Adverse Reactions to HIV Vaccines:

Medical, Ethical, and Legal Issues

September 1995

OTA-BP-H-163

GPO stock #052-003-01429-7
Recommended Citation: U.S. Congress, Office of Technology Assessment, Adverse

Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues, OTA-BP-H-163

(Washington, DC: U.S. Government Printing Office, September 1995).
iii

oreword

IDS researchers are investigating new vaccines that would prevent infection

with HIV and reduce the spread of AIDS. Some have argued that product liability concerns have discouraged investment in HIV vaccine research and development. The purpose of this OTA background paper is to describe the current

state of development of HIV vaccines, and to discuss what is known about adverse reactions that may occur. The background paper provides an overview of ethical issues that

arise in the conduct of HIV vaccine trials. The report also discusses alternatives to the

current product liability system to encourage the development of HIV vaccines and to

fairly compensate those who are harmed as a result of adverse reactions to the vaccine.

This background paper was prepared in response to a request from the Subcommittee

on Health of the House Ways and Means Committee. It is eleventh in OTA’s series of

studies on HIV-related issues. The preceding papers in this series were:

Do Insects Transmit AIDS? (9/87),

AIDS and Health Insurance: An OTA Survey (2/88),

How Effective is AIDS Education? (6/88),

The Impact of AIDS on the Kaiser Permanente Medical Care Program (Northern

California Region) (7/88),

How Has Federal Research on AIDS/HIV Disease Contributed to

Other Fields? (4/90),

The Effectiveness of Drug Abuse Treatment: Implications for Controlling AIDS/HIV

Infection (9/90),

HIV in the Health Care Workplace (11/91),

The CDC’s Case Definition of AIDS: Implications of the Proposed Revisions (8/92),

Difficult-to-reuse Needles for the Prevention of HIV Infection Among Injecting Drug

Abusers (10/92), and

External Review of the Federal Centers for Disease Control and Prevention’s HIV

Prevention Programs (9/94).

Other OTA reports addressing AIDS-related issues include:

Blood Policy and Technology (1/85),

Review of the Public Health Service’s Response to AIDS

(technical memorandum, 1/85),

The Cost of AIDS and Other HIV Infections: Review of the Estimates 

(staff paper, 5/87),

Medical Testing and Health Insurance (8/88),

Adolescent Health (11/91), and

The Continuing Challenge of Tuberculosis (9/93).

ROGER C. HERDMAN

Director
iv

roject Staff

Clyde J. Behney

Assistant Director, OTA

Sean Tunis

Health Program Director

ADMINISTRATIVE STAFF

Louise Staley

Office Administrator

Carolyn Martin

Word Processing Specialist

Monica Finch

Word Processing Specialist

Charlotte Brown

Word Processing Specialist

Carolyn Swann

PC Specialist

PRINCIPAL PROJECT STAFF

Robert S. McDonough

Study Director

Jay Randolph

Research Analyst1

Thomas McDaniels, Jr.

Research Assistant2

PRINCIPAL CONTRACTORS

David T. Karzon

Vanderbilt University Medical

Center

Wendy Mariner

Boston University School of

Public Health and School of

Medicine

CONTRACTORS

Nancy Kass

Johns Hopkins University

School of Hygiene and Public

Health

David Schwartz

Johns Hopkins University

School of Hygiene and Public

Health

Robert Stein

Blicker & Stein

PUBLISHING STAFF

Mary Lou Higgs

Manager

Arna Lane

Production Editor

Bonnie Sparks

Electronic Publishing Specialist

Christine Onrubia

Senior Graphic Designer

________________

1Through September 1994

2From September 1994
v

orkshop Participants

ISSUES IN THE DEVELOPMENT AND MARKETING OF AN AIDS VACCINE—April 6, 1994

Lawrence Miike, Chairman

Health Care Administration Division

Department of Human Services

State of Hawaii

Honolulu, HI

Don Des Jarlais

Research Director

Chemical Dependency Institute and

Grants Management

Research Support

Beth Israel Medical Center

New York, NY

Christine Grady

Research Associate

National Institute of Nursing

Research

National Institutes of Health

Bethesda, MD

Derek Hodel

Director of Treatment and

Research Issues

AIDS Action Council

Washington, DC

Rodney Hoff

Chief, Vaccine Trials

Vaccine Trials and Epidemiology

Branch

Division of AIDS

National Institute of Allergy

and Infectious Diseases

National Institutes of Health

Bethesda, MD

Michael Horowitz

Senior Fellow

Manhattan Institute

Washington, DC

Peter Barton Hutt

Partner

Covington & Burling

Washington, DC

David T. Karzon

Professor of Pediatrics, Microbiology

and Immunology

Division of Pediatric Infectious

Diseases

Vanderbilt University Medical Center

Nashville, TN

Nancy Kass

Assistant Professor

Program in Law, Ethics, and Health

Department of Health Policy

and Management

School of Hygiene and Public Health

Johns Hopkins University

Baltimore, MD

Wendy Mariner

Professor of Health Law

Health Law Department

Boston University School of Public

Health and School of Medicine

Boston, MA

Tom Matthews

Associate Professor of Experimental

Surgery

Department of Surgery

Duke University School of Medicine

Durham, NC

David Schwartz

Assistant Professor

Department of Immunology and 

Infectious Diseases

School of Hygiene and Public Health

Johns Hopkins University

Baltimore, MD

John Siegfried

Associate Vice President for Medical

Affairs

Pharmaceutical Research and 

Manufacturers Association

Washington, DC

Robert Stein

Partner

Blicker & Stein

Washington, DC

Tom Vernon

Executive Director

Medical, Scientific, and Public Health

Affairs

Merck Vaccine Division

Bluebell, PA

Roy Widdus

Consultant

National Vaccine Program Office

Washington, DC

Note: OTA appreciates and is grateful for the valuable assistance and thoughtful critiques provided by the participants in OTA’s

workshop on April 6, 1994. The workshop participants do not, however, necessarily approve, disapprove, or endorse this background paper.

OTA assumes full responsibility for the background paper and the accuracy of its contents.
vii

1 Overview of Findings and Executive

Summary 1

Overview of Findings 1

Executive Summary 5

Potential for Adverse Reactions to HIV Vaccines 6

Ethical Issues in HIV Vaccine Trials 13

Liability and Compensation for Adverse Reactions 17

2 Potential for Adverse Reactions from HIV

Vaccines 27

Role of Vaccines in the Control of Infectious

Disease 28

HIV is a Unique Virus 33

Animal Models 36

Immune Correlates of Protection 37

Development and Clinical Evaluation of HIV

Vaccines 38

Adverse Reactions 41

New Generation Vaccines: Implications for Safety 49

Social Harms as Adverse Events 52

Clinical Trials in HIV Infected Individuals 53

Phase III Efficacy Trials 55

Chapter 2 References 58

3 Ethical Issues in the Design and Conduct

of HIV Vaccine Trials 65

Basic Ethical Principles 65

Clinical Trials of Vaccines 66

Ethical Issues in the Design of Clinical Trials 67

Selection of Sample 69

Informed Consent 70

Research in Developing Countries 73

Compensation for Adverse Reactions 76

Incorporation into Clinical Practice 76

Conclusion 77

Chapter 3 References 77

ontents
viii

4 Liability and Compensation for Adverse

Reactions to HIV Vaccines 79

Responsibility for Injury and Compensation 80

Reasons for Compensating Injuries 80

Social Goals of Allocating Responsibility for

Injury 83

Potential Deterrents to HIV Vaccine Development 86

Current Vaccine Research and Development 99

Tort Liability for Adverse Reactions to Vaccines 101

Product Defects 102

Potential Liability for Adverse Reactions to HIV

Vaccines 112

Alternative Compensation Policy Options 119

Tort Liability Reform 120

Voluntary Contractual Arrangements 125

Government-Funded Insurance Arrangements 126

Public Compensation Systems 128

Elements of A No-Fault Compensation Program 139

Alternative Incentives for HIV Vaccine

Development 145

Chapter 4 References 146

APPENDICES

A A Technical Review of the Evidence for

Adverse Reactions to HIV Vaccines 161

B Acknowledgments 173

C References and Glossary 179
Overview of

Findings and

Executive

Summary

OVERVIEW OF FINDINGS

❚ Potential and Risks of HIV Vaccines

 Although the human immunodeficiency virus (HIV) that

causes acquired immunodeficiency syndrome (AIDS) is the

most intensively studied virus of all time, a successful preventive vaccine lies at least several years ahead. In addition, we

have yet to define the immune response elements necessary for

protection from HIV infection.

 HIV is endowed with an unusual set of capacities that enables

it to evade or manipulate normal immune responses. Because

of these unique capacities, a model for an effective HIV vaccine is much more complicated than the model for other vaccines.

 More than 1,400 volunteers have participated in U.S. trials of

HIV vaccines since 1988. Most vaccinees have received envelope-based vaccines (proteins present on the surface of the virus). Adverse reactions following immunization with HIV

vaccines have been minimal.

 Of the more than 1,400 individuals who have participated in

U.S. trials, 17 have become infected with HIV. There is no evidence that the experimental vaccines increased susceptibility

to HIV infection or increased the rate of disease progression in

these individuals.

 A number of vaccines are being developed that use new strategies, and each of these strategies may carry special risks.

| 1

“Each of the

HIV vaccine

strategies

may carry

special risks.”
2 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

1. Vaccines using live vectors, such as the vaccinia virus shown to be attenuated in laboratory

animals, may prove to be inadequately attenuated, producing the disease caused by the unattenuated vector:

2. Naked DNA vaccines have been shown to

create potent immune responses, but there are

theoretical reasons to be concerned that they

might produce tumors or autoimmune diseases,

or be transmitted from mother to fetus.

3. Although inactivated whole virus vaccines

have generally been successful in protecting

from infection with other viral diseases, it

would be difficult to assure that all HIV particles in such a vaccine were inactivated.

4. Live attenuated virus vaccines have also been

successful in protecting from other viral diseases, but there is the potential for the viruses

to be inadequately attenuated, for an adequately attenuated viral vaccine to cause disease in

immunocompromised individuals, and for an

adequately attenuated virus to revert to virulence. There is also concern that a live attenuated HIV vaccine could induce tumors.

 A number of social harms—nonmedical adverse consequences—may result from vaccination:

1. Vaccines may cause a false-positive HIV

screening test, making the diagnosis of HIV infection more difficult. This vaccine-induced

positivity on HIV screening tests may result in

discrimination against vaccine recipients in,

for example, military service, health insurance,

life insurance, employment, and travel.

2. Participation in an HIV vaccine trial, in itself,

may result in stigmatization, as others may assume that all vaccine trial participants are

members of groups, such as injection drug users and men who have sex with men, who are

at increased risk for HIV infection.

3. Vaccinees, relying on the protection afforded

by an experimental vaccine, may engage in behaviors that increase their risk for HIV infection.

 In June 1994, the AIDS Research Advisory

Committee (ARAC) of the National Institute of

Allergy and Infectious Diseases (NIAID) recommended that Phase III clinical trials with envelope vaccines should not proceed in the

United States. Factors contributing to the decision included scientific, political, and ethical

issues, and the significant level of scientific uncertainty about the wisdom of immediate trials.

Phase I and Phase II clinical trials of HIV vaccines will continue.

❚ Ethical Issues in HIV Vaccine

Development

 Procedures must be in place to ensure the confidential handling of research data, given the sensitive nature of the information collected in the

trial.

 Community involvement with the trial is important to ensure sensitivity to trial participants

concerns and to better protect the rights of trial

participants.

 Pregnant women should not be excluded from

HIV vaccine trials because the efficacy of vaccines to prevent transmission of HIV from an

infected mother to her fetus can only be demonstrated in pregnant women.

 It may be ethically acceptable to recruit persons

who have little control over their ability to

avoid exposure to HIV, such as women whose

high-risk male partners refuse to wear condoms, because such persons may be targeted

for HIV vaccination, once it is approved.

 Vaccine efficacy trials will target for enrollment individuals from high-risk groups, many

of whom may be involved in illegal behaviors

(such as injection drug user, prostitution, and,

in certain jurisdictions, male-to-male sex).

These individuals may increase their risk of

detection as a result of trial participation. Assurances of confidentiality are essential to ensure their participation.
Chapter 1 Overview of Findings and Executive Summary | 3

 In addition to the general requirements for informed consent, potential subjects of HIV vaccine trials need to be informed of the potential

social harms of participation.

 Investigators have an ethical obligation to ensure that research subjects are counseled about

avoidance of risk behaviors because some subjects will be randomly assigned to receive placebo vaccine, there is no assurance that the experimental vaccine will be effective, and no

vaccine is completely effective.

 If potential subjects are to be screened for HIV

infection, there should be an informed consent

process for this screening, in addition to the informed consent process for participation in the

vaccine trial.

 Investigators have an ethical obligation to provide subjects with documentation of their trial

participation, and to make available sophisticated tests necessary to distinguish vaccine-induced false positivity from true HIV infection.

 Trial participants should agree not to be tested

for HIV outside of the study; participant’s

knowledge of their assignment may bias study

results.

 Vaccine trials also need to be conducted in developing countries because AIDS is a devastating problem in these countries, and because the

circulating strains in each part of the world differ, so that findings from vaccine trials in developed countries may not be generalizable to the

developing world.

 Local representatives should be consulted at all

stages of vaccine trials in developing countries.

Both Western requirements and local requirements for informed consent must be met. Efforts must be made to ensure that potential subjects have an adequate understanding of the

study’s risks, and the importance of avoiding

risk behaviors in order to provide informed

consent, but potential subjects and investigators need not have a completely shared understanding of disease causation.

 Investigators have the ethical obligation to ensure that the trial does not interfere with other

health care or public health efforts.

 To ensure fairness in the distribution of benefits

and burdens, the vaccine must be made available to the communities where trials were conducted. In poorer communities, this may require that the vaccine be made available either

at cost or free of charge.

 Although vaccine sponsors have no legal obligation to provide compensation to subjects

for injuries incurred as a result of their participation, there is an ethical obligation to do so.

❚ Liability and Compensation for Adverse

Reactions

 Any system that limits compensation to injuries from one specific cause, like an HIV vaccine, raises questions of fairness to people with

similar injuries from a different vaccine. A

compensation system limited to persons with

adverse reactions to an HIV vaccine invites the

question why people living with injuries from

other vaccines or from other causes should not

be compensated as well.

 More companies are engaged in HIV vaccine

research than in research for any other type of

vaccine. Potential liability may have discouraged some companies, but it has not stopped

HIV vaccine development.

 Some have argued that drug and vaccine makers should be exempt from liability because

their products confer significant benefits and

their designs and labeling are approved by the

Food and Drug Administration (FDA). Supporters of liability argue that no exemption

should be granted because not all drugs provide

significant social benefits, and that manufacturers should be held to at least the same standards as manufacturers of ordinary consumer

goods because consumers are vulnerable to undetectable risks in pharmaceutical and biological products.
4 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

 Physicians are more likely than vaccine

manufacturers to be the target of complaints

that patients were not informed of vaccine

risks. The “learned intermediary” rule permits

the maker of prescription drugs or vaccines to

warn only the prescribing physician, and not

the patient who receives the product. Physicians have an independent legal obligation to

obtain their patients’ informed consent to immunization.

 Although the legal basis for liability is the

same, both the likelihood of claims and the

probability that any such claims would succeed

in practice is far lower with respect to investigational vaccines than with marketed vaccines.

 For a number of reasons, there has been little

concern about liability for adverse reactions to

therapeutic vaccines, in contrast to preventive

vaccines.

 Liability claims based on low levels of effectiveness have not been brought against existing

vaccines. The likelihood of success of a claim

of lack of effectiveness of an HIV vaccine is

speculative, but probably small as long as those

who take the vaccine are warned of its limited

efficacy and advised to take precautions against

exposure to HIV infection.

 The likelihood of a successful claim of liability

for enhanced susceptibility to infection of disease progression would depend upon whether

the manufacturer knew or should have known

that the vaccine was capable of causing the

reaction, and whether the plaintiff could prove

that the vaccine was the only cause of the reaction in his or her case.

 Given the need for an HIV vaccine, it appears

unlikely that a manufacturer would be held responsible for distributing a vaccine with a risk

of development of cancer that could not be verified at the time it was released.

 The decision whether or not to invest in the development of a vaccine depends on complex financial considerations of a number of factors,

including the scientific obstacles to vaccine development, the potential market for the vaccine, the price at which the vaccine could be

sold, and the potential liability for vaccines.

The major factor influencing vaccine development is the expected return on investment or

profitability, and the major obstacles to developing an HIV vaccine are scientific.

 Evidence that liability may deter some companies from developing an HIV vaccine comes

from anecdotal reports that several companies

interrupted HIV vaccine research or testing and

sought immunity from liability before they

would consider proceeding. Other factors,

however, including scientific problems with

the candidate vaccine, inadequate financing,

poor market predictions, patent problems, and

internal corporate restructuring, may also explain their decisions about whether to pursue

testing.

 Nonrecombinant vaccines that use killed, inactivated, or attenuated virus may be unappealing

to vaccine makers because of the consequences

of the failure of the manufacturing process to

inactivate a virus that could cause active infection. Companies may not wish to pursue a type

of vaccine that might produce HIV infection,

regardless of exposure to liability, especially if

they believe that they cannot eliminate the risk

of a manufacturing error.

 Vaccine manufacturers are not likely to be responsible for harms resulting from the bigotry

of others. Physicians who administer HIV vaccines may be the more likely targets for any

claim that a vaccine recipient was not adequately warned about possible discrimination.

 Preventive vaccines may be more susceptible

to claims of liability than most drugs and biologics, primarily because they are used in large

numbers of healthy people. The rate of actual

liability, however, has been quite low.

 Since liability is so rarely imposed for vaccines, the fear of liability may be more accurately described as the fear of having to litigate

at all. Complaints about the litigation process,

however, are not limited to cases involving
Chapter 1 Overview of Findings and Executive Summary | 5

HIV vaccines, so that any alternative that is intended to remedy tort litigation’s inefficiencies

would have application beyond HIV vaccines.

 Tort reform proposals have sought to change

the substantive grounds for liability, the procedures or evidence used in litigation, or the

amount of compensation payable. Similar proposals to reform the law of medical malpractice

and product liability have been the subject of

considerable debate. If considered for HIV vaccines, they may have to be considered for other

types of injuries.

 Voluntary agreements between companies and

individuals to provide compensation for an adverse reaction without the necessity of litigation reduce the time and expense of resolving

claims. Voluntary agreements are unlikely to

work well with new HIV vaccines, because the

company and the vaccinee do not have the relationship necessary for contract, and because

there are likely to be substantial unresolved issues about whether the injury was caused by the

vaccine.

 Government-funded excess insurance would

limit the amount of financial exposure companies face from liability payments, but the primary difficulties are in estimating the amount

of excess insurance needed for a new vaccine

and determining the amount of liability expenditures that should be considered excessive for

manufacturers. In addition, an excess insurance

program might set a precedent for government

reinsurance of liability expenses for other types

of tort claims.

 Vaccine-related injuries could be compensated

through government disability insurance programs. A more general expansion of disability

insurance to cover injuries regardless of cause

avoids questions of justice to persons with injuries from other causes and the costs of such a

program would be more predictable than the

costs of a program that compensates only those

injuries caused by new HIV vaccines. But a

government disability insurance program

would be costly.

 No-fault compensation programs eliminate the

need to prove negligence or legal responsibility

for injury, so that administrative costs can be

lower than those of litigation. No-fault compensation systems that are limited to injuries

from a specific cause, like adverse reactions to

vaccines, require proof of causation, which is

often difficult, time-consuming, and expensive, especially where the scientific evidence is

uncertain or conflicting. No-fault compensation programs also have the disadvantage of

treating one group of people differently from

others with similar injuries or needs. Also, nofault compensation systems may generate

more, rather than less, costs and typically compensate more people than would recover compensation in tort law.

 The National Vaccine Injury Compensation

Program may provide a model for a no-fault

system of compensation for adverse reactions

to HIV vaccines. Adding HIV vaccines to the

program would expand its scope beyond children’s vaccines, but it would also avoid the

need for creating a new administrative structure

to provide compensation.

 By themselves, compensation programs cannot

guarantee that any vaccine is developed. Alternative methods of encouraging vaccine development may be necessary, including tax incentives, expedited FDA review, purchase

guarantees, expanded patent protection, and facilitation of collaborative efforts.

EXECUTIVE SUMMARY

AIDS researchers are investigating new vaccines

that would prevent HIV infection and reduce the

spread of AIDS. Some have claimed that potentially promising approaches to developing a vaccine against HIV have been deferred due to concerns about liability of vaccine manufacturers,

and have urged legislation that would limit the liability of manufacturers of HIV vaccines. This

study examines the current state of HIV vaccine

development, the adverse reactions that may be

associated with HIV vaccines, and proposals to re-
6 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

form product liability to encourage the development of an HIV vaccine. The findings of this study

may be used in considering legislation that addresses HIV vaccine liability, and also have important implications for the reform of product liability in general.

The next three chapters address the medical,

ethical, and legal issues in the development and

marketing of an HIV vaccine. Chapter 2 addresses

the potential safety problems that may emerge

from vaccines for the prevention of HIV infection.1 The chapter reviews the biological basis for

development of a vaccine to prevent AIDS, the

difficulties that must be overcome in developing

an effective HIV vaccine, and the unique features

of the virus and disease it produces that elude vaccine control. The chapter also reviews the adverse

events that have occurred to date in clinical trials

of HIV vaccines. The chapter explains the difficulties in predicting the types and rates of adverse

reactions that may occur with HIV vaccines; this

uncertainty has important implications for the design of a compensation scheme. The chapter concludes with a discussion of the important adverse

social consequences of being vaccinated for HIV.

Chapter 3 provides an overview of the basic

ethical principles that guide human subjects research, and shows how these ethical issues apply

to each stage of HIV vaccine development. The

chapter discusses ethical issues in the design of

clinical trials, selection of research subjects, the

informed consent process, compensation for trialrelated injuries, and incorporation of HIV vaccines into clinical practice. The chapter also addresses special ethical issues that arise in clinical

trials in developing countries.

Chapter 4 summarizes existing product liability law and relevant literature on liability for vaccine-related injury and analyzes how that law

might apply to vaccines to prevent HIV infection

or progression to AIDS. To gauge how liability

might affect the vaccine industry’s ability or willingness to develop and market new HIV vaccines,

the report reviews other factors that influence such

decisions, such as the feasibility of identifying an

effective HIV vaccine and the attractiveness of the

potential market. Although there is little basis for

assuming that liability itself will halt HIV vaccine

development, some highly risk-averse companies

may avoid specific types of vaccine products that

they fear may induce severe adverse reactions.

Whether such products should be encouraged depends upon their safety and effectiveness

compared with available alternatives.

Liability’s effect on vaccine development does

not answer the question whether society should

endorse compensation for vaccine-related injuries, which may be desirable to achieve other social goals. For this reason, chapter 4 begins with a

brief description of common reasons for compensating injuries and assigning responsibility (liability) to different entities for paying compensation. Finally, the chapter summarizes several

types of compensation systems as a guide to issues

that should be considered in any debate on the desirability of establishing a new compensation system for HIV vaccine-related injuries.

Appendix A provides a detailed technical discussion of adverse reactions that may, in theory, be

predicted to occur. These include late-occurring

reactions and rare adverse reactions that may not

be detected until after an HIV vaccine has been approved for marketing. The appendix also assesses

the strength of the support for these potential

harms from HIV vaccines.

POTENTIAL FOR ADVERSE REACTIONS

TO HIV VACCINES

❚ Role of Vaccines in Control of Disease

One way to control the spread of AIDS is to vaccinate individuals against HIV infection. Vaccines

have been credited with eliminating smallpox and

of reducing the number of cases of measles,

mumps, rubella, diphtheria, pertussis, tetanus,

and other infectious diseases. Vaccines consist of

1 In this report, the term HIV will refer to human immunodeficiency virus type 1 (HIV-1), unless otherwise indicated.
Chapter 1 Overview of Findings and Executive Summary | 7

a microorganism or its components, in a safe

form, which are administered to stimulate, or

“prime,” the body’s immune system to generate

protective defenses specifically directed against

the microorganism. The portions of the microorganism that stimulate the body’s immune system

are called antigens.

The immune system has three response components: 1) antibody circulating in the bloodstream

(humoral immunity); 2) a network of immune

white cells in the blood and tissues (cellular immunity); and 3) a specialized system of antibody

and immune cells located at mucous membranes

(mucosal immunity), such as those covering the

surface of the vagina, anus, and penile urethra (the

routes of sexual transmission of HIV infection).

Antibodies are produced by immune white cells

called B lymphocytes. Each antibody is antigenspecific, and can neutralize virus particles that are

free in the circulation, but cannot inactivate virus

that is located inside infected cells. Another type

of white cell, the T lymphocyte, participates in

cellular immunity. Among the types of T lymphocytes are the CD4+ “helper” T lymphocytes,

which are necessary for the development of mature functional lymphocytes, and the CD8+ “cytotoxic” T lymphocytes, which can kill cells undergoing active viral infection.

Vaccines in use today follow only a few basic

designs. Most common are live attenuated vaccines, which are composed of a live virus or other

pathogenic organism that has been altered to reduce or eliminate its potential to produce disease.

Also common are inactivated virus vaccines,

which use virus that has been killed (i.e., rendered

unable to replicate). Two are protein subunit vaccines, which are composed of antigenic proteins

from the pathogenic organism. And one vaccine,

Hepatitis B, is prepared by recombinant biotechnology. The number of infectious agents for

which we have failed to develop a satisfactory

vaccine, however, is far greater than the number of

those that have been successful.

❚ Unique Features of HIV

Although HIV is the most intensively studied virus of all time, a successful vaccine lies several

years ahead. Because of several unique features of

HIV, a model for an effective HIV vaccine is much

more complicated than the model for contemporary vaccines. HIV is endowed with an unusual set

of capacities that enables it to evade or manipulate

normal immune responses. These include the following:

 HIV is a “retrovirus” that integrates its genome

into the human genome through a process

called “reverse transcription.” Once this happens, it cannot be detected and eliminated by

the immune system.

 HIV is able to evade immune recognition

through a process of rapid genetic mutation and

selection.

 The virus selectively invades and can injure

CD4+ lymphocytes and macrophages, the very

cells that play central roles in immune defenses.

 The virus can spread through direct cell-to-cell

contact, avoiding immune activation.

 During the years of apparent clinical wellness

before the onset of HIV-related symptoms, the

virus continues to multiply to high concentrations in lymphoid tissues of the body, and is silently transmissible.

 HIV is transmissible by three different routes

(through sexual contact with mucous membranes, by direct inoculation into the bloodstream, or by transfer from mother to fetus or

infant), which, in itself, can complicate the task

of developing a vaccine that mounts an effective immune blockade.

 HIV can be transmitted as free virus as well as

virus inside cells; it is more difficult to block

the transmission of virus inside cells.

 Unlike other viral infections that are self-limited, there are few, if any, instances of recovery
8 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

from HIV infection to offer clues for understanding the key immune response elements

necessary for protection from the virus.

 Primate models of human HIV infection have

not yielded definitive guidance to the immune

elements necessary for protection.

❚ Animal Models of HIV Infection and

Disease

Animal models of infection historically have contributed to the development of vaccines by helping to define the immune responses associated

with control of infection, and to predict the behavior of a candidate vaccine in man. The chimpanzee

is the only animal in which HIV will replicate. But

in the chimpanzee, the virus causes a minimal persistent infection, waning over time, with no disease manifestations. Macaque monkeys can become infected with simian immunodeficiency

virus (SIV), a retrovirus that is closely related to

HIV. SIV is highly virulent in macaques, and

causes a persistent infection leading to an AIDSlike syndrome within 6 to 24 months after infection. Thus, the HIV/chimpanzee system models

HIV infection in humans, while the SIV/macaque

system parallels HIV disease progression in humans.

There are examples of vaccine protection or

partial protection in primates, largely under conditions that are optimal for protection, but do not

mirror typical conditions. Also, large doses of antibody administered to the chimpanzee provide

passive protection to infection with HIV for several hours, but no longer. Live attenuated vaccines

show a high level of protection against SIV infection in macaques, but there are safety concerns

that may have inhibited the development of live

attenuated HIV vaccines for human use.

❚ Development and Clinical Evaluation of

HIV Vaccines

The U.S. Public Health Service has established a

program of basic science and clinical research toward the development of a safe and effective preventive HIV vaccine. The effort is centered at the

National Institutes of Health (NIH), with the National Institute of Allergy and Infectious Diseases

as the lead institute. The NIAID Division of AIDS

(DAIDS) has created an AIDS Vaccine Clinical

Trial Network (AVCTN), which has several components. The AIDS Vaccine Evaluation Group

(AVEG) includes six AIDS Vaccine Evaluation

Unit (AVEU) trial sites at university research centers. Each unit has an associated Community Advisory Board. Other AVCTN elements include a

Central Immunology Laboratory, a Mucosal Immunology Laboratory, a Data Coordinating and

Analysis Center, and a Data and Safety Monitoring Board.

The process of testing a candidate vaccine in

clinical trials is initiated by a sponsor, which presents preclinical data for review by the Food and

Drug Administration’s Center for Biologicals,

Evaluation and Research (CBER). The FDA is

also responsible for approval and oversight of experimental protocols as vaccines progress through

clinical trials. The AIDS Vaccine Selection Group

determines whether a vaccine will be entered into

federally funded AVEG trials. Other major participants in HIV vaccine development include the

National Cancer Institute, the Center for Disease

Control and Prevention (CDC), vaccine manufacturers, the World Health Organization (WHO),

and the Department of Defense, with capacities

for research, product development, and conduct of

clinical trials in the developed and developing

world.

Promising candidate vaccines are selected for

initial assessment of immune responses and safety

in carefully monitored, randomized, controlled

trials. The first phase (Phase I) of clinical trials of

vaccine focuses on the safety and immunogenicity

of the vaccine. The Phase I protocol involves 25 to

100 individuals at low risk for HIV infection, assigned to one or more experimental groups and to

a placebo group for comparison. If immune responses and safety warrant further studies, the

vaccine may undergo Phase II trials involving up

to several hundred individuals. Phase II studies refine and enlarge on the database, may directly

compare vaccine products or sequences, or may

include individuals at higher risk of acquiring infection.
Chapter 1 Overview of Findings and Executive Summary | 9

HIV vaccine sponsors have been, to a large extent, small biotechnology companies, private research institutions, and universities; some of the

large pharmaceutical manufacturers in the United

States are not represented among vaccine sponsors. A number of considerations influence corporate decisions to enter into the development of an

HIV vaccine, including the opportunity costs of

vaccine development relative to development of

drugs, potential markets for HIV vaccines, the

scientific feasibility of vaccine development, and

the potential for liability for adverse reactions to

HIV vaccines. Because of concerns about vaccine

safety, manufacturers have primarily pursued the

development of HIV vaccines composed of envelope protein subunits, proteins present on the surface of the virus, which have inherently more limited immune capability, but have fewer inherent

safety risks, than vaccines composed of inactivated or live attenuated virus.

❚ Adverse Reactions to HIV Vaccines

The standard of safety applied to preventive vaccines has been extremely high; even the rare occurrence of significant injuries to uninfected,

healthy individuals has been considered unacceptable. Despite the inherent potential for injury from

vaccines, currently licensed vaccines have been

extremely safe, and have provided a highly costeffective method for disease prevention.

Initial approaches to HIV vaccines have concentrated on gp120 and gp160, glycoproteins that

are present in the membrane or “envelope” of the

virus. Purified envelope proteins have been produced using recombinant biotechnology. A second method of immunization uses live vaccinia

virus (derived from the strain used to prevent

smallpox) as a delivery “vector, which has been

genetically altered to express HIV gp160 on its

surface. From the initiation of the AVEG program

in 1988, more than 1,400 volunteers have participated in trials. Twelve envelope-based vaccine

products have been used, prepared by five

manufacturers, using three different strains of

HIV.

Envelope vaccines have induced neutralizing

antibody against strains of HIV that are homologous (identical) to strains used in vaccine preparation. The titers (concentrations) of antibody induced by envelope vaccines have been 5- to

10-fold lower than titers of antibody seen in HIVinfected individuals, and have fallen rapidly after

each vaccine dose. Heterologous (nonidentical)

strains of HIV were neutralized less well, and

strains of HIV that were recently isolated in the

community were entirely resistant to the vaccine.

Envelope vaccines failed to generate cytotoxic T

lymphocyte responses (cellular immunity).

Adverse reactions following immunization

with envelope products have been minimal. Sequential measurements of biochemical, blood,

and immune status, and kidney and liver function

tests have shown no significant vaccine-related

abnormal findings. Importantly, there has been no

evidence of adverse effects on immune function.

Envelope vaccines that were combined with

alum “adjuvant” (a substance used to enhance the

vaccine’s immunogenicity) were accompanied by

local reactions at the injection site, consisting of

mild pain, tenderness, redness, and swelling for 1

to 2 days after injection. Vaccinations with some

of the newer adjuvants were accompanied by transient moderate to severe local reactions and febrile

flu-like illnesses for one to three days after injection in a number of recipients.

Ten vaccinees developed a rash to several products, and one also developed joint pain. A few individuals developed a positive antinuclear antibody (ANA) test (which may at times be

associated with autoimmune disease, such as

rheumatoid arthritis). However, further testing

ruled out any vaccine-related diseases. Despite

careful screening and counseling, 14 pregnancies

occurred during these trials. There was no evidence of vaccine-related adverse events to the fetus.

The trials permitted comparison of the side effects of an attenuated vaccinia/gp160 vector with

the commercial vaccinia virus strain used to prevent smallpox. Reactions to the vaccine re-
10 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

sembled those seen following classical smallpox

vaccination. There were no differences in the development of pustules at the inoculation site, regional lymph node swelling, or level of systemic

symptoms. The vaccinia virus vector did not appear to be adequately attenuated and thus could

carry the risk of vaccinia complications known to

occur with classical vaccination. With broad use

of an HIV vaccine, substitution of a more attenuated virus vector, such as canarypox, is preferable.

As of May 1994, 10 neoplasms (tumors) were

observed among participants in 9 vaccine trial

protocols. One of the neoplasms was benign.

Cases of malignancy tended to occur among older

participants. Analysis by the Data Safety and

Monitoring Board and an ad hoc expert committee

found no evidence that the neoplasms were linked

with any vaccine products. Because of the wide

variety of tumor types, it was judged to be biologically implausible that the tumors had a causal relationship to the vaccine.

To date, 12 of the 1,400 individuals in AVEG

trials since 1988 have become infected with HIV.

Of the 12 infected vaccinees, three received a placebo vaccine, eight received an envelope protein

vaccine, and one received a vaccinia/gp160 vaccine. Five of the infected vaccinees received one

or two doses of vaccine, and only four infected

vaccinees received an adequate series of three to

four doses. Three additional “breakthrough cases”

occurred in an intramural NIAID trial, and two

others occurred in non-NIAID trials, so that a total

of 17 infections have occurred in all HIV vaccine

trials to date. Envelope vaccines of all participating manufacturers were involved. A number of

breakthrough infections was to be expected because some volunteers received placebo, some

volunteers had not completed a full dosage schedule, and the protective efficacy of the vaccines being tested is not known.

