polyepitopes as vaccines. In practice, a good humoral immune response may be

elicited, but genetic restrictions may limit the

ability to respond to these immunogens. How

to optimize the arrangement of epitopes and

how to present antigens to the immune system

in a manner that maintains conformational and

functional integrity (either as synthetic peptides

or as expressed peptides in vectors such as vaccinia virus) have not yet been determined but

are under investigation in a number of laboratories. Although epitope-based approaches

stimulate good antibody responses, they do not

stimulate potent cellular immunity, especially

cytotoxic T cell responses.

Therefore, other approaches are being pursued.

One interesting approach is the use of MultipleAntigen Peptide Systems (MAPS), which 
Appendix 3

January 1998 57

consist of selected T and B cell epitopes that are

conjugated to a polylysine core without a 

carrier protein (Lu et al., 1991). MAPS are

structurally defined, contain a quantifiable

amount of well-characterized pure antigen, can

be administered intraperitoneally, and generate

antibodies with high specificity. This approach

has been applied to the development of totally

synthetic vaccines for hepatitis B virus, malaria,

and HIV infection. Genetic fusion of 

immunogenic peptides with the nontoxic B

subunit of cholera toxin functions as an 

adjuvant for inducing mucosal immune

responses. This combination targets the Peyer’s

patches in the intestine and results in a brisk,

sustained immune response to the attached

peptide sequence. Nontoxic derivatives of

cholera toxin (and the related E. coli heat-labile

toxin) are also being evaluated.

Approaches to Enhancing

Immunogenicity—Particulate Antigens 

Liposomes and microspheres can protect antigens from proteolytic destruction in the stomach, allowing antigen to pass into the intestines

intact for presentation to gut-associated lymphoid tissue. Different types of liposomes have

been tested over the past 20 years.

Immunostimulating reconstituted influenza

virosomes, spherical unilamellar vesicles that

combine the hemagglutinin membrane glycoprotein of the influenza virus with antigen, have

been tested in a hepatitis A vaccine formulation

in humans. 

A microcapsule consists of an inner reservoir of

antigen surrounded by an outer biodegradable

polymer wall (most recently lactide-co-glycolide

polyesters) that slowly releases antigen in the

lymphoid tissue. The technology has been

available for 30 years but has only recently been

explored with vaccines. The composition and

size of microcapsules are varied; they produce

high, sustained immune responses to toxoids

and viral antigens. Although the microcapsules

consist of the same material used to make

resorbable sutures, the possibility of adverse

reactions to a slow-release allergen remains a

safety concern, albeit a theoretical one at this

point. Because microcapsules between 5 μm

and 10 μm in diameter are taken up by the

Peyer’s patches of the gastrointestinal tract, oral

administration of microspheres has been shown

to elicit immune responses in mice. The effectiveness of this approach will require careful

evaluation because, although microcapsules

maintain the peptide in the dry state, avoiding

the need for a cold chain, the process exposes

antigens to organic solvents, thereby decreasing

immunogenicity.

Another approach has been to incorporate antigens into solid particles called ISCOMs

(immunostimulatory complexes). These structures are generated by mixing antigen with the

detergent Quil A. The ISCOM self-assembles

into stable 35-nm cage-like structures held

together by the hydrophobic interactions

among the matrix (Quil A), added lipids, and

the antigen. ISCOMs containing viral membrane proteins have been tested in animals and

found to stimulate tenfold increases in antibodies compared to controls. When complexed

with glycoprotein, ISCOMs may also induce

cytotoxic T cell responses, perhaps through the

delivery of antigen directly to the cytosol for

presentation with MHC class I molecules.

Cytosolic antigen delivery by membrane-active

adjuvants mimics the antigen presentation that

occurs during viral infection or after immunization with live attenuated vaccines.

Protein cochleates, which are stable proteinphospholipid-calcium precipitates, represent

novel formulations to enhance the immunogenicity of antigens. The name derives from

their unique structure, a rolled-up lipid bilayer

maintained by calcium bridges. Membrane

proteins or peptides with lipid anchors can be

integrated into this lipid bilayer, which, when
58 January 1998

rolled up, protects them from intestinal acid

and allows them to be slowly taken up by the

Peyer’s patches. They can thus serve as efficient methods for multiple antigen presentation

and stimulate strong circulating and mucosal

antibodies that protect against infection upon

challenge in the mouse model. This approach

is being tested with influenza, parainfluenza,

and HIV vaccines.