Envelope vaccines, in themselves, cannot

cause HIV infection. The possibility that the vaccine may increase susceptibility to HIV infection

or may increase the rate of disease progression (a

phenomenon called “antibody-dependent enhancement”) must be considered and investigated. Although there is laboratory evidence of an

increase in growth of virus in cell cultures in the

presence of antibodies from the serum of vaccinees, there is no evidence of enhancement with

SIV or HIV in primate experiments.

There is concern that HIV vaccines have the potential to cause autoimmunity (an immune reaction against the bodies own tissues), because HIV

shares several envelope proteins that are identical

to proteins on human tissues. For example, there

is a similarity between one HIV envelope protein

region and a normal human blood-type protein.

Autoimmunity has not been observed among vaccine recipients to date, although in theory, autoimmune phenomena could first appear months to

years after vaccination.

❚ New Generation Vaccines: Implications

for Safety

Because of HIV’s unique abilities to evade immune controls, all immune response elements

may need to be invoked to provide protection, including humoral immunity, cellular immunity,

and mucosal immunity. Vaccines using new strategies may be needed to fulfill these immune requirements for protection. Each vaccine formulation or variation on a formulation is regarded as a

new product by the FDA and requires a separate

evaluation. Each new approach may carry special

risks, some unique to that strategy.

Proteins that duplicate viral antigenic proteins

may be artificially synthesized. These “synthetic

peptides” have been shown to induce cytotoxic T

lymphocyte responses to SIV in macaques. In

clinical trials, reactions to synthetic peptide vaccines have been benign.

Vaccines using a number of vectors (e.g., canarypox virus, adenovirus, Salmonella, Shigella,

and attenuated poliovirus) are being studied.

These live vectors are better able to induce cytotoxic T lymphocyte responses, and vectors that

grow on body surfaces (e.g., adenovirus and Shigella) are better able to induce mucosal immune

responses to HIV. Live vectors, however, carry inherent safety concerns. If they are inadequately or

unstably attenuated, they may produce the disease
Chapter 1 Overview of Findings and Executive Summary | 11

caused by the unattenuated vector. They may result in unwanted spread to contacts and the community at large. And even an adequately attenuated vector may cause disease in individuals

with impaired immunity.

Some new vaccines are composed of “naked

DNA,” pure viral genetic material. Persistent antibody and cytotoxic T lymphocyte responses have

been induced in laboratory animals immunized

with naked DNA. The mechanisms leading to the

potent immune responses are not understood.

Concerns about naked DNA involve the theoretical possibilities of tumor formation, production of

autoimmune disease, or the transmission of DNA

to the fetus.

Development of inactivated whole virus vaccines against HIV was seriously considered in early deliberations. Although inactivated whole virus vaccines have generally been successful in

protecting from infection with other viruses, this

strategy has not been applied to HIV by vaccine

manufacturers because of inherent risks. The primary concern with these vaccines is the difficulty

in assuring inactivation of all HIV particles. Of

particular concern is whether cell cultures or animal models are sufficiently sensitive to detect

minimal amounts of residual live virus capable of

infecting humans.

Vaccines using live attenuated viruses have

also been successful in protecting from other viral

diseases. Live attenuated vaccines are capable of

inducing a vigorous and broad antibody response,

as well as inducing cellular immunity and mucosal immunity. Live attenuated SIV vaccines were

able to protect monkeys against challenge with

large doses of virulent virus. In addition, the attenuated virus used in these vaccines was shown to

be stable, not reverting to a virulent form over an

observation period of several years.

However, there are a number of concerns about

the safety of attenuated viral vaccines. First, there

is the potential for the viruses used to be inadequately attenuated, resulting in the induction of

the disease that the vaccine was designed to prevent. By contrast, viruses that are overattenuated

may not be able to induce protective immune responses. Second, even an adequately attenuated

virus may be virulent in individuals whose immune system is impaired by immunosuppressive

drugs, cancers, or other causes.

Third, there is concern about the “stability” of

attenuation of the virus—the potential for an attenuated strain of virus to undergo genetic reversion

to a more virulent form during replication in the

vaccinee. Spread of the attenuated virus to contacts (secondary spread) provides the virus with

further opportunities to revert to virulence.

Fourth, live attenuated HIV may induce tumors.

Other retroviruses have been shown to produce tumors, and in theory, the prolonged residence of an

attenuated HIV strain in humans could allow the

production of tumors. There is recent evidence

that HIV has a direct role in the etiology of some

T-cell lymphomas, a type of immune cell cancer.

❚ Social Harms as Adverse Reactions to

HIV Vaccines

Individuals may suffer social harms—non-medical adverse consequences—as a result of HIV vaccination. Vaccines may cause a “false-positive”

screening test for HIV infection. The false-positive tests from envelope vaccines can only be distinguished from HIV infection by the Western blot

test, which is widely used to confirm the results of

positive screening tests. These false-positive

screening tests could potentially result in discrimination against false-positive individuals, for example, in eligibility for military service, employment, health or life insurance, or restriction of

travel. Volunteers in NIAID-sponsored trials have

received identification documents certifying their

participation in these trials, although AVEG personnel have had to provide validation of confounding Western blot confirmatory tests. This

problem may be greater with new generation vaccines that include many more types of antigenic

proteins than are currently used, which may render the Western blot tests incapable of distinguishing false-positive screening tests from HIV infection. Reliance must then be placed on more

expensive and time-consuming polymerase chain

reaction (PCR) tests and viral cultures.
12 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Participation in an HIV vaccine trial, in itself,

may engender social harms. Others may perceive

that trial participation implies that the volunteer is

a member of a group at special risk for acquiring

HIV infection, resulting in stigmatization of that

volunteer. Furthermore, volunteers immunized

with one vaccine may be precluded from participation in clinical trials of subsequent, possibly

more effective, vaccines. Also, trial participants,

assuming that the vaccine protects them from infection, may increase their risk-taking behaviors.

This may occur despite intensive counseling

about the possibility of assignment to placebo

vaccine and about the unknown efficacy of the experimental vaccine.

❚ Clinical Trials in HIV-Infected

Individuals

A number of vaccines to prevent transmission of

HIV from an infected mother to her fetus or infant

(maternal-fetal transmission) are being developed. Although pregnancy had been a cause for

exclusion from Phase I and II clinical trials of HIV

vaccines, Phase I clinical trials of HIV envelope

vaccines, involving 23 infected pregnant women,

are now in progress. Such trials are specifically

designed to study safety and possible efficacy of

vaccines in prevention of infection in the infant.

No significant vaccine-related adverse events

have occurred in the mothers or in the 20 infants

that have been delivered thus far.

A number of vaccines are being developed to

treat individuals with established HIV infection.

Approximately 35 Phase I and Phase II trials of

therapeutic HIV vaccines are being conducted in

the United States and abroad. Thus far, there has

been no clear evidence that these vaccines have

delayed or prevented disease progression in infected individuals. Conversely, there is no evidence that these vaccines have accelerated or enhanced HIV infection in vaccinees.

❚ Phase III Efficacy Trials

The purpose of Phase III efficacy trials of HIV

vaccine is to determine its capability to protect

against infection, and to provide a more definitive

assessment of vaccine safety. Efficacy trials of

HIV vaccines will be large, complex, lengthy, and

expensive, involving several thousand volunteers

per experimental group. Trials will be conducted

among groups with a high incidence of HIV infection, such as injection drug users and men who

have sex with men; members of these groups may

feel disenfranchised and socially stigmatized, and

may distrust government and scientific experimentation.

In anticipation of these large-scale efficacy

trials, preparatory studies involving several thousand injection drug users and men who have sex

with men with high HIV incidence are under study

by the HIV Evaluation Network (HIVNET), sponsored by the NIAID, the CDC, and the National

Institute of Drug Abuse. The purposes of these

trials are multiple: to study the social and cultural

factors affecting trial recruitment and retention; to

measure the effect of trial participation, counseling, and unblinding on risk behaviors; to determine the basis for attitudes toward vaccine acceptance; to develop educational strategies and

consent forms appropriate to the groups that will

be targeted; and to study the dynamics of trial acceptance and feasibility. Information derived

from such studies will help to prepare for fullscale HIV vaccine efficacy trials in the United

States.

A number of criteria may be used to select vaccine candidates for Phase III efficacy trials: 1) evidence of the vaccine’s safety and immunogenicity

in Phase I and Phase II trials; 2) the ability of the

vaccine to induce high and sustained titers of

broadly reactive antibody capable of neutralizing

strains circulating in the community; 3) the ability

of the vaccine to induce cytotoxic T lymphocyte

responses; 4) evidence of vaccine protection in

primate models. Because of the scientific uncertainty, the relative emphasis given to each of these

criteria have varied.

Two vaccines, Biocine SF2 with MF59 and Genentech MN with alum adjuvant, have completed

Phase II efficacy trials. In June 1994, the NIAIDS

AIDS Subcommittee and the AIDS Research Advisory Committee recommended that Phase III

clinical trials with the envelope vaccines should
Chapter 1 Overview of Findings and Executive Summary | 13

not proceed in the United States at this time. Factors contributing to the decision included scientific, political, and ethical issues, as well as the significant level of scientific uncertainty about the

wisdom of immediate efficacy trials. Phase I and

Phase II clinical trials of HIV vaccines, however,

will continue. New products recently entered into

Phase I trials or in preclinical testing are designed

to increase and improve the quality of the protective immune response to the vaccine. Additional

vaccines should be available for consideration for

Phase III trials within two to three years.

Long-term followup of large numbers of vaccine trial participants and controls allows for surveillance of events that are infrequent or occur after an interval of years. The trial participants

constitute prospectively defined cohorts that are

not easily duplicated once controlled efficacy

trials are completed. Vaccinated cohorts from efficacy trials could be compared with unvaccinated

cohorts currently under epidemiologic and virologic surveillance. Provision for long-term followup should be an integral part of trial efficacy

design to allow surveillance for adverse events,

such as enhanced infection, autoimmune disease,

tumors, or reversion to virulence.

The NIAID and U.S. military are working with

governments in the Americas, Africa, and Asia to

establish sites for HIV vaccine trials. Trials of

HIV vaccine in developing countries provide opportunities to study diverse population groups in

highly endemic areas, including heterosexual and

maternal-fetal transmission of HIV and a variety

of cultural and health settings, and to test vaccines

targeting a multiplicity of HIV subtypes.

ETHICAL ISSUES IN HIV VACCINE TRIALS

Ethical issues arise in all stages of vaccine development and marketing. A prophylactic vaccine for

HIV infection raises some unique ethical issues.

❚ Principles of Research Ethics

All biomedical research should be conducted in a

manner that seeks not to violate three primary ethical principles: beneficence, respect for autonomy, and justice.

The principle of beneficence addresses one’s

obligations toward the well being of others. In

clinical research, beneficence requires that the

welfare of research subjects be protected. In vaccine trials, the investigators and vaccine sponsors

are responsible for protecting research subjects

from undue or excessive risks, and this responsibility cannot be avoided merely by informing subjects of those risks. There are certain risks that are

too great for any altruistic volunteer to consent to,

regardless of whether the volunteer understands

the risks. In clinical trials, an external review

board determines whether the risks of the trial are

excessive.

Respect for autonomy obligates investigators

to recognize research subjects as individuals who

have the right to make their own decisions. The

doctrine of informed consent is derived from this

principle.

Justice requires fairness in the distribution of

benefits and burdens. In research, this requires

that no individuals or groups bear a disproportionate share of the risks of research without justification, and that all groups have equal access to the

benefits of research participation.

❚ Design of Clinical Trials

In designing clinical trials of HIV vaccines, a

number of ethical issues should be addressed.

First, investigators should determine whether a

randomized trial is ethical. Random assignment to

an experimental intervention is ethical only in

cases of “clinical equipoise”—that is, where there

is a lack of consensus in the medical or scientific

community about whether the experimental intervention is beneficial. It is not ethical to randomly

assign research subjects to vaccine and placebo

control groups if there is consensus that the experimental vaccine is effective. Given the serious

consequences of erroneous vaccine research findings, it is also unethical to base conclusions about

vaccine efficacy on nonrandomized studies, because of the risk of bias. Thus, it is ethical to con-
14 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

duct randomized clinical trials to determine

whether a vaccine is effective, but not to provide

confirmatory data.

Second, investigators have an ethical obligation to ensure that research subjects are counseled

about avoidance of risk behaviors. Behavioral

counseling is ethically required in HIV vaccine

trials because some subjects will be assigned to

placebo vaccine, because there is no assurance

that the experimental vaccine will be effective,

and because no vaccine is completely efficacious.

Also, it would be good to give research subjects

some benefit in return for participation, if it can be

provided at not at too great an expense.

Third, procedures should be in place to ensure

the confidential handling of research data. Protection of confidentiality is important in any clinical

research, but especially in HIV-related research,

because of the sensitive nature of the information

being collected. A number of practical measures

should be taken to better ensure that confidentiality is maintained: each research subject should be

assigned a unique identification number to be

used, instead of full names, for labeling written

forms, specimens, and any other information

about the subject; all research data should be kept

in locked storage cabinets or computer files with

restricted access; only a select group of investigators should be allowed access to the “master key”

that links subjects’ names to their unique identifiers; all research staff should be educated in procedures that ensure the protection of research subjects’ confidentiality.

Vaccine sponsors should pay for all trial-related

medical procedures. Patient confidentiality may

be threatened if investigators are allowed to bill

the subject’s insurer for medical procedures related to the trial.

Research subjects should be assured that they

may have access to their own files upon completion of the trial, and that they may obtain documentation of their trial participation, even years

later, if they need to demonstrate, for example,

that the experimental vaccine was the source of a

positive HIV antibody test.

Fourth, community involvement in the trial is

important. A community board, usually composed of trial participants, meets with investigators periodically throughout the course of the trial

to discuss plans, to review progress, and to make

recommendations to the investigators. The community board can serve as a liaison between research subjects and investigators, and can help ensure that the rights of research subjects are

protected. The research subjects’ resultant greater

involvement with and “ownership” of the research

could improve retention and compliance.

❚ Sample Selection

Research ethics has been concerned with protecting vulnerable populations from being enrolled in

human subjects research without their (or their

guardian’s) knowledge and without adequate justification for their specific inclusion. More recently, there has also been a concern that vulnerable

populations not be denied the benefit of participation in research.

Vulnerable” populations are those that are unable to provide valid informed consent, either because they do not have the mental capacity to provide consent (such as children or the mentally ill),

or because they may not be able to provide consent

voluntarily (such as prisoners or patients who are

in a dependent relationship with the investigator).

Such vulnerable populations should only be included if they will contribute knowledge that cannot be obtained from studying other, less vulnerable populations, and if the members of the

vulnerable population (or their guardians) believe

that the research will be beneficial.

Until recently, pregnant women have been excluded from trials of HIV vaccines because of concerns about harm to the fetus. However, the efficacy of vaccines to prevent transmission of HIV

from an infected mother to her fetus can only be

demonstrated in pregnant women. Three clinical

trials of vaccines to prevent maternal-fetal HIV

transmission have now enrolled infected pregnant

women.
Chapter 1 Overview of Findings and Executive Summary | 15

Certain populations targeted for vaccine trials

may be considered vulnerable, not because they

are unable to provide consent, but because they

may be at greater risk of social harms as a result of

their trial participation. Persons involved in illegal behaviors (such as injection drug user, prostitution, and, in certain jurisdictions, male-tomale sex) may increase their risk of detection as a

consequence of trial participation. At the same

time, it is important to include members of these

groups in HIV vaccine trials, given the higher incidence of HIV infection in these groups, and given that members of these groups would be candidates for a vaccine once it is approved. Measures

to protect their confidentiality are important to ensure their participation.

Members of racial minority groups are more

highly represented among populations at increased risk of HIV infection, so they are more

likely to participate in HIV vaccine trials. Members of racial minority groups may be less trustful

of investigators, given the history of abuses of minorities in research, such as in the Tuskegee syphilis study. Community boards should be established to ensure that minority group participants’

needs are addressed and that investigators are sensitive to cultural concerns.

❚ Informed Consent

Rooted in the principle of respect for autonomy is

the ethical obligation on the part of investigators

to obtain informed consent from prospective research subjects. Federal law requires that all federally funded research be approved by external review boards, which have the responsibility to

ensure that investigators have obtained informed

consent. Virtually all academic institutions require that all research involving human subjects

(not just that which is federally funded) secure

such approval.

The process of informed consent requires the

following: 1) prospective subjects must be provided with information relevant to their decision

about participation; 2) they must understand that

information; 3) they must provide consent voluntarily; 4) their consent must be documented. Prospective research subjects should be given the following information: a statement that explains that

they are being asked to participate in research, not

clinical care; the purpose of the research; the reason why they were selected; all procedures that are

required, including the location, duration, and frequency of study visits; a description of foreseeable risks; the alternatives to the experimental intervention; a description about how confidentiality will be maintained; whether there will be compensation for injuries resulting from trial participation; information about who to contact for questions or problems; and a declaration that the

subjects have both the right not to participate and

to cease their participation at any time.

In addition to these general requirements, there

are a number of special requirements for informed

consent in HIV vaccine trials. If potential subjects

are to be screened for HIV infection, they must

provide informed consent for this screening. This

is in addition to the informed consent that they

must provide for participation in the trial. The informed consent process for HIV testing of potential research subjects should include the pre- and

post-test counseling, as is required for HIV testing

in other contexts, and referrals should be made

available for those who test positive for HIV.

Potential subjects of HIV vaccine trials need to

be informed of the following:

 The experimental vaccine has not been demonstrated to be effective, and it is unlikely that any

HIV vaccine will be completely effective. In

addition, the subject may be randomly assigned

to a placebo vaccine. Compensation will not be

provided for failure of the experimental vaccine to protect research subjects from HIV infection.

 Receipt of the experimental vaccine may complicate the diagnosis of HIV, because vaccinees

may falsely test positive on conventional HIV

screening tests. The investigators will make

sure that more sophisticated tests are available

to distinguish vaccine-induced positivity from

true HIV infection.

 Trial participants should not be tested for HIV

outside of the study, since knowledge of their
16 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

assignment could bias the study’s results. They

should also be told that investigators have

made arrangements to provide trial participants

with HIV testing, should they wish to be tested.

 Social harms may result from testing positive

on an HIV screening test, such as problems

with health or life insurance, employment, military service, and travel. All subjects will be

provided with documentation of their trial participation.

 Anyone who participates in an HIV vaccine

trial risks being socially stigmatized. Investigators also have the ethical obligation throughout

the trial to provide subjects with any other information that might influence the subjects’

continued willingness to participate in the trial.

❚ Vaccine Trials in Developing Countries

Vaccine trials need to also be conducted in developing countries because AIDS is a devastating

problem in these countries, and because the circulating HIV strains differ in each part of the world,

so that findings from vaccine trials in developed

countries may not be generalizable to developing

countries. Local representative should be consulted at all stages of vaccine trials in developing

countries.

Questions have been raised about whether it is

ethically acceptable to recruit persons who have

little control over their ability to avoid exposure to

HIV, such as women whose male partners refuse

to wear condoms. Such persons, however, may be

targeted for vaccination, once an HIV vaccine is

approved.

In developing countries, both local and Western requirements for informed consent should be

met. In some societies, permission for trial participation is granted by some individual other than the

potential research subject, such as a community

leader or the female subject’s husband. This does

not abrogate the responsibility of the investigator

to obtain consent from the potential subject as

well.

Potential subjects should have an adequate understanding of the study and its risks in order to

provide informed consent. If the potential subject

is illiterate, investigators must provide information orally, using the local language or dialect.

In some societies, broad understandings about

disease causation are completely different than

Western understandings. Potential subjects and

investigators need not have a completely shared

understanding of disease causation, so long as no

harmful consequences are likely to ensue.

In developing countries, there may not be available the more sophisticated tests that are necessary

to distinguish vaccine-induced positivity from

true HIV infection. In that case, investigators have

the responsibility to make these sophisticated

tests available to trial participants, should they

need them.

Investigators also have the ethical obligation to

ensure that the trial does not interfere with other

health care or public health efforts. Finally, investigators and vaccine sponsors have an ethical obligation to make vaccine available to the communities where the trial was conducted; to ensure that

vaccine is available to members of poor communities, they may have to provide it either at cost or

free of charge.

❚ Compensation for Adverse Reactions

There is general agreement that, although vaccine

sponsors and investigators have no legal obligation to provide compensation to subjects for injuries incurred as a result of participation, there is an

ethical obligation to do so. If compensation will

not be provided, this should be explained to subjects as part of informed consent.

❚ Incorporating an HIV Vaccine into

Clinical Practice

In considering whether to incorporate a partially

effective HIV vaccine into clinical practice, one

should consider whether the benefits of a partially

effective vaccine are outweighed by the harmful

increase in risk behaviors that may result in reliance on the vaccine.

Less rigorous standards of informed consent

are applied to clinical practice, even though the

consequences of vaccination are just as important.

There is no requirement for signed written con-
Chapter 1 Overview of Findings and Executive Summary | 17

sent, except for certain types of medical interventions, typically surgery and uncommon procedures. For public health interventions, the

requirements for informed consent have been limited (although the requirements for informed consent for HIV screening is an exception). The risk

that confidentiality will be breached in the clinical

setting is greater, because insurance companies

and other outside parties have access to patients’

medical information.

LIABILITY AND COMPENSATION FOR

ADVERSE REACTIONS

❚ Responsibility for Injury and

Compensation

With every injury, the question arises whether its

financial losses should be shifted to someone else,

and if so, to whom. Although the injured person

inevitably bears the physical and emotional consequences of injury, financial losses may be either: 1) left where they lie, with the injured person,

or 2) transferred, in whole or in part, to someone

else by requiring that party to compensate the injured person. There are no other options; the

losses do not disappear. The threshold question,

therefore, is whether it is necessary or desirable to

compensate people who incur particular injuries.

Reasons for Compensating Injuries

Arguments for and against compensating people

who are injured have been based on economic,

ethical, and social policy grounds. Economic arguments tend to focus on total social costs of injuries and do not necessarily justify compensation

for all injuries. Whether society believes it has a

moral obligation to ensure that injured persons are

compensated may depend upon how society perceives the injured person. In different circumstances, compensation can be: 1) morally required, because not providing it is unjust; 2)

morally desirable, but not morally required; or 3)

not morally required and possibly unjust. Compensation has also been viewed as a pragmatic

means to provide for people in need.

Tort liability for adverse reactions to vaccines

has been justified as a reasonable method of compensating people who are injured from specific

causes, but more commonly as providing a deterrent to creating products that pose unreasonable

risks of injury to others. Compensation and liability for injury appear to be linked in policy discussions of vaccine-related injury because of a general sense that injured vaccine recipients deserve

compensation, but that vaccine producers should

not be responsible for paying compensation for all

the injuries that occur.

Social Goals of Allocating Responsibility for

Injury

If injury compensation is desirable or morally required, responsibility for providing compensation

may be allocated to the vaccine manufacturer, the

person who prescribed or administered the vaccine, the government, or some other party, depending upon the goals to be achieved. Any of the

following might serve as goals for allocating responsibility for adverse reactions to a future HIV

vaccine to different parties:

1. The development of an effective vaccine to prevent HIV infection or AIDS.

2. The marketing and distribution of an HIV vaccine.

3. The marketing and distribution of an HIV vaccine at a reasonable cost to users.

4. The use of HIV vaccine to prevent HIV infection or progression to AIDS.

5. Compensating persons injured as a result of

vaccination with an HIV vaccine.

6. Minimizing the total social cost of HIV vaccine

development, marketing, and injury compensation.

7. Minimizing the total costs of HIV infection, including prevention and transaction costs.

None of these goals can be achieved solely by

assigning responsibility (or liability) for injuries.

Rather, by assigning responsibility to different

parties, society may encourage or discourage

progress toward specific goals. The choice of system depends upon the goals to be achieved by liability and compensation and how alternative sys-
18 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

tems affect the achievement of other important

goals, such as prevention of disease, deterrence of

injury-producing products and activities, and the

just distribution of resources.

Systems that satisfy one goal may undermine

another. For example, a system that minimized the

costs of compensation to vaccine makers might

encourage vaccine development, but also reduce

incentives to limit potential safety risks. A system

that required vaccine makers to provide generous

financial assistance might achieve the goal of equitable compensation, but might be too expensive

for many companies that society, for other reasons, wishes to attract to vaccine development. If

government were to assume responsibility for

compensation, the cost to government might conflict with other societal goals to minimize government expenditures or to fund other important programs. Any system that limits compensation to

injuries from one specific cause, like an HIV vaccine, raises questions of fairness to people with

similar injuries from a different cause. A compensation system limited to persons with adverse

reactions to an HIV vaccine invites the question

why people living with HIV infection or AIDS or

other serious illnesses or injuries should not be

compensated as well.

❚ Potential Deterrents to HIV Vaccine

Development

Companies in private industry necessarily make

choices about what products to make. Because

new biologic products require a substantial investment of both time and money, choices may have

long-term consequences for a company’s product

line. Thus, the decision whether or not to invest in

the production facilities and equipment, as well as

human expertise, necessary to produce an HIV

vaccine is a complicated business decision in

which companies must weigh the financial risks

against the financial rewards.

Scientific Obstacles

The major obstacles to developing an HIV vaccine

are scientific. Unfortunately, too little is known

about how to produce an immune response in human beings that would protect against infection or

development of disease to be assured than an effective vaccine can be produced in the foreseeable

future. The National Institute of Allergy and Infectious Disease’s decision in June 1994 not to

proceed with large Phase III field trials of the leading candidates, for lack of adequate promise of effectiveness, is indicative of the difficulty of surmounting scientific and technical obstacles.

Potential Market for HIV Vaccines

If scientific obstacles can be overcome and an HIV

vaccine appears technically feasible, the major

factor influencing vaccine development is its expected return on investment or profitability. Profitability depends on the size of the market for an

HIV vaccine and the price at which it can be sold.

Although the worldwide population at risk for

HIV infection numbers in the millions, the relevant market for HIV vaccine sales consists of paying purchasers: individuals who can pay for vaccination either out-of-pocket or with insurance

and government agencies that purchase vaccine

for distribution to individuals.

Not everyone in the potential market may be

willing to buy an HIV vaccine, either because they

do not wish to be vaccinated or because they cannot afford the market price. The United States may

be the most profitable market for HIV vaccines.

The prices at which vaccines can be sold are limited in many foreign countries, either by government regulation or competition from foreign vaccine makers who may receive government

subsidies. Many developing countries have severely limited budgets for vaccine purchases and

are unable to pay in the hard currency demanded

for most transnational sales. A disproportionate

number of people at risk for HIV infection are unable to pay for vaccination and are not likely to obtain vaccines without government assistance.

Government purchasers, however, may demand

substantial discounts from market prices, as the

U.S. federal government does for pediatric vaccines, which limits the potential revenues from

vaccine sales.
Chapter 1 Overview of Findings and Executive Summary | 19

Potential Liability

An HIV vaccine would have considerable appeal

to companies that believe that market demand will

be strong, the price will not be regulated, and users

would pay the price. HIV vaccine development

may appear unattractive to companies that perceive any of these factors to be absent. Liability

for vaccine-related injuries may affect the profitability of vaccines. If the financial costs of defending and paying expected liability claims are predicted to be too large a proportion of expected

revenues, then companies are likely to pursue

more profitable lines of product development.

Thus, liability may influence decisions about

whether to develop a specific product, but it is

weighed with other factors. If scientific and financial factors argue against pursuing HIV vaccine

development, it is unlikely that changes in liability can outweigh them.

The evidence that liability may deter some

companies from developing an HIV vaccine

comes from anecdotal reports that several companies interrupted HIV vaccine research or testing

and sought immunity from liability before they

would consider proceeding. Other factors, however, including scientific problems with the candidate vaccine, inadequate financing, poor market

predictions, patent problems, and internal corporate restructuring, may have influenced their decisions about whether to pursue testing. One company later developed a new candidate HIV

vaccine. Another proceeded with testing after all.

A third attempted to test its preventive vaccine

candidate in a single location but enrolled only

two subjects before the trial was closed after about

a year. The same company actively pursued tests

of a therapeutic vaccine. At the same time, other

companies developed and tested their candidate

vaccines without raising liability concerns. Almost 30 candidate vaccines have been in clinical

trials.

In summary, decisions about whether to develop an HIV vaccine, or any other product, entail

predictions about its scientific, technical, and financial feasibility and profitability compared

with alternative investments. However, the number of companies engaged in HIV vaccine development and testing is encouraging. More companies are engaged in HIV vaccine research than in

research for any other type of vaccine. Potential liability may have concerned a few companies, but

it is not likely to stop HIV vaccine development.

❚ Tort Liability for Adverse Reactions to

Vaccines

Principles of Strict Liability and Negligence

Like manufacturers of all products, vaccine makers are responsible under state law for personal injuries caused by their own negligence or by a defect in their products. Negligence is conduct by

the manufacturer that deviates from standards of

acceptable conduct adhered to by the ordinary

manufacturer of similar products and that causes

harm to the product user. Strict liability holds the

seller (including a manufacturer) responsible for

physical harm caused by a product that is in a defective condition unreasonably dangerous to the

user. As a practical matter, most people claiming

vaccine-related injury assert several causes of action to avoid losing their claim because of a technical characterization. Thus, the distinction primarily determines the success of a specific cause

of action, rather than whether a claim is brought

at all.

Product defects

Traditionally, product defects have been divided

into three categories: 1) manufacturing defects, 2)

design defects, and 3) errors or omissions in warnings accompanying the product. Concern about liability for vaccine-related injuries tends to focus

more on strict liability for design defects and inadequate warnings, and less, if at all, on liability for

negligence or strict liability for manufacturing errors. Critics of the former two causes of action argue that drug and vaccine makers should be exempt from liability because their products confer

significant benefits and their designs and labeling

are approved by the FDA. Supporters of liability

argue that no exemption should be granted because not all drugs provide significant social

benefits, and that manufacturers should be held to

at least the same standards as manufacturers of or-
20 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

dinary consumer goods because consumers are

vulnerable to undetectable risks in pharmaceutical

and biological products. Courts have upheld both

positions.

Design defects

An increasing number of states have held that

makers of FDA-approved prescription drugs or

vaccines are entirely exempt from strict liability

for design defects, regardless of the product in

question, largely for reasons of public policy. Other states have refused to grant a blanket exemption

from liability for all drugs and vaccines. Instead

they would exempt only those drugs and vaccines

that are shown to be unavoidably unsafe, on a

case-by-case basis.

Warnings of risks

In view of the impossibility of creating a risk-free

vaccine, manufacturers have an obligation to provide a warning of the vaccine’s inherent risks. The

history of the legal doctrine and its application in

litigated cases parallels that of the doctrine of informed consent to medical care.

A vaccine manufacturer’s duty to warn differs

from a physician’s duty to obtain informed consent for medical care in one respect, however: who

is entitled to receive the warning. The doctrine of

informed consent to medical care requires a physician to tell his or her patient about the risks and

benefits of taking a drug or vaccine, as well as any

alternatives. Although the general rule is that all

manufacturers have a duty to warn those who use

their products of dangers that are not readily apparent, an exception, known as the “learned intermediary rule,” permits the maker of prescription

drugs or vaccines to warn only the prescribing

physician, and not the patient who receives the

product. This is because it is the physician—

acting as a “learned intermediary” between the

manufacturer and the patient—who ordinarily

makes the medical judgment that a vaccine is appropriate to recommend for an individual patient.

Thus, vaccine manufacturers do not ordinarily

have a duty to provide a warning directly to a vaccine recipient. Similarly, the National Childhood

Vaccine Injury Act of 1986 barred any cause of action for a manufacturer’s failure to warn a recipient (or a recipient’s parent or guardian) about the

risks of a childhood vaccine covered by the compensation program. It also created a rebuttable

presumption that warnings approved by the FDA

are adequate.

Under the learned intermediary rule, a warning

is generally not considered inadequate unless the

missing information would have caused a physician not to give the vaccine to the patient. A few

reported cases have found specific warnings inadequate because they did not mention known risks

of a vaccine. In most cases, warnings have been

found adequate because they disclosed all reasonably known risks, or manufacturers have not been

held liable because the warning would not alter the

physician’s decision to recommend the vaccine.

Physicians have an independent obligation to obtain their patients’ informed consent to immunization. This means that physicians are more likely

than vaccine manufacturers to be the target of

complaints that patients were not informed of vaccine risks.

❚ Types or Uses of HIV Vaccines

The above principles of liability apply to

manufacturers of all vaccines, regardless of

whether they are preventive (intended to prevent)

or therapeutic (intended to treat or cure infection

or disease), and regardless of whether the vaccines

are experimental (investigational) or approved

and licensed. The likelihood of adverse reactions

and liability claims occurring may differ, however, depending upon the way in which a vaccine

is used.

Investigational Vaccines

The potential liability for adverse reactions to investigational preventive vaccines is less than that

for marketed vaccines. Although the legal basis

for liability is the same in both cases, both the likelihood of claims and the probability that any such

claims would succeed in practice is far lower with

respect to investigational vaccines than with marketed vaccines. Historically, there have been no
Chapter 1 Overview of Findings and Executive Summary | 21

reported product liability cases involving vaccine

research, probably because there has been a very

low incidence of injury among research subjects

in general. Claims of defective design are also

minimized, if not precluded entirely, by the fact

that the research is being conducted to find out

whether the vaccine works and whether it has dangerous side effects.

Therapeutic Vaccines

Therapeutic HIV vaccines, which are used to treat

people who are already infected with HIV, are

more comparable to drugs than to preventive vaccines. Patients who take therapeutic vaccines may

be willing to accept accompanying risks in order

to receive any benefit the therapeutic vaccine

might afford. Adverse reactions may be difficult

to distinguish from other symptoms arising from

existing illness. The potential for damages is also

limited because of the perceived limited life expectancy of people with AIDS. Perhaps for these

reasons, there has been little concern about liability for adverse reactions to therapeutic vaccines.

❚ Potential Adverse Reactions to HIV

Vaccines

In the absence of any approved HIV vaccine, predictions about adverse reactions are based on

somewhat limited experience with the candidate

vaccines in clinical trials, laboratory research, and

theoretical hypotheses. The following are the

most commonly mentioned hypotheses.

Low Levels of Effectiveness

There has been speculation among researchers

that some candidate HIV vaccines now in clinical

trials may ultimately prove effective in only a

small percentage of the vaccinated population. If

the vaccinated population is at risk for HIV infection, as anticipated, then some proportion may become infected after taking a vaccine of limited efficacy, even if the vaccine is not defective. Claims

based on low levels (or lack) of effectiveness have

not been brought against existing vaccines. The

likelihood of success of a claim of lack of effectiveness of an HIV vaccine is speculative, but

probably small as long as those who take the vaccine are warned of its limited efficacy and advised

to take precautions against exposure to HIV infection.

Enhanced Susceptibility to Infection or

Disease Progression

Researchers have theorized that candidate vaccines might have the potential to increase one’s

susceptibility to infection with HIV or other organisms, or to increase the rate of disease progression in people who become infected with HIV in

spite of vaccination. Both hypotheses raise the

possibility of a claim for defective design if they

are not investigated, or a claim for inadequate

warning if they are not disclosed. The likelihood

of a successful claim would depend upon whether

the manufacturer knew or should have known that

the vaccine was capable of causing the reaction,

and whether the plaintiff could prove that the vaccine did cause the reaction in his or her case.

Development of Cancer

There has been speculation that, because HIV is a

retrovirus, an HIV vaccine might cause cancer

many years after vaccination. Although a

manufacturer is not liable for injuries caused by

unforeseeable dangers in its products, there may

be some question as to whether a manufacturer adequately investigated a suggested risk. Given the

need for an HIV vaccine, it appears unlikely that

a manufacturer would be held responsible for distributing a vaccine with a risk that could not be

verified at the time it was released.

Vaccine-Induced HIV Infection

Non-recombinant vaccines that use killed, inactivated, or attenuated virus raise the possibility that

the manufacturing process might inadvertently

fail to remove or render harmless part of the virus

that could actively infect a person. Although

claims of vaccine manufacturing errors have been

rare in the past, the consequences of a batch of vaccine accidentally escaping inactivation are sufficiently serious to make this type vaccine un-
22 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

appealing to many vaccine makers. However,

companies may not wish to pursue a type of vaccine that might produce HIV infection, regardless

of exposure to liability, especially if they believe

that they cannot eliminate the risk of manufacturing error.

Social Harms

HIV vaccination may pose risks of social harm

that are not adverse reactions to the vaccine itself.

People who receive HIV vaccines may be especially vulnerable to denials of health or life insurance or permission to travel abroad, loss of employment or housing, segregation in institutions,

or rejection by family and friends. Most such

harms result from lawful conduct for which the

vaccine recipient would have no legal recourse.

Manufacturers are not ordinarily responsible for

the bigotry of others. Physicians who administer

HIV vaccines may be the more likely target for

any claim that a vaccine recipient was not adequately warned about possible discrimination.

❚ Susceptibility of HIV Vaccines to

Liability Claims

Preventive vaccines may be more susceptible to

claims of liability than most drugs and biologics,

primarily because they are used in large numbers

of healthy people. As with drugs, the majority of

claims have affected only a few vaccines, and the

number of reported cases that impose liability on

the vaccine maker is very small. Thus, although

the probability of claims of liability may be higher

than that for drugs, the probability of actual liability is quite low.

Plaintiffs rarely succeed on a claim of design

defect, probably because of the difficulty of proving that a safer, equally effective vaccine could

have replaced a vaccine that was approved by the

FDA. Although most states still permit claims that

a vaccine was defectively designed, only one vaccine (Quadrigen) has been found to have a defective design (in a warranty, not product liability, action). No reported court decision after 1969 has

held a vaccine maker liable for a design defect.

Few courts have found a vaccine maker liable

for an inadequate warning of risks. More extensive and sophisticated warning statements may

have increased manufacturers’ protection against

such liability. In addition, vaccine makers are

largely exempt from any duty to warn vaccine recipients themselves of vaccine risks. Instead,

manufacturers have a duty to warn the prescribing

physician, who bears the responsibility for disclosing vaccine risks to patients. Thus, physicians

may now be more vulnerable to claims (of lack of

informed consent) than vaccine makers.

Fear of liability for adverse reactions to vaccines may have been based on a perception in the

1970s and early 1980s that courts were expanding

the grounds for product liability. That expansion

appears to have halted, although it cannot be assumed that it would never recur. Since liability itself is so rarely imposed, the fear of liability may

be more accurately described as fear of having to

litigate at all. This is understandable, given the

time and expense of pursuing and defending

claims. Complaints about the litigation process,

however, are not limited to cases involving HIV

vaccines (there have been none). Concerns about

the efficiency and fairness of tort litigation as a

means of resolving disputes are generic. This does

not mean that an alternative means of allocating

responsibility for injury and compensation is not

warranted for other reasons. It does mean that any

alternative that is intended to remedy tort litigation’s inefficiencies would have application beyond HIV vaccines.

❚ Alternative Compensation Options

The following outlines several major options for

allocating responsibility for compensating adverse reactions to HIV vaccines.

Tort Liability Reform

Tort liability imposes legal responsibility for

compensating injuries. Tort reform proposals seek

to change the substantive grounds for liability, the

procedures or evidence used in litigation, or the

amount of compensation payable. Any single reform can only be unidirectional: it either increases
Chapter 1 Overview of Findings and Executive Summary | 23

or decreases the opportunity for a plaintiff to bring

or succeed on a claim.

Currently, most tort reform proposals seek to

limit the liability of potential defendants. By

themselves, limitations on liability are cost control measures, not compensation mechanisms.

Such limitations are best suited to circumstances

in which the primary goal is to save potential defendants money and where providing compensation to those who would not qualify under the reform is not relevant or desirable.

Reforms expanding plaintiffs’ opportunities to

recover compensation would further a goal of increased compensation, but are likely to increase

total costs. Reforms such as scheduling compensation are intended to make compensation

more consistent across different claimants with

similar injuries, without necessarily altering the

grounds for recovery.

Other reforms are intended to reduce the time

and expense of litigation and the possibility of inconsistent results, without changing the bases for

liability. Similar proposals to reform the law of

medical malpractice and product liability have

been the subject of considerable debate. If considered for HIV vaccines, they may have to be considered for other types of injuries.

Voluntary Contractual Arrangements

Private companies and individuals are free to reduce the time and expense of resolving claims by

voluntarily agreeing to provide compensation

without the necessity of litigation or legislation.

The voluntary contract model, exemplified by the

Moore-Gephardt bill introduced in Congress

(99th Congress, 1st Session, 1985) but never

passed, would permit a vaccine maker or administering physician to agree, at the time of vaccination, to pay the vaccine recipient compensation for

out-of-pocket expenses promptly if an adverse

reaction occurred. Such contracts may encourage

compensation even in cases in which the vaccine

recipient would have no recourse in tort law. They

may work reasonably well in circumstances in

which the payor and payee know each other and

where the cause of injury is relatively easy to establish. Neither circumstance is likely to apply to

new HIV vaccines. The process of deciding how

much, if any, compensation to offer resembles the

process of settling a claim in litigation, and may

be equally difficult in many cases.

Government-Funded Insurance

Arrangements

Government-funded excess insurance

Government-financed insurance programs can

fund compensation for injuries. Government

might purchase private excess insurance or reinsurance or use its own revenues to finance compensation awards that exceed a predetermined

amount. This would limit the amount of financial

exposure private companies face from liability

payments, and lower premiums for basic liability

insurance. The primary disadvantage of government-funded excess insurance is the difficulty of

estimating the amount of excess insurance needed

for a new vaccine, and the amount of liability expenditures that should be considered excessive for

manufacturers. Reinsurance systems do not alter

the legal bases for liability and would not remedy

concerns about inefficiencies of tort litigation and

inconsistent awards. In addition, an excess insurance program might set a precedent for government reinsurance of liability expenses for other

tort claims, from medical malpractice to automobile accidents.

Government-funded disability insurance

Vaccine-related injuries could be compensated

through government disability insurance programs. For example, the Social Security program

could be amended to specifically include coverage

of injuries resulting from HIV vaccines. A more

general expansion of disability insurance to cover

injuries regardless of cause would be more in

keeping with the general function of Social Security, which already covers AIDS-related disability. A general disability insurance program avoids

hard questions of horizontal justice about why injuries resulting from one cause should be compensated while others are not. The cost of such a program may require new government revenues, but,
24 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

because the costs of disability for the entire national population are relatively consistent over

time, they are more predictable than the costs of

compensating injuries caused by new HIV vaccines.

If the health care system is reformed to ensure

universal coverage, a significant expense of injury

would be covered outside the disability insurance

program. In the absence of universal insurance

coverage, continued pressure for financial assistance to pay for medical care may be expected.

Public No-Fault Compensation Systems

Federal and state governments have created several publicly administered injury compensation programs, such as state workers compensation programs, the Federal Black Lung Benefits Act, the

Radiation Exposure Compensation Act, Virginia

and Florida’s Birth-Related Neurological Injury

Compensation acts, and the National Vaccine Injury Compensation Program.

Most such programs provide compensation on

a no-fault basis for specific injuries from specific

causes. As long as the injury is demonstrated to result from the specified cause, compensation is

granted without the need to prove negligence or

legal responsibility for the injury. Parties that

might be liable for the injury typically need not

participate in the claims determination process.

Administrative costs can be less than those of litigation. Compensation can be funded from different sources to achieve different goals.

No-fault compensation programs have the disadvantage of treating one group of people differently from others with similar injuries or needs.

Those who do not qualify for compensation may

object to such special treatment or demand equivalent treatment themselves as a matter of horizontal justice. The more programs that exist for specific causes, the more difficult it becomes to

defend excluding the remaining injuries from a

no-fault system.

No-fault systems that are limited to injuries

from a specific cause, like adverse reactions to

vaccines, require proving that an injury resulted

from that specific cause. Determining causation is

often difficult, time-consuming, and expensive,

especially where the scientific evidence is uncertain or conflicting. Yet no-fault systems are often

recommended in order to provide desired compensation in circumstances where causation is unclear or controversial. Thus, many of the complexities that make litigation frustrating and

expensive are often necessarily part of causebased, no-fault compensation proceedings.

No-fault compensation systems may sometimes generate more, rather than less, cost, depending upon the level of compensation to be

awarded and the scope of eligibility for compensation. No-fault systems typically compensate more

people than would recover compensation (or even

file a claim) in tort law. In the absence of reliable

estimates of the number and type of compensable

injuries, it may be difficult to predict system costs.

The National Vaccine Injury Compensation

Program may provide a model for compensating

adverse reactions to HIV vaccines. A no-fault system funded by federal revenues (for administration) and surtaxes on vaccines (for compensation),

it provides compensation for adverse reactions

that are caused by specific vaccines. Although the

program was originally intended to cover only

vaccines required by state law for children before

they enter school or day care, it has been amended

to permit coverage of vaccines that are recommended for children. Adding HIV vaccines to the

program would expand its scope beyond children’s vaccines, but it would also avoid the need

for creating a new administrative structure to provide compensation.

Table 1-1 lists the basic elements of a no-fault

compensation program and key questions that

must be answered in constructing a suitable system.

❚ Alternative Incentives for HIV Vaccine

Development

By themselves, compensation programs cannot

guarantee that any vaccine is developed. If HIV

vaccines are not sufficiently attractive to private

industry for reasons of the difficulty and expense

of research compared with the expected financial
Chapter 1 Overview of Findings and Executive Summary 25

Eligibility

Who should be eligible for compensation?

U.S. citizens, U.S. residents, nonresidents?

What, if any, time period should be the limit for bringing claims?

Covered vaccines

Should the program cover all or only some vaccines? Investigational vaccines?

Compensable injuries

Should all injuries be covered, or only Injuries at a minimum level of severity (in either physical or financial

terms)?

Should injuries include HIV infection? Social harms?

Causation

How IS causation to be determined?

Is causation understood well enough to permit a Iist of compensable injuries?

Who has the burden of proving causation?

What kind of evidence should be required to prove causation?

Compensation benefits

Is compensation to be calculated on the basis of actual losses, a fixed schedule of injuries, a fixed amount per

person or injury, or some other basis?

Which, if any, actual expenses wiII be compensated?

Payment mechanisms

Should payment of compensation be made in a lump sum, periodic payments, by an annuity providing periodic

income, or a health Insurance policy providing coverage for medical expenses?

Decisionmaking authority and procedures

What entity is authorized to make decisions about eligibility and compensation?

Should any third party be required or permitted to participate in the decisionmaking process?

What, if any, type of review or appeal should be available?

Relationship to tort law

Should the compensation system be an optional alternate to the tort system or the exclusive source of

compensation for claimants?

Should people who have filed claims in court be eligible for compensation?

If the program ceases operation or IS repealed, what, if any, rights should the claimants have?

Financing

What should be the source of funding for the compensation and administration? Government revenues? Taxes

on products or manufacturers? Private insurance?

Period of operation

Should the program’s continuance be contingent upon future events, such as the development of a vaccine the

sale of a vaccine at a specified price, the disposition of a maximum number of claims, adequate funding or

some other event?

SOURCE Office of Technology Assessment, 1995

return, then other initiatives will be necessary to

encourage vaccine development. Among the

types of initiatives that might foster increased ■

attention to HIV vaccine development are:

■ Tax incentives for investment in vaccine ■

development.

■ Mechanisms for increased collaboration and ■

in- formation-sharing among vaccine researchers to increase productivity and expedite research.

Simplification of collaborative arrangements

between government and industry researchers.

Expanded access to preclinical nonhuman animal models for testing investigational vaccines.

Expedited review by the FDA of applications

for vaccine licensing.
26 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

 International harmonization of national vaccine licensing standards.

 Guaranteed purchase of vaccine supplies by

government.

 Expanded patent protection for approved vaccines.

 National coordination of vaccine research and

distribution policies.

 Creation of a National Vaccine Authority to

foster research and product development by

providing grants, facilities, and consultation,

as well as arranging procurement contracts.

Social goals for HIV vaccines go beyond mere

development and marketing of a vaccine. The vaccines developed should be reasonably safe and effective to prevent the continued expansion of a

devastating epidemic. FDA regulation is one

mechanism to assess the safety and effectiveness

of vaccines. One of tort law’s objectives is to provide additional incentives to produce safe and effective products. Whatever one’s view of the FDA

or tort law’s effectiveness in this respect, some

mechanism to ensure adequate quality in vaccines

is necessary. In addition, effective mechanisms for

distributing and encouraging the use of vaccines,

especially by those unable to buy them, will be required if the benefit of HIV vaccines is to be realized.
Potential for

Adverse Reactions from

HIV Vaccines

he potential safety problems in the development and

introduction of a vaccine for the prevention of HIV, type 1

(HIV-1) infection are addressed in this chapter.1 Ethical,

social science, and legal issues are presented more fully in

chapters 3 and 4.

This chapter begins with a brief review of the biological basis

for development of a vaccine to prevent AIDS. Next, principles

underlying the preparation of a protective vaccine are reviewed,

including observations on the unprecedented hurdles posed by

HIV infection compared with successful vaccines developed in

the past. This chapter also discusses the biological basis for safety

concerns and why the nature, frequency, and severity of adverse

reactions with HIV vaccines cannot be predicted at this point. In

addition to adverse events that may be associated with biological

mechanisms of injury, important adverse social consequences,

termed “social harms,” are addressed here and in chapters 3 and 4.

This chapter has been written for a diverse target audience, including legislators, policymakers, lawyers, ethicists, social scientists, and the AIDS community, in addition to biological scientists. Experts in the several disciplines will recognize the

abbreviated and simplified approach in some areas. A more

1 In this background paper, reference to HIV will refer to human immunodeficiency

virus, type 1 (HIV-1), unless otherwise noted. HIV-1 has been found throughout the

world. Human immunodeficiency virus, type 2 (HIV-2) is found in West Africa and is in

the same retrovirus family as HIV-1. Infection with either HIV-1 or HIV-2 can lead to the

development of AIDS.

| 27

by

David T. Karzon 

Vanderbilt University

Medical Center

Nashville, TN
28 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

technical discussion of the theory and proposed

mechanisms of HIV vaccine risks are presented in

appendix A.2

ROLE OF VACCINES IN THE CONTROL OF

INFECTIOUS DISEASE

❚ Options for the Control of Infectious

Diseases

There are three major options for controlling HIV

infection: 1) halt transfer of virus from person to

person through education and behavioral changes;

2) treat HIV-infected individuals with therapeutic

drugs after infection is recognized; 3) prevent disease through introduction of “prophylactic” HIV

vaccines3 that prevent the establishment of infection. The possible uses of an HIV vaccine are described in box 2-1. The magnitude of the medical,

social, and political impact of the AIDS epidemic

will, for the foreseeable future, require continued

intensive efforts using all three options.

Measures to control HIV infection have met

formidable difficulties, and infection is spreading

uncontrollably around the globe. Prevention of viral transfer by limiting risk behavior and the extensive research directed at development of drug

treatments have had limited success (2). Treatment of infected pregnant women with the antiviral drug zidovudine (AZT) has decreased transmission of HIV infection to newborns, a

significant achievement.

Vaccines capable of preventing infectious diseases are generally regarded as the most successful instrument of cost-effective, humane health

care. Vaccines are credited with the global elimination of smallpox and, more recently, elimination of poliomyelitis from the Americas

(26)—(105). In addition, the childhood vaccines,

measles, mumps, and rubella (MMR), Haemophilus influenza type B (HIB), and diphtheria, tetanus, and pertussis (DTP)—have markedly reduced the number of cases and deaths from

infectious diseases. More widespread use of influenza, pneumococcus, and hepatitis B virus

(HBV) vaccines, in addition to the availability of

hepatitis A virus (HAV) and varicella (chickenpox) vaccines, will add significantly to reduction

of morbidity and mortality from infectious diseases. The historical success of conventional vaccines in preventing and even eradicating disease

has stimulated an extensive quest for a safe and effective preventive HIV vaccine. This chapter will

review the progress toward development of an

HIV vaccine through 1994.

❚ How a Vaccine Works

HIV is the most intensively studied virus of all

time. Details of its molecular structure, replication strategies,4 host-cell interactions,5 and

pathology are known. Despite a decade of research and advances in biotechnology, a successful HIV vaccine lies at least several years ahead.

Most currently licensed vaccines for infectious

diseases were developed when much less was

known about the target microbe and its infection.

The reasons an HIV vaccine has been so difficult

to prepare, the unique features of the virus that

elude vaccine control, and the implications for

possible safety problems from an HIV vaccine

will are discussed below.

Stated in its simplest form, a viral vaccine consists of a microorganism (such as a virus or2 Selected review articles are noted in the references. However, references are also cited in the text insofar as they may be linked to design

and outcome of clinical trials of HIV vaccines.

3 This background paper will focus on prophylactic HIV vaccines, and not on therapeutic HIV vaccines. Prophylactic vaccines prevent

infection or disease in uninfected individuals (so-called classic prophylaxis) or reduce their infectivity should the vaccinated individual subsequently become infected. Therapeutic vaccines prevent or reduce disease progression in infected individuals, or reduce disease transmission to

persons who come in contact with infected individuals.

4 The viral genome is reproduced in a process called replication.

5 In microbiology, the host refers to the organism or cells that are being infected by the microorganism.
Chapter 2 Potential for Adverse Reactions from HIV Vaccines 29

HIV vaccines have been proposed for prevention of HIV Infection (classic prophylaxis) and for therapy of HIV infection (as a form of post-infection immunotherapy). HIV vaccines have also been advocated as a tool to reduce the infectivity of HIV-infected individuals (i.e., to reduce the risk of transmission of HIV from infected vaccinees to their contacts or offspring) These approaches have been

reviewed previously (9, 13, 29, 80) and are briefly outlined below.

1 Classic Prophylaxis, The classic prophylactic vaccination strategy requires a high rate of vaccination in the general population at childhood or adolescence, yielding individual immunity as well as “herd

immunity” (inhibited spread of Infection through the population) if a sufficient percentage of the general

population is Immunized Examples of successful classic prophylactic vaccination strategies include

the worldwide smallpox vaccination program and, in the Unites States, the mandatory childhood vaccination program

2 Targeted prophylactic vaccination. Another well-established strategy IS to prevent infection by targeting “at-risk” populations for vaccination An example of this prophylactic vaccination strategy is the

targeting of tropical disease vaccines, such as yellow fever, to travelers

3 Immediate post-exposure vaccination. Falling between prophylaxis and treatment IS the concept

of vaccination immediately after exposure to an infectious pathogen to prevent establishment of permanent infection. Rabies vaccine, in which anti-rabies immunoglobulins are administered immediately following exposure to rabies virus, IS a model for this vaccination strategy

An Immediate post-exposure HIV vaccine would be most useful in cases of accidental exposures to

HIV, such as following a needle-stick injury. A clinical trial of such a vaccine, however, would be unlikely

to yield significant results due to the low rate of HIV infection following needle sticks or other accidental

exposures (72),

4. Therapeutic vaccination. Therapeutic vaccination to prevent disease progression in an Infected

individual has been proposed for several pathogens and has a long history as a concept (13) However, there are few examples of the successful application of this vaccination strategy for any infectious

disease, with a recent report of decreased genital herpes lesions following vaccination with herpes glycoprotein a noteworthy exception (93).

Until recently, there has been little evidence that envelope-based HIV vaccines (77) or whole inactivated HIV vaccines (81 ) have had therapeutic benefits in HIV-infected individuals. However, recent results from a Phase II trial of a whole Inactivated envelope depleted virus vaccine in HIV-infected individuals suggests the possibility of an antiviral effect from the vaccine (94).

Likewise, there are no examples of a vaccine that can prevent disease transmission from infected

vaccinees to susceptible contacts But passive transfer of antibodies to infected pregnant women has

been discussed as a potential means for reducing maternal-fetal transmission of several Infectious

agents, including HIV.

There has been discussion of development of a therapeutic vaccine for HIV-infected women of childbearing age to prevent infection of their offspring, since there is a 15 to 50 percent probability of transmission of HIV infection from untreated infected mothers to their newborns, Recently, however, a clinical

trial showed that the antiviral drug AZT (zidovudine), when given to infected mothers during pregnancy,

was able to reduce the rate of maternal-fetal HIV transmission from 24 to 8 percent (Pediatric ACTG

Protocol 076), Thus, the efficacy of AZT in reducing maternal-fetal HIV transmission is the standard

against which the efficacy of any vaccine to reduce maternal-fetal transmission will be compared.

(continued)
30 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

5. Vaccines to reduce infectivity Another strategy involves the vaccination of uninfected members of

high risk groups to reduce their infectivity in the event of subsequent infection; in this case, the vaccine

is not expected to actually prevent chronic infection in subsequently exposed individuals, but to decrease their infectivity by reducing the rate of viral replication. Presumably, the reduction in the rate of

viral replication would probably be accompanied by a decreased rate of disease progression, and so

this vaccination strategy represents a variant of the classic prophylactic vaccination strategy. There are

no examples of human vaccines that follow this strategy, but an analogous situation occurs naturally in

some diseases (e.g., tuberculosis, Hepatitis B infection), where persistently infected individuals that

mount a strong immune responses have been shown to have decreased infectivity This decreased infectivity has also been shown to occur in vaccinated monkeys that are infected with SIV (85, 86). HIV

vaccines that do not clear all virus (achieve “sterilizing immunity”) may also reduce infectivity, although

this has not been demonstrated.

This vaccination strategy has not yet received much attention from experts in the field of HIV vaccine

research. Investigators would have difficulty demonstrating the efficacy of a vaccine to reduce infectivity because it would require a clinical trial that followed not only a large number of high-risk vaccine and

placebo recipients, but the recipients’ contacts as well.1 In addition, conclusions about the effect of the

vaccine on the transmissibility of infection could only be drawn from observation of incidence of HIV

infection among those persons whose only risk for HIV infection is from contact with a vaccine trial participant (e.g., the vaccinee’s offspring or monogamous sexual partners). Nevertheless, this may be the

vaccination strategy that has the greatest chance of success in controlling the AIDS epidemic in the

foreseeable future. Therefore, designing the necessary studies to test the efficacy of vaccines to reduce

infectivity is important.

The efficacy of a vaccine to reduce infectivity could be tested, for example, in a clinical trial involving

intercity truckers in India. These truckers are at high risk for HIV infection due to their frequent contact

with female sex workers. The wives of these truckers, however, tend to be monogamous. Such a trial

would require investigators to monitor incidence of HIV infection not only in the truckers participating in

the trial, but in their wives as well. Another way to test this strategy would be to vaccinate uninfected

women of child-bearing age who are at high risk of acquiring HIV, and then monitor HIV infection incidence in these women and their offspring.

The efficacy of this vaccine in reducing the infectivity of subsequently infected individuals may also

be approximated by testing the vaccine in individuals that are already infected with HIV. Such a trial

would require enrollment of far fewer participants. To demonstrate the efficacy of such a vaccine in reducing infectivity, however, one would still need to follow up the vaccinees’ monogamous sexual contacts. Furthermore, a vaccine may not be nearly as effective in reducing infectivity when given after

infection as it is when given before infection.

SOURCE: David Schwartz, “Analysis of ‘Worst Case Scenarios’ for Theoretical Risks Associated with Experimental HIV Vaccines,”

unpublished contractor report prepared for the Office of Technology Assessment, US. Congress, Washington, DC, July 7, 1994.

1 For example, assuming a 5-percent annual incidence of HIV infection in the high-risk target population, and 5-percent annual

transmission from this population to their monogamous sexual partners, there would be a 0.25 percent annual incidence of HIV infection among the sexual partners. More than 40,000 participants from the high-risk target population would be required for a Phase Ill

efficacy trial of a vaccine using this strategy.
Chapter 2 Potential for Adverse Reactions from HIV Vaccines 31

Type of Immune response Elements Function of elements

Humoral immunity Antibody produced by B lymphocytes Inactivates free virus

Cellular immunity T lymphocytes Helper cells

CD4+ Cytotoxic lymphocytes

CD8+

Macrophages Immune intermediary cells

Mucosal immunity Antibody plus immune cells Blocks mucosal invasion

SOURCE. Office of Technology Assessment, 1995.

bacteria) or its components, in a safe form, designed to protect against future disease. Administration of a vaccine stimulates the body’s immune

system to generate protective defenses specifically directed against the microorganism. This vaccine-induced protective immune response is rapidly restimulated when a vaccinated individual is

subsequently exposed to the microorganism.

Thus, the vaccine “primes” the immune system to

respond to a microorganism, so that upon exposure to that microorganism, spread of the microorganism through the body is dampened before it

can cause disease (51). This is the mechanism by

which traditional vaccines protect against establishment of infection.

Immune Response Elements

Selection of starting material for a vaccine begins

with identification of the important sites on the

microorganism that stimulate the immune system.

These sites are known as antigens, which are usually composed of proteins, which are long chains

of amino acids.6 The term epitope describes the

specific amino acid sequence and configuration of

the antigenic protein. Epitopes are the functional

sites that are recognized by the body’s immune defense system, and that induce the body to produce

an immune response. These epitopes are incorporated in various forms into the vaccine.

Knowledge of the nature of the elements of the

immune system and how each element functions

is important in understanding how a new vaccine

is designed. The immune system can be thought of

as having three major response elements: 1) humoral immunity, the immune response to foreign

substances from antibody7 circulating in the

blood; 2) cellular immunity,8 immune response

from a network of immune white cells in the blood

and tissues, and 3) mucosal immunity, a specialized system of antibody and immune cells located

at the smooth, moist mucous membranes (mucosa) that cover-inner body surfaces, including the

routes of sexual transmission of HIV: the vagina,

anus, and penile urethra (table l-l).

Each of the three immune response elements

plays a unique role and each may be stimulated

differentially by altering the design of the vaccine

or its method of administration (1, 62, 63). One

type of immune white cell, the B lymphocyte, produces antibody. Each antibody is antigen-specif6 Proteins are composed of long chains of amino acids. A protein’s shape, properties, and biological functions are determined in part by the

specific sequence of its constituent amino acids. Peptides are short amino acids.

7 Antibodies are blood proteins produced in B lymphcytes, a type of white blood cell, in response to the introduction Of a specific antigen

(e.g., an invading virus, incompatible red blood cells, inhaled pollen grains, or foreign tissue grafts). Once produced, the antibody has the ability

to combine with the specific antigen that stimulated antibody production, and thereby render the antigen harmless, a process called neutralization.

8 Cellular immunity is also called cell-mediated immunity.
32 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Preparation Vaccine

Live attenuated virus

Inactivated whole virus

Protein subunit (recombinant)

Protein subunit (purified)

Adenovirus

Measles

Mumps

Polio

Rubella

Smallpox (vaccinia)b

Varicella a

Yellow Fever

Hepatitis Aa

Japanese Encephalitis

Polio

Rabies

Hepatitis B

Influenza

a Under review for Iicensure.

b No longer recommended; smallpox globally eradicated

SOURCE: Office of Technology Assessment, 1995.

ic and can bind and inactivate (“neutralize”) virus

particles that are free in the circulation but cannot

inactivate virus located inside of infected cells.

Another type of white cell, the T lymphocyte, participates in cellular immunity. Subtypes of T lymphocytes include CD4+ (helper T) lymphocytes

and CD8+ (cytotoxic T) lymphocytes. Cytotoxic

T lymphocytes can kill cells undergoing active viral infection. CD4+ (T helper) lymphocytes are

necessary for the development of mature functional lymphocytes. A third type of immune white

cell, the microphage, is an important intermediary

in the development of the immune response.

❚ Historically Successful Vaccines

Review of the design of contemporary viral vaccines provides background for understanding the

strategies available for the design of an HIV vaccine. Contemporary viral vaccines, in fact, follow

only a few basic designs (table 2-2). Eight are live

attenuated (weakened) vaccines, four are inactivated (killed) whole virus vaccines, and two are

protein subunit vaccines. Hepatitis B is the sole

vaccine prepared using recombinant biotechnology (gene splicing) techniques. Both attenuated

and inactivated poliovirus vaccines are available.

Most successful viral vaccines are live attenuated

and, less frequently, inactivated whole-virus

products.

A common feature of vaccines currently in use

is their ability to induce durable circulating antibody, usually persisting for many years. A low

level of antibody directed against the virus maybe

sufficient for protection against establishment of

viral infection. For some viruses, such as measles

virus, the rapid immune recall due to vaccine

priming may be sufficient to protect against infection; for protection against other viruses, such as

influenza virus, a preexisting threshold level of virus-specific antibody is necessary. For other vaccines, a vaccine-induced cytotoxic T lymphocyte

response may also participate in protection (e.g.,

varicella).

Currently used vaccines are capable of preventing the initial viral infection from becoming established and progressing to disease; they are not capable of preventing the initial viral infection. This

distinction is important to understanding the requirements for an effective HIV vaccine. Live attenuated vaccines, composed of live virus that has

been altered to make it incapable of producing disease, most closely reproduce the immune state

seen after natural infection. Attenuated vaccines

may induce, in addition to circulating antibody, a
Chapter 2 Potential for Adverse Reactions from HIV Vaccines 33

Structure Viral Function Immune Significance

Envelope proteins Cell attachment and penetration Induce antibody

gp160 Precursor of gp120, gp41

gp120 External protein

gp41 Membrane anchor

Internal proteins Important CTL sites

gag Structural, viral assembly

pol Facilitates replication

Auxiliary proteins (6) Regulate level of virus activity Selective deletion produces attenuated

e.g., nef virus vaccine

RNA genome Genetic code for all viral Use of infectious DNA as vaccine

proteins (virus has a latent DNA stage

in host chromosome)

KEY: CTL = Cytotxic T lymphocytes

SOURCE: Office of Technology Assessment, 1995

cytotoxic T lymphocyte response and mucosal

immunity. Further, unlike nonreplicating vaccines, live attenuated vaccines generally do not require multiple primary and booster doses. In practice, before the era of modern biotechnology,

inactivated whole virus and live attenuated viruses were usually tried empirically, and live attenuated vaccines were preferred as a more reliable

source of long-term protection.

❚ Historically Unsuccessful Vaccines

The number of infectious agents for which we

have failed to develop a satisfactory vaccine, even

those targeted as high priority (49), is far greater

than the number for which we have been successful. Examples of viruses for which we have failed

to develop a vaccine include the viruses herpes

simplex, infectious mononucleosis, cytomegalovirus, respiratory syncytial virus, and rotavirus;

vaccines against many sexually transmitted disease agents, such as syphilis and gonorrhea; vaccines against parasitic diseases, such as malaria

and schistosomiases; and vaccines against numerous bacterial infections, including tuberculosis.

Individually, these infections are characterized by

such features as chronic persistence of the organism, restriction of the organism to mucosal sites,

genetic variability of the organisms, and lack of

spontaneous recovery from the disease that they

cause. Vaccines that have been successful are

more likely to be directed against acute, self-limiting systemic9 infections, where immune responses can readily clear residual organisms.

HIV ISA UNIQUE VIRUS

❚ HIV Structure: Starting Point for

Vaccine Design

A brief description of HIV structural elements and

their function will facilitate later discussion. The

virus is bounded by a membrane with the gp160

protein projecting through the membrane surface

or envelope (see table 2-3 and Figure 2-1 ). The envelope gp160 protein is composed of, and is precursor to, the gp120 and gp41 envelope proteins. 1

° The envelope protein gp120 bears the V3

9 Systemic infections involve the whole body, in contrast to localized infections, which may involve one specific organ or body part.

10The "gp" refers to its composition of glycoproteins (proteins bound with sugars), and the numbers 160, 120, and 41 refer to a measure of

each glycoprotein’s weight.
34 I Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Electron micrograph of HIV virions budding from an infected

cell.

loop, which is the site of attachment of the human

immunodeficiency virus to its receptor on the surface of the CD4+ lymphocyte. The V3 loop of the

gp120 protein is also the site for induction of

neutralizing antibody (antibody that specifically

binds to, or “neutralizes,” the antigen); antibody

to gp120 can block HIV from entering and propagating in cells.

The viral membrane encloses two major internal components, the gag and proteins, and several small auxiliary proteins that control the rate of

virus replicationll 

(see figure 2-l). The genetic information, or genome, of HIV is composed of ribonucleic acid (RNA); by contrast, the human genome (and that of most other species) is composed

of deoxyribonucleic acid (DNA). The RNA genome of HIV is associated with the internal proteins. Epitopes on the gp120 and gag proteins, as

well as those on other internal proteins, can induce

Electron micrograph of free HIV virions.

cytotoxic T lymphocyte responses necessary for

cellular immunity (4).

■ Properties of HIV That Handicap

Vaccine Development

Because of several unique features of HIV, the

model for an effective HIV vaccine is much more

complicated than the model for contemporary

vaccines. HIV is endowed with an unusual set of

capacities that enable it to evade or manipulate

normal immune defenses (table 2-4). These capacities are listed below:

1. HIV incapable of evading immune surveillance

by integrating its genome into the genome of

infected cells. During replication, the human

immunodeficiency virus undergoes a stage

“ where its RNA genome is transcribed into

DNA by a process called “reverse transcription.” As a necessary part of its life cycle inside

11 These small auxiliary proteins are called regulatory or accessory proteins.
Chapter 2 Potential for Adverse Reactions from HIV Vaccines 35

DNA Lipid

Glycoproteins \ . membrane

Protein

Reverse

transcriptase

(pol)

p 66

SOURCE: G C. Schild, and P D Minor, “Human lmmunodeficiency Virus

and AIDS, Challenges and Progress, ” Lancet 335 1081-1084, 1990

2.

the cell, HIV DNA must integrate into the DNA

of the human chromosome in the cell nucleus.

While the HIV genome is integrated into the

human genome, it is hidden from immune surveillance and cannot be recognized and eliminated. While it is integrated, the HIV genome

is latent and not replicating. HIV may persist in

this sanctuary, later to reactivate, replicate, and

shed new virus from the cell.

The virus can undergo genetic change through

a process of rapid genetic mutation and selection of viral mutants resistant to preexisting antibody. Viral mutations can occur at epitopes,

the key sites normally recognized and attacked

by antibody and immune cells. These mutations may render the epitopes unrecognizable,

allowing the virus to avoid immune elimination. During the lengthy course of infection in

a single individual, new genetic variants of

HIV emerge.