Cytokines

An emerging area of immunologic enhancement involves the use of cytokines to direct and

boost immune responses. CD4+ T-helper lymphocytes have been subdivided into two classes

depending on the pattern of cytokines they produce, Th1 and Th2 responses. Th1 cells are

prominently involved in cell-mediated immunity and produce cytokines such as interleukin-2

(IL-2) and interferon-λ while Th2 cells help

antibody production and produce cytokines

such as IL-4 and IL-10. In certain chronic

infections, such as leishmaniasis or schistosomiasis, whether the predominant immune

response is Th1-like or Th2-like determines the

severity of disease. In principle, therefore, the

ability to manipulate the immune response

toward a Th1- or Th2-like response may permit

the enhancing of immunologic protection and

minimize immunopathology.

IL-12 is a recently characterized cytokine that

may play a pivotal role in immunomodulation.

The adjuvant activity of IL-12, when given with

antigens, has been demonstrated in a leishmania

vaccine in mice. Immunization of BALB/c

mice with Leishmania major antigens and IL12 induced leishmania-specific CD4+ Th1 cells

that conferred protection against L. major.

Immunization of control animals with antigen

alone elicited Th2-type immune responses that

were not protective.

Nucleic Acid Vaccines

The injection of relatively simple DNA-containing bacterial plasmids into muscle of mice has

been shown to result in expression of genes

encoded by the plasmid. These “DNA” or

plasmid DNA vaccines appear to be capable of

stimulating both humoral- and cell-mediated

immune responses. After a single dose of this

type of vaccine, IgG antibodies have been

shown to increase for 1 to 2 months, and then

either remain stable or gradually fall.

Furthermore, cellular immunity has been

induced, with both effective priming and boosting observed in mice. The duration of the

immune response is observed for at least 19

months after injection. Second, the route of

administration may be parenteral, mucosal, or

via a gene gun that delivers tiny amounts of

DNA-coated gold beads. Finally, this strategy

results in relevant antigen production in primates without the use of infectious agents.

Thus, this approach to vaccine development is

relevant to a number of diseases, including

HIV, and can be expected to continue to

receive intense scrutiny. Evaluation of the safety of this approach will be central to its safe

development and testing in humans.

Appendix 3
Appendix 4

January 1998 59

I

n the last decade several new or previously

unidentified infectious diseases have been

recognized as important pathogens. A number

of these diseases are currently the subject of

intensive vaccine research. The causative agent

of Lyme disease, the spirochete Borrelia

burgdorferi, was identified less than 10 years

ago. Lyme disease is now the most common

vector-borne disease in the United States, with

several highly endemic regions recognized.

HIV, the human retrovirus that is the causative

agent of AIDS, has now taken the lives of more

than 200,000 Americans. The disease was first

identified in the United States in 1981 and has

since become a global pandemic. Seven outbreaks of multidrug-resistant Mycobacterium

tuberculosis have occurred in U.S. hospitals and

prisons. These antibiotic-resistant tuberculosis

(TB) strains are challenging to treat and represent a new and potentially life-threatening

occupational hazard for health care workers,

correctional facility staff, and staffs of shelters

and service agencies for the homeless, as well as

an important nosocomial risk for any hospitalized patient. 

Each of these three diseases has presented

major challenges to vaccine research. The

development of a safe and effective vaccine

against HIV is now an international effort.

HIV is the first human retrovirus for which vaccine development has been attempted. The

current candidate HIV vaccines illustrate the

application of biomedical advances to vaccine

development; they employ transformed cell

lines, recombinant antigens and vectors,

ISCOM technology, and monoclonal antibody

assays. A number of HIV vaccines have been

tested in HIV-infected patients, and a therapeutic role for these vaccines is a potential benefit

of HIV vaccine research. Clearly, an important

concern with any HIV vaccine is adventitious

transmission of the HIV virus. Development of

such vaccines is challenged by concerns about

lack of efficacy, transmission of the AIDS virus

or any part of its genome, and production of

high titers of antibody against an immunodominant, nonneutralizing epitope. The public’s

concern about these issues may be a barrier to

the clinical testing of HIV vaccines and their

acceptance. 

The Lyme disease agent is the first tick-borne

spirochete for which intensive vaccine research

has been done. Vaccines for Lyme disease have

been successfully tested in humans and found

to be efficacious, and an animal vaccine has

shown protection in mice, one of the principal

host species of the organism. Research focused

on characterizing the immune response to B.

burgdorferi, identifying the antigenic determinants of the organism, and understanding the

transmission of the disease to humans has been

critical to the development of safe and effective

vaccines for Lyme disease.

Although there is a vaccine for tuberculosis, the

efficacy of BCG (bacille Calmette-Guérin) in

adults is uncertain for any indication. Its efficacy in children is controversial but generally

agreed to be limited to the prevention of extrapulmonary complications of TB infection such

Appendix 4. 