Latency in chromosomal DNA

Extensive genetic diversity

Virus infects and destroys critical immune cells

Spread by microphage and direct cell fusion

Silent transmission during prolonged latent

infection

Transmitted by three routes, as free- or

cell-associated virus

Recovery from infection not known, providing no

clues to protective mechanisms

Primate models offer no clear guidance to

protective mechanisms

SOURCE Off Ice of Technology Assessment, 1995

3.

4.

Globally, at least six major subtypes (clades)

of HIV have been identified based upon genetic

analysis (70). Subtype B has been isolated in

the Americas, Western Europe, and in parts of

Southeast Asia. Substantial genetic variation is

found even within each subtype of HIV (73). A

significant consequence of the genetic diversity of HIV is that the immune response directed

to one HIV strain may not necessarily protect

an individual from other subtypes of HIV or

from different strains within the same subtype

of HIV. Therefore, there is consensus that HIV

strains used to prepare vaccines must match

HIV specimens that are freshly isolated from

infected individuals in the region where the

vaccine is to be used (so called “fresh primary

field isolates”) (103).

Virus spreads through the body soon after initial contact with the surface mucus membranes

(the mucosa) of the vagina, anus, and penile

urethra, the sites of sexual transmission. The

virus selectively invades and can injure the

very cells that play central roles in immune defense, the CD4+ (T helper) lymphocytes and

the macrophages.

Virus that infects and is sheltered by macrophages may spread to other sites, such as the

central nervous system, a body compartment
36 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

where access of immune cells and antibody is

poor.12 Virus can also spread by direct cell-tocell contact through a process of direct fusion,

again avoiding immune inactivation.

5. HIV infection is chronic, with a variable number of years of apparent clinical wellness preceding the onset of HIV-related illnesses. Despite the presence of vigorous, sustained

antibody and cytotoxic T lymphocyte responses to HIV, the virus continues to multiply

to high concentrations (titers) in immune cells

in lymphoid tissues of the body. The virus remains silently transmissible. When a sufficient

number of CD4+ lymphocytes are injured and

lost, the acquired immunodeficiency syndrome, AIDS, becomes clinically apparent,

with eventual death. The progression of HIVrelated immune dysfunction is classically monitored by measuring the fall in concentration of

circulating CD4+ lymphocytes.

6. HIV can be transmitted by three different

routes, which, in itself, can complicate the task

of developing a vaccine that can induce an effective immune blockade. HIV is acquired by

sexual contact with mucosa of the vagina, rectum, or penis; by direct inoculation into the

blood stream; or by transfer from mother to fetus or infant through the uterus, at birth, or

through breast milk. Protecting the mucosa

against infection presents special challenges

because of the difficulty in inducing mucosal

immunity through vaccination. Virus may be

transmitted as free virus or as virus carried inside cells (see photos 2-1 and 2-2). It is more

difficult to block the transmission of virus in infected cells; different immune mechanisms are

required.

7. Unlike other viral infections that are self-limited, there are few, if any, instances of recovery

from HIV infection to offer clues for understanding the key immune response elements

that are necessary for protection from the virus.

8. Animal models of human HIV infection, using

monkeys and other primates, have not yet

yielded definitive guidance to the immune elements necessary for protection.

ANIMAL MODELS

❚ What Has Been Learned from Animal

Models?

Animal models of infection historically have contributed to the development of vaccines in two

general ways: 1) use of animal models has helped

to define interactions between the virus and the infected organism or host, particularly in understanding the immune responses necessary for control of infection; and 2) animal models have

provided a system to predict the behavior of a candidate vaccine in man. The primate model can be

used to provide an initial assessment of vaccine

concepts, test a vaccine’s immune potential, provide evidence of protection against challenge virus, and screen the vaccine for safety. Scientific

opinion varies concerning the significance and validity of primate studies as a guide to HIV vaccine

development and as a criterion for judging the eligibility of a vaccine for participation in efficacy

trials (83). However, as our understanding expands, patterns of primate infection are emerging

that should permit more focused studies.

❚ Primate Systems

The chimpanzee is the only animal in which HIV

will replicate. However, chimpanzees have severe

limitations as animal models. Chimpanzees are

expensive and their supply is limited; a typical

study may involve two chimpanzees given experimental vaccine and one chimpanzee receiving

placebo vaccine for comparison. In the chimpanzee, the virus causes a minimal persistent infection, waning over time, with no disease manifesta12 The central nervous system includes the brain and spinal cord, and is separated from the other body compartments by the “blood-brain”

barrier. Certain immune response components, including certain white cells and antibody, are limited in their ability to traverse this brain barrier.
Chapter 2 Potential for Adverse Reactions from HIV Vaccines | 37

tions. Some fresh human HIV isolates may

actually fail to infect chimpanzees.

Macaque monkey infection with simian immunodeficiency virus (SIV) provides an important

parallel to HIV infection in humans. SIV, a retrovirus that is in the same virus family as HIV, is

highly virulent in macaques, with induction of

high concentrations (titers) of antibodies and persistent infection leading to an AIDS-like syndrome within 6 to 24 months of the infection. The

rapidity of disease progression varies with the level of virulence13 of the SIV strain used. Unlike

chimpanzees, the macaque is readily available.

Human immunodeficiency virus, type 2

(HIV-2) causes human AIDS restricted to West

Africa. HIV-2 is more closely related to SIV than

HIV-1, grows poorly in monkeys, and does not

grow at all in chimpanzees.

Protection Under Optimal Conditions

There are examples of vaccine protection or partial protection in primates, largely under optimal

circumstances, for example where vaccinated primates were exposed to virus immediately following the final dose of vaccine (which corresponds

to the height of the immune response elicited by

the vaccine), where vaccinated primates were

“challenged” with virus that was homologous to

(i.e., of the same strain as) the virus used in the

preparation of vaccine, and where small doses of

cell-free virus were inoculated directly into the

blood stream by the intravenous route (8, 30, 47,

83, 101). Also, large doses of antibody administered to the chimpanzee have been shown to provide passive protection from infection with HIV

for several hours, but no longer (24).

Studies using the SIV/macaque model have

shown that it may not be necessary for a vaccine to

attain sterilizing immunity (to clear all virus) to

protect against disease (44). If this is also true of

HIV in humans, it may lower the requirements for

an effective HIV vaccine. Importantly, vaccine

protection against SIV infection of the vaginal

mucous membranes of macaques has been accomplished recently using microspheres, which permit slow release of antigen (58).

Live attenuated vaccines show a high level of

protection against SIV infection in macaques. The

promise of live attenuated vaccines and their safety concerns are discussed later in this chapter (19,

20, 21).

Inconsistent Results in Primate Studies

Primate studies conducted over the past decade

have been subject to inconsistent results that are

sometimes difficult to duplicate. It is now appreciated that the outcome of a vaccine challenge experiment can vary depending on the relative virulence of viral infection in different primates, the

choice of virus strain, the dose of virus, the route

of viral inoculation, the history of the virus, and

other specific conditions of viral challenge (10,

83). Understanding these variables allows investigators to select primate systems that pose higher

or lower hurdles for vaccine protection. For example, protection against HIV infection in the chimpanzee (the HIV/chimpanzee model) appears to

be more readily accomplished than protection

against the more lethal SIV infection in the macaque (the SIV/macaque model). Success in the

less virulent HIV/chimpanzee model frequently

cannot be duplicated in the more virulent SIV/macaque model. Both models are helpful in understanding HIV in humans. The HIV/chimpanzee

system models silent persistent HIV infection of

humans; the SIV/macaque model parallels HIV

disease progression in humans.

IMMUNE CORRELATES OF PROTECTION

Knowledge of the specific elements of an immune

response required to protect against HIV infection

(the immune correlates of protection) would help

guide the design of an effective HIV vaccine. Two

approaches to understanding such correlates are

available: 1) experiments using experimental vaccines in primates, and 2) observations that may

13 The virulence of a microorganism refers to its capacity to produce disease.
38 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

suggest the development of a protective immune

response in human HIV infection. While primate

studies have shown examples of protection under

limited circumstances, as yet the immune responses required for a successful HIV vaccine remain undefined. Levels of antibody induced in

primates by vaccines are, in themselves, not well

correlated with protection against HIV infection.

What is the evidence for natural immunity to

HIV infection in man? Studies of the natural history of long-term survivors of HIV infection have

helped us know what are the clinical indicators of

sustained favorable prognosis in HIV infection.

But these studies have been less useful in helping

us understand the requirements for a protective

immune blockade to HIV infection (57). Studies

of individuals who have remained seronegative14

despite intense exposure to HIV, such as infants of

seropositive mothers (78) and multiply-exposed

men (17) have shown that some of these individuals have developed protective patterns of immune

response, suggesting that “natural immunization”

to HIV infection may occur.

DEVELOPMENT AND CLINICAL

EVALUATION OF HIV VACCINES

❚ U.S. Program of HIV Vaccine

Development

The U.S. Public Health Service established a program of discovery, development, and clinical

trials directed toward making available a safe and

effective preventive HIV vaccine. The effort is

centered at the National Institutes of Health (NIH)

with the National Institute of Allergy and Infectious Diseases (NIAID) as the lead institute. Fundamental and applied studies of HIV molecular

biology, pathogenesis, and immunopathology and

of HIV vaccine development have been fostered

by a variety of funding strategies, enabling interactive research among scientists in the U.S. and

abroad.

The NIAID Division of AIDS (DAIDS) created

a network of primate centers to study HIV infection in the chimpanzee and SIV infection in lower

primates. The DAIDS AIDS Vaccine Clinical

Trial Network (AVCTN) has several components.

The AIDS Vaccine Evaluation Group (AVEG) includes six AIDS Vaccine Evaluation Unit (AVEU)

trial sites at university research centers. Each unit

has an associated Community Advisory Board.

Other AVCTN elements include a Central Immunology Laboratory, which develops standards

and performs most of the immunological assays, a

Mucosal Immunology Laboratory, and a Data

Coordinating and Analysis Center. A Data and

Safety Monitoring Board exercises independent

oversight of HIV vaccine trials.

The process of testing a candidate vaccine in

clinical trials is initiated by a sponsor, which presents preclinical data to the Food and Drug Administration’s (FDA’s) Center for Biologicals Evaluation and Research (CBER) for review. FDA

assesses data from laboratory studies of the vaccine, data from animal studies, and other “preclinical data” for evidence of the vaccine’s safety, potency, and potential for efficacy. The FDA is also

responsible for approval and oversight of experimental protocols as vaccines progress through

clinical trials.

Vaccine sponsors may present data from preclinical studies of their vaccines to the AIDS Vaccine Selection Group; the group will consider this

material in determining which vaccines will be

entered into federally funded AVEG trials. A unified approach to trial design, clinical assessment,

laboratory assays, and data analysis permits direct

comparisons among multiple vaccine strategies

and products.

Other major participants in HIV vaccine development include the National Cancer Institute, the

14 An individual that is seronegative for HIV infection has a negative result on a test for HIV infection, and a seropositive individual has a

positive test. The enzyme-linked immunosorbant assay (ELISA) is the most commonly used screening test for HIV infection. The ELISA indirectly determines whether one is HIV infected by testing for the presence of antibodies to HIV. Because antibodies to HIV may not appear for

two or more weeks after initial HIV infection, some “seronegative” individuals may actually be infected with HIV.
Chapter 2 Potential for Adverse Reactions from HIV Vaccines | 39

Centers for Disease Control and Prevention

(CDC), vaccine manufacturers, universities, the

World Health Organization (WHO), and the Department of Defense. These participants contribute capacities for research, product development,

and conduct of clinical trials in the United States

and other developed countries, as well as in the developing world.

❚ Design of Clinical Trials

(Phases I and II)

Promising candidate vaccines are selected for initial assessment of immune responses and safety in

carefully monitored, prospectively randomized,

double-blind, placebo-controlled clinical trials.15

Phase I and II are described below, and Phase III

(large controlled clinical trials of a vaccine’s efficacy) are described in a later section. The FDA approval process involves three phases.

Phase I focuses on an assessment of vaccine

safety and the immune responses to the vaccine.

Phase I study protocols involve 25 to 100 individuals who are randomly assigned to either a placebo control group or one or more experimental

groups. Recruitment for Phase I studies involves

selection of healthy noninfected individuals who

are prescreened and undergo a full physical and

laboratory examination. Volunteers are selected to

be at low risk for HIV infection to minimize their

potential for acquiring confounding HIV infection during the trial. Trial participants receive detailed individual counseling and education on the

experimental nature of the vaccine, the design of

the trial, and possible adverse consequences of the

vaccine. Informed consent for trial participation is

obtained from each volunteer. The effects of varying the vaccine’s dose of antigen, schedule of administration, and ratios of adjuvant to antigen are

determined in Phase I studies.

If the immune responses to the vaccine and the

safety profile of the vaccine warrant further studies, it may undergo Phase II trials, which involve

up to a few hundred individuals. These studies refine and enlarge the database, may directly

compare products or sequences, or may include

individuals at higher risk of acquiring infection.

Role of Industry

The role of U.S. industry, traditionally a world

leader in vaccine development and marketing, deserves special comment. There is a long list of

candidate vaccines in trials or in development

(tables 2-5, 2-6, 2-7). Not all vaccines in development will be eligible for Phase I trials. HIV vaccine sponsors, to a large extent, are small biotechnology companies, private research

institutions, and universities (98). Some of the

large pharmaceutical manufacturers in the Unites

States are not sponsoring an HIV vaccine. There

may be different market forces affecting large

companies and small companies that affect their

decisions to become involved in HIV vaccine development. Some have argued that the compelling

global progression of the AIDS epidemic warrants

exploration of special incentives to attract increased participation of both small and large companies.

Corporate decisions to invest in the development of an HIV vaccine are based on several considerations, including the opportunity costs of

vaccine development relative to drug development, the potential market for an HIV vaccine,

15 A prospective, randomized, double-blind, placebo-controlled study design minimizes threats to the validity of the study. Prospective

studies are ones where the investigator observes the participants from the beginning of the study on; in retrospective studies, observations are

made after the study is completed. A randomized trial refers to one in which participants are randomly assigned to experimental and control

groups; random assignment helps ensure that each of the groups are equivalent. A double-blind trial is one in which both the clinician and the

subject are unaware of the group to which the subject has been assigned; this minimizes the risk of bias that may be introduced when either the

clinician or subject is aware of the subject’s assignment. A controlled trial is one in which one group of participants (the control group) is assigned to a receive a either a placebo or a standard comparison treatment. A placebo is an inert substance which, in the context of a controlled

trial, is made to appear identical to the active experimental treatment. Comparison of one or more experimental groups with the control group

allows the investigators to determine the impact of the experimental treatment.
40 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Vaccine

Envelope proteins

rgp160-LAI b (insect) c

rgp160-LAI (mammalian)

rgp160-MN (mammalian)

rgp120-LAl (mammalian)

rgp120-MN (mammalian)

rgp120-SF2 (yeast)

rgp120-SF2 (mammalian)

Virus-like particles

Ty.p24.VLP

Peptides

V3-MAPS

V3-MAPS (15 component)

V3 peptide PPD conjugated

V3 peptides PPD conjugated

V3 peptides conjugated to

Pseudomonas aeruginosa toxin A

HGP-30 (p17 peptide)

Vectors

Vaccinia-gp160-LAI

Canarypox-gp160

Combinations of Vaccines

Vaccinia-gp160 plus rgp160

Vaccinia-gp160 plus rgp120 (yeast) or

rgp120 (mammalian cell produced)

Vaccinia-gp160 plus rgp160 plus 3

envelope peptides

Vaccinia-gp160 plus rgp160 or rgp12

(MN, LA1 or SF2)

Canarypox-gp160 plus rgp160

Vaccinia - env, gag, pol

rgp160 plus V3 peptide

rgp120 (LA1)) plus rgp120 (MN)

(sequentially or simultaneously)

Developer

MicroGeneSys

Immuno AG

Immuno AG

Genentech

Genentech (Phase II)

Biocine

Biocine (Phase II)

British Biotechnology, Ltd.

United Biomedical, Inc.

United Biomedical, Inc.

SSVI

SSVI

SSVI

Viral Technologies, Inc.

Bristol-Myers Squibb

Pasteur-Merieux-Connaught

Bristol-Myers Squibb, MicroGeneSys

Bristol-Myers Squibb, Biocine

G. Beaud, Institut Jacques Monod;

A. Burney, University Libre de Bruxelles

Bristol-Myers Squibb; Immuno AG;

Genentech; Biocine

Pasteur-Merieux-Connaught (Virogenetics,

Transgene)

Therion

Pasteur-Merieux-Connaught (Transgene)

Genentech

a All vaccines listed are in Phase I trials, unless otherwise indicated .

Trial sites or sponsor

AVEGd

/LIR

AVEG

AVEG

AVEG

AVEG

AVEG

AVEG, SFGH

London, UK

AVEG, SFGH, China, Australia

AVEG

SSVl

Israel

Switzerland

SFGH/United Kingdom

AVEG/University of Washington

AVEG

AVEG, University of Washington

AVEG

Paris, France

AVEG

PMSV/ANRS

AVEG

PMSV/ANRS

AVEG

b HIV-strains represent a group of clade B isolates from the United States and Europe, which includes LAI, IIIB, MN, and SF2.

c Cell substrate for recombinant subunit protein.

d The AIDS Vaccine Evaluation Group is a component of the AIDS Vaccine Clinical Trials Network, The network includes Johns Hopkins University,

Baltimore, MD; St. Louis University, St. Louis, MO; University of Rochester, Rochester, NY; University of Washington, Seattle, WA; Vanderbilt

University, Nashville, TN. Former members were Baylor University, Houston, TX and University of Maryland, Baltimore.

KEY: AVEG = AIDS Vaccine Evaluation Group of AIDS Vaccine Clinical Trials Network; LIR = Laboratory of Immunoregulation; SFGH = San Francisco

General Hospital, CA.

SOURCE: Adapted from M.C. Walker and P.E. Fast, Clinical Trials of Candidate AIDS Vaccines (in press).
Chapter 2 Potential for Adverse Reactions from HIV Vaccines 41

Vaccine Developer Adjuvants Compared Adjuvant Source Trial Site

rgp120-MN Biocine Alum Superfos/AS AVEG

MPL Ribi lmmunoChem Res.

Liposome-encapsulated C. Alving/WRAIR

MPL with alum

MF59 Biocine

MF59 + MTP-PE Biocine

SAF/2 Syntex/Biocine

SAF/2 + MDP Syntex/Biocine

rgp120-MN Genentech Alum Reheis AVEG

QS21 Cambridge Biotech

Alum + QS21 Reheis/Cambridge Biotech

KEY: alum = Aluminum hydroxide; AVEG = AIDS Vaccine Evaluation Group of AIDS Vaccine Clinical Trials Network; MDP = Muramyl dipeptide;

MF59 = Microfluidized oil-in-water emulsion; MPL = Monophosphoryl lipid A; MTP-PE = Muramyl tripeptide-phosphatidylethanolamine, QS21 = Purified saponin adjuvant; SAF = Syntex adjuvant formulation; WRAIR = Walter Reed Army Institute of Research

SOURCE: Adapted from M.C. Walker, and P E Fast, Clinical Trials of Candidate AIDS Vaccines, in press

whether the development of an effective HIV vaccine is scientifically feasible, and potential liability for unforeseen adverse reactions to HIV vaccines. Of the disincentives to HIV vaccine

development, scientific feasibility is a primary

concern. The development of an HIV vaccine is

hampered by a lack of clear scientific objectives, a

consequence of the undefined protective immune

requirements for an HIV vaccine.

Concerns surrounding the safety of an effective

vaccine may also play a role in corporate decisions. Notably, manufacturers have pursued the

development of HIV vaccines composed of envelope subunit proteins, which have inherently more

limited immune capability than HIV vaccines

composed of whole inactivated virus or live attenuated virus. Manufacturers have not, however,

pursued the development of inactivated virus vaccines or live attenuated virus vaccines because of

the greater inherent potential for safety problems

from these vaccines. This is despite the fact that

HIV vaccines based on these more classical vaccine designs are far more promising. Recognizing

this, research on attenuated virus vaccines for HIV

has been supported by the DAIDS program. (Recently, some manufacturers have expressed interest in developing an inactivated virus vaccine.)

There appears to be no unanimity on the relative importance of concerns about potential liability in corporate decisions to invest in the development of an HIV vaccine. Some cite potential for

liability as a part of the “cost of doing business,” to

be considered along with scientific feasibility,

marketing potential, and other business considerations. Industry may need further encouragement

through special incentives to undertake unusual

risks.

ADVERSE REACTIONS

❚ Safety Lessons Learned from

Experience with Traditional Vaccines

Safety Standards for Prophylactic Vaccines

The standard of safety applied to prophylactic

vaccines is higher than that applied to other tools

in the medical armamentarium. Historically, vaccines, especially those designed for universal use

in children, have been held to extremely high safety standards. A vaccine is given to uninfected,

healthy individuals to prevent potential disease

for which the vaccinee mayor may not be at risk

at a future time. In this setting, any significant injury, even occurring in one in a thousand or million recipients, may be considered unacceptable.
Expression system/

Candidate production method Adjuvant or delivery system Developer

Strategy: Targeting of immune response to specific HIV neutralization (B cell) epitopes and/or cytotoxic T lyrnphocyte (CTL) epitopes.

rgp160

rgp120

V3-MAPSa

Ty.V3.VLP

T1 -SPIO(A)

V3-T helper epitope peptides

(PCLUS 3-18, PCLUS 6-18)

CLTB-34, CLTB-36, p24E-V3MN

V3 and gag peptidesa

coupled to Iysine copolymers

V3-BCG

V3-BCGa

V3 peptide coupled to

Mycobacterium protein

env peptides coupled to beta-gal

CD4 binding domain peptomer

HBcAg-v3 particles

Recombinant rhinovirus - HIV

V3 peptides

Recombinant mengovirus - HIV,

V3, V4 peptides

Mammalian

Insect

Synthetic

Yeast

Synthetic

Synthetic

Synthetic chimeric V3-p24 gag peptides

Synthetic

Recombinant mycobacteria

Recombinant mycobacteria

Synthetic

E. coli

Synthetic, conformationally constrained

E. coli

Recombinant human rhinovirus (HRV14)

Recombinant murine mengovirus

(attenuated)

Oil/water, 3-deacyl

monophosphoryl Lipid A

Oil/water, 3-deacyl

monophosphoryl Lipid A

Alum (slow release for mulation)

Alum/none

IFA

IFA, QS21

Alum, QS21

Alum

—

—

10K mycobacterium protein

IFA

Alum

—

—

—

SmithKline Beecham

SmithKline Beecham

United Biomedical, Inc.

British Bio-tech., Ltd.

B. Haynes, Duke University

National Cancer Institute,

Connaught

Yokohama City University, Japan

Nagasaki and Osaka Universities, Japan

NIH, Japan

SSVl

WRAIR-Univax

F.A. Robey, NIDR

Max V. Pettenkofer-lnstitut, FRG

Rutgers University

Institut Pasteur

(continued)
Expression system/

Candidate production method Adjuvant or delivery system Developer

Strategy: Mimicry of attenuated or inactivated HIV

Whole inactivated HIV Inactivated with betapropiolactone,

BEI, formaldehyde

Mammalian/vaccinia

Digitonin Retroscreen, Ltd./lSl

HIV env, gag, pol Therion Biologics

pseudovirionsb

Alum

HIV env, gag, pol

pseudovirions b

Mammalian (Vero) — Connaught

Gag-V3 virus-like particles Insect cells/baculovirus

Recombinant vaccinia

Recombinant vaccinia

Universitat Regensburg, FRG

Universitat Regensburg, FRG

Therion Biologics

—

—

—

p55gag/V3 chimeric vaccinia

TBC-3B, (vaccinia-HIV env,

gag, pol)b

Vaccinia-HIV env, gag, pol b

Attenuated recombinant vaccinia

(NYVAC)

Recombinant canarypox (ALVAC)

Pasteur-Merieux-Connaught

(Virogenetics) —

— Canary pox-HIV env, gag, pol b

Pasteur-Merieux-Connaught

(Virogenetics)

particle acceleration device HIV expression vector coated

with 1.0 micron gold

particles

DNA Agracetus

University of Pennsylvania School of

pM160, (HIV envelope gp160 Medicine

DNA construct)

DNA

—

Strategy: Induction of mucosal immune responses in gastrointestinal and genitourinary tracts.

Adenovirus-Hiv env or gag Recombinant adenovirus (Ad4, Ad5, —

Ad7 vaccine strains)

Wyeth-Ayerst

Poliovirus-HIV Recombinant poliovirus . —

Poliovirus-HIV envelope Recombinant dicistronic poliovirus — SUNY, Stony Brook

peptides

Poliovirus-HIV nef, gag, env Recombinant poliovirus (Mahoney —

type 1, Sabin types 1 and 2)

Gladstone Institute, UCSF

Encapsidated recombinant Encapsidate recombinant poliovirus —

poliovirus HIV env, gag, or

pol minireplicons

(continued)

UAB

II
Expression system/

Candidate production method Adjuvant or delivery system

Strategy: Induction of mucosat immune responses in gastrointestinal and genitourinary tracts. (Cent’d.)

Mengovirus-HIV nef

Shigella-V3 peptide

Salmonella-HIV gp120, p24,

nef

BCG-HIV env peptides

BCG-HIV

Recombinant Lactococcus-V3

peptide

Env-PND-gag-HGP-30

conjugate

rgp 120

V3-MAPSa

Tetravalent MAP-gp120

sequence coupled to a

ipophilic moiety

Recombinant mengovirus (attenuated

Ml 6 Murine strain)

Recombinant Shigella flexneri

(attenuated strain SC602)

Recombinant Salmonella typhi

(CVD 908 vaccine strain)

Recombinant BCG

Recombinant BCG

Fusion of V3 peptide to TT fragment

C in Lactococcus Iactis

Synthetic peptide

Recombinant protein

Synthetic

Recombinant protein

Whole inactivated HIV-2

gp125

gp130

rgp160

Vaccinia-HIV-2 env, gag, pol

Canarypox-HIV-2 env, gag,

pol

Vaccinia HIV-2 env

Triton or formalin inactivation

Purified native glycoprotein

Purified native glycoprotein

Baculovirus

Attenuated recombinant vaccinia

(NYVAC)

Recombinant canarypox (ALVAC)

Recombinant vaccinia

—

—

—

—

—

—

Cholera toxin B

Liposome/Cholera toxin

Microparticles

Synthetic Iopophilic moiety

IFA, alum, RIBI adjuvant, ISCOMS

ISCOMS, RIBI adjuvant

IFA, alum

—

—

—

Salmonella-HIV-2 env, gag Recombinant Salmonella typhimurium

aContains non-clade B strains.

—

Developer

Gladstone Institute UCSF

Institute Pasteur, France

University of Maryland

Medimmune, Inc.

—

University of Cambridge, UK

Viral Technologies, Inc.; Alpha-1

Biomedical:

UAB/Connaught

United Biomedical, Inc.

Vanderbilt University

National Bacteriological

Laboratory, Sweden

National Bacteriological

Laboratory, Sweden

National Bacteriological

Laboratory, Sweden

German Primate Center,

Virogenetics

Virogenetics

German Primate Center,

FRG

FRG

National Cancer Institute

bMultiple genetic deletions introduced for Safety.

KEY: BCG = Bacille-Caimette Guerin; bovine tuberculosis; IFA = incomplete Freund’s adjuvant; LAl = group of closely related HIV isolates that includes LAV, IIIB, BRU, etc ; MAP = multiple

antigent peptide; MAPS = multiple antigen peptide; MAPS = multiple antigen Presentation system; NIDR = National Institute of Dental Research, National Institutes of Health, SSVI = Swiss

Serum and Vaccine Institute, Berne, Switzerland; SUNY= State University of New York; 11 = tetanus toxin; UAB = University of Alabama at Birmingham; UCD = University of California, Davis;

UCSF = University of California, San Francisco; WRAIR = Walter Reed Army Institute of Research.

SOURCE: Adapted from Walker, MC., Fast, PE., Clinical Trials of Candidate AIDS Vaccines, in press
Chapter 2 Potential for Adverse Reactions from HIV Vaccines | 45

By contrast, there is greater tolerance for adverse reactions accompanying the administration

of a therapeutic drug given as treatment for an existing disease. Further, this tolerance is proportionate to the severity and unfavorable prognosis

of the illness treated. For example, severe side effects may be considered acceptable in cancer chemotherapy.

The concept of an “acceptable” risk has not

been applied to vaccines. Good public health practice at the population level may at times be in conflict with the goal of near-zero risk to the individual. Attenuated polio vaccine has eradicated

poliomyelitis from the Americas, yet each of the

few vaccine-associated paralytic cases annually

has given rise to a compensation claim.

Types of Adverse Events Seen with

Traditional Vaccines

Vaccines are prepared from biologically active

starting materials with inherent potential for

harmful effects. Early adverse reactions, occurring within hours or days after vaccination, may

be local (e.g., sore arm) or systemic (e.g., fever,

malaise), and typically are minor, transient, and

without residual effects. Severe reactions have occurred very rarely to vaccines currently in use;

these include anaphylaxis (a severe allergic hypersensitivity reaction) (e.g., tetanus toxoid) and

neurologic disease (e.g., pertussis vaccine).

Causal relationships with illnesses occurring

long after vaccination may be particularly difficult

to document and to distinguish from the occurrence of unrelated diseases. Relationships may be

perceived between illnesses and vaccination that

are not, in fact, causally related. The difficulty in

assigning cause is exhaustively reviewed in two

reports by the Institute of Medicine (IOM) of the

National Academy of Sciences (48, 49).16 The

IOM reports are based on accumulated experience

with millions of doses of licensed vaccines used

worldwide, many in use for decades. The findings

provide the basis for compensable awards by the

Vaccine Injury Compensation Program (Statutory

Basis for the National Vaccine Plan: Title XXI of

the Public Health Service Act, Public Law

99-660). The IOM reports point to need for: 1) research on mechanisms of induction of adverse

events; and 2) prospective, long-term, post-marketing surveillance. Both undertakings are expensive and technically difficult.

Despite the inherent potential for injury from

vaccines, licensed vaccines in the United States

have a record of remarkable safety and have provided a highly cost-effective method of disease

control.

❚ Safety Experience in Phase I and II

Trials

Trial Design Using Envelope-Based Vaccines

Initial approaches to HIV vaccine have concentrated on envelope proteins gp160 or gp120. Purified proteins have been produced in three different

cell types by recombinant techniques. These envelope proteins may be combined with carrier mole16 In a retrospective analysis of worldwide published studies, the weight of evidence for or against causality of possible adverse events was

examined for each of the childhood vaccines. There often was difficulty in assigning cause, but difficulty also in proving lack of cause. Four

types of primary evidence were considered: a) biological plausibility; b) case reports, case series and uncontrolled observational studies; c)

controlled observational studies; and d) controlled clinical trials. Based on these categories of evidence, the presumed adverse events were

classified into five levels of certainty: a) no evidence bearing on a causal relation; b) evidence inadequate to accept or reject a causal relation; c)

evidence favors rejection of a causal relation; d) evidence favors acceptance of a causal relation; and e) evidence establishes a causal relationship.

These analyses are then reviewed in the context of the compensable injuries covered by the Vaccine Injury Compensation Program established by Congress in 1986. The childhood vaccines have been in widespread use for many years, and millions of doses have been administered.

Despite this historical experience, the data was difficult to interpret. The vast majority of adverse events came from uncontrolled studies and

individual case reports. The pathologic conditions under consideration often were uncommon or rare in the population. Because comparative

age-specific incidence rates and relative risk estimates of the condition in the general population are rarely available, it was not possible to

calculate a statistical rate of excess vaccine-related cases, if any. Controlled epidemiological studies are lacking (48, 49).
46 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

cules and injected into the individual to produce

an immune response. A second method of immunization with envelope protein uses live vaccinia

virus as a “delivery vector” (vaccinia/gp 160 vector); the vaccinia virus genome has been genetically altered to incorporate the HIV envelope

gp160 gene. Replication of vaccinia virus in the

dermal layer of the skin results in expression of

gp160 protein, which in turn induces the immune

response. From the initiation of the AVEG program in 1988, more than 1,400 volunteers have

participated in trials of envelope-based HIV vaccines (tables 2-5 and 2-6). Twelve envelope-based

vaccine products or combinations, formulations,

and adjuvants17 were used, prepared by five

manufacturers using three subtype B virus strains.

Additional independent trials of envelope-based

vaccines have been conducted by U.S. and foreign

sponsors.

Immune Responses

The immune responses provide an initial measure

of the potential value of envelope vaccines and

must be considered in context of adverse reactions

accompanying the use of these vaccines (5, 4, 38,

53, 60, 61). Envelope-based vaccines have induced antibodies directed against the strains of virus used to prepare the envelope proteins (homologous strains). The titers (concentrations) of

antibody induced by envelope-based vaccines

were 5- to 10-fold lower than the titers of antibody

found in HIV-infected individuals. Antibody titers are not sustained, falling rapidly after each

dose of vaccine. Other subgroup B strains (heterologous strains) were neutralized less well, and

freshly isolated strains were entirely resistant.

The evasion of neutralization by freshly isolated strains is of concern and remains under intensive study to determine its significance.

Envelope vaccines, with or without adjuvants,

produced no consistent cytotoxic T lymphocyte

responses. Priming with vaccinia/gp160 vector

vaccine followed by a booster dose of envelopebased vaccine resulted in modest cytotoxic T lymphocyte responses in a few recipients. Envelopebased vaccines that were combined with new

adjuvants to enhance vaccine immunogenicity

produced modest increases in titers of neutralizing

antibody; this enhanced immunogenecity occurred at the expense of an increased rate of local

or systemic reactions in some of these vaccines.

Thus, envelope-based vaccines preferentially

generated antibody responses and were disappointing in that they failed to generate substantial

cytotoxic T lymphocyte responses. The antibody

responses elicited by envelope-based vaccines

have been judged by many scientists to be marginal with respect to their magnitude, duration, and

cross-reactivity with other strains.

Safety Overview

Adverse reactions following vaccination with envelope-based products have been minimally

greater than adverse reactions following placebo

vaccination. (Eighteen percent of participants in

trials of envelope-based vaccines received a placebo vaccination.) In general, the experience with

envelope-based HIV vaccines suggests that they

have a benign adverse reaction profile, similar to

currently licensed vaccines. Sequential measures

of biochemical, hematological, and immunological status and kidney and liver function tests

showed no significant vaccine-related abnormal

findings. Importantly, there has been no evidence

of adverse effects on immune function, including

CD4+ and CD8+ lymphocyte counts.

Early Self-Limited Adverse Reactions

Envelope-based vaccines with alum adjuvant

were associated with local reactions at the injection site, consisting of mild pain, tenderness, redness, and swelling for one to two days. The incidence and type of systemic complaints, such as

fever and malaise, were similar to those of placebo

17 In immunology, an adjuvant is a substance, such as alum, that is added to a vaccine to non-specifically enhance the vaccine’s immunogenicity (the vaccine’s ability to produce an immune response).
Chapter 2 Potential for Adverse Reactions from HIV Vaccines | 47

recipients. Addition of some of the new adjuvants,

Genentech QS21 and Chiron/Biocine SAF/2, induced transient moderate to severe local reactions

and febrile flu-like illnesses for one to three days

in a number of recipients (53). None of the vaccinees dropped out of the trials, missed school or

work, or had residual consequences. No further

studies were undertaken with these adjuvants.

Ten vaccinees developed a rash to several products, and one also developed painful joints (arthralgias). A positive antinuclear antibody (ANA)

test (which may at times be associated with autoimmune disease, such as rheumatoid arthritis) was

found in a few individuals. However, further testing ruled out any vaccine-related disease. Despite

careful screening and counseling, 14 pregnancies

occurred. There was no evidence of vaccine-related adverse effects.

Level of Attenuation of the Vaccinia Vector

The trials permitted comparison of the side effects

of vaccinia/gp160 vector with the commercial

vaccinia strain used to prevent smallpox, from

which it had been derived. Smallpox vaccine virus, injected into the dermal layer of the skin, can

spread and cause severe or fatal disease in rare

instances, especially in individuals with compromised immune systems. The vaccinia vector has

been attenuated (rendered incapable of producing

disease) as measured in laboratory tests. Reactions to the vaccine resembled those seen following classical smallpox vaccination in individuals

who had not been vaccinated previously (36).

There were no differences in rates of pustule development at the inoculation site, regional lymph

node swelling, or systemic symptoms. The vaccinia virus did not appear to be attenuated and,

thus, could carry the risk of vaccinia complications known to occur with classical vaccination

(75). Under the controlled conditions of the trial,

occlusive dressings were used over the inoculation site, and no secondary spread to other individuals was observed. With broad use of an HIV vaccine, substitution of a more attenuated poxvirus

vector, such as canarypox virus, is preferable.

Neoplasms

As of May 1994, 10 neoplasms (tumors) were observed in 9 different protocols (52). One of the

neoplasms was benign. At the time of review,

more than 1,300 volunteers were in AVEG trials,

18 percent of whom were assigned to a placebo

control group. Those neoplasms that were malignant tended to occur in older groups. Analysis by

the Data and Safety Monitoring Board and an ad

hoc expert committee found no evidence that

these neoplasms were linked to any vaccine. The

wide variety of tumor types seen in these vaccinees was judged to be biologically incompatible

with the hypothesis that there was a causal relationship between these neoplasms and vaccine.

The occurrence of such coincidental events exemplifies the need for placebo-controlled trials of

HIV vaccines, with careful long-term followup

and independent review.

HIV Infections Among Trial Volunteers

A Phase II trial of envelope-based vaccine was

conducted in 300 noninfected individuals from

groups at high risk for HIV infection. These included men who have sex with men, injection

drug users, sexual partners of infected individuals,

and teenagers engaged in high-risk sexual behavior. A control group of individuals at low risk for

HIV infection was also included for comparison.

The trial has provided experience with recruitment, counseling, cohort retention, and compliance. It has also provided information about the

acceptability of the vaccine and the effect of vaccine trial participation on risk behaviors. The trial

was not designed to determine the efficacy of the

vaccine because inadequate numbers of individuals were included. Despite counseling, HIV infections have occurred among vaccinees. “Breakthrough cases” of HIV infection in all protocols

have been entered into a special study.

To date, 12 of the 1,400 individuals in AVEG

trials since 1988 have become infected with HIV

(37). Of the 12 breakthrough cases, three received

placebo vaccine, eight an envelope-based vaccine, and one received a vaccinia/gp160 vector
48 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

vaccine boosted with rgp160 vaccine. Five breakthrough cases received one to two doses of vaccine, and only four breakthrough cases received an

adequate series of three to four vaccine doses. Notably, five of nine breakthrough cases occurred

among volunteers enrolled in vaccine trials involving low-risk groups. Three additional infections occurred among individuals enrolled in an

intramural NIAID trial, and two others occurred

among individuals enrolled in non-NIAID vaccine trials, so that a total of 17 volunteers have become infected in envelope-based vaccine trials.

Envelope-based vaccines of all participating

manufacturers were involved (Genentech, Chiron/Biocene, Bristol-Myers Squibb/Oncogen and

MicroGeneSys) (95).

Breakthrough infections among vaccine trial

participants were to be expected because: 1) some

volunteers received placebo; 2) the protective efficacy of the vaccine, if any, is not known; 3) maximum protection is afforded only after a full vaccine dosage schedule (involving 3 or more doses);

and 4) antibody-dependent enhancement of infectivity must be considered as a possible reason for

breakthrough infections.

Despite intensive counseling, on retrospective

review, all HIV infections among vacinees accompanied high-risk behavior (5). Intensive study

of recipient and donor viruses and of immune titers may provide clues to mechanisms of protection or failure.

Antibody-Dependent Enhancement

Some experts have questioned whether priming

with an HIV vaccine can potentiate subsequently

acquired natural HIV infection (12). The historical prototype giving rise to this concern is dengue

virus, a tropical viral disease. The presence of serum antibodies induced by a first attack of mild

dengue can facilitate the development of severe

disease on subsequent infection with a related

dengue virus (40). This “antibody-dependent enhancement” (ADE) of infection can be demonstrated in the laboratory by an increase in growth

of virus in cell culture in the presence of antibodies from the serum of exposed individuals.

Recipients of envelope vaccines have been

shown to develop small amounts of enhancing antibodies (66). The clinical significance of HIV

vaccine-induced ADE is unclear. No direct evidence exists at this time that ADE has any clinical

significance. Many scientists consider it to be an

unrelated laboratory phenomenon only. Enhancement of disease has not been duplicated with

HIV-1 or SIV in primate experiments, although it

has been recommended that studies in primate

models should continue (59, 67).

Other Mechanisms of Enhanced Disease

Historically, two other vaccines have been

associated with an accompanying subsequent natural infection that is atypically severe: an experimental respiratory synitial virus (RSV) vaccine

and a licensed measles virus vaccine (27, 54).

Both were vaccines composed of whole virus inactivated by formalin. While the mechanisms of

disease enhancement remain unclear, they both

appear to occur by mechanisms unrelated to ADE

of the dengue fever type. The enhanced disease

experiences with these vaccines were wholly unexpected and have had a significant effect on further vaccine development. For measles, a live attenuated vaccine has supplanted the inactivated

vaccine, and currently there is no licensed RSV

vaccine. It has been suggested recently that inactivated RSV vaccine may induce inappropriate cytokines, or cell-to-cell communication substances,

that are responsible for enhancement (35).

These experiences with vaccine-related enhancement of disease severity have only theoretical implications for HIV vaccines, such as inactivated whole-virus vaccines.

Induction of Autoimmunity

HIV vaccines may have potential for causing an

immune reaction against the body’s own tissues.

Such “anti-self” antibodies could, in theory, be the

basis for autoimmune injury (56, 84). Concern

arises because HIV shares several envelope protein sequences that are identical (homologous) to

sequences on human tissues, a phenomenon

known as molecular mimicry. One example is the
Chapter 2 Potential for Adverse Reactions from HIV Vaccines | 49

similarity of an HIV envelope protein region to a

normal human blood type protein (32). Immunization with such viral structures can induce immune responses to the cells of vaccinated individuals. Adverse effects of the autoimmune type have

not been observed among HIV vaccine recipients

to date, although, in theory, autoimmune phenomena could appear months to years after vaccination.

NEW GENERATION VACCINES:

IMPLICATIONS FOR SAFETY

❚ Immune Goals Drive Vaccine Design

and Enlarge Potential for Risk

As has been discussed, the immune determinants

of protection against HIV infection remain undefined. The unique ability of HIV to evade immune

controls in natural disease and in experimental

systems suggests that all avenues of immune containment should remain on the research agenda.

Based on classical theory, three elements may be

required to prevent infection: 1) neutralization of

free virus would be more effective with a more

vigorous, broadly strain-reactive, sustained antibody response; 2) destruction of infected cells requires induction of cytotoxic T lymphocytes that

recognize multiple HIV epitopes; and 3) protection against sexual transmission of HIV requires

an antibody and cellular response at genital and

rectal mucosal surfaces.

New vaccine strategies may be needed to fulfill

these immune requirements (14). Some of the

new-generation concepts are novel, never before

applied to vaccines used in humans. Each vaccine

formulation or variation on a formulation is regarded as a new product by the FDA, and separate

evaluations of each are required. New approaches

may carry special risks, some unique to that system. The potential for minimizing known, suspected, or theoretical risks is limited. Tests of vaccine in vitro laboratory studies and in animal

models can be poor predictors, particularly of infrequent or late events. The major types of experimental vaccines in development are addressed

below, along with implications for their safety

(table 2-8).

❚ Synthetic Peptides

Defined epitopes on viral proteins are simply and

cheaply duplicated by artificial synthesis of short

amino acid chains (41, 99). Specific B and T lymphocyte epitopes selected to stimulate antibody

and cytotoxic T lymphocytes may be combined.

Vaccines directed at multiple epitopes (multivalent vaccines) have been prepared containing subtypes of HIV that are endemic in diverse regions

of the globe. Immune responses have been improved by arranging peptides into complex structural forms, as well as by adding new adjuvants or

carrier molecules. Peptide-based vaccines have

induced cytotoxic T lymphocyte responses in the

SIV/macaque model. Clinical reactions to peptide

products have been benign in initial clinical trials.

❚ Live Vectors Carrying Genes Coding for

Immunizing Antigens

A vector is a living virus or bacterium used as a

carrier to express one or more “foreign” genes encoding desired antigens. Vectors under study include canarypox virus (a relative of vaccinia virus), adenovirus (a cause of respiratory disease),

BCG (an attenuated bovine tuberculosis organism), Salmonella or Shigella (typhoid-like

bacteria), and attenuated poliovirus. Canarypox

can be altered to express HIV antigens, but canarypox does not itself multiply in the human. Canarypox therefore serves as a safe substitute for vaccinia as a vector (3, 15, 16, 69, 74, 91).

Live vectors have important advantages in inducing protective responses. First, protein antigen

synthesized in a vector can induce cytotoxic T

lymphocyte responses not expected with antigen

administered as inert protein. Second, vectors carrying multiple env, gag, and pol genes but not

RNA or other sequences essential for viral replication can assemble into a viral configuration, or

pseudovirion (55). The nonreplicating structure of

the pseudovirion is designed to duplicate advantages of a whole inactivated vaccine but eliminate
50 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

its risks. Vaccines using virus-like particles (VLP)

have also been produced without use of live vectors (102). Third, vectors that grow on body surfaces, such as adenovirus or Salmonella, can induce HIV local mucosal immune responses.

Live vectors also carry inherent safety concerns. The vector must be: 1) stably attenuated and

unable to produce the natural human disease

caused by the vector, 2) safe from unwanted

spread to contacts and community at large, and 3)

safe for individuals with impaired immunity. The

safety problems that have occurred in licensed

smallpox (vaccinia virus) vaccines allow us to

predict potential safety problems with vaccines

using live vaccinia virus vectors. These may include severe skin and mucous membrane infections, invasive and neurological diseases, and

even death in susceptible immunosuppressed individuals (75).

❚ Infectious DNA

The development of vaccines composed of pure

viral genetic material, infectious or “naked”

DNA, is a novel departure from traditional vaccines. Viral DNA coding for a single or multiple

genes, injected directly into the muscle or skin,

provides the genetic code for synthesizing new

protein, which in turn behaves as a potent antigen.

Persistent antibody and cytotoxic T lymphocyte

responses have been induced in laboratory animals (42, 100). Mechanisms leading to the potent

immune responses are not understood. Safety

questions, which are highly theoretical at this

time, involve possible tumor formation, production of autoimmune disease, or even the possibility of DNA transmission to the fetus.

❚ Inactivated Whole Virus Vaccine

Development of inactivated as well as live attenuated HIV vaccines, using classical approaches,

were seriously considered in early deliberations.

Historically, the empiric use of either of these two

pathways was generally successful with other viruses. These strategies have not been applied to

HIV by vaccine manufacturers because each may

carry significant risk.

Stage of

development Vaccine design

Phase I/II Trials Envelope proteins (gp160, gp120)

Vaccinia vector/gp160

Currently entering Synthetic peptides

trials Live vectors/multiple proteins

Virus-like particles

Pseudovirions

Immune modulators/delivery systems

Preclinical research Infectious DNA

Inactivated whole virus

Live attenuated virus

SOURCE Off Ice of Technology Assessment, 1995

Preparation of a safe inactivated whole-virus vaccine, exemplified by the Salk-type of inactivated

polio vaccine, requires inactivation of a high-titered preparation of live virus using gentle physical-chemical means to preserve full immunogenicity, yet ensuring inactivation of all live viruses.

The process must guarantee absence of even a

single infectious dose in large volumes (hundreds

of thousands of patient units) of vaccine. There is

a narrow margin between surviving virus and the

destruction of viral immunogenicity; this was

highlighted early in the use of licensed polio vaccine when a number of vaccinated individuals developed paralytic poliomyelitis from vaccine lots

containing residual live virus (71 ). The safety

problem was resolved by simple refinements in

the inactivation process. By contrast, assuring inactivation of all HIV particles could prove difficult. In particular, concern exists as to whether cell

cultures or animal models are sufficiently sensitive to detect the minimal residual live virus capable of infecting humans. There has also been

theoretical concern regarding residual reactive viral DNA in the product.

In addition, the safety of the “lymphoblastoid”

cell lines used to prepare the virus is unknown.

“Adventitious agents,” that is, unwanted agents

growing silently in the cell cultures used to prepare vaccine stock, have posed safety problems in
Chapter 2 Potential for Adverse Reactions from HIV Vaccines | 51

the past. As an example, SV40, a monkey tumor

virus, contaminated early lots of inactivated polio

vaccine prepared in monkey cells (68).

The safety of an inactivated whole-virus vaccine for HIV was reviewed at a workshop in 1990.

It was the consensus that a safe product is technically feasible but that product development

should proceed with caution (82).

❚ Live Attenuated Vaccine

Vaccines using live attenuated virus, exemplified

by polio or measles vaccines, are capable of producing immune responses that closely mimic the

solid, long-term protective immune response afforded by natural viral infection. In addition to a

more vigorous and broader antibody response, attenuated virus vaccines may more effectively induce cytotoxic T lymphocytes and mucosal immunity compared with vaccines composed of

inert antigens, such as envelope protein vaccines.

Using the SIV/monkey model, attenuated live

virus vaccines have been constructed using selective deletions of nonessential auxiliary genes that

are required for SIV replication (21). The attenuated virus is stable, not reverting to a virulent

form of virus (i.e., a form of virus capable of producing disease) over an observation period of several years. Monkeys vaccinated with an SIV nef

gene deletion show protection against challenge

with large doses of virulent virus. By contrast, the

control vaccinated monkeys acquired an AIDSlike disease and died in two years.

Safety Concerns Associated with Attenuated

Virus

There are four primary safety concerns about attenuated viral vaccines that have been recognized

(11, 22, 104).

1. Level of attenuation. Inadequate attenuation

(reduction of virulence) of virus may result in

a vaccine that induces the disease that it was designed to prevent; over-attenuated virus may

fail to induce protective immune responses.

However, even an appropriately attenuated virus may show virulent behavior when not

constrained by a competent immune system,

such as in vaccine recipients with immune systems compromised by cancers, immunosuppressant drugs, and other non-AIDS causes.

The highly infectious nature of SIV administered orally to monkeys at birth, before the

monkey’s immune system has fully developed,

has raised new questions about safety of vaccines in immunocompromised individuals (79).

2. Stability of attenuation. The vaccine strain

could undergo genetic reversion to a more virulent form during the lengthy course of replication in the vaccinee. This risk is of particular

concern with vaccines using attenuated strains

of HIV, as the human immunodeficiency virus

is characterized by rapid and frequent genetic

mutations.

3. Possibility of secondary spread. Spread of attenuated virus to contacts of vaccinees (secondary spread) may provide the virus with further

opportunity to revert to virulence (e.g., vaccine-induced poliomyelitis in contacts of vaccinees). However, if it can be assured that the

level of attenuation of the virus remains stable,

secondary spread of the virus may be beneficial, because the attenuated virus could induce

protective immunity in contacts. Sufficient

spread of the attenuated virus would result in

the induction of herd immunity (as had occurred with poliovirus vaccine).

4. Possibility of induction of tumors. Other members of the retrovirus family regularly produce

tumors (e.g., mouse tumors and a form of human leukemia). Theoretically, the prolonged

residence of a live attenuated HIV vaccine

strain in vaccinees could allow the retrovirus to

produce tumors. Recent evidence for a direct

role for HIV infection in the etiology of some

T-cell lymphomas suggests a need to proceed

cautiously while continuing to investigate the

long-term potential of these vaccinees to produce tumors (92, 104).

The gene deletion approach to attenuation

holds special promise. Deletion of one or more

auxiliary genes essential for viral replication

should make the risk of reversion to virulence unlikely. Because of safety concerns, viral mutants
52 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

with multiple gene deletions are being explored

for level of stability and attenuation, duration of

protection, and long-term safety. It is hoped that

these attenuated viral vaccines will prevent subsequent superinfection with a second, virulent but

genetically different HIV strain.

The protective mechanism of attenuated SIV

vaccine is unclear. It is not correlated with antibody or cytotoxic T lymphocyte responses, and

mucosal immunity is not involved. This observation raises the question of whether another means

of blocking virus exists. Attenuated vaccines in

the SIV/monkey model offer interesting opportunities to explore immune determinants of protection.

❚ New Approaches to Improve Vaccine

Performance

Mucosal Immunity

No vaccine has yet provided an immune barrier at

the mucosal membranes of the rectum, vagina,

and urethra—the sites of sexual transmission of

HIV (62, 63, 64). The mucosal administration of

vaccine vectors that grow on mucosal surfaces

may provide a critical tool for the prevention of

HIV transmission by sexual routes. Antigen uptake from mucosal surfaces is poor compared with

injection. New strategies to improve the uptake of

antigens from mucosal surfaces involve use of

biodegradable microspheres, cholera toxin B,

liposomes (phospholipid droplets), and immunostimulating complexes (iscoms) to enhance

passage of antigen through cell membranes for

more efficient processing (58).

New Adjuvants and Delivery Vehicles

Adjuvants are nonviral materials incorporated

into vaccine formulations to augment the magnitude or spectrum of immune responses to vaccines

(31). Since the 1940s, however, alum compounds

have been the only adjuvants accepted for vaccine

products licensed by the FDA. Adjuvants have

been discovered largely empirically, and are commonly derivatives of bacteria or plants. They may

be combined with chemical surfactants (emulsifiers), forming complexes with specific HIV proteins or individual peptides. The introduction of

new adjuvants into clinical practice has been

slowed by concerns about the adjuvant’s toxicity.

Significant transient toxicity was shown in comparative trials of experimental adjuvants (table

2-6).

Exploration of adjuvants is currently undergoing a renaissance in an effort to selectively enhance HIV antibody, cytotoxic T lymphocyte, or

mucosal immune responses. The hope is to move

from an empiric to a rational approach to attaining

specific immune response goals.

The microsphere is a new delivery vehicle that

can add flexibility to the antigen’s disposition (23,

58, 65). Antigen is coated with an inert plastic

polymer, which becomes soluble in body tissues.

The microsphere particle size and polymer composition can be altered to target a single dose of antigen to specific tissue sites such as mucous membranes, and to release the antigen in pulses,

obviating the need for a multiple dose vaccination

schedule.

Cytokines

Cytokines comprise a family of soluble substances (e.g., 1L-2, 1L-4, interferons, etc.) that

mediate functions of immune cells. Cytokines can

play a significant role in providing protective immune responses following vaccination (18). Specific cytokines may be included in a vaccine, or

may be induced in the body by altering the form

in which vaccine antigens are presented.

Any of the above approaches to improve vaccine performance may have unexpected side effects. So far, several new adjuvants have caused

early transient difficulties and have been withdrawn from use.

SOCIAL HARMS AS ADVERSE EVENTS

Adverse consequences or harms may be expected,

not attributable to the biological properties of the

vaccine, but rather falling into the realm of “social

injury” (2, 90). Vaccines may cause a “false-positive” screening tests for HIV infection. This vaccine-induced seropositivity can result in discrimination against false-positive individuals, such as
Chapter 2 Potential for Adverse Reactions from HIV Vaccines | 53

in eligibility for military service, employment,

health or life insurance, or restriction of travel.

Seropositivity following inoculation with envelope vaccines can usually be distinguished from

HIV infection by the Western blot test which is

used to confirm the results HIV of enzyme-linked

immunosorbant assay (ELISA) tests used in HIV

screening. Volunteers in NIAID-sponsored trials

have received identification documents certifying

their participation in these trails, although AVEG

personnel have had to intervene to provide validation of confounding Western blot confirmatory

tests (5).

The problem may become more acute in the future as new generation vaccines that include many

more types of antigenic proteins than are currently

used may render the Western blot test unable to

distinguish vaccine-induced seropositivity from

true HIV infection. Reliance must then be placed

on time-consuming and expensive polymerase

chain reaction (PCR) tests which detect the presence of virus directly, and on viral cultures. Simpler methods of distinguishing vaccine-induced

immune responses from immune responses induced by natural infection are being actively pursued.

Participation in an HIV trial, in itself, may engender social harms. Others may perceive a volunteer’s participation in the trial as implying that

the volunteer is in a group at special risk of acquiring HIV infection, and this may result in personal

stigmatization of the volunteer. Further, volunteers who are immunized with one candidate vaccine may be precluded from participating in clinical trials of subsequent, possibly more effective,

vaccine products. Also, trial participants may assume that they are protected from HIV infection,

and as a consequence may increase their risk-taking behaviors. This increased risk-taking behavior

may occur despite intensive counseling on the

possibility of assignment to placebo vaccine and

the unknown efficacy of the trial vaccine.

HIV vaccines will fall short of protecting all recipients. None of the currently licensed vaccines

in public health use, even the most effective, vaccines protects all recipients; estimates of protection range from 50 to 70 percent for influenza vaccine, to 95 percent for measles and polio vaccines.

Failure of vaccine to protect is expected in clinical

trials. These failures may be perceived as vaccineinduced enhancement of infection, manifest as an

increased susceptibility or a more aggressive

course of infection. Lastly, questions of responsibility and legal liability for vaccine injury, provision of health care, or other services to trial participants remain unresolved (2). The concept of social

harms is developed further in the discussion of efficacy trials below. These issues are also discussed

in further detail in chapters 3 and 4.

CLINICAL TRIALS IN HIV-INFECTED

INDIVIDUALS

❚ Infected Pregnant Women

Prevention of newborn HIV infection by vaccination of the infected mother deserves special note.

HIV-infected pregnant women transmit infection

to 15 to 40 percent of their progeny. In this complicated situation, vaccination can potentially prevent infection of the fetus or newborn and treat the

infection of the mother. The goal of a vaccine in

this setting is to favorably alter the immune status

of the mother during pregnancy, thereby lowering

the risk of transmission of the virus from mother

to fetus (vertical transmission) (98).18. Possible

risks to the mother, fetus, and newborn have not

been formally tested in clinical trials of HIV vaccines. Previously, pregnancy has been cause for

exclusion in all Phase I and II trials. Despite counseling designed to exclude pregnancy, overall 16

pregnancies have occurred in AVEG trials conducted in uninfected subjects with no adverse

events attributable to vaccine.

18 The use of vaccines to prevent vertical transmission is reviewed by M. Walker and P. Fast, 1995(98).
54 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Vaccine Developer Trial site

In HIV infected pregnant women

rgp160-LAI MicroGeneSys AVEG, ACTG

rgp120-MN Genentech AVEG, ACTG

rgp120-SF2 Biocine ACTG

In infants born to H/V-infected women

rgp120-MN Genentech ACTG

rgp120-SF2 Biocine ACTG

KEY: ACTG = NIAID AIDS Clinlcal Trial Group, AVEG = AIDS Vaccine Evaluation Group of AIDS Vaccine Clinical Trials Network

SOURCE. Adapted from M C Walker, and P E Fast, Clinical Trials of Candidate AIDS Vaccines, in press

While there is no a priori reason to expect adverse events, such as injury to the developing fetus

or newborn, from HIV vaccine, the outcomes of

these pregnancies will be carefully monitored. Injuries to the newborn that are causally related to

the vaccine must be distinguished from the recognized high background rate, approximately 3 percent, of naturally occurring birth defects or developmental problems in newborns. Phase I clinical

trials of HIV vaccine in 23 infected pregnant

women, using three rgp120 vaccine products, are

in progress (table 2-9) (106). The vaccine products were pre-screened for fetal toxicity in rodents. No significant vaccine-related adverse

events occurred in mothers or in the 20 infants that

have been delivered to date.

In regions of the developing world where there

is a high incidence of HIV infection and where effective chemotherapy (Zidovudine) is not widely

available, trials of vaccines to prevent vertical

HIV transmission remain appropriate. These trials

should be a high priority, because HIV-infected infants usually progress rapidly to severe disease.

❚ Trials of Therapeutic Vaccine for

Treatment of Established Infection

Use of an HIV vaccine as an agent to treat individuals with established HIV infection (therapeutic

vaccination) is based upon concepts that are different from vaccine used as a preventive agent

(prophylactic vaccination). In established infection, a vaccine is used for its potential to favorably

modulate the immune system. The objective of

therapeutic vaccination is to selectively enhance

the immune processes that reduce viral replication

and increase viral suppression. This, in turn, may

control or eliminate persistent virus and delay or

prevent disease progression.

However, there has never been a vaccine that

has been able to slow progression of an infectious

process once the infection has been established.

Post-exposure immunization in some viral infections, such as rabies, is only effective if the vaccine is administered early in the incubation period

of the virus, before infection is established in the

target organ. Approximately 35 Phase I and II

trials of therapeutic HIV vaccines are active in the

United States and abroad, using envelope and core

proteins, novel vectors, inactivated virus, and other products (98).

Several things can be learned from trials of

therapeutic HIV vaccines that bear on the development of a preventive HIV vaccine. First, the

more favorable risk/benefit ratio in a treatment

setting versus a preventive setting, permits more

widespread study of novel products. Second,

trials of therapeutic vaccines permit the assessment of the safety and specificity of immune responses to the vaccines (77). Third, there has been

no clear evidence that therapeutic vaccines benefit

the course of HIV infection, although more definitive randomized, controlled Phase 11 clinical trials

are in progress. Finally, there is no evidence that

HIV infection has been accelerated or enhanced in

recipients of therapeutic HIV vaccines. One study

of HIV vaccines in chimpanzees reported a
Chapter 2 Potential for Adverse Reactions from HIV Vaccines 55

Total sample sizea

Annual rate HIV infection

Length of Trial 1% 2% 3%0 4%

2 years 28,896 14,540 9,690 7,290

2,5 years 22,266 11,224 7,496 5,650

3 years 18,294 9,238 6,180 4,668

a Two-arm study, 90% power to detect a 30°A reduction m the risk of infection, 10% annual loss to followup.

SOURCE" Wasima N. Rida, Division of AIDS, NIAID, Bethesda, MD, June 1995.

transient rise in HIV-infected cells after vaccination; this transient increase in HIV-infected cells

was of unknown significance (28).

PHASE Ill EFFICACY TRIALS

❚ General Concepts of Efficacy Trial

Design

The capability of a vaccine to protect against infection is determined in Phase III efficacy trials

(96) (97). The quality and quantity of vaccine-induced immune responses measured in Phase I and

II trials may predict, but do not demonstrate, efficacy of the vaccine. The second major function of

the Phase III efficacy trial is to provide a more definitive assessment of vaccine safety.

Efficacy trials of HIV vaccines will be large,

complex, lengthy, and expensive. The design requires a prospectively randomized, double-blind,

placebo-controlled study, which will involve several thousand subjects assigned to one or more

vaccines or to placebo. The trial site must be prepared with competence in epidemiology capabilities in behavioral, clinical and laboratory roles,

and data management skills. The number of subjects, duration of recruitment, and followup are

determined by several key variables. These include the number of arms (i.e., vaccine and placebo groups) in the study, seroincidence (annual rate

of new infection), length of recruitment period,

rate of retention, assumptions about level of efficacy of the experimental vaccines, and the definition of infection or disease endpoint(s) or outcomes that are measured. An example is provided in

table 2-10.

Persistent infection accompanied by delay or

prevention of clinical disease or reduced transmission of virus requires many years or lifetime followup.

Possible endpoints, including “intermediate

endpoints” in vaccine trials, are described in table

2-11. Documentation of the validity of intermediate endpoints as predictors of vaccine protection

will require intensive laboratory studies. Multiple

efficacy trials will be needed; the initial vaccine

formulations may well be less than optimal.

❚ Preparing for Efficacy Trials in the

United States

Successive vaccine candidates with potential for

improved efficacy and safety will be compared in

randomized, double-blind, controlled clinical

trials with prior vaccines serving as benchmarks.

HIV efficacy trials in the U.S. will be unique in the

history of vaccinology. While the underlying epidemiological and statistical principles of trial design are the same as those used in trials of classical

vaccines, the groups that are targeted for HIV vaccination and their community settings have special characteristics. This, together with the special

biological and social implications of HIV infection, has a great impact on the conduct and outcome of the trial (43, 45, 96, 97).

Populations with high rates of seroconversion

(incidence of HIV infection) are required, such as

intravenous drug users and men who have sex

with men. Such communities may feel disenfranchised and socially stigmatized, have concerns regarding access to health care and other services,

and harbor distrust of the government and of
56 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Possible outcomes of trial Intertxetation

Sterilizing Immunity Vaccine has prevented infection.

Minimal infection without antibody Vaccine has induced immune memory only.

Abortive infection Early transient viremia and/or antibody response; vaccine

has prevented establishment of infection.

Modified infection Vaccine has decreased viral load, delayed disease, or

reduced transmission,

Unmodified infection and disease Vaccine has failed.

Rapid progression or increased incidence Immune enhancement of infection as a result of vaccination, —

SOURCE: Office of Technology Assessment, 1995

scientific experimentation (90). These underlying

ethical, social, legal, and political issues will require sensitive attention.

In anticipation of conducting large-scale efficacy trials, preparatory studies have been initiated

(89, 96). Several thousand injection drug users

and homosexual and bisexual gay men with a high

HIV seroincidence are under study in the HIV

Evaluation Network (HIVNET), sponsored by the

NIAID, CDC, and the National Institute of Drug

Abuse. The goals are multiple: 1) to study sociocultural factors affecting recruitment and retention; 2) to measure the frequency of risk behaviors, to assess the effect of trial participation,

counseling, and unbinding on risk behaviors, and

to develop strategies to reduce the frequency of

risk behaviors (undocumented changes in personal risk behavior can have confounding effects on

the apparent efficacy of a vaccine) (87); 3) to determine the basis for attitudes toward vaccine acceptance; 4) to develop educational strategies and

consent forms appropriate to the subject groups;

and 5) to study the dynamics of trial acceptance

and feasibility. Information derived from such

studies will enhance the feasibility and readiness

to undertake full-scale HIV vaccine efficacy trials

in the U.S. Continued research into the measurement of socio-behavioral variables is critical to

planning, trial design and data analysis.

❚ Criteria for Selection of a Vaccine for

Efficacy Trials

The criteria for selecting an HIV vaccine candidate that merits study in a Phase III efficacy trial

has been extensively discussed over the past few

years. Because we do not know what specific type

of immune response is required to provide protection from HIV infection, the criteria to be used to

select vaccine candidates are not sharply defined.

Discussions have involved consideration of the

following elements: 1) evidence of safety and immunogenicity of the vaccine in Phase I and 11

trials; 2) the vaccines ability to induce high-titered, broadly reactive, and sustained levels of antibody capable of neutralizing primary field HIV

isolates; 3) the vaccines ability to induce cytotoxic

T lymphocyte responses, and 4) evidence of vaccine protection in a primate model. However, in

the face of scientific uncertainty and a rapidly

evolving knowledge base, the relative emphasis

and stringency given to each of these criteria have

varied in successive recommendations. More

clearly defined criteria for selection of vaccine

candidates for entry into Phase III efficacy trials

would be of obvious value.

❚ Envelope Proteins as Candidates for

Efficacy Trials

Two candidate vaccines, Biocine SF2 with MF59

and Genentech MN with alum adjuvant have completed Phase II trials. A Phase III clinical trial of

envelope vaccine would test the following hypothesis: can neutralizing antibody, with certain

limitations in its magnitude, cross-reactivity,

durability, and mucosal localization, protect a

high-risk population with a measurable level of

efficacy?

In June 1994, the NIAID AIDS Subcommittee

and AIDS Research Advisory Committee (ARAC)
Chapter 2 Potential for Adverse Reactions from HIV Vaccines 57

Biological factors Factors favoring efficacy trials Factors weighing against efficacy trials

Safety ■

Immune response ■

■

Primate model ●

Social, political, ■

ethical factors

■

●

■

■

Only minimal transient local and sys- ■

temic reactions have occurred.

Neutralizing antibody has been induced ■

by envelope vaccines.

CTL may not be essential.

■

Envelope vaccine protects chimpanzees ■

against mild HIV infection under limited

conditions.

Vaccine need is a public health impera- ■

tive.

Infrastructure for trials is ready. ■

Modest protection valuable. ■

Scientific gains may result, e.g., immune ●

determinants of protection.

Product is ready ●

KEY: CTL = cytotoxic T lymphocytes

Breakthrough infections; Possibility of immune

enhancement.

Need increased titer, duration, and cross-reactivity of antibody in response to envelope protein, as well as neutralization of primary isolates.

CTL may be important to protection.

Envelope vaccine offered; poor protection in

more stringent SIV/monkey disease model.

An inconclusive trial may result, with loss of

public confidence.

A better behavioral database is needed,

Trial may involve large investment of funds and

human resources for questionable gains, False

security may increase risk-taking.

Trial lacks sensitivity to detect immune determinants of infection,

Setback for industry if trials fail.

SOURCE Adapted from A. Hause, “Report on the April HIV Vaccine Working Group Meeting," paper presented at the NIAID AIDS Research Advisory

Committee (ARAC) meeting, June 17, 1994

recommended that Phase III clinical efficacy trials

with the envelope vaccines should not proceed in

the United States at that time (25). Factors contributing to the decision included scientific, political, and ethical issues (39) (table 2-1 2). There was

a significant level of scientific uncertainty regarding the wisdom of immediate efficacy trials, with

advocates on both sides of the question. Two trial

designs were discussed (46). A definitive threearmed trial with a sample size of 9,000 high-risk

individuals would permit detection of statistically

significant protection from a vaccine with only 30

percent efficacy. Alternatively, a smaller trial, involving 4,500 individuals, would allow detection

of significant protection from a vaccine with 60

percent efficacy, but have little chance of detecting the protection from a vaccine with 30 percent

efficacy. 1 9

Phase I and II clinical trials of HIV vaccines

continue. New generation products recently entered into Phase I trials or in the preclinical pipeline are designed to expand the quality and quantity of the protective immune response to the

vaccine. These products should be available for

consideration for Phase III efficacy trails within

two to three years.

❚ Monitoring Adverse Events in Efficacy

Trials

The long-term followup of large numbers of vaccinees and controls allows for surveillance of

events that are infrequent or occur after an interval

of years. The prospectively defined populations

that participated in vaccine efficacy trials constitute unique epidemiologic cohorts, not easily du19 Larger trials are able to defect smaller degrees of vaccine efficacy.
58 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

plicated after controlled efficacy trials are completed. “Vaccinated cohorts” from efficacy trials

could be compared to the unvaccinated cohorts

that are currently under epidemiologic and virologic surveillance.