New and Emerging Infectious Diseases: 

Unexpected Challenges to Vaccinology
as tuberculous meningitis or osteomyelitis

(CDC, 1988). Clearly, new TB vaccines are an

urgent research priority. The BCG vaccine, one

of the oldest vaccines in use, contains a live

attenuated organism. The new generation of

TB vaccines will undoubtedly employ new

strategies, and efforts are under way to create

safer and more effective acellular, recombinant,

and epitope vaccines that will protect against

TB infection while preserving the usefulness of

TB skin testing, with which BCG interferes.

The emergence and reemergence of these infectious diseases point to the need for continued

epidemiologic and basic research in infectious

diseases, as well as the development of vaccines

to control and prevent disease in the future.

60 January 1998

Appendix 4
Appendix 5

January 1998 61

Polymerase Chain Reaction (PCR). PCR

is a new technology for detecting the presence of genetic material. PCR works on the

principle of gene amplification, so that previously undetectable amounts of nucleic acid, if

present in a sample, can be chemically amplified

and detected. Because of its extreme sensitivity,

PCR represents a major improvement in the

ability to detect small amounts of nucleic acid

that could not have been detected with earlier

methods; thus, its application to vaccines may

represent an advancement in the assessment of

vaccine purity. PCR can be used to rapidly

identify, clone, and sequence microbial genes

responsible for disease, abilities that may have

important applications for vaccine development

and safety. The likelihood of adventitious viral

agents in vaccines, or of such agents in vaccines

grown in tissue culture, could be substantially

reduced by the use of PCR. In addition, PCR

is able to detect short segments of altered

genetic material. With this capability, PCR has

been used to detect altered nucleotide

sequences in polio vaccine strains that correlated with reversion to neurovirulence. In one

experiment, neurovirulent strains that had

passed undetected in the intraspinal monkey

neurovirulence test were detected by PCR

(Chumankov et al., 1991). This finding could

be of considerable importance and presents one

approach to decreasing the risk of vaccine-associated polio. Interpretation of PCR assays,

however, may be difficult and requires careful

consideration of false-positive results.

Transgenic Animals. There have long been

theoretical and practical challenges to the

extrapolation of animal model immune responses to human diseases. In terms of vaccines,

especially for those diseases where animal models are problematic or nonexistent, the evaluation of safety, immunogenicity, and antigenicity

has been difficult. The use of transgenic animals

and the development of animal models with

genetically altered immune systems have

improved this situation considerably. Before the

development of a transgenic mouse model, the

only animal model for evaluating the polio vaccine strain and its potential for reversion to neurovirulence was the intraspinal injection model

in monkeys. This monkey model was expensive

and, because it did not involve the gut, less than

ideally suited to the evaluation of human disease. The transgenic mouse model offers

promise of an improved system for the evaluation of this important vaccine safety concern.

Informatics Revolution. The cross-reactivity

of vaccine antigens with human proteins has

been considered a potential threat to the safety

of vaccination. In theory, if vaccines induce

antibodies to proteins that have cross-reactivity

with human proteins, these induced antibodies

could cause immune-related disease states. This

concern has been raised in regard to vaccines

against Streptococcus pneumoniae type 14, group

B streptococcus, and Neisseria meningitidis.

Certain antigens of the type-14 pneumococcus

may share epitopes with human red blood cell

membranes. Polysaccharide units of group B

streptococcus share sugar structures with

human glycoproteins (Hayrinen et al., 1989).

There is also some evidence of antigenic similarity between the meningococcus and antigens

of developing neural tissue (Finne et al., 1983).

At present these potential examples of crossreactivity are all theoretical, and there is little

evidence that such antigenic similarities are of

Appendix 5. 

Laboratory Evaluation of Vaccine Safety
Appendix 5

62 January 1998

clinical significance. The ability to identify and

sequence antigen genes that may cross-react

with human proteins could, however, greatly

reduce the possibility of autoimmune or

immune-complex complications of vaccination.

The informatics revolution, which has resulted

in powerful computer systems that facilitate

multiple comparisons and storage of information, has greatly improved the sensitivity of

these investigations and allows comparisons of

human and microbial gene sequences, as well as

their amino acid and glycoprotein products.

Control of Manufacture and Release.

Improvements in the safety of vaccines in use

today have also been the goal of widespread

promulgation of standards for good laboratory

practices and current good manufacturing practices by the pharmaceutical industry. These

standards have been used to upgrade and standardize the procedures used in the manufacture

of all vaccines in the United States. However,

although the World Health Organization has

issued guidance documents on manufacture and

control authorities, consistent high standards

are not used worldwide. Manufacturers, working with the Food and Drug Administration,

are collaborating with the International

Conference on Harmonization to harmonize

requirements and establish a higher set of standards for ensuring vaccine safety. Harmonized

preclinical testing standards will enable international test data to be used in the FDA review

and licensure process, thereby facilitating availability of foreign-manufactured vaccines in the

United States, as well as availability of United

States-manufactured vaccines globally.
Appendix 6

January 1998 63

Measles. A single dose of live measles vaccine was recommended when the measles

vaccine was first licensed. In 1963, the recommended age for vaccination was 9 months; in

1965, it was changed to 12 months. In 1976,

the recommended age was changed again to 15

months because vaccine efficacy was found to be

lower in children vaccinated at 12 to 14 months.

The 1989-1990 measles epidemic in the United

States was principally due to failure to immunize children at appropriate ages; this led to

low coverage levels, particularly in high-risk

groups (National Vaccine Advisory Committee,

1991). However, even before these outbreaks,

immunization strategies were being evaluated

because of random measles outbreaks, predominantly among school-age children. Studies of

the transmission patterns in the United States

during the 1985-1986 period described two

major types of outbreaks: among preschoolers

(26 percent) and among school-age children

(67 percent). Investigation of the outbreaks

among highly vaccinated school-age children

revealed that vaccination between 12 and 14

months was a risk factor for the outbreaks.

However, investigation of the preschool outbreaks revealed that national measles elimination strategies were functioning suboptimally

because a large number of cases were occurring

in unvaccinated, vaccine-eligible children 16

months to 4 years of age. Various policy

changes were considered at that time, including

a routine two-dose schedule that would be

expected to reduce the number of primary vaccine failures and potentially raise immunity levels above 95 percent (Markowitz et al., 1989).

The next series of investigations of measles outbreaks during the 1989-1990 period revealed

other important factors to consider in policy

changes. Investigations of those outbreaks

demonstrated that financial and situational barriers existed to immunization and that opportunities were frequently missed to assess the vaccination status of children when services were

delivered for reasons other than well-child care.

An important consequence of the 1985-1986

and 1989-1990 measles epidemics was that the

Advisory Committee on Immunization Practices

(ACIP) reevaluated current measles dosage and

schedule recommendations. The resulting

ACIP recommendations called for a routine

two-dose schedule, both doses preferably given

as combined measles, mumps, and rubella

(MMR). The first dose was recommended to

be given at 15 months except in measles transmission areas, whose infants were immunized at

12 months. The second dose was recommended at 4 to 6 years except in high-risk geographic

areas. A subsequent recommendation required

documentation of receipt of two doses after the

first birthday or other evidence of measles

immunity for individuals in post-high school

settings such as college and persons beginning

training in the medical field.

One of the findings from the measles investigations was that many practitioners were failing to

immunize at appropriate ages due to such false

contraindications such as mild respiratory 

illness. Thus, as another important consequence of the 1989-1990 measles epidemic, 

the National Vaccine Advisory Committee 

Appendix 6. 

Evolving Recommendations for the Use of Vaccines
Appendix 6

64 January 1998

recommended standards of immunization practice that set forth true versus false contraindications for administering all mandatory childhood

vaccines. Standards for both the private and

public sectors were developed by the Centers

for Disease Control and Prevention (CDC) in

consultation with a diverse group of interested

parties and subsequently adopted by the advisory groups. They include standards for ensuring

that vaccine is administered safely.

Most recently, ACIP has examined evidence for

the decreasing level of antibody in the cohort

of young mothers who have obtained protection from vaccine. As a result, the recommended age for administration of the first MMR has

been dropped to 12 months. 

Pertussis. Work has been ongoing for more

than 20 years to identify and purify the antigens

of Bordetella pertussis that can be incorporated

into protective acellular vaccines that are less

reactogenic than whole-cell vaccines. Concern

about reactogenicity varies widely by countries.

Industry enthusiasm for development of a vaccine that would replace an already licensed,

effective vaccine required encouragement from

the Public Health Service. In the 1987 Swedish

trial, acellular pertussis vaccines had been evaluated earlier in infants, and, although clinical vaccine efficacy was considered good, the estimates

were not considered superior to those previously

obtained for whole-cell vaccine (there was not a

concurrent whole-cell arm in this trial). Thus,

the data did not result in licensure of acellular

pertussis vaccine for infants in the United States

or Sweden. In 1991, the immunogenicity and

safety of 13 acellular products were compared

with those of whole-cell vaccine in a multicenter, randomized, double-blind study of more

than 2,400 U.S. infants conducted at six NIAID

Vaccine Evaluation and Treatment Units. The

trial demonstrated that most of the acellular

products were of equal or superior immunogenicity compared to whole-cell vaccine (Decker

and Edwards, 1995). Without a serologic correlate of protection, however, immunogenicity

data cannot be used for conclusive determination of efficacy. 