Provision for long-term followup should be an

integral part of the design of efficacy trials, allowing surveillance of safety issues, such as enhanced

infection, autoimmune disease, tumors, or reversion to virulence. Rigorous assessment will be required before acceptance of a causal relationship

between a vaccine and adverse events. Despite

difficulties and expense, decades of experience

with childhood vaccines emphasize the singular

need for maintaining followup capability.

❚ Efficacy Trials in the Developing World

While the current document addresses domestic

issues, it is clear that HIV-1 efficacy trials at international sites will be an important and integral

part of the process of developing and evaluating

AIDS vaccine candidates. Such sites provide opportunities to study diverse population groups in

highly endemic areas, including heterosexual and

maternal-infant transmission of HIV, a variety of

cultural and health settings, and vaccines targeting

a multiplicity of HIV subtypes. In addition, it affords the possibility of direct benefit to the participating population in a tangible way. Vaccine affordability, ease of administration (given in a few

doses or orally), and stability of protection will be

critical to widespread use of vaccine. The NIAID

and U.S. Department of Defense (DOD) are developing sites in concert with national governments in the Americas, Africa, and Asia. A multivalent peptide vaccine is currently the only

approach in advanced stage of development that

addresses the diversity of global subtypes. Opportunities for assessing subtype B strains are available in the Americas and Western Europe, as well

as in a locus in Thailand.

The June 1994 decision to defer Phase III clinical efficacy trials in the U.S. does not preclude

clinical efficacy trials of envelope-based vaccines

in the developing world. Applying standards of

safety and efficacy to populations with a rapid and

uncontrollable rise in HIV infection alters the risk

to benefit ratio of the vaccines. While ethical principles of such decisions remain universal, it is recognized that biological circumstances can validly

affect the decision process. The attendant risks of

adverse reactions or social harms in a developing

world setting engender a separate level of issues,

involving U.S. industry, institutions, and investigators, as well as the host foreign nationals. Issues

surrounding vaccine trials in developing countries

are discussed in chapters 3 and 4.

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Ethical Issues in the

Design and

Conduct of

HIV Vaccine Trials

lthough of crucial importance, human trials of HIV vaccines should not go forward without appropriate attention

to ethical considerations. This chapter provides an overview of the ethical considerations that arise in the design

and conduct of clinical trials of preventive HIV vaccines.1 The

primary focus of this chapter is on Phase III (efficacy) trials; however, many ethical issues relevant to early stage (Phase I and II)

clinical trials and to the marketing of HIV vaccines are also addressed. 

This chapter begins with a review of some basic ethical principles and background information about clinical trials. The

chapter then discusses ethical issues in clinical trial design, sample selection, informed consent, trial termination, and compensation for adverse reactions. The chapter concludes with a discussion of ethical issues relevant to clinical trials in developing

countries, and issues arising from the incorporation of HIV vaccines into clinical practice.

BASIC ETHICAL PRINCIPLES

All biomedical research should be conducted in a manner that

seeks not to violate three primary bioethical principles: 1) beneficence, 2) respect for autonomy, and 3) justice (3).1 The principle

1 This paper is concerned with ethical obligations, rather than legal ones. Ethical obligations tell us how we ought to act, in accordance with a series of morals, values, and

principles. In certain contexts, including in the research context, organizations have put

forward codes of behavior to guide ethical conduct. Typically, these codes are not binding

legally, and at most, carry weight in determining the standard of care. Legal obligations

tell us what we are required to do, in accordance with a government’s legal system, as defined by regulations, legislation, and court decisions. Breach of legal obligations typically

results in specified penalties.

| 65

by

Nancy E. Kass

Johns Hopkins University

School of Hygiene and

 Public Health

Baltimore, MD
66 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

of beneficence addresses one’s obligations to ensure the well being of others. Included within the

principle are both the obligation to do no harm

(called nonmaleficence) and the obligation to do

good. In the context of clinical trials, the principle

of beneficence requires that the welfare of research participants be protected. Participants must

not be exposed to undue or excessive risks. This

obligation may not be waived merely by informing subjects of these risks.

Moreover, initial responsibility for ensuring

that risks are not excessive lies with the investigator, the vaccine sponsor, and an external review

board. This responsibility may not be delegated to

the research participant, for two reasons. First, research volunteers are unlikely to understand the

risks of research as well as do the investigators and

research sponsors. Second, it is a central tenet of

research ethics that, unless personal benefit can be

gained from trial participation, there are certain

risks that are just too great for anyone to consent

to, regardless of one’s level of understanding of

those risks. In trials involving human research

subjects, an external review board, in collaboration with the investigators, is charged with assessing whether a given level of risk is justified. External review boards are given this responsibility

because of concern that investigators directly involved in the study have interests that may bias

their assessment of research risks. Also, external

review boards typically include lay persons and

persons from disciplines other than that of the investigator, who provide balance in the assessment

of the reasonableness of risks.2

There are further obligations arising out of beneficence. When persons are included in research

who might be particularly vulnerable to being exploited (e.g., prisoners, children, persons with

little formal education), beneficence requires us to

provide special protections to ensure that these

participants are not harmed by the research.

Respect for autonomy, or respect for persons,

obligates investigators to recognize research subjects as individuals who have the right to make

their own decisions, even when those decisions

are based on values or world views that are different from those of the investigator. The doctrine of

informed consent (described below) is derived

from the principle of respect for autonomy.

Justice requires fairness in the distribution of

both benefits and burdens. In research, this requires that no individuals or populations bear a

disproportionate share of the risks of research

without justification, and that all populations have

access to the benefits of research participation.

Each of these three principles create independent obligations that may conflict. For example,

decisions about what is the “reasonable” level of

risk above which participants cannot be exposed

(based on beneficence) may conflict with the right

of potential participants to determine this level for

themselves (based on respect for autonomy).

Another example is the potential conflict among

the obligation of external boards to protect certain

groups or individuals from research risks (based

on justice), the obligation to allow individuals to

make that assessment for themselves (autonomy),

and the obligation to obtain findings that will

benefit society as a whole (beneficence). There are

no clear rules for balancing these obligations.

In actual practice, the investigators and an outside

board first determine what harms are unreasonable. If the risks of trial participation are not

unreasonable, potential research participants must

provide “informed consent” to trial participationresearch participants should be given information

about the trial in question, including its risks, and

allowed to decide whether they wish to participate, according to their own values and preferences.

CLINICAL TRIALS OF VACCINES

There are two main categories of vaccines being

developed for HIV: prophylactic vaccines and

therapeutic vaccines. Prophylactic HIV vaccines

2 For further history of Institutional Review Boards, see R.J. Levine, 1988 (20).
Chapter 3 Ethical Issues in the Design and Conduct of HIV Vaccine Trials | 67

have as their primary purpose the prevention of infection (although, in certain cases, the term is used

for vaccines intended to prevent establishment of

infection). Therapeutic HIV vaccines are given to

persons who are already infected to slow, halt, or

reverse the progression of disease. In this sense,

therapeutic vaccines are similar to any other treatment.3 This chapter discusses ethical issues surrounding clinical trials of prophylactic HIV vaccines.

While the three phases to the testing of vaccines

in human populations were described in detail in

chapter 2, the focus of this chapter is on ethical issues related to the conduct of clinical efficacy

(Phase III) trials of HIV vaccines, although many

of these issues are also relevant to the conduct of

Phase I and Phase II trials. The final portion of this

chapter discusses some ethical issues related to

the use of an approved HIV vaccine in clinical

practice.

ETHICAL ISSUES IN THE DESIGN OF

CLINICAL TRIALS

These are a number of ethical considerations in the

design of a clinical trial of a prophylactic HIV vaccine. Fundamentally, a trial that is not designed to

yield valid, scientifically new, or confirmatory results is unethical and should not be conducted because no burden or risk on the part of research participants is justified if some benefit is not likely to

result. Assuming that there is scientific justification to proceed with a clinical trial, specific questions related to design must be addressed.

❚ Is Randomization Ethical?

Benjamin Freedman argued that it is only ethical

to randomly assign trial participants to an experimental intervention where there is “clinical equipoise—“that is, where there is uncertainty in the

medical or scientific community generally about

whether the intervention is beneficial (10). This

does not require, however, that the investigators

themselves not have a “treatment preference.”

Because HIV is such a serious condition and

the consequences of erroneous vaccine research

findings would be great, it may be less ethical to

conduct a vaccine trial that does not randomly assign trial participants. Randomized clinical trials

are not the only means of assessing effectiveness,

but because they minimize the potential for bias,

they are considered the “gold standard” for clinical research (30). Randomized trials of HIV vaccines are particularly important because factors

that affect HIV transmission, such as risk behaviors or concurrent infection with other sexually

transmitted diseases, have the potential to bias the

results of an observational study of vaccine efficacy.

Once there is consensus that an HIV vaccine is

protective, it would not be ethical to conduct a

vaccine trial that randomly assigns research participants to a placebo vaccine.4 It is ethical to conduct randomized clinical trials to test hypotheses,

but not to provide confirmatory data.

❚ Will Trial Participants Receive

Counseling About Risk Behaviors?

Any clinical trial of an HIV vaccine should include behavioral counseling about risks for HIV

transmission at every study visit. This is ethically

required, not only because the vaccine is unlikely

to be completely efficacious and some participants in a randomized trial will not receive the

vaccine, but also because there is a responsibility

to provide trial participants with some benefit if

possible at not too great an expense. Moreover, the

provision of behavioral counseling reinforces the

message to trial participants that vaccines are but

one part of an overall strategy to prevent HIV

transmission, which also includes the avoidance

of behaviors that increase one’s risk of infection.

This will also be an important message to convey

3 The possible uses for an HIV vaccine are described in chapter 2, box 2-1, “The Spectrum of Possible Strategies for Uses of HIV Vaccines.”

4 After an HIV vaccine is approved, new generation experimental vaccines would be tested against the approved vaccine.
68 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

when HIV vaccines are incorporated into clinical

practice.

Although the power of a study to detect differences between vaccine and placebo recipients will

be reduced if the recipients’ baseline rate of seroconversion falls, ethically the most effective behavioral counseling should be provided to participants.

❚ Are Procedures Adequate for the

Confidential Handling of Research

Data?

In research, it is imperative that all aspects of data

collection, including recordkeeping, data storage,

and the sharing of information be performed in a

manner that maintains participants’ confidentiality. Persons known or even suspected of being

HIV positive have experienced discrimination in

housing, employment, and insurance, as well as

social discrimination from peers (14). Because the

HIV-related information gathered in HIV vaccine

trials is particularly sensitive, the maintenance of

confidentiality in these trials is especially important.

Procedures should be established to maintain

the confidentiality of trial participants. A number

of practical measures should be taken. For example, participants should be assigned unique identification numbers, and all interactions with participants should be conducted using those unique

identifiers (or first names if trial participants prefer), rather than the trial participants’ full names.

A “master key” that links participants’ full names

to their unique identification numbers should be

kept in a locked cabinet or other secure place, and

accessible by only a limited number of investigators.

The participants’ full names should not be revealed to those who interview the participant,

draw his or her blood, provide behavioral counseling, administer the vaccine, or otherwise personally interact with the participant. All written information and specimens should be labeled with

the participants’ unique identifiers, and these

should be kept in locked storage units or computer

files with controlled access. Most important, staff

at all levels should be trained in procedures for

maintaining confidentiality.

Participants in clinical trials of HIV vaccines

should be assured that they may have access to

their files once the trial is completed. Participants

should be provided with documentation of their

participation in the HIV vaccine trial, as it may be

needed later to demonstrate, for example, that vaccine is the source of a false-positive HIV screening test.

Some researchers have sought to bill participants’ insurers for any trial-related procedures

(e.g., laboratory analyses, screening tests, etc.).

The primary legal reason why insurers rarely pay

for these procedures is that insurance policies only

provide reimbursement for “medically necessary”

treatments. One’s decision to participate in a clinical trial is completely discretionary and the efficacy of the preventive therapy or treatment is unproven, so the experimental therapy cannot be

considered medically necessary. There is also an

important ethical reason such claims should not be

filed: the filing of claims would pose unjustifiable

risk to trial participants’ confidentiality. In HIV

vaccine trials, the filing of a claim would require

the disclosure of the participants’ names and sensitive HIV-related information to individuals who

have no relationship to the trial. The disclosure of

sensitive HIV-related information may put the

participants’ access to future coverage at risk.

Therefore, payment for trial-associated medical

procedures should be the responsibility of the investigators and vaccine sponsors, and funds for

these procedures should be included in the trial

budget.

❚ Is There Community Involvement in the

Planning and Conduct of the Trial?

Although the importance of a community board is

usually emphasized in discussions of clinical

trials in developing countries, a community board

is equally important for trials conducted in the

United States or other developed countries. A

community board often is comprised of approximately 10 persons, usually trial participants, who

meet with the investigators periodically through-
Chapter 3 Ethical Issues in the Design and Conduct of HIV Vaccine Trials | 69

out the course of the trial, beginning with its developmental stage. Community boards often review and make recommendations about how the

trial should be conducted. In some settings, new

staff must be interviewed and approved by the

board before they are hired. The community board

benefits both the trial participants and the investigators. Participants can contact board members,

who may seem more accessible than investigators, with questions and concerns. The members

of the board are intended to be representative of

trial participants, and will help ensure that participants’ rights are protected. Researchers are likely

to benefit from participants’ greater involvement

and, perhaps, “ownership” of the research, that is

engendered by the community board; this could

result in greater retention and better adherence by

participants to study protocols.

SELECTION OF SAMPLE

There are a number of ethical considerations in recruitment and selection of trial participants. Generally, individuals suitable for clinical efficacy

(Phase III) trials are from populations with a high

incidence of HIV infection, and should be from

communities with sufficient willingness and infrastructure to support a trial (31). A candidate

vaccine should be tested in the populations in

which it would be used in clinical practice because

a study’s findings may not be generalizable to

populations other than those from which the study

sample was chosen.

❚ Special Populations

Historically, a major thrust of research ethics has

been the protection of vulnerable populations

from enrollment in human subject research without their (or their guardians’) knowledge or consent (an autonomy-based concern) or without justification for their specific inclusion (a

justice-based concern) (25, 33). More recently,

concerns about not burdening any population disproportionately have been supplanted by concerns

that there be fair access among populations to

what may be the benefits of participation in research. In both cases, the key concern is one of justice: all populations have a right to the potential

benefits of research, and no population, particularly those unable to provide voluntary consent,

should bear the burdens of research unjustly.

“Vulnerable” populations, or those that may be

unable to provide valid informed consent, can be

divided into two general categories. First are those

who have the mental capacity to consent, but, because of their situation, do not have the practical

ability to provide consent voluntarily. Examples

of this category of vulnerable populations include

prisoners, women in certain societies, some desperately ill patients, or those in a dependent relationship with the investigator, such as medical

students or patients. Second are those who are unable to consent by virtue of a characteristic or

condition inherent to them. Examples include

children and persons with mental illness or mental

retardation who do not have the mental capacity to

provide consent. The obligation to protect vulnerable participants, particularly in light of gross

harms to which they have been submitted in the

past,5 remains paramount. At the same time, all of

these populations also have a claim to what may

be considered the benefits of participating in a

trial.

In determining whether to include any vulnerable population in research, two questions should

be answered. First is whether it is necessary to include the vulnerable population to obtain knowledge that cannot be gained from studying other,

less vulnerable populations. For example, one can

only determine the efficacy of a drug or vaccine

for children by conducting clinical trials involving children. Second, do the members of the vulnerable population (or their guardians) consider

the research to be of benefit to themselves.

5 An initial expose of unethically conducted biomedical research was presented in a book by Beecher and colleagues in 1966 (4).
70 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

The question of whether to include pregnant

women in clinical trials has been given particular

attention in recent years (24). Until recently, pregnant women have largely been excluded from

clinical trials because of concerns about risks to

the fetus. However, the only way to study whether

a vaccine prevents transmission of HIV from

mother to fetus (vertical transmission) is to include infected pregnant women in clinical trials.

As discussed in chapter 2, although pregnant

women have been excluded from HIV vaccine

trials in the past, there are now clinical trials of

vaccines to interrupt vertical transmission that

have enrolled infected pregnant women.

Certain populations at increased risk for HIV

infection may be considered vulnerable, not because of a hampered ability to provide consent,

but because they are at particular risk of social

harms from trial participation. For example, some

high-risk behaviors are illegal (e.g., injection drug

use, prostitution, and, in certain jurisdictions,

male-to-male sex). Members of these high-risk

groups may increase the chance of detection as a

result of trial participation. At the same time, such

high-risk individuals are targeted for HIV vaccine

clinical efficacy trials because they have high rates

of seroconversion and because they offer an opportunity to study the interaction between the vaccine and specific risk behaviors. Investigators

should assure these potential research participants

that their confidentiality will be protected.6

❚ Members of Racial and Ethnic Minority

Groups

African American and Hispanic persons are likely

to be recruited for HIV vaccine trials in greater

proportion than their representation in the population, given that they are highly represented among

groups at risk for HIV infection. There is reason

to believe that African American and Hispanic

persons are more likely to be suspicious of the

intentions of investigators, given the history of

abuses of members of racial minority groups in

clinical research, most notably in the Tuskegee

syphilis study (29). Involvement of community

boards and “gatekeepers” is especially important

from the outset of HIV vaccine trials to better ensure that trial participants’ needs are addressed

and that investigators are sensitive to cultural concerns.

It is also important to ensure that members of

racial minority groups are recruited for participation in research trials given that the prevalence of

infection is higher among these groups and that

many members of these groups would be candidates for a vaccine once approved.

INFORMED CONSENT

Rooted in the principle of respect for autonomy is

an ethical obligation on the part of investigators to

engage potential research participants in the process of informed consent and to obtain adequate

consent from all participants.7 The U.S. Public

6 Investigators may want to obtain a Federal certificate of confidentiality to better ensure protections for this category of participants. Public

Health Service Act, § 301(d), 42 U.S.C. The Act states that special protection will be granted “sparingly” to research projects of a “sensitive

nature where the protection is judged necessary to achieve the research objectives.” 42 U.S.C. § 301(d). Examples of the types of research that

may qualify are those that collect “information relating to sexual attitudes, preferences, or practices; alcohol, drugs, or other addictive products;

illegal conduct; information that if released could reasonably be damaging to an individual’s financial standing, employability, or reputation;

information that would be recorded normally in a patient’s medical record, and the disclosure of which could reasonably lead to social stigmatization or discrimination; information pertaining to an individual’s psychological well-being or mental health.” Researchers who have obtained

a certificate of confidentiality “may not be compelled in any Federal, State, or other local civil, criminal, administrative, legislative or other

proceedings to identify [research participants].”

7 See Beauchamp and Childress, 1989 (3), for further discussion of ethical principles.
Chapter 3 Ethical Issues in the Design and Conduct of HIV Vaccine Trials | 71

Health Service established a policy in 1966 (revised substantially in 1974)8 that all federally

funded research must be approved by external review boards that have as part of their responsibility ensuring that investigators obtain informed

consent.9 Essentially all academic institutions require that all research involving human subjects

(not just that funded by the federal government)

secure such approval. The need for this external

oversight arose from the recognition that there

may be conflicts of interest among clinical investigators.

The process of informed consent for a clinical

trial involves: 1) providing the prospective participant with information relevant to his or her decision about participation in the trial, 2) ensuring

that the participant understands that information,

3) ensuring that the participant is choosing to participate voluntarily, and 4) documenting the consent of the participant.10

The following information should be provided

to potential participants: an explanation that they

are being asked to participate in research, not clinical care; a statement of purpose of the research; an

explanation of why they were selected; a description of all procedures that they may undergo, including duration, location, and frequency of study

visits; a description of the “foreseeable” risks and

benefits (both to the participant and others); the alternatives to trial participation (or to the experimental therapy or intervention); a description of

how confidentiality will be protected; a description of whether there will be compensation for injuries resulting from participation; a list of those

of who can be contacted for questions or problems; and a declaration that participants have the

right both not to participate in the trial and to cease

their participation at any time, and that by so doing, the receipt of medical care or other benefits

will not be compromised.

In addition to these general requirements, there

are considerations specifically for HIV vaccine

trials. Any clinical efficacy trial examining HIV

transmission will need to limit its sample to persons who are not HIV-infected. Therefore, all potential enrollees will first be screened for HIV infection. There needs to be an informed consent

process for this testing that is distinct from the informed consent process for enrollment in the research trial. The usual procedures for pre- and

post-test counseling must be adhered to. In addition, information should be provided to the potential enrollee that explains that a positive HIV test

renders the potential subject ineligible for participation. Moreover, some means of referral for

those found to be infected must be established.

Particular problems may arise from HIV testing, in that certain states require the names of all

persons who test positive for HIV be reported to

the state health department. If such name reporting is required in the state where the research is being conducted, this should be disclosed to potential trial participants and included in the consent

form. If the investigators, however, have received

an exemption from this requirement, then there is

the concern that persons will volunteer for the trial

just to receive a confidential HIV screening test,

8 45 Code of Federal Regulations, §§ 46.101-46.509.

9 Institutional Review Boards (IRBs) are established by an institution conducting medical research to assess the legal, ethical, and scientific

aspects of research on human subjects. IRB approval is required by the Department of Health and Human Services (DHHS) before proposals

can receive federal funding. IRBs must review research protocols on a regular basis, but not less than once a year.

Federal regulations for human subjects research require both a generalized as well as specific informed consent for subjects to ensure that

they understand the nature of the trial, the lack of any expected benefit, and the risks that are involved. 45 C.F.R. 46.101 (1993). Additional

requirements apply to trials involving pregnant women and prisoners. The regulations are administered by the DHHS Office of Research Risks.

Agencies and departments outside of DHHS are also required to adopt similar requirements. Although U.S. courts have not always relied on

federal requirements to determine the standard for informed consent in clinical trials, failure to comply with these requirements could also give

risk to a suit in tort.

10 For a much more detailed discussion of informed consent see, e.g., Faden and Beauchamp, 1986 (8); and Appelbaum, et al., 1987 (2).
72 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

but with no intention of ultimately participating in

the trial.

Once potential trial participants are selected

from a pool of eligible persons, they should be

provided with specific information as part of the

disclosure component of the informed consent

process, and investigators must ensure that each

potential participant understands this information:

1. The meaning of incomplete efficacy. Potential

trial participants should be informed that the investigators have no assurance that the particular vaccine being tested will actually be effective in preventing HIV infection, and, even if

the candidate vaccine is effective, it is not likely

that it would be completely effective in preventing HIV infection. Trials participants

should therefore avoid high-risk behaviors, as

they would had they never received the vaccine.

2. The meaning of a placebo and the meaning of

randomization. Potential participants in a randomized clinical trial should be informed that

there is a chance that they will not receive the

experimental vaccine, and they should be informed of the likelihood of that chance. In

some trials, investigators are choosing to provide the control arm of studies with an alternative vaccine, such as Hepatitis B vaccine, rather

than a placebo vaccine. If so, this should be disclosed to potential trial participants.

Various analogies have been used to explain the

concept of random assignment, including the

flipping of a coin or choosing marbles from a

jar, depending on the number of experimental

and control groups employed in the study.

What is most important is that participants understand that they may not be assigned to the

group(s) receiving the experimental vaccine,

that this assignment is made by chance, that

they will not be told if they have received the

experimental vaccine until the study is completed, and that the persons administering the

vaccine as well as most of the other research

personnel will also not know to which group

they have been assigned.

3. The importance of not being tested outside of

the study. Potential participants should be informed that they must commit to not be tested

for HIV outside of the trial since that could reveal whether they have received the experimental vaccine. Participants’ knowledge of their assignment could bias the results of the trial by

affecting the participants’ risk behaviors, their

reports of side effects, and so forth. Admittedly,

many investigators have hesitated to warn potential participants to not obtain HIV testing

outside of the study, fearing that this knowledge may increase the likelihood that participants would obtain such testing.

At the same time, participants should be told

that if they need to know whether they have become infected with HIV, they may obtain HIV

tests from the investigators. Investigators

would use the appropriate tests to diagnose

HIV infection, and would inform participants

if they have become infected with HIV.

4. That vaccine recipients testing positive on commonly used HIV screening tests may suffer social harms as a result. Potential trial participants should be made aware that certain social

harms may occur as a result of trial participation. Vaccinees may test positive on the

ELISA (enzyme-linked immunosorbant assay)

screening test, and other commonly used

screening tests, which may result in problems

in obtaining health or life insurance, employment, military service, or in travel to other

countries. Participants should also be told that

they will receive a document that certifies their

participation in the vaccine trial and explains

that they may test positive for that reason. More

specific tests may be used to determine whether

they are infected with the virus; if requested,

these tests would be conducted at the investigators’ expense.

Potential participants should be told that vaccination may increase the difficulty of diagnosing HIV infection. Standard ELISA screening

tests cannot determine whether a vaccinee is

HIV infected; more specific tests must be used.
Chapter 3 Ethical Issues in the Design and Conduct of HIV Vaccine Trials | 73

5. That other social or personal harms might result. Others may assume that trial participants

are members of groups at increased risk for

HIV infection and social stigmatization could

result. Some have suggested that social harms

from trial participation be monitored, just as are

biological adverse events. A board could be established to monitor and review social harms

and decide if these harms to trial participants

are sufficiently severe to warrant termination of

the trial.

6. That participation in this trial may make participants ineligible for other HIV vaccine

trials. Because multiple vaccinations may confound interpretation of results, trial participants

that receive the experimental HIV vaccine may

not be eligible for participation in trials of subsequent and trials of possibly more effective

HIV vaccines.

Cause of the large amount of information that

must be conveyed in the informed consent

process, some investigators have chosen to

give potential participants a written test of their

understanding of this information. (Tests could

also be administered orally to participants who

cannot read.) This test would be completed

upon enrollment and at each subsequent visit.

A participant’s continued participation in the

trial could be made contingent on their successful completion of the test. Participants who do

not “pass” the test would receive more education before the test is readministered.

Investigators and sponsors have an ethical obligation to ensure that there is an independent Data

Safety and Monitoring Board (DSMB) to examine trial data at preestablished intervals for convincing evidence of either significant effectiveness or unacceptable harm from the experimental

vaccine requiring termination of the trial.

Investigators also have the ethical obligation

throughout the trial to provide participants with

any other information that may reasonably be expected to influence their willingness to participate, and to evaluate whether continued participation in the trial is in the participants’ best interests.

The ethical obligation of investigators goes beyond providing information to the DSMB; it also

could include information that becomes available

through the vaccine research of others, HIV research in other realms, such as behavioral research, or relevant changes in public policy, if this

can reasonably be expected to influence participants’ willingness to participate.

RESEARCH IN DEVELOPING

COUNTRIES11

It is not ethical for investigators or vaccine

manufacturers to conduct trials in developing

countries merely because it is less expensive or

more convenient. To ignore the need for effective

vaccines in developing countries, however, would

be ethically unacceptable because HIV is an overwhelming problem in so many of these countries.

Moreover, strains of HIV from different parts of

the world vary, as do cofactors that influence

transmission of infection and disease progression;12 thus, findings from vaccine trials conducted in the United States or other developed

countries, would not be generalizable to developing countries. For these reasons, it is appropriate

to conduct HIV vaccine trials in developing countries that have a high incidence of HIV infection.

Box 3-1 describes international guidelines for human subjects research.

11 International guidelines for human subjects research developed by the World Health Organization (WHO) and the Council for International Organizations of Medical Science (CIOMS) are described in box 3-1. See also Lurie, et al., 1994 (23) ; Katongole-Mbidde, 1993 (16); and

Lawrence, et al., 1993 (19).

12 HIV is not a single, genetically homogenous virus, but exists in multiple strains, which differ among individuals from different regions, as

well as among individuals from the same region (22). It has been estimated that isolates of HIV differ as much as forty percent in their envelope

sequences (9), and that at least five major families or clades of HIV exist around the globe (12).
74 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

In 1993, the Council for International Organizations of Medical Sciences (CIOMS), in collaboration

with the World Health Organization (WHO), approved a revised set of guidelines for human subjects

research (6) The International Ethical Guidelines for Biomedical Research Involving Human Subjects

begins with a statement of general ethical principles, and includes 16 guidelines.

The Introduction to the guidelines notes that one of the reasons for the revision of the guidelines,

initially promulgated in 1982, was the prospect of clinical trials of HIV vaccines and drugs for AIDS

Guideline 8 provides that, in conducting human subjects research in developing countries, investigators must ensure the following: that persons in developing countries will not ordinarily be revolved in

research that may equally well be carried out in developed countries, that the research should be responsive to the health needs and priorities of the community in which the research is being conducted,

that every effort should be made to secure the Informed consent of individual research participants,

and that proposals for the research should be reviewed and approved by an ethical review committee.

Guideline 15 states that the agency that is initiating the research should submit the research protocol

to ethical and scientific review according to the standards of the initiating country, and the ethical standards applied should be equal to those applied to research conducted in the initiating country The

guideline also states that the appropriate authorities of the host country should assure themselves that

the proposed research also meets the host country’s own ethical requirements

Although the guidelines do not address Iiability for adverse reactions, guideline 13 states that participants who suffer physical injury as a result of their participation are entitled to equitable compensation

the guideline does not define, however, what compensation is equitable The sponsor of the research

whether it be a pharmaceutical company, a government, or an Institution, should agree to provide compensation before the human subjects research is initiated, and research participants should be informed that such compensation is available The guidelines also state that the ethical committee has

the responsibility to determine what Injuries are compensable and by whom

SOURCE: R.E. Stein, Blicker & Stein, Washington, DC, “Selected Issues of AIDS Vaccine Liability, ” unpublished contractor report

prepared for the Office of Technology Assessment, U S Congress, Washington, DC, Sept. 30, 1994

—

Local representatives should be included in the

preparation and conduct of the vaccine trial. Such

involvement will enhance mutual respect, which

is ethically linked to respect for autonomy. Moreover, from a practical perspective, inclusion of local representatives can help ensure the success of

the trial. Local representatives can provide a conduit for information relevant to the logistical operations of the research, can enlist support for the

research, and can provide outside investigators

with a greater understanding of local customs and

expectations. Involvement of a senior investigator

from the local site is crucial, as is the involvement

of other local scientists. To involve local scientists, outside investigators may need to provide

them with further training.

❚ Recruitment

Questions have been raised over whether it is ethically acceptable to recruit participants who have

little control over their ability to contract HIV infection, such as women whose male partners refuse to wear condoms or are not forthcoming

about their own HIV status. However, this is the

context in which some vaccines would be administered if proven to be efficacious. For this reason,

it is appropriate to include such populations, with

a commitment to trying to encourage these persons to protect themselves. It has been argued that

it would be unethical to recruit participants from

a community that denies the existence of HIV infection (16, 23, 27). Recruitment of these partici4
Chapter 3 Ethical Issues in the Design and Conduct of HIV Vaccine Trials | 75

pants would be ethically acceptable only if targeted education were provided as part of

recruitment.

❚ Informed Consent

The issue of how to obtain valid informed consent

in developing countries is paramount.13 Many of

the issues that arise are the same as when obtaining consent in developed countries and many are

not unique to HIV trials. Those that are special

will be given attention here.

Ethics requires that both local and Western

standards of informed consent be followed. Although there are debates about whether there exists “ethical universalism” (one set of principles

that applies everywhere) or “ethical pluralism”

(different principles in different contexts of cultures) (21), societies have different rules about

who may grant permission for participation in research. In some societies, permission must be

granted by a community leader or by someone

other than the research participant (e.g., a

woman’s husband). Ethics requires that all local

customs and requirements be met out of respect

for both the community and the individuals involved; however, this does not abrogate the obligation of the investigator to seek and obtain consent from the potential trial participant as well.

Although some may consider this latter obligation

to be ethnocentric on the part of Westerners, this

remains the ethical standard for international research (6). 

Potential trial participants should have an adequate understanding of the study and its components in order for informed consent to be valid. If

the potential trial participants are illiterate, this

would alter the means by which informed consent

is obtained. Information would need to be provided in the local language or dialect and read to

potential participants rather than conveyed in

written form. Visual aids or diagrams might be included among the materials given to the potential

participants. Similarly, if some sort of a “test” of

understanding is required, this would need to be

conducted orally.

A more difficult situation occurs if the broad

understanding of disease causation is completely

different from Western understandings (1). For

valid informed consent, it is not necessary for potential participants and investigators to have a

completely shared understanding of disease

causation. If the differences mean that, by virtue

of participating, harmful consequences are likely

to ensue, however, these persons cannot ethically

be enrolled. Differences in beliefs must be evaluated on a case-by-case basis, and balanced with

the need to ensure that any potential benefits of research participation not be denied to such populations.

Developing countries may not have the sophisticated tests necessary to detect HIV infection in

vaccinees. Outside investigators should provide

support, including these specific tests and necessary technical assistance. Investigators should

also assist participants in securing documentation

that they were enrolled in a vaccine trial. Although

most vaccinees from developing countries would

not have use for such documentation, it may be

helpful in certain contexts, such as for immigration.

❚ Other Responsibilities of Investigators

Investigators have the ethical obligation to not interfere with other prevention or public health efforts and not to draw the necessary number of local, trained health care personnel away from other

important responsibilities. It also may be necessary to provide training to local personnel.

Once the vaccine is marketed, justice obligates

the researchers and vaccine sponsors to make vaccine available to the community in which the trial

was conducted. In developing countries, the obligation to ensure access to the benefits of vaccine

13 See Council for International Organizations of Medical Sciences and World Health Organization, 1993 (6). See box 3-1.
76 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

research would require the manufacturer to provide the vaccine for free or at cost.

COMPENSATION FOR ADVERSE

REACTIONS

Although there may be no legal obligation to provide compensation for injuries incurred through

research, it is generally agreed that there is an ethical obligation to do so (6, 18). Moreover, it need

not be demonstrated that there was negligence on

the part of researchers, but simply that harm resulted that would not have occurred had the person

not participated in the trial. If compensation will

not be provided, this should be explained in the informed consent process and included as part of the

informed consent statement. Compensation need

not be provided for harms that are not a direct result of research participation, such as for HIV infections not caused by the vaccine. Compensation

decisions should be guided by the laws of the

country in which the trial is occurring (17).

Potential trial participants should be informed

that, even if investigators plan to provide compensation for harms resulting from trial participation, compensation will not be provided for harms

resulting from the vaccine being less than completely effective in preventing HIV infection.

INCORPORATION INTO CLINICAL

PRACTICE

A number of important ethical issues arise when

a vaccine is approved and is used in clinical practice.

❚ Efficacy

HIV vaccines are unlikely to be completely effective or efficacious. (The efficacy of licensed vaccines for other serious diseases ranges from 50 to

95 percent). Persons who believe that they are protected against infection because of the vaccine

may be more likely to engage in high-risk behaviors. Further research is needed about the magnitude of this change in risk behaviors, and whether

this outweighs the benefits of a partially effective

vaccine. The public will need to be educated about

the partial nature of protection from an HIV vaccine.