The phase 3 efficacy trials in Sweden and Italy

demonstrated excellent safety and efficacy compared to U.S. whole-cell vaccine in 1995.

Once these vaccines were licensed for infants,

ACIP recommended them as the preferred pertussis vaccine. This recommendation will

remain unless and until acellular pertussis vaccines have been licensed for infants. 

None of the clinical trials, however, will have

the statistical power to demonstrate an association, should it exist, between acellular pertussis

vaccines and serious but rare neurologic adverse

events. Therefore, other approaches to determine causality, such as large linked databases,

must be used (see Appendix 7). 

Hepatitis B. The reported incidence of acute

hepatitis B virus (HBV) infection increased 37

percent between 1979 and 1989. The U.S.

estimate is that approximately 1.25 million persons with chronic HBV infection are potentially

infectious to others. In the past, the recommended strategy for preventing infection had

been to vaccinate high-risk groups only. This

strategy alone in the United States was insufficient because it was difficult to identify highrisk persons and vaccinate them before infection, and also because many already infected

individuals continue to infect others through

their lifestyles, behavior, or occupations.

Transmission patterns that tend to vary geographically have made the disease very difficult

to control. 

The failure of past strategies to reduce disease

transmission and the resulting increase in incidence of disease prompted the recommendation

to vaccinate all infants as part of a routine universal vaccination schedule to promote a comprehensive approach to elimination of disease

transmission. Initially, the recommendation for
universal HBV vaccination was not widely distributed to private practitioners; many physicians were not aware of the new recommendations, and others did not agree with the recommendation for immunizing all infants with

HBV vaccine (Freed et al., 1993a). Recent

CDC initiatives have addressed the education of

both health care professionals and the public,

and new vaccine policies address the financial

barriers to effective adoption of new immunization recommendations for HBV. Finally, combination vaccines in development will address

the perceived deterrent of multiple injections at

single visits.

January 1998 65

Appendix 6
Aperson is vaccinated and experiences an

adverse medical event in the following

days. Did the vaccine cause the adverse

event—is it a true reaction? If it happens frequently to a number of people in the few days

after immunization with one vaccine, laboratory

results define the vaccine as the cause, or if the

patient develops a unique clinical syndrome

attributable only to the vaccine, this question

can be readily evaluated and answered. If the

event is extremely rare, however, and frequently

occurs in response to other stimuli, then the

question is difficult to answer. This is especially

important when the “medical event” is life

threatening or causes permanent damage,

because it will lead both the individual and the

public health system to reevaluate the risks and

benefits of the vaccine.

The clinical studies required before vaccines are

licensed by the FDA demonstrate vaccine safety

and efficacy. However, for financial and logistical reasons, phase 3 trials are generally limited to

fewer than 10,000 children, commonly several

thousand children. It is obvious that these carefully controlled studies will not be able to answer

questions of causation for very rare adverse

events—on the order of 1 per 100,000 children.

In addition, universal immunization programs

make it difficult to find people who are similar

except for their vaccination status. Because lack

of immunization is not random, unvaccinated

people are likely to differ in other ways that are

related to the outcomes of interest.

The creation of linked systems of information

derived from hospital charts, clinic charts, and

immunization records—large linked databases

(LLDBs)—are a recent innovation made possible

by powerful computers. In 1990, the CDC

funded an LLDB called the Vaccine Safety

Datalink (VSD) to monitor vaccination and rare

adverse reactions. The VSD links computerized

records from four large group health plans, creating a database of medical records that includes

vaccinations, hospital discharge diagnoses, emergency room visits, other outpatient medical care,

and additional ancillary information. The population under active surveillance numbers over 0.6

million and is composed of children during their

first 7 years of life. This is roughly 2 percent of

the U.S. population in this age range. 

Vaccine Safety Datalink 

Development of the VSD makes possible the

conduct of observational studies in very large

populations to help determine plausible associations between vaccines and rare adverse events.

The VSD is the first LLDB study in the United

States with sufficient population to permit routine study of rare events. Table 3 identifies

health outcomes that are being evaluated for

association with respective vaccines.

Having identified people with the illness, treatment, or test of interest, VSD links this information with their immunization records, allowing a

comparison of the frequency of recent vaccination (e.g., within 7 days) with those of individuals of similar age, gender, and ethnicity without

the illness. Another approach compares rates of

illness or condition of interest to those of otherwise similar groups that differ only in timing of

immunization. 