One model of HIV vaccine efficacy concluded

that “earlier use of a 60 percent effective vaccine

would prevent more new HIV infections than later

use of a more efficacious vaccine” (7). Nonetheless, this model considered the theoretical efficacy

of vaccines, rather than their effectiveness in actual populations whose risk-taking behaviors may

increase in response to vaccination, affecting the

incidence of infection.

❚ Informed Consent in Clinical Practice

The informed consent process in clinical practice

is less rigorous than that applied in research. Although the law requires that clinical trials be approved by external review boards and that research participants sign detailed written informed

consent forms, there are no similar legal requirements for informed consent in clinical practice.

In clinical practice, written informed consent is

only required for certain types of medical interventions, typically surgery and nonroutine medical procedures. Public health interventions in particular have an extremely limited tradition of

informed consent (although one exception is the

informed consent process for HIV testing). Generally, American common law requires that the patient be given sufficient information upon which

to make “an intelligent and informed choice” (32).

Case law does not provide clear guidance, however, about the requirement for an “intelligent and

informed” choice. Some courts have concluded

that all information must be provided to participants, and others have found that information that

a “reasonable” person would consider to be relevant must be provided. Negligence typically is

based on a breach of the standard of care, and a

tradition of rigorous informed consent is not part

of the standard of care in clinical practice.

This is not to say that most clinicians fail to ensure that each patient has an adequate level of understanding before consent to medical interventions is obtained. However, the lack of

standardization and regulation of informed con-
Chapter 3 Ethical Issues in the Design and Conduct of HIV Vaccine Trials | 77

sent means that the extent to which this happens is

unknown.

For HIV vaccines the consequences of an inadequate informed consent process may be severe.

For consent to vaccination to be adequate, patients

will need to understand that the vaccine is not

completely effective and that they should continue to practice protective behaviors. Patients

would also need to know the consequences of their

testing positive on standard HIV screening tests.

They also will need to be aware of the potential social harms from vaccination, particularly since

vulnerable and “at risk” groups may be targeted

for the first rounds of immunization. The risk of

breach of confidentially is greater in clinical practice, because outside parties (such as insurance

companies) have access to medical records.

Lapses in confidentiality would increase the potential for social harms to vaccinees.

CONCLUSION

Scientific progress is occurring in the development of HIV vaccines and some vaccines have entered clinical trials. Clinical testing of vaccines

should not move forward, however, without the

incorporation of appropriate ethical standards. A

lack of attention to ethical principles not only

would be morally reprehensible, but would lead to

less effective research and compromised clinical

findings.

CHAPTER 3 REFERENCES

1. Ajayi, O.O., “Taboos and Clinical Research

in West Africa,” Journal of Medical Ethics

6:61-63, 1980.

2. Appelbaum, P.S., Lidz, C.W., and Meisel, A.,

Informed Consent: Legal Theory and Clinical

Practice (New York, NY: Oxford University

Press, 1987).

3. Beauchamp, T.L., and Childress, J.F., Principles of Biomedical Ethics (New York, NY:

Oxford University Press, 1989).

4. Beecher, H.K., “Ethics and Clinical Research,” New England Journal of Medicine

274:1354-1360, 1966.

5. “Can a Healthy Subject Volunteer To Be Injured in Research?” Hastings Center Report

31-33, August 1986.

6. Council for International Organizations of

Medical Sciences (CIOMS) and World Health

Organization (WHO), “International Ethical

Guidelines for Biomedical Research Involving Human Subjects,” Proceedings of the

XXVIth CIOMS Conference, Geneva, Switzerland, 5-7 February 1992, published by

CIOMS, 1993.

7. Dixon, D.O., et al., “HIV Vaccine Trials:

Some Design Issues Including Sample Size

Calculation,” Journal of Acquired Immune

Deficiency Syndrome 6:485-496, 1993.

8. Faden, R.R., and Beauchamp, T.L., A History

and Theory of Informed Consent (New York,

NY: Oxford University Press, 1986).

9. Federal Coordinating Council on Science,

Engineering, and Technology, Committee on

Life Sciences and Health The Human Immunodeficiency Challenge: Issues in Development and International Trials (Washington,

DC: July 1993).

10. Freedman, B. “Equipoise and the Ethics of

Clinical Research,” New England Journal of

Medicine 317:141-145, 1987.

11. Fultz, P.N., et al., “Vaccine Protection of

Chimpanzees Against Challenge with

HIV-1-Infected Peripheral Blood Mononuclear Cells,” Science 256:1687-1690, 1992.

12. Gardner, M., University of California at Davis, Department of Medical Pathology, personal communication, July 1993.

13. Gardner, M., University of California at Davis, Department of Medical Pathology, personal communication, Aug. 23, 1994.

14. Gostin, L., “The AIDS Litigation Project: A

National Review of Court and Human Rights

Commission Decisions, Part II: Discrimination,” Journal of the American Medical

Association 263:2086-2093, 1990.

15. Karzon, D., “Potential for Adverse Reactions

in the Development of an HIV-1 Vaccine,” final draft report prepared for the Office of
78 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Technology Assessment, U. S. Congress,

Washington, DC, December 1994.

16. Katongole-Mbidde, E., “Expectations of

Host Countries in HIV Vaccine Trials,” AIDS

Research and Human Retroviruses 9(suppl.

1): S17-S19, 1993.

17. Katongole-Mbidde, E., Director Uganda

Cancer Institute, Kampala, Uganda, personal

communication, Mar. 22, 1994.

18. Keystone Center, Keystone AIDS Vaccine

Liability Project: Final Report (Keystone,

CO: The Keystone Center, 1990).

19. Lawrence, D.N., Esparza, J., and Zoon, K.C.,

“Considerations on Criteria for Commencement of HIV Vaccine Efficacy Trials: a Working Group Summary,” AIDS Research and

Human Retroviruses 9(suppl. 1): S65-S69,

1993.

20. Levine, R.J., Ethics and Regulation of Clinical Research (New Haven, CT: Yale University Press, 1988).

21. Levine, R.J., “Applying Relevant International Ethical Principles,” AIDS Research and

Human Retroviruses 9(suppl. 1): S155-S156,

1993.

22. Louwagie, J., et al., “Genetic Subtypes of

HIV-1,” AIDS Research and Human Retroviruses 9(suppl. 1): S147-S150, 1993.

23. Lurie, P., et al., “Ethical, Behavioral, and

Social Aspects of HIV Vaccine Trials in Developing Countries,” Journal of the American

Medical Association 271:295-301, 1994.

24. Mastroianni, A.C., Faden, R., and Federman,

D. (eds.), Women and Health Research

(Washington, DC: National Academy Press,

1994).

25. “The Nuremberg Code,” Trials of War Criminals Before the Nuremberg Military Tribunals

Under Control Council Law No. 10 (Washington, DC: U.S. Government Printing Office, 2:181-182, 1949).

26. Public Health Service Act, S. 301(d), 42

U.S.C.

27. Serwadda, D., and Katongole-Mbidde, E.,

“AIDS in Africa: Problems for Research and

Researchers,” Lancet 335:842-843, 1990.

28. Sheon, A.R., “Overview: HIV Vaccine Feasibility Studies,” AIDS Research and Human

Retroviruses 10:S1-2, 1994.

29. Thomas, S.B., and Quinn, S.C., “The Tuskegee Syphilis Study, 1932 to 1972: Implications for HIV Education and AIDS Risk

Education Programs in the Black Community,” American Journal of Public Health

81:1498-1504, 1991.

30. U.S. Congress, Office of Technology Assessment, Tools for Evaluating Health Technologies: Five Background Papers, BP-H-142

(Washington, DC: U.S. Government Printing

Office, February 1995).

31. Vermund, S.H., et al., “Building Partnerships

Toward HIV Vaccine Trials,” AIDS Research

and Human Retroviruses 9(suppl. 1):S127-

S132, 1993.

32. Wing, K.R., The Law and the Public’s Health

(Ann Arbor, MI: Health Administration

Press, 1985), p. 224.

33. World Medical Assembly, “Declaration of

Helsinki”, adopted by the 18th World Medical

Assembly, Helsinki, Finland, 1964; revised

by 29th World Medical Assembly, Tokyo,

Japan, 1975.
Liability and

Compensation for

Adverse Reactions to

HIV Vaccines

iability for personal injuries related to vaccines has been a

matter of intermittent controversy for a quarter of a century (191, 201). Some pharmaceutical and biotechnology

companies have said that the possibility of being liable for

adverse reactions to vaccines or drugs may deter them from developing or distributing new products that could help reduce the

spread of disease or its toll on the population (32, 160, 162, 209).

Although there is little evidence to prove or disprove the effect

of potential liability on vaccine development, research on vaccines has lagged behind other pharmaceutical research, and several bodies have considered limiting the liability of vaccine makers

in the hope of encouraging the continued development and sale of

important vaccines (82, 140). Some have recommended a nofault compensation system to largely replace liability litigation

involving adverse reactions to vaccines (95). Congress enacted

the National Childhood Vaccine Injury Act in 1986 (42 U.S.C.

300aa-10 et seq.) to establish a no-fault compensation program

for injuries resulting from pediatric vaccines and to limit vaccine

manufacturer liability for such injuries (115). Congressman Fortney “Pete” Stark circulated a proposal for a similar bill to create a

no-fault compensation program for injuries arising from the use

of any future vaccine to prevent AIDS (170).

In spite of decades of debate and several changes in state and

federal laws, the controversy over liability for vaccine injuries

has never been put to rest. In part, this may be because whether or

how liability affects vaccine development has not been, and perhaps cannot be, measured empirically to reach reliable answers.

But the controversy also reflects fundamental differences of opinion regarding responsibility for goods of social importance and

responsibility for injury. Should government or private industry

by

Wendy Mariner

Boston University

 School of Medicine

 and School of

 Public Health

Boston, MA

| 79
80 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

be responsible for ensuring the production of

products that benefit society by preventing disease? Who should be responsible for injuries resulting from such products? Reasonable people

may answer such questions quite differently. Even

if they temporarily agree on a practical solution to

a specific problem, the underlying political and

ideological differences resurface with each new

product that promises social benefit. Today they

appear in a new debate over whether liability may

deter companies from developing and marketing

new vaccines to prevent HIV infection or progression to AIDS.

This chapter examines whether alternative injury compensation systems may facilitate the development and marketing of new vaccines to prevent HIV infection or AIDS. The first section of

this chapter summarizes the possible goals of

compensating people who experience adverse

reactions to HIV vaccines. The second section reviews several factors that may deter private companies from developing an HIV vaccine and the

possible influence of potential liability. The third

section reviews basic concepts of tort liability applicable to personal injury and how they might apply to an HIV vaccine. The final section of this

chapter considers alternatives for compensating

adverse reactions to HIV vaccines and how they

might affect the goals of HIV vaccine development and equitable compensation for injuries.

RESPONSIBILITY FOR INJURY AND

COMPENSATION

Compensation systems can be classified into four

broad categories on the basis of their organizational structure and the mechanism for determining

who is entitled to what kind of compensation for

what injuries and from whom: tort liability systems, voluntary contractual arrangements, public

and private insurance systems, and administrative

compensation programs. The choice of system depends upon the goals to be accomplished by compensation. A threshold decision, therefore, is the

need for or desirability of compensating injuries.

Obviously, if there is no need to compensate injuries, there is no need to establish a compensation

system. This section describes the reasons most

commonly put forth for compensating injuries.1

REASONS FOR COMPENSATING

INJURIES

Injuries give rise to both physical and financial

losses, as well as emotional turmoil. The injured

person inevitably bears the physical consequences. Financial losses, however, may be

shifted to someone else by requiring that party to

compensate the victim with money.2 These are the

only choices available with respect to financial

losses: leave them where they lie (with the injured

person), or transfer all or part to someone else.

With every type of injury, therefore, the question

arises whether the financial losses should be

shifted to someone else, and, if so, to whom. Compensation for injury has been justified for economic, philosophical or ethical, and pragmatic or

social policy reasons.

❚ Economic Reasons

Economists and legal scholars have argued both

for and against compensating the victims of injury

to achieve economic efficiency (26, 51, 80, 104,

161). The general idea is to minimize the total social costs of injury or maximize net social utility,

taking into consideration both the benefits of a

product or activity and the injuries it produces. Although opinions vary on what should be the optimal model, none necessarily requires that the

number of injuries themselves be minimized. For

example, it may be cheaper to pay compensation

1 This section draws heavily upon Mariner, 1994 (116).

2 Compensation may also take the form of in-kind services provided to the injured person, but because these have a monetary value and are

ordinarily paid for with money, they will not be separately discussed.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 81

for injuries than to modify a product to prevent the

injuries.

Many conceptions of economic efficiency are

difficult to apply in practice. Models based on perfect competition may not take into account how

buyers and sellers behave in an imperfect world.

Not everyone necessarily agrees on what counts as

a benefit or a cost, especially where benefits and

injuries fall on quite different segments of the population.

It is frequently assumed that companies can internalize the costs of injuries (recoup compensation payments) by raising the prices of their products, thereby spreading the costs over a large

population. Even if compensation costs cannot be

fully recouped from sales, the loss experienced by

the company is relatively small when compared

with the loss an uncompensated individual would

suffer. Compensation then serves to spread the

costs more equitably.

When injuries are frequent or severe enough to

require a company to pay substantial costs that

threaten its continued viability, it is ordinarily believed to be more economically efficient for a

company to make the product safer, if possible, or

cease producing the product. Some commentators

have argued that this is economically inefficient if

the product produces a significant social benefit

(79). In theory, such an imbalance should not occur because the product’s price should reflect its

social benefit.

Economic analyses of loss allocation have influenced thinking about the nature of compensation, but have rarely been decisive on the question

of whether compensation should be paid at all.3

That question is more often answered with reference to moral arguments about who should bear

responsibility for the consequences of injury.

❚ Ethical Reasons

Injury compensation has long been justified as the

moral duty of those who are responsible for causing injury. It is perhaps the most widely accepted

basis for legal liability in tort (59). Principles of

justice derived from the works of such diverse

scholars as Kant, Bentham, and Locke support

compensation for injury caused by an identifiable

entity.

There is, however, room for debate on what

counts as causing injury and the circumstances in

which moral responsibility for injury, and therefore compensation, should be ascribed. Depending upon the circumstances, compensation may

be:

1. morally required, so that not providing it is unjust;

2. morally desirable as an act of virtue, but not

morally required; or

3. not morally required and possibly unjust.

Swazey and Glantz offer a useful paradigm to

describe why society may apply different moral

rules to different injuries (179). They argue that

social conceptions of moral or ethical obligations

to human research subjects may vary depending

upon whether the subjects are seen as victims, heroes, or contractors.4 Victims are characterized as

those who have been misused or injured without

their consent5 (9). They may be especially vulnerable or targets of exploitation who have few

3 For example, Philipson and Posner apply economic theory to the AIDS epidemic and conclude that the federal government “has no, or

even a negative, stake in the development of treatments, such as the drug AZT, that merely prolong the lives of persons [with HIV because AZT]

may increase the total medical costs by extending the period during which infected persons demand and receive treatment (138).” Fortunately,

such reasoning has not halted AIDS treatment research.

4 Their analysis is directed only to compensation for research injuries. It is pertinent to this discussion, however, because it describes generalizable theories and because the question whether human subjects in clinical trials of candidate HIV vaccines deserve compensation will

necessarily have to be addressed first.

5 Well-known research examples include subjects in the Tuskegee Syphilis Study (88), the Willowbrook Hepatitis B Study (90), and, more

recently, radiation experiments conducted under the sponsorship of the Department of Energy (162, 188, 209).
82 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

means to avoid the injury in question. Victims

have a strong moral claim to compensation, especially where society has facilitated the research or

benefited by the use of a product (42, 200).

Heroes, in contrast, are seen as willing volunteers who assume risks in order to accomplish a

goal, ordinarily for someone else’s sake (179).

Since heroes are not supposed to seek any reward,

there is no obligation to compensate them. At the

same time, society may wish to reward them voluntarily for their heroic efforts.

Contractors are often seen as businessmen

striking a bargain (179). As long as the bargaining

process is fair, contractors may be entitled to no

more than they bargained for, and may be seen as

seeking an unfair advantage if they later demand

more. Thus, for example, those who voluntarily

buy a product without initially contracting for

compensation may have little, if any, moral claim

to it later.

This paradigm offers some insight into why

some people may view entitlement to compensation for vaccine-related injuries so differently.

Those who focus on principles of distributive justice view vaccine recipients as benefiting society

by preventing disease transmission. In this view,

injured recipients who are perceived as victims are

morally entitled to compensation and not providing it would be unjust. Recipients who are perceived as heroes, such as subjects of research in

clinical trials, have a lesser claim, but compensation is a morally desirable act of caring for those

who benefited society.

In contrast, those who focus on respect for persons and autonomous choices may perceive vaccine recipients as contractors with no moral claim

to compensation. In this view, the recipient has

agreed to assume the risks of vaccination (and has

received its benefits), and providing compensation would be wrong because it does not respect

the subject’s autonomous choice. This is the effect

of informed consent in tort law. A person who has

agreed to vaccination with knowledge of any attendant risks (including the possibility of unknown risks) is not entitled to compensation if a

disclosed risk materializes to his injury. As long as

the initial contract discloses the risk so that the recipient can decide whether or not to accept it, the

contract is fair. In moral discourse, society has, at

best, a privilege to compensate such persons as an

act of charity, and not doing so is not unjust.

The view based on autonomy can be criticized

on two grounds. First, it may be wrong to believe

that consent to assume the risks of vaccination

necessarily includes consent to assume the financial costs of injury. Indeed, it may be unfair to ask

anyone to assume such costs if the injury is severe.

Second, as a practical matter, one may question

whether the contract can be made on fair terms.

The ideal of voluntary, understanding, informed

consent is not always achieved in practice, especially in a research setting (10, 92).

We do not yet know whether people who take

an HIV vaccine will appreciate the consequences

of their decision. In particular, we do not know

whether people would consent to waive compensation for injury because they are rarely given

the option of compensation. Most research studies

advise potential subjects that compensation is not

available. People who take vaccines are rarely advised that their consent will be deemed to be an assumption of the risks of financial loss. Of course,

people take many risks from driving automobiles

to white water rafting for which no one else is financially responsible.

Tort law has taken a somewhat broader view of

entitlement to compensation by basing it on responsibility for injury. In 1951, Glanville Williams identified four possible goals of tort law imposing liability for personal injury: 1) justice

(imposing the cost of injury on the one who causes

it); 2) compensation (replacing the victim’s

losses); 3) deterrence (creating disincentives for

socially undesirable activity that could result in

personal injury); and 4) appeasement (assuaging

the victim’s desire for vengeance through compensation) (210). Most discussions of tort liability

goals have used the same or a similar formulation

(59, 142). Although justice may provide tort law’s

primary moral justification, compensation and

deterrence are its most commonly recognized

functions.

Sunstein has noted that traditional principles of

compensatory justice have found compensation
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 83

appropriate when: 1) “[t]he event that produced

the injury is both discrete and unitary”; 2) “[t]he

injury is sharply defined in time and in space”; 3)

an identifiable defendant has clearly caused the

harm suffered by an identifiable plaintiff; and 4)

the harm is not attributable to some third party or

to “society”6 (177). He argues that these criteria

are not well suited to affording justifiable compensation where the relevant harm cannot be connected to a discrete event, where there is scientific

uncertainty, where the risk is shared or collective,

or where the defendant has an ambiguous relation

to the harm, as in environmental hazards.7

Current tort law would not readily accommodate compensation for increased risks rather than

actual injuries. This has obvious implications for

injuries to those who are vaccinated because of

possible uncertainties about the cause of some injuries and the degree to which any risk may have

been avoidable. It suggests that there may be some

circumstances in which compensation should be

provided even if it would not be granted under tort

principles.

❚ Social Policy Reasons

Compensation for vaccine-related injury has been

seen as a pragmatic solution to a social problem.

That social problem is sometimes characterized as

unfairness to those with vaccine-related injury

who suffer significant financial losses as well as

physical and emotional damage and who have no

legal claim to compensation from others. Compensation may benefit society as a whole if injuries are deterred and injured persons are adequately provided for. More commonly, the problem is

seen as a means to relieve vaccine producers from

an unfair burden of liability for injuries that

should not be compensated or are compensated

excessively through product liability claims. If

compensation costs less than litigation, society, as

well as manufacturers, may benefit by reducing

litigation expenses. If liability deters the production of socially beneficial products, society may

benefit from the availability of those products if

they are produced.8

Compensation and liability appear to be linked

in discussions of vaccine-related injuries because

of a general sense that injured vaccine recipients

deserve compensation, but that vaccine producers

should not be responsible for paying compensation for all the injuries. Compensation can be justified on the ground that society benefits from reduction in disease and those who are willing to

join the disease prevention effort should be compensated if injury results, perhaps even if the injuries were unforeseeable. This would grant compensation in many cases in which tort principles

would deny compensation.

The fact that injury compensation can be justified, and is even desirable, however, does not answer the question of who should be responsible

for compensating the injury. If compensation is to

be provided beyond that currently permitted under

tort principles, should the vaccine producer, government, or someone else be responsible?

SOCIAL GOALS OF ALLOCATING

RESPONSIBILITY FOR INJURY

If compensation is warranted for all vaccine-related injuries that are not caused by negligence,9

the central questions are: who should provide the

compensation, and how? Financial responsibility

6 One might add that compensation is generally precluded if the plaintiff has effectively consented to the injury by assuming the risk.

7 Many regulatory programs (environmental protection, occupational health and safety, and food and drug regulation) are intended to prevent or minimize social risks that may arise in the future, often to a class or group of people whose affected members cannot be identified in

advance. Sunstein argues that these programs operate to provide a mechanism for deterring risks, but not for compensating actual injuries (177).

8 Where law mandates vaccination, as with pediatric vaccines, people have little opportunity to refuse to be vaccinated. The social benefit

conferred by mandatory childhood immunization was one reason for creating the federal National Vaccine Injury Compensation Program in

1986.

9 Because negligence is a deviation from acceptable conduct, and is not an inherent vaccine risk, injuries resulting from the negligence of a

vaccine producer or one who administers a vaccine are ordinarily believed to remain the responsibility of whoever caused the injury.
84 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

for adverse reactions to a future HIV vaccine may

be structured to help achieve one or more of the

following goals:

1. to assure the development of an effective vaccine to prevent HIV infection or AIDS;

2. to assure the marketing and distribution of an

HIV vaccine;

3. to assure the marketing and distribution of an

HIV vaccine at a reasonable cost to users;

4. to assure the use of HIV vaccine to prevent HIV

infection or the development of AIDS;

5. to assure compensation to persons injured as a

result of an HIV vaccine;

6. to minimize the total social costs of HIV vaccine development, marketing, and injuries; and

7. to minimize the total social costs of HIV infection, including prevention and transaction

costs.

It should be noted that none of these goals can

be achieved solely by assigning responsibility (or

liability) for injuries. Rather, by assigning responsibility to different parties, society may encourage

or discourage progress toward specific goals. The

ways by which the allocation of responsibility affects progress towards each of these social goals is

described below.

❚ Development and Marketing

The first two goals—HIV vaccine development

and marketing—might be achieved by assigning

financial responsibility to government, the producer, or the injured person. The choice depends

upon who is to develop and market vaccines and

how responsibility for injury affects their decisions.

The federal government has both funded and

conducted HIV vaccine research and might assume responsibility for product development, if

not marketing. It is more likely, however, that the

private sector, which has also conducted vaccine

research, will pursue product development and

marketing, as it has in the past. Responsibility for

injury might encourage the type of vaccine desired

or it might discourage vaccine development entirely.

In theory, the key goal of responsibility for injury is deterrence: to provide an incentive to produce products of acceptable quality and to deter

the production of products with avoidable risks.

But the degree to which responsibility for injury

actually promotes product safety and effectiveness is debatable and difficult to verify (20, 61,

178). Other mechanisms, such as the U.S. Food

and Drug Administration (FDA), may achieve the

goal equally well.

Currently, it is impossible to predict the degree

to which either FDA regulation or potential responsibility for injury may affect an HIV vaccine’s safety and effectiveness. Some would argue

that, in the absence of such knowledge, responsibility should be retained. Others would argue that

it should not because it may discourage producers

from developing or marketing any vaccine. This

assumes that producers who are otherwise willing

and able to develop a vaccine would refuse to do it

if they retained financial responsibility for adverse reactions. As discussed in the next section of

this chapter, it may be impossible to confirm or refute that assumption, although HIV vaccines development has not been halted by the potential for

liability.

❚ Reasonable Vaccine Costs and Vaccine

Use

The third and fourth goals of allocating responsibility for injury—offering vaccines at a reasonable price and assuring vaccine use—address the

need for access to HIV vaccines. The obvious purpose of developing an HIV vaccine is to prevent

HIV infection and stop the AIDS epidemic. A safe

and effective vaccine must not only be produced,

it must be used by those at risk for HIV infection.

Unless an HIV vaccine is to be given away free to

anyone who wishes it, the cost to vaccine purchasers, whether private individuals or government

entities, must be affordable. If the cost of injuries

drives the price of vaccine too high, it will not be
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 85

used.10 In that event, it may be cheaper (in theory)

to rely on behavioral education to help prevent

some modes of HIV transmission. Thus, if responsibility for injury causes producers to set an

unaffordable price on vaccines, many people may

not be able to obtain it.

On the other hand, if individual vaccine recipients must bear the financial burden of adverse

reactions, then they may be unwilling to use the

vaccine. Either result undermines the goal of vaccine distribution and use. One alternative for government is to limit the price at which vaccine is

sold, either by negotiating government prices with

producers or by legislation limiting prices. However, vaccine makers may be unwilling to produce

a vaccine that is subject to such price limitations.11

❚ Compensation for Adverse Reactions

Responsibility for injury may be allocated so as to

achieve the fifth social goal—to provide compensation to those injured in the most efficient,

fairest or least costly manner. If the goal is to

spend the fewest dollars on injuries, then the

choice might be to leave injured people to pay for

their injuries. This would avoid any administrative or transaction costs associated with transferring compensation to the injured, but not the burden on injured persons. This option has little

appeal because the financial costs of injury are

sometimes more than one person can bear. It also

seems unfair to the individuals when society as a

whole benefits from the vaccine’s use. Moreover,

if responsibility for injury has the effect of deterring injuries, then requiring compensation may reduce total costs by reducing the number of injuries. It may be more efficient to spread the cost of

injuries across the population of vaccine users or

the larger society by making government or vaccine producers financially responsible.

❚ Minimizing Vaccine and Injury Costs

If responsibility for injury is to be allocated so as

to provide compensation to injured people, then

the responsible party may be selected so as to

achieve the sixth social goal—to minimize the total social costs of vaccine development and marketing and the costs of injury. This takes into account the fact that injuries do impose costs on

individuals, even though they may be less visible

to society than the costs reflected in the price of

products.

Often this goal is erroneously invoked by those

who wish to achieve the narrower objective of

minimizing the costs to one participant in an endeavor. For example, if only the costs to manufacturers were recognized, limiting liability and compensation would reduce manufacturers’ costs.

The remaining injury costs would not disappear,

however; they would rest with injured people or

government. If government wishes to minimize

its own costs, then it would ordinarily impose financial responsibility on vaccine producers.

However, if the price of vaccine rose higher than

the cost to government of providing compensation, and government purchased a significant proportion of vaccine, government would incur much

of the cost theoretically imposed on producers.

The least costly option would depend upon whether government controlled the price of vaccine, either by regulation or negotiation.

❚ Minimizing Total Social Costs of HIV

Infection

The seventh goal of responsibility is to minimize

the total social costs of HIV infection. In assessing

the social costs and benefits of HIV vaccine development, production, and distribution, all of the social costs of HIV infection should be taken into account. Society is already paying a high price, in

terms of human suffering as well as economic

10 Of course, this ignores the human cost of not preventing HIV transmission if the vaccine is not used. It also assumes that vaccination is

voluntary.

11 It may be difficult to achieve both the goals of affordability and production if production is to remain entirely with the private sector.
86 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

losses, for the persistence of HIV infection. Moreover, current efforts to prevent HIV transmission

also impose social costs. The benefits to be gained

by preventing additional disease are likely to outweigh the costs of vaccine development, marketing, and injury compensation. If so, then the question is how to allocate responsibility for injury in

order to maximize those benefits and minimize

those costs.

❚ Conclusion:

Any system for assigning responsibility for injury

that satisfies one goal may undermine another. For

example, a system that minimized the costs of

compensation to vaccine makers might encourage

vaccine development, but also reduce incentives

to limit potential safety risks, and result in more

injuries. A system that provided generous compensation to all injured parties might achieve the

goal of equitable compensation, but might be too

expensive for many companies that society

wishes to attract to vaccine development to

achieve other goals. Government assumption of

responsibility for compensation might conflict

with other goals to minimize government expenditures or to fund other important programs. The

amount of compensation may also affect the price

of marketed vaccines. At some point, high prices

may deter potential vaccine recipients from taking

the vaccine. Systems that discourage either vaccine development or vaccination may work

against the goal of preventing HIV transmission

and disease.

Most important, any system that limits compensation to injuries from one specific cause, like

an HIV vaccine, raises questions of fairness to

people with similar injuries caused by something

else. A compensation system limited to persons

with adverse reactions to an HIV vaccine invites

the question why people living with HIV infection

or AIDS (or any other illness or injury, for that

matter) should not be compensated in the same

manner.

POTENTIAL DETERRENTS TO HIV

VACCINE DEVELOPMENT

As the first section of this chapter illustrates, who

should bear responsibility for adverse reactions to

HIV vaccines depends upon the goals of HIV vaccine development and compensation for injury

and how responsibility for injury may affect vaccine producers’ decisions about vaccine development. If society intends to rely on the private sector to develop and distribute an HIV vaccine, then

private sector attitudes toward responsibility for

injury must be considered. If private companies

are unwilling or unable to distribute an HIV vaccine if they are charged with responsibility for injury, then arguments that they should have that responsibility will not suffice to produce a

vaccine.12 If, on the other hand, responsibility for

injury has little impact on their decisions, then

even elimination of responsibility for injury will

not improve the prospects for private sector vaccine development.

This section examines the degree to which legal

responsibility or liability for adverse reactions

might affect private companies’ decisions whether to develop and market an HIV vaccine.13 Unfortunately, there is no empirical evidence that of12 If government were to produce or distribute the vaccine, such concerns would be unnecessary.

13 This examination is based on a literature review; an empirical study was beyond the scope of this report. The possible approaches to

studying potential liability’s effect on product development have inherent biases and limitations. These parallel the approaches to studying

defensive medicine described in the Office of Technology Assessment’s 1994 report Defensive Medicine and Medical Malpractice (195), and

have similar limitations. One approach is to ask vaccine companies why they did or did not develop specific vaccines. Such surveys may elicit

biased responses. If respondents believe that the survey is intended to measure sensitivity to liability, they may exaggerate liability’s role in their

decision making in the hope of gaining added protection against liability in general. If liability is not mentioned, respondents may underplay its

role in favor of emphasizing purely scientific or other reasons. An alternative approach is to compare the products developed, marketed and

abandoned by companies with their exposure to liability. Such a study requires access to information concerning products not marketed as well

as data on companies’ liability experience which companies are generally unwilling to disclose.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 87

fers a clear answer to the question. There are no

epidemiologic studies of the effect of liability like

those ordinarily required to prove vaccine risks.

Inferences might be drawn from past behavior but

are highly speculative because the reasons underlying decisions about research and marketing are

not independently verifiable. The available evidence consists largely of anecdotes.14 Analyses of

the effect of liability have been forced to rely on

inferences from history and assumptions based on

logic (and sometimes ideology).

Companies in private industry necessarily

make choices about what business to pursue and

what products to make. Because new biologic and

pharmaceutical products require a substantial investment of both time and money, choices by

companies in the pharmaceutical and biologic industry may have long-term consequences for their

product line (194).

An initial fundamental decision is whether to

invest in the production facilities and equipment,

as well as human expertise, necessary to produce

an HIV vaccine. Factors influencing such a decision include: whether the company already has (or

has access to) adequate facilities that can be used

or adapted for HIV vaccine purposes or financial

resources to construct such facilities; whether existing or new facilities can be used or adapted to

other purposes within the company’s business if

vaccine development is unsuccessful; whether the

company has sufficient regulatory and clinical

trials expertise, as well as financial resources, to

pursue testing an investigational product in clinical trials with human subjects and applying for

FDA approval; whether the market for the product

is likely to support a price that will cover the costs

of development and marketing and still produce

an acceptable profit; the likely length of patent

protection that will preclude other companies

from marketing a similar product and competing

on price; and whether other potential investments

and products are more likely to produce the same

or higher profit (82, 121, 194).

It seems logical that potential liability for product-related injuries can influence decisions about

whether to pursue developing a specific product.

Whether that influence becomes significant depends on its relative weight compared with other

factors, especially the scientific and technical feasibility of HIV vaccine development and its expected financial return compared with alternative

investments.

❚ Scientific and Technical Feasibility

The major obstacle to developing an HIV vaccine

is HIV itself.15 Despite remarkable advances in

scientific knowledge about HIV, too little is

known about how to produce an immune response

in human beings that would protect against infection or development of disease to be assured that

an effective vaccine can be produced in the foreseeable future.16 For example, it remains unclear

how to protect against multiple or mutating strains

of HIV, how to prevent mucosal infection or infection through sexual contact in addition to infection through the blood stream, whether cell mediated immunity is required in addition to

14 Two Institute of Medicine committees attempted to evaluate existing evidence that certain adverse reactions were or were not caused by

pediatric vaccines (85, 87, 174). They classified the evidence into 5 categories: 1) No evidence bearing on a causal relation; 2) The evidence is

inadequate to accept or reject a causal relation; 3) The evidence favors rejection of a causal relation; 4) The evidence favors a causal relation; 5)

The evidence establishes a causal relation (174). Applying their categories to the available evidence bearing on a causal relationship between

liability for adverse reactions to vaccines and private industry’s willingness to develop or distribute an HIV vaccine, one can at best conclude

that the evidence is inadequate to accept or reject a causal relation.

15 The journal Science surveyed “more than 100 of the [vaccine] field’s leading researchers, public health officials, and manufacturers” for

their opinion on why vaccines have not been developed for many serious infectious diseases, especially those considered priorities by the Institute of Medicine (37). The 67 respondents reported that the “Scientific unknowns are the highest hurdles...but they also stressed that the field

lacks strong leadership and funding to speed progress (37).”

16 For a description of current HIV vaccine research and development, see chapter 2.
88 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

humoral immunity (to free virus), and whether infection mediated by both cell-free and cellassociated virus can be prevented. Moreover, it is

not known whether a vaccine that does not prevent

initial infection by the virus could prevent the development of disease and reduce or prevent active

HIV transmission to others. Promising research is

beginning to answer such questions, but, historically, it has been especially difficult to develop

vaccines to prevent viral infections—and HIV is

an extraordinarily complex virus (99).

In April 1984, Secretary of Health, Education

and Welfare Margaret Heckler optimistically announced that an HIV vaccine would be ready for

testing in 1986 (151). A decade later, the scientific

community may not be much closer to developing

an effective vaccine, although it may better understand why. The difficulty of determining the precise mechanism by which the virus might be

neutralized in human beings may discourage companies from mounting the research effort that is

likely to be required to solve the problem.