Appendix 7

January 1998 67

Appendix 7. 

Assessing the Causality of Adverse Medical Events

Following Vaccination: Large Linked Databases
Appendix 7

68 January 1998

Conditions Vaccines

Neurologic

Aseptic meningitis DTP, OPV, MMR

Increased intracranial pressure DTP

Encephalitis and encephalopathy DTP, MMR

Ataxia MMR

Seizures and persistent seizure disorders DTP, MMR

Reye’s syndrome DTP

Transverse myelitis DTP, OPV, MMR

Guillain-Barré syndrome DTP, O-IPV, MMR, Hib, HbPV

Cranial nerve disorders DTP

Peripheral nerve disorders DTP, MMR, IPV

Hearing loss MMR

Polio and acute paralytic syndromes OPV

Allergic

Anaphylaxis DTP, O-IPV, MMR, Hib

Asthma and bronchitis MMR

Hematologic

Hemolytic anemia DTP

Thrombocytopenia DTP, MMR

Infectious and Inflammatory

Diarrhea DTP, MMR

Invasive bacterial disease DTP, Hib, HbPV

Autoimmune and immune complex diseases DTP, MMR

Vaccine-preventable diseases DTP, MMR, Hib 

Other Infections

Myocarditis MMR

Pancreatitis MMR

Parotitis MMR

Arthropathy and arthritis MMR

Metabolic

Hypoglycemia DTP

Diabetes MMR

Other

Site abscesses DTP

Persistent crying DTP

Collapse—hypotonic, hyporesponsive episodes DTP

Breath holding DTP

Sudden infant and other unexpected deaths DTP

Apnea DTP

Adverse events All

Table 3.

CDC Vaccine Safety Datalink Project Vaccines and 

Conditions Whose Associations Are Being Evaluated 
Appendix 7

January 1998 69

The first 15 months of investigation failed to

show, with a few exceptions, any associations

between studied outcomes and vaccination.

Several relatively common outcomes were found

to be associated with vaccination, among them

seizures with diphtheria, tetanus, and pertussis

(DTP) and measles, mumps, and rubella (MMR)

vaccines (table 3). Risk of seizure on the same

day as DTP vaccination was three times higher

among vaccinated children than among those

who had not had a documented vaccination

within 30 days. Similarly, the relative risks of

seizures within 4 to 7 and 8 to 14 days following

receipt of MMR were 2.7 and 3.3, respectively.

Many factors suggest that these seizures are

related to fevers. These include the tendency of

children to have high fevers and febrile seizures,

and DTP’s ability to cause fever compared to

MMR’s side effect of mild illnesses. A nested

study of conventional medical records is now in

progress. The risk of any seizure event, particular types of seizures, and newly diagnosed seizure

disorders will be examined for each vaccine independently and for various combinations of simultaneously administered vaccines. Results may

improve the safety of vaccines by using fevercontrolling medications with certain vaccinations. This practice may reduce the possibility of

fevers, fever-associated seizures, and related

health sequelae in young children.

Challenges of LLDBs

Despite the size of the LLDB (over 0.6 million

children), there are not enough cases of some

rare adverse events to be evaluated. For

instance, aseptic meningitis cases are rarely documented after receipt of the MMR, oval

poliovirus (OPV), Haemophilus influenzae

type b (Hib), DTP, and hepatitis B (HepB) vaccines. The numbers of cases were so few (fewer

than 15 cases for each vaccine) that it is impossible to determine whether the vaccine was associated with aseptic meningitis or whether these

cases happened by chance. 

Vaccines are almost always co-administered with

other needed vaccines, making determination of

causation by a given vaccine very difficult. Also,

vaccine combinations will vary depending on the

needs of the client, preference of the health care

provider, and State policies. For instance, of the

total 324,500 OPV vaccines provided, only

3,631 were given alone. The rest were given in

some combination that may have included DTP,

MMR, Hib, and HepB. 

VSD is typical of LLDBs in that most of the

records being screened were automated for

administrative or clinical purposes, and quality

may not meet scientific standards. For many

reasons, all medical charts must be reviewed by

VSD staff. Record reviews have also helped in

identifying cases through use of ancillary information. 

Future Plans

By October 1995, 800,000 more records were

available for evaluation.