Other technical considerations may affect vaccine development decisions. On the plus side, the

technologies used to produce new recombinant

vaccines may be adaptable to other promising

products, like diagnostics (192). New recombinant vaccines can be produced in large quantities

and, because they are usually stable for long periods, are generally less expensive to produce than

other biologic products. At the same time, vaccines pose numerous technical challenges.17 Animal testing requires special facilities and money

to maintain the animals. Finding a suitable adjuvant to enhance the immunogenicity of a candidate vaccine has already proved difficult. Candidate vaccines produced from laboratory adapted

strains in cell lines may not protect against other

HIV strains that infect human beings in the real

world, that is, field isolates.

One way to increase the effectiveness of vaccination may be to combine two or more candidate

vaccines made by different companies. This requires the cooperation of different companies in a

highly competitive industry. The difficulty of

sharing technical information while protecting

trade secrets and patents may make such joint ventures unattractive to some companies. Moreover,

products that are developed in collaboration with

governmental agencies, such as the National Institute of Allergy and Infectious Diseases (NIAID)

or the National Cancer Institute (NCI), may give

rise to disputes over patent ownership, such as that

between Burroughs-Wellcome Co. and National

Institutes of Health’s (NIH’s) licensee, Barr Laboratories, over Zidovudine (AZT) (55). Some companies prefer not to collaborate with the NIH because of the constraints imposed by its

“reasonable price” requirements.

Another technical barrier is the need for dedicated product development facilities to produce

vaccines. These must comply with FDA regulations specific to biologics, are estimated to cost as

much as $10 million to construct, and may have to

be updated periodically (121). They also must include expensive ongoing production and quality

control processes conforming to Current Good

Manufacturing Practice (CGMP) to ensure the potency and purity of each batch of vaccine. The cost

of conducting large field trials has also been cited

as a major obstacle to vaccine development (121).

Large research-based vaccine manufacturers have

an advantage in these respects, since few small

biotechnology companies have large production

facilities or clinical field trial capabilities. Those

that can get the financing may prefer to pursue

products with a higher probability of success.

It is encouraging that almost thirty candidate

HIV vaccines are currently being tested in Phase I

and II clinical trials18 (207). According to public

reports, most of these vaccines have been well tolerated and have produced few side effects so far,

which supports predictions that they should be

reasonably safe. Whether any of these candidate

17 For a further discussion of difficulties with vaccine development, see chapter 2.

18 For a description of current HIV vaccines in development, see chapter 2.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 89

vaccines will prove to be effective enough to prevent HIV infection or disease progression in a significant proportion of human vaccine recipients

remains to be seen. Indeed, the reported results are

somewhat discouraging so far (34, 100).

Phase III trials, in which vaccine efficacy can

be studied, remain in the proposal stage, with

some companies and prospective study populations eager to begin large field trials with the candidate vaccines that have completed phases I and

II trials (3, 133). In late 1993, NIAID expected to

begin Phase III trials between 1994 and 1998, “as

soon as promising candidates are available,” and

awarded two contracts to administer feasibility

studies and multi-site phase III trials both in the

United States and abroad (122). On June 17, 1994,

however, an NIAID advisory committee voted to

delay phase III clinical trials of the two vaccine

candidates that have proceeded the furthest in

clinical testing (40, 125).19 Committee members

were not convinced from prior test data that these

candidate vaccines could prevent HIV infection in

enough people to warrant their use in a large Phase

III field trial. Ultimately, NIAID recommended

proceeding with efficacy trials only if and when

more compelling data could be produced. This is

likely to delay such trials for one to three years

(125).20

Regardless of the merits of the specific vaccines at issue, the decision not to go forward with

phase III trials in 1994 may send a discouraging

signal about the difficulty of surmounting the

scientific obstacles to developing a suitable vaccine.

Some AIDS researchers argue that it would be

worthwhile to proceed with the candidates that

have already been tested, even if they are not expected to prevent disease transmission or progression in most recipients. They point out that some

lives could be saved even if the vaccines are effective in only 30 percent of recipients or if they reduce (while not eliminating) clinical disease or the

virulence of the virus and its likelihood of transmission to others.21 This is of special concern in

countries with rising rates of infection, such as

Thailand, Uganda, and Zaire.22

Others would prefer to concentrate on developing new vaccine candidates with greater promise

of effectiveness. They argue that using the tested

candidates for immediate Phase III field trials

could delay or deter the development of a more effective vaccine. The logistics of organizing a large

field trial, especially overseas, are formidable (although perhaps less expensive than in the U.S.),

and it may be difficult to use the same population

for more than one vaccine. The combined difficulty and expense of mounting such trials may deter

some companies from launching a later trial if

another vaccine has already been tested and approved.

Researchers at a November 1994 meeting on

Advances in AIDS Vaccine Development sponsored by NIAID heard additional discouraging

news (126). Newborn monkeys who received a

promising prototype simian immunodeficiency

(SIV) vaccine derived from live attenuated virus

exhibited symptoms of SIV disease and one

19 Both candidates, one by Genentech, Inc., the other by Biocine Company, a joint venture of Chiron and CIBA-Geigy, are recombinant

vaccines using gp120, an HIV-surface protein. For further discussion of these vaccines, see chapter 2.

20 This does not mean that trials cannot go forward in other countries. The companies may try to persuade the World Health Organization or

national governments that their vaccines deserve to be tested in phase III trials.

21 Such a vaccine could not be counted on to prevent HIV infection, so a recipient would still have to practice safe behaviors to avoid becoming infected, or, if infected, to avoid infecting others.

22 There may also be concern about imposing on private companies an obligation to provide any vaccine that is ultimately approved to the

population of research subjects that were used to test it, a principle accepted by most, but not all, scholars of research ethics (110). Industry

representatives have argued that this would mean giving the vaccine away free in foreign countries that cannot afford market prices or pay in

hard currency. Their resistance persuaded the CIOMS not to include such a requirement in its 1993 International Ethical Guidelines for Biomedical Research Involving Human Subjects (42). For a discussion of the CIOMS Ethical Guidelines, see chapter 3.
90 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

monkey died. This may set back efforts to develop

HIV vaccine using a similar model. In addition,

eighteen human research subjects who received

candidate HIV vaccines in clinical trials have become HIV infected despite having high titers of

neutralizing anti-body (36). Although their infection may indicate only that the vaccine is ineffective or less than completely protective, the possibility that the vaccine might increase susceptibility to infection may be considered.23 Some researchers worry that no vaccine that is currently in

Phase II trials can achieve even very low levels of

efficacy.

Current HIV vaccine research is both exciting

and frustrating because so much has been learned

yet progress toward an effective vaccine has been

so slow. If a private company does not believe that

research can identify an adequate vaccine candidate over the next decade, or if it does not have the

resources to develop one, then it is not likely to

pursue HIV vaccine development.

❚ Market and Financial Factors

If scientific obstacles can be overcome and an HIV

vaccine appears technically feasible, the major

factor influencing vaccine development is its expected return on investment or profitability. Private industry must look to the potential market to

predict the revenues it may yield in order to

compare them to the predicted costs of development and marketing, and the potential profits from

alternative investments.

The potential market for HIV vaccines is

worldwide. However, from a company’s perspective, the relevant market consists of paying purchasers. Potential HIV vaccine markets, then, include individual vaccine recipients who can pay

for the vaccine either out-of-pocket or with insurance and government agencies which purchase

vaccine for distribution to individuals. The paying

market may include health care workers, people

with hemophilia, and people at risk for HIV infection (such as employed men who have sex with

men). This parallels the market for hepatitis B

vaccine (HBV) and exists primarily in the United

States, Europe, Australia, and possibly Japan. It

may also exist in the “carriage trade” in other

countries (like Thailand, India, and Egypt). This

market may be quite profitable, even though it includes fewer people than the market for other vaccines, like those against polio and influenza.

It is possible, however, that not everyone in this

market would be willing to buy an HIV vaccine,

perhaps because they mistakenly do not consider

themselves at risk for HIV infection, because they

prefer to avoid risk behaviors instead of being vaccinated, or because they fear adverse reactions (or

acquiring HIV infection) from a vaccine. Some

people may fear being labeled as “at risk” if they

seek vaccination or being stigmatized as having

HIV infection if they become seropositve as a result of vaccination. National or local laws requiring vaccination would maximize the use (and purchase) of HIV vaccines. HIV vaccination appears

unlikely to be made mandatory for the entire population, at least in industrialized countries. It

might be possible to generate legislative support

for mandatory vaccination of certain populations

at high risk of HIV infection, such as newborns

born to HIV-positive women or certain health care

workers. But even targeted mandates are likely to

face opposition and may depend upon the perceived safety and effectiveness of the vaccine to

be used.

The market may also be affected by the price of

the vaccine. Some potential purchasers may be

unwilling to pay more than a certain price for the

23 For a discussion of possible HIV vaccine enhancement of susceptibility to HIV infection, see chapter 2.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 91

vaccine unless it is covered by health insurance.24

Physicians in the U.S. have traditionally placed

little emphasis on preventive care, other than the

required childhood immunizations, perhaps because they, in turn, are paid comparatively little

for such services (105).

The United States may be the most profitable

market for vaccines in the world. Many foreign

markets are not attractive because they are highly

regulated and vaccine prices are often limited, either by governments (which purchase drugs and

vaccines for national health programs) or by competition with foreign vaccine makers (who may receive government subsidies). Many developing

countries have severely limited budgets for vaccine purchases and are unable to pay in the hard

currency demanded for transnational sales

(147).25 U.S. companies are reluctant to sell at a

lower price abroad than in the United States for

fear of charges of price-gouging in this country.26

Thus, the United States offers the most attractive

market for HIV vaccines made by United States

companies.

Federal, state, county, and city government

purchasers may provide a secure market for HIV

vaccine. The volume of government purchases

may be higher than the total population willing to

pay for vaccination because the government may

provide vaccine for those unable to pay or not covered by insurance. The population at risk for HIV

infection includes a disproportionate number of

people who are uninsured for immunizations and

who could not afford to pay for vaccination themselves. Government purchasers may not be willing to pay the price that private companies wish to

charge for vaccine, however, especially if they

purchase large volumes. There is precedent for

governments demanding a lower-than-market

price for vaccine. The federal government negotiates prices for pediatric vaccines that are significantly lower than “catalog” prices (121). It is also

beginning to do the same for drugs,27 which may

make companies fearful that all governmental

purchase prices may be regulated more strictly in

the future (33).

At the same time, greater price regulation of

drugs may make vaccines relatively less unattractive as compared with drugs, which historically

and in general, have commanded significantly

higher prices than vaccines. If government purchasers were unwilling to pay a high price for an

HIV vaccine, companies might be unwilling to

sell to them (172). However, it would be awkward

for companies to sell a vaccine to private individuals and clinics or physicians while refusing to sell

to government.

Vaccines suffer from the disadvantage of not

being advertised to the public (as compared with

over-the-counter drugs). This means that companies cannot build a market directly, but must rely

24 Private health insurance policies in the U.S. rarely cover the cost of preventive vaccination. President Clinton’s proposed Health Security

Act would have included childhood and certain other immunizations in its comprehensive benefit package that must be covered by all health

insurers. (U.S. Congress, Senate, S. 1757, Health Security Act, Sec. 1128, (Washington, DC: U.S. Government Printing Office, 1993).) Immunization against HIV has not been included in health reform proposals, presumably because no vaccine is available.

25 The price of some U.S. vaccines is higher than the per capita budget for health care in some developing countries (147).

26 In 1982 Congressional hearings, a vaccine maker was chastised for charging the U.S. government a higher price than that for foreign

countries. After the hearing, U.S. companies no longer bid for UNICEF or PAHO contracts to sell vaccines at low prices in the developing world.

27 The Medicaid program receives rebates on outpatient drug prices from manufacturers (Social Security Act, s.1927), and certain Public

Health Service grantees and certain disproportionate share hospitals receive discounts on outpatient drug purchases (Public Health Service Act,

s.340B). Many private health insurers, health maintenance organizations, and large hospitals have negotiated new, lower prices for bulk purchases to reduce health care costs. President Clinton’s proposed Health Security Act would have encouraged negotiated price reductions and

rebates on certain drugs purchased by Medicare. (U.S. Congress, Senate, S. 1757, Health Security Act, Sec. 1128, (Washington, DC: U.S. Government Printing Office, 1993).)
92 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

on physicians and health agencies to buy the product and use it with their patients.28 In addition,

vaccines do not create a loyal market of users

(105). Unlike drugs that are used repeatedly for

chronic diseases, vaccines are used only once or a

limited number of times per person. A highly successful vaccine would eliminate its own market by

eradicating the disease. Indeed, this is the goal for

an HIV vaccine. On the other hand, if only one

HIV vaccine is approved, a company is likely to

hold a monopoly for many years and will not need

to spend money persuading physicians to use it.

Government agencies may be counted on to encourage vaccine use, and fear of AIDS may be sufficient incentive for many people.

The most profitable product for a private pharmaceutical company is a patented product that is

the only available or effective means to treat or

prevent a serious disease.29 An HIV vaccine

would surely qualify in this category. This monopoly position, coupled with strong demand for

the product, often allows pricing at whatever the

market will bear, (61, 194) as experience with

AZT (12) and Clozaril demonstrated. Market potential is ordinarily assessed by comparison with

other products that a company might pursue

instead of HIV vaccines. Because so few products

ever emerge from the research and regulatory

pipeline with FDA approval, it makes economic

sense to invest in the product with the highest

profit potential.

An HIV vaccine is likely to have considerable

appeal to companies that believe that market demand will be strong, the price will not be regulated, and users will pay the price. HIV vaccine

development may appear unattractive to companies that perceive any of these factors to be absent.

❚ Potential Liability for Adverse

Reactions

HIV Vaccine Experience

The evidence that fear of liability has dissuaded

companies from pursuing HIV vaccine development comes from reports of companies that withdrew, some only temporarily, from research. A review of these cases, however, reveals that other

factors typically were present—a disappointing

product, lack of financing, poor market predictions, internal corporate restructuring, or potential

patent problems—that could account for the action.

Genentech

Genentech stopped research on a preventive HIV

vaccine in 1986, citing liability concerns as one

reason. Observers close to the company noted that

the vaccine was set aside after it failed to protect

chimpanzees against HIV infection and the vaccine-producing cell line was suspected of having

retroviral particles. Genentech has since resumed

research with a different recombinant vaccine,

now in clinical trials, which it hopes to take to

market.

In 1986, before Genentech dropped its first vaccine, California had enacted legislation limiting

the liability of California makers of an AIDS vaccine, with support from Genentech (Calif. Health

& Safety Code 5. 199.49). In 1988, the California

Supreme Court issued an opinion endorsing immunity from strict liability for prescription drug

makers, which is thought to be equally applicable

to vaccine makers, (225) and California repealed

its statutory protection against liability (Calif.

Stats. 1988, ch. 1555, 5.3). The company also be28 Recently, some pharmaceutical companies have begun advertising prescription drugs directly to consumers. It is possible that vaccines

could be advertised directly to consumers in the future.

29 It is not known whether any vaccine candidate would not qualify for patent protection.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 93

came part of Hoffman-La Roche, a large Swiss

pharmaceutical company, which may provide it

with financial backing to pursue expensive vaccine development. Large companies with substantial assets, however, are often thought to be more

vulnerable to liability claims than small companies with few assets because of their deeper pockets (61).

Finally, the company apparently clarified or resolved earlier scientific questions about vaccine

production, safety and efficacy. Which, if any, of

these factors persuaded the company to proceed

with a new HIV vaccine is unknown outside the

company. By mid-1994, Genentech and Biocine

were prepared to test their candidate vaccines in

the first U.S. phase III field trials. After the NIAID

decided not to proceed in June 1994, the companies were reportedly disappointed, and ready to

seek alternative ways to pursue the trials without

NIAID support (40).

Oncogen

Oncogen, a subsidiary of Bristol-Meyers Squibb,

stopped producing preventive vaccine (using live

vaccinia virus as a vector to express recombinant

gp 160) in 1992 before testing its efficacy in human subjects. A researcher reportedly attributed

the decision to “fear of lawsuits from injured vaccine trial subjects” together with “other commercial negatives like a questionable market and patent snafus” (32). Others note that lack of data

indicating potential efficacy prompted discontinuation.

Immune Response Corp

Immune Response Corp., co-founded by Jonas

Salk, was also reported to delay testing its whole,

killed-virus vaccine in uninfected subjects because of liability concerns, but other reports said

the company was willing to go forward if the vaccine showed evidence of effectiveness (32).

The vaccine has been tested, without liability

issues, in HIV-positive people as a therapeutic

means to prevent disease progression to AIDS.

Although the whole, killed-virus approach has

shown promise, (124) it has raised safety concerns

it might cause HIV infection if any of the virus

survived processing. Recent tests of live attenuated SIV vaccine in newborn monkeys lend

weight to such fears (126).

MicroGeneSys

MicroGeneSys reportedly refused to conduct

trials of its vaccine to prevent HIV transmission

from HIV-positive pregnant women to their newborns, unless the state legislature granted it immunity from liability (172). Lobbyists for MicroGeneSys argued that children born to HIV positive

mothers, many of whom had used illegal drugs,

are at high risk for medical problems which might

be blamed on the vaccine. The company’s president reportedly claimed that a new law was needed to establish a parent’s right to consent to involving a fetus in research (169).30 The company

refused to conduct trials in Tennessee which offered no special protection against liability.

Connecticut, the company’s home state, enacted a statute in 1991 granting Connecticut

manufacturers, research institutions, and researchers immunity from civil liability for personal injury to research subjects resulting from administration of any investigational AIDS vaccine

(Conn. Gen. Stat. 19a-591-591, 1992c). The law,

which offered no compensation to injured subjects, provides immunity from both strict liability

and negligence in cases involving research subjects, but retains liability for gross negligence, and

reckless, willful or wanton misconduct. At the

same time, Connecticut provided substantial economic support to the company, which had no income-producing product and needed substantial

capital to construct a plant to produce vaccine

(17). MicroGeneSys insisted on conducting the

30 It is questionable whether a company would be liable under existing common law for fetal injuries resulting from research to which the

pregnant woman consented (31).
94 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

trial at Yale University only, rejecting other

planned and proposed sites in Connecticut. After

about a year, only two subjects were enrolled. The

trial was then closed because it could not produce

useful data.

Elsewhere, Genentech conducted trials of its

vaccine to prevent maternal HIV transmission in

the NIAID-supported sites around the country, although only California had statutory protection

against manufacturer liability for injuries arising

out of such trials. Preliminary results have not

supported hopes for the vaccine effectiveness in

pregnant women, and Genentech is dropping its

therapeutic vaccine research to concentrate on

preventive vaccines.

MicroGeneSys did not mention liability when

it lobbied successfully for a $20-million congressional appropriation to the Department of Defense

(DOD) to finance trials of its vaccine for therapeutic use in HIV-positive adults. The appropriation,

for a specific project proposed by an individual

company outside the usual peer review channels,

created considerable controversy, was opposed by

DOD, NIH, and FDA, and was ultimately rescinded (38). NIH, FDA, and DOD preferred a

trial comparing several candidate vaccines chosen

by peer review.

The first vaccine to be approved for testing in

human beings (in 1987), MicroGeneSys’s product

might not fare well against the more recent generation of candidate vaccines. MicroGeneSys’s

corporate partner, American Home Products,

Wyeth-Ayerst Laboratories, which had financed

the company and acquired worldwide marketing

rights to the vaccine, terminated its agreement

with MicroGeneSys and its involvement with the

vaccine’s development in January 1994 without

comment (39).

Abbott

Another report involved Abbott Laboratories’ human immunodeficiency virus immune globulin

(HIVIG), which was intended to stop the transmission of HIV from HIV-positive mothers to

their newborns. Not a preventive vaccine, HIVIG

contains antibody against HIV derived from the

plasma of HIV-positive people with strong immune responses to the virus. Researchers hoped it

would reduce the viral load in pregnant women

with HIV and prevent infection of their children,

either before or during delivery. A large multicenter trial of HIVIG had been planned under the

sponsorship of Abbott and the National Heart

Lung and Blood Institute, the NIAID and the National Institute of Child Health and Human Development. After two years of planning, Abbott suddenly withdrew in 1992, citing liability concerns

(41). Researchers could not recall earlier mentions

of liability, even though high-level company representatives had met with them to plan the trials.

Some participants and observers believed that

Abbott was seeking to get rid of its blood products

division in a reorganization to improve profitability and used the trial as the excuse to do so. According to news reports, Abbott’s interest in the trial

dropped after the head of its transfusion medicine

branch left the company. Abbott first objected to

certifying that its costs and prices to government

were properly computed, a standard NIH requirement that NIH finally waived (41). Then Abbott

objected to patent rights arrangements. Finally,

Abbott asked for indemnification against liability

(citing the Swine Flu Program31 as precedent),

which NIH could not provide without Congressional action. Other organizations that make immunoglobulin did not consider liability an ob31The Swine Flu Program, created by Congress in 1976 to encourage the development and marketing of a vaccine against a strain of swine

flu which was expected that fall and winter, held manufacturers harmless from injuries arising from the swine flu vaccine, and permitted claims

for vaccine-related injuries to be filed with the U.S. government. The program is discussed in more detail in the next section.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 95

stacle.32 One AIDS organizer opined that Abbott

was trying to manipulate activists and researchers

to lobby Congress for liability protection (41).

Abbott employees active in transfusion medicine

later formed their own company and successfully

bid to produce HIVIG for the multi-center trials,

which finally began in 1993.

Summary

These examples fail to clarify the role of potential

liability in HIV vaccine development. It is plausible that liability was a concern. It is also plausible

that liability was not a serious consideration. In all

cases, other factors could explain not pursuing an

HIV vaccine, most commonly lack of evidence of

effectiveness, but also inadequate financing, poor

market predictions, corporate restructuring, and

potential patent problems.

Garber argues that when a company says it is

withdrawing a socially beneficial product from

the market because of fear of liability, such statements should have credibility (61). But vaccines

may be an exception. If the primary reason for

withdrawal is financial—such as a desire to focus

on products with much higher returns—a company may be loath to state publicly that it is foregoing a socially beneficial product in order to make

more profit. The public is likely to find ordinary

concern for profits less acceptable when the product it loses is greatly needed, and more likely to

tolerate the loss if it seems beyond a company’s

control.

Moreover, from the company’s perspective,

there is always the possibility that Congress might

take action to limit liability, which would decrease

expenses. The only risk in attributing withdrawal

to liability is that Congress might require the company to guarantee production or to sell at a low

price in return for limiting liability. But Congress

has never imposed such a quid pro quo, so the risk

is probably negligible.

Drugs Withdrawn from the Market

A look at drugs that have been the target of liability claims and whether they remained on the market may yield some clues as to whether potential

liability is a serious threat to HIV vaccine development. Studies of product withdrawals recognize the impossibility of identifying the reasons

for withdrawal in many cases (61, 178). It is often

difficult to sort out whether producers acted out of

concern for consumers, fear of regulatory action,

actual regulatory action, disappointing financial

returns, changing business opportunities, litigation experience, fear of liability, or some combination of these.

Relatively few drugs have been withdrawn after marketing.33 Some undoubtedly were withdrawn or never marketed because risks materialized that made them too hazardous to use. Such

withdrawals for safety reasons are sometimes attributed to liability. To be sure, a drug that turned

out to be dangerous to use, especially if its benefits

were limited, could be the subject of liability

claims. As Bovbjerg notes, however, one must assume that “right-thinking” producers would withdraw a dangerous drug because they did not wish

to subject consumers to its dangers, or their reputations to public wrath, not merely because of potential liability (21). To assume that liability is the

sole cause of such withdrawal would mean that liability is the sole deterrent to marketing unsafe

drugs.

Drugs that have been withdrawn from the market include Bendectin, DES (diethylstilbestrol),

MER-29, Merital, Oraflex, Selacryn, Versed and

Zomax. Bendectin and DES were the subject of

mass tort claims in which thousands of claimants

32 Burroughs Wellcome Co. jointly sponsored trials of AZT in pregnant women to determine whether it would reduce HIV transmission.

Preliminary results are encouraging.

33 Most medical products that have been withdrawn have been medical devices rather than pharmaceuticals: the Dalkon Shield; Copper-7

and other IUDs; Bjork-Shiley Heart Valve; and silicon-gel breast implants (61, 178).
96 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

have filed suit amid substantial publicity. The last

five drugs were not involved in extensive liability

claims and are rarely mentioned in discussions of

liability effects on product marketing. Garber suggests that perhaps the fact that other alternatives

were available mitigated their withdrawal (61).

The few studies of product liability claims for

medical products indicate that the claims are highly product-specific, with Bendectin accounting

for the majority (194).34 Bendectin, the drug to

prevent morning sickness during pregnancy, is the

best example of a drug that can be said with any

confidence to have been withdrawn for liability

reasons. There is little, if any, evidence that the

drug causes serious side effects. The producer,

Merrell Dow Pharmaceutical, has won all but a

few of the litigated cases.35 The FDA did not require withdrawal of the product, although warnings were strengthened (61, 105). Yet the cost of

defending or settling the more than 2,000 suits

that have been filed may not have been worth the

effort or expense.36

DES, a synthetic estrogen produced by several

companies (including Abbott Laboratories, Eli

Lilly & Co., Squibb Corp., and Upjohn Co.), is a

more complicated example because it did cause

cancer in the daughters of women who used the

drug to prevent miscarriage. The FDA approved

DES in 1941 and banned its use in 1971. Although

many have decried its withdrawal (80) and no

drugs to prevent miscarriage are being marketed

now, no one suggests that withdrawal of DES itself is a great loss to society. One reason it has become a cautionary tale for liability seems to lie in

the fact that the risk was latent, exposing several

companies to lawsuits a generation after the drug

was used.

It may be that the possibility for mass tort litigation involving risks to a fetus unknown at the

time of marketing is a special case which deters

marketing certain drugs. Bendectin and DES were

both intended for use by pregnant women who

wanted to have a child. Drugs used for pregnancy

are more susceptible to claims alleging serious

permanent harm to children than other drugs

(194). Until quite recently, few drugs prescribed

for pregnant women were tested in pregnant

women before marketing (118), so that their effects on the fetus were often unknown.

Several drugs with recognized serious side effects (such as Accutane, Clozaril, and Cytotec) remain on the market in spite of successful claims of

liability. The FDA reportedly estimated that Accutane, Hoffman-La Roche’s drug to treat severe

cystic acne, had caused perhaps 1,300 birth defects by 1986 (61, 164). Hoffman-La Roche has

provided special information kits to prevent the

drug’s use in pregnant women, but has not withdrawn the product, as might be expected if liability claims determined product availability.

Similarly, Sandoz’s Clozaril (used to treat

schizophrenia) has potentially fatal side effects in

perhaps two percent of patients (139). It requires

careful monitoring of white blood cell counts to

avoid agranulocytosis. It is possible that the potential for liability is diluted by the physician’s involvement in supervising the drug’s use.37 Still,

contrary to conventional wisdom, the severity of

the side effects has not been sufficient to deter

34 Although claims involving pharmaceuticals and medical devices have risen since the 1960’s, there is no information on whether the baseline level of claims was too high, too low, or about right, because the merits of such claims were not (and probably could not be) investigated.

35 Bendectin was the subject of Daubert v. Merrell Dow Pharmaceutical, Inc., 113 S.Ct. 2786 (1993), in which the U.S. Supreme Court held

that the Frye rule for admitting scientific evidence in Federal court was superseded by the Federal Rules of Evidence, which permits the admission of “all relevant evidence” unless specifically excepted by the Rules (8).

36 One commentator suggests that mothers who had used Bendectin may have viewed the company with suspicion because it had acquired

other problem products, including Thalidomide, MER-29, DES, and Agent Orange (154).

37 The limited potential for damages in the case of people with severe schizophrenia who are unable to work, even while using the drug, may

also reduce the financial exposure for liability, although it is unclear what proportion of patients would fall into that category. Damages for the

death of an individual are typically less than damages for permanent injury.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 97

marketing. Cytotec would appear to have even

greater potential for withdrawal because its benefits have less dramatic social value. The drug is

used to prevent ulcers in patients who take nonsteroidal anti-inflammatory drugs (like aspirin

and ibuprofen) for arthritis, but can cause abnormal bleeding and miscarriage or abortion in pregnant patients (61, 139). G.D. Searle still markets

Cytotec with strong warnings of the risks.

Another factor influencing product withdrawal

may be the importance of the revenues it produces

for a company. Prozac (an antidepressant) reportedly accounts for about 25 percent of Eli Lilly’s

drug sales, $1 billion in the United States. Lawsuits have claimed that the drug causes suicide,

violence, and even murder, but the validity of such

claims is uncertain at best. The background rate of

such behavior among users means that some cases

may be misattributed to the drug but that it will

also be difficult to prove causation. Such circumstances appear to be precisely the sort that would

prompt a manufacturer’s withdrawal of a drug for

fear of unfounded liability claims. Indeed, they

parallel Bendectin’s claims experience (61).

Nonetheless, Lilly is not expected to withdraw

Prozac and is vigorously defending all claims

against it. The generally favorable publicity it has

received suggests that a significant proportion of

the population wants the drug on the market (102).

Halcion, the most widely prescribed sleeping

pill in the United States, has also been the subject

of claims that it causes suicide and violence.38 The

Upjohn Co. is keeping the drug on the market—it

has reportedly produced about $2 billion in

sales—although alternative medicines are available. The company recently brought a libel suit in

England against the British Broadcasting Corporation and an expert witness who testified for

plaintiffs and publicly criticized Upjohn (18).

In sum, it is difficult to generalize about the effect of liability concerns on marketing from these

examples. In particular, they say nothing about

products that were never marketed in the first

place.39 They do suggest, at a minimum, that

whatever weight potential liability may have, it is

balanced with other factors to predict the net social and financial returns that marketing a specific

product may bring.

Different companies may give such factors different weights. Arguably, breakthrough drugs for

diseases without any current cure, or drugs that offer a significant improvement over existing drugs,

are more likely to be marketed (and remain on the

market) than “me-too” drugs or those with only

marginal additional benefits or fewer risks. Drugs

that may harbor serious latent hazards, especially

those that might become the subject of mass tort

claims, might be considered more susceptible to

withdrawal, before or after marketing; but all the

drugs discussed fall into this category, yet not all

were withdrawn.

Perhaps the higher financial returns from a

large market can offset concerns about potential

exposure to large numbers of claims. The severity

of inherent risks may not be determinative, especially if the drug can produce substantial revenues. If the hazards can result from multiple

causes, the probability of claims attributing injury

to the drug is higher than when causation is clear,

but the proportion of claims resulting in liability is

lower.

Where the risks are known, some companies

may feel they can protect themselves against inappropriate liability by ensuring that proper warn38 One woman, criminally indicted for homicide for fatally shooting her mother after taking Halcion, Valium, and codeine, had the charges

dropped on the grounds that she was intoxicated by the drug. She sued Upjohn for negligence and received an $8 million settlement (18). A

decision by the Supreme Court of Utah (255) held that makers of FDA-approved drugs were immune from strict liability for defective design.

39 Thalidomide may be an example of a drug that is not being marketed now because of its potential to cause severe birth defects when used

by pregnant women to relieve nausea (105). Merrell reportedly settled claims that the drug caused birth defects among residents in Canada and

the United States (154). Although the FDA had not approved thalidomide, it was distributed for investigational use. It is currently being investigated as a therapy for patients with leprosy or AIDS wasting.
98 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

ings are given, as they have with Accutane, Clozaril, and Cytotec.40 Others may not. Where adverse

reactions cannot reasonably be predicted, there is

always the possibility that serious harm could materialize in the future and, with it, liability claims.

Although lengthier and more sophisticated premarket testing has probably lowered the risk of

unforeseen adverse reactions, no drug is free from

that risk.

Vaccines Withdrawn from the Market

Conventional wisdom has held that, whatever the

reasons for withdrawing particular drugs from the

market, vaccines have been withdrawn primarily

because of fear of liability for adverse reactions

(13, 61, 79, 80, 105). As with drugs, there can be

many reasons for withdrawing a vaccine; the lack

of empirical data makes it difficult to draw generalizable conclusions.

The two examples of vaccines that were withdrawn or delayed to market are the swine flu and

DPT (diphtheria-pertussis-tetanus) vaccines. In

1976, makers of swine flu vaccine said they would

not produce or market the vaccine unless the Federal government assumed liability for adverse

reactions. Their insurers would not provide liability insurance covering such reactions. The vaccine

was developed hurriedly in response to public

health officials’ fears of a new influenza epidemic

like the one that killed tens of thousands of people

in 1918 (129). Amid substantial publicity, then

President Gerald Ford encouraged everyone in the

country to be vaccinated. There was insufficient

time to test the swine flu vaccine in the same manner that other non-influenza vaccines were tested

if the vaccine were to be available to vaccinate the

entire American population by flu season. In response, Congress enacted the National Swine Flu

Immunization Program, whereby the Federal government assumed legal liability for non-negligent

adverse reactions to the vaccine (180).41

The lessons from swine flu are conflicting. On

the one hand, vaccine makers could not get liability insurance for the vaccine,42 and fear of liability

apparently stopped vaccine production. Congress

took such fears seriously enough to pass protective legislation (56). In addition, Guillain-Barré

syndrome, an unexpected serious adverse reaction

resulting in paralysis, did materialize, and with it,

about 4,000 claims against the government. This

gives credence to liability fears.

On the other hand, the government paid out less

than $2 per dose of vaccine distributed in awards

and settlements to claimants.43 The government

agreed to accept responsibility in any case in

which the symptoms of Guillain-Barré syndrome

appeared within ten weeks of vaccination (a generous assumption of causation that would probably not be accepted by any vaccine maker), so

that it paid a larger proportion of claims than

would have been paid had the cases been litigated

under ordinary tort requirements.44 In litigated

cases involving Guillain-Barré syndrome appearing after ten weeks or other conditions, court decisions awarded compensation in only six reported

cases (247, 260, 286, 305, 308, 315).

Swine flu probably represents a worst case scenario for vaccine liability. The legislation was enacted as a temporary measure and was not designed to resolve liability issues systematically

40 The tobacco industry has succeeded in defeating claims of liability for the use of cigarettes largely by virtue of warnings.

41 The federal government assumed responsibility for defending all claims and had a right of abrogation against the manufacturer in cases in

which the manufacturer’s negligence caused injury, allowing the government to obtain payment from the manufacturer for awards in negligence. However, the government also provided $230 million in liability insurance for vaccine manufacturers, thereby paying for its own indemnity.

42 Most vaccine makers now self-insure in whole or in part.

43 Total awards and settlements were approximately $76 million, excluding administrative costs.

44 According to one court, the government agreed to liability in Guillain-Barré cases not only to provide compensation to those who could

not prove negligence, but also because the syndrome was not mentioned as risk in the consent document (315).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 99

(82). As the Institute of Medicine noted, the legislation “only changed the defendant” (82). Certainly Congress is not anxious to repeat the experience

and would shy away from assuming liability for

any new vaccine. At the same time, the total

amount of awards may be manageable if the vaccine is appropriately priced. This suggests that the

price at which a vaccine can be sold may determine how much room there is for liability payments.

Swine flu development also differed from the

circumstances surrounding most other vaccines

because of its necessarily hasty development and

its immediate use in millions