By enlarging the LLDB, it will be possible to

evaluate some rare adverse events, including aseptic meningitis, thrombocytopenia (decreased 

Vaccines and their acronyms 

Diphtheria, tetanus toxoid, and pertussis vaccine (DTP)

Measles, mumps, and rubella live viral vaccine

(MMR)

Oral poliovirus vaccine (OPV) and enhanced

inactivated poliovirus vaccine (eIPV)

Haemophilus influenzae type b conjugate

(Hib) and polysaccharide vaccines (HbPV)

“All” includes hepatitis B vaccine (HBV),

varicella vaccine (trade name VARIVAX),

and others that are included in the childhood

vaccination schedule.
clotting cells in blood), seizures, and other neurological outcomes. Other issues to be investigated include the risks of vaccinating children

with various illnesses and the implications of

simultaneous vaccinations. The latter is particularly important with the introduction of varicella

and other new vaccines. Completion of these

projects will require extensive coordination

among CDC, FDA, and the investigators

involved in managing the LLDB. Results may

affect recommendations regarding vaccine schedules, combinations, and policies for new vaccines.

Appendix 7

70 January 1998
Appendix 8A

January 1998 71

Conclusion Adverse Event Reviewed

DPT Vaccine1 RA 27/3 Rubella Vaccine2

1. No evidence bearing on a

causal relation3

Autism

2. Evidence insufficient to

indicate a causal relation4

Aseptic meningitis

Chronic neurologic damage

Erythema multiforme or other 

rash

Guillain-Barré syndrome

Hemolytic anemia

Juvenile diabetes

Learning disabilities and 

attention deficit disorder

Peripheral mononeuropathy

Thrombocytopenia

Radiculoneuritis and other 

neuropathies

Thrombocytopenia purpura

3. Evidence does not indicate a

causal relation5

Infantile spasms

Hypsarrhythmia

Reye’s syndrome

Sudden infant death syndrome

4. Evidence is consistent with a

causal relation6

Acute encephalopathy7

Shock and “unusual shock-like

state”

Chronic arthritis

5. Evidence indicates a causal

relation7

Anaphylaxis

Protracted, inconsolable crying

Acute arthritis

Source: Howson, C.P.; Howe, C.J.; Fineberg, H.V., eds.

Adverse Effects of Pertussis and Rubella Vaccines.

Washington, DC: National Academy Press; 1991. 

1 Evidence does not differentiate between DPT

vaccine and the pertussis component of DPT vaccine except

in the case of protracted, inconsolable crying where the evidence implicates the pertussis component specifically.

2 RA 27/3 MMR, Trivalent measles-mumpsrubella vaccine containing the RA 27/3 rubella strain.

3 No category of evidence was found bearing on

a judgment about causation (all categories of evidence left

blank in Table 1-1).

4 Relevant evidence in one or more categories

was identified but was judged to be insufficient to indicate

whether or not a causal relation exists (no category of evidence checked as supporting causation in Table 1-1:

exceptions are this designation under biologic plausibility

for erythema multiforme and hemolytic anemia).

5 The available evidence, on balance, does not

indicate a causal relation (one or more categories of evidence checked as not supporting causation in Table 1-1,

with evidence supporting causation being either absent or

outweighed by other evidence).

Appendix 8A.

Summary of Conclusions From Institute of Medicine Study 

of Adverse Effects of Pertussis and Rubella Vaccines
Appendix 8A

72 January 1998

6 The available evidence, on balance, tends to

support a causal relation (one or more categories of evidence checked as supporting causation in Table 1-1, with

evidence checked as insufficient or not supporting causation being absent or outweighed by the other 

evidence).

7 Defined in controlled studies reviewed as

encephalopathy, encephalitis, or encephalomyelitis.

8 The available evidence, on balance, supports a

causal relation and the evidence is more persuasive than in

level 4 above (the categories of evidence are coded similarly to 4 above, with evidence checked as insufficient or not

supporting causation in Table 1-1 being absent or fewer

than in level 4).
Category

Residual seizuredisorder other thaninfantile spasmsDemyelinating diseases of the centralnervous systemMononeuropathyArthritisErythema multiforme

EncephalopathySubacute sclerosingpanencephalitisResidual seizure disorderSensorineural deafness(MMR)Optic neuritisTransverse myelitisGuillain-Barré syndromeThrombocytopeniaInsulin-dependent diabetes mellitus

NeuropathyResidual seizure disorder

Transverse myelitis(IPV)Thrombocytopenia(IPV)Anaphylaxis (IPV)

Guillain-BarrésyndromeDemyelinatingdiseases of thecentral nervoussystemArthritisDeath fromSIDSc

Guillain-Barré syndrome

Transverse myelitisThrombocytopeniaAnaphylaxisDeath from SIDSc

1. No Evidence

Bearing on a CausalRelation

DT/Td/T Measlesa Mumpsa OPV/IPVb Hepatitis B H. influenzae type b

EncephalopathyAseptic meningitisSensorineural deafness (MMR)Insulin-dependentdiabetes mellitusSterilityThrombocytopeniaAnaphylaxisd

2. The Evidence is

Inadequate toAccept or Reject aCausal Relation

Anaphylaxisd

EncephalopathycInfantile spasms(DT only)fDeath from SIDS(DT only)f, g

Transversemyelitis (OPV)Guillain-Barrésyndrome (IPV)Death from SIDSc

Guillain-Barrésyndrome (OPV)

Early onset H.influenzae type b disease (conjugate vaccines)

Guillain-Barré syndromeh

Brachial neuritish 

3. The Evidence

Favors Rejectionof a CausalRelation 

4. The Evidence

Favors Acceptanceof a CausalRelation

Thrombocytopenia(MMR)Anaphylaxis (MMR)dDeath from measles vaccine-strain viral infectionc,i

Early onset Hib disease in children ages18 months or olderwho receive theirfirst Hib immunization with unconjugated PRP vaccine

Anaphylaxish 5. The Evidence

Establishes aCausal Relation

Poliomyelitis inrecipient or contact (OPV)Death from poliovaccine-strain viralinfectionc,i

Anaphylaxis

Appendix 8B. 

Summary of Conclusions From Institute of Medicine Study of Adverse Events Associated With Childhood Vaccine

January 1998 73

Appendix 8B
Appendix 8B

74 January 1998

Source: Stratton, K.R.; Howe, C.J.; Johnston, R.B., eds.

Adverse Events Associated with Childhood Vaccines.

Washington, DC: National Academy Press; 1994.

a If the data derive from a monovalent preparation, then in the committee’s judgment, the causal relation extends to multivalent preparations. If the data

derive exclusively from MMR, that is so indicated by

(MMR). In the absence of any data on the monovalent

preparation, in the committee’s judgment, the causal relation determined for the multivalent preparations does not

extend to the monovalent 

components.

b For some adverse events, the committee was

charged with assessing the causal relation between the

adverse event and only oral polio vaccine (OPV) (paralytic

and nonparalytic poliomyelitis) or only inactivated polio

vaccine (IPV) (anaphylaxis and thrombocytopenia). If the

conclusions are different for OPV than for IPV for the

other adverse events, that is so noted.

c This table lists weight-of-evidence determinations only for deaths that are classified as SIDS and deaths

that are a consequence of vaccine-strain viral infection.

However, if the evidence favors the acceptance of (or

establishes) a causal relationship between a vaccine and an

adverse event, and that adverse event can be fatal, then in

the committee’s judgment, the evidence favors the acceptance of (or establishes) a causal relation between the vaccine and death from the adverse event. Direct evidence

regarding death in association with a vaccine-associated

adverse event is limited to tetanus-diphtheria toxoid for

adult use (Td) and Guillain-Barré syndrome, tetanus toxoid and anaphylaxis, and OPV and poliomyelitis. Direct

evidence regarding death in association with a potentially

fatal adverse event that itself is causally related to the vaccine is lacking for measles vaccine and anaphylaxis, MMR

and anaphylaxis, OPV and Guillain-Barré syndrome,

hepatitis B vaccine and anaphylaxis, and H. influenzae

type b unconjugated PRP vaccine and early-onset H.

influenzae type b disease in children ages 18 months or

older who receive their first Hib immunization with

unconjugated PRP vaccine. See Chapter 10 for details.

d The evidence that establishes a causal relation

for anaphylaxis derives from MMR. The evidence regarding monovalent measles vaccine favors acceptance of a

causal relation, but is less convincing, mostly because of

incomplete documentation of symptoms or the possible

attenuation of symptoms by medical intervention.

e The evidence derives from studies of diphtheria-tetanus toxoid for pediatric use (DT). If the evidence

favors rejection of a causal relation between DT and

encephalopathy, then in the committee’s judgment, the

evidence favors rejection of a causal relation between Td

and tetanus toxoid and encephalopathy.

f Infantile spasms and SIDS occur only in an age

group that receives DT but not Td or tetanus toxoid.

g The evidence derives mostly from DPT.

Because there are supportive data favoring rejection of a

causal relation between DT and SIDS as well, if the evidence favors rejection of a causal relation between DPT

and SIDS, then in the committee’s judgment, the evidence favors rejection of a causal relation between DT and

SIDS.

h The evidence derives from tetanus toxoid. If

the evidence favors acceptance of (or establishes) a causal

relation between tetanus toxoid and an adverse event,

then in the committee’s judgment, the evidence favors

acceptance of (or establishes) a causal relation between

DT and Td and the adverse event as well.

i The data come primarily from individuals

proven to be immunocompromised.
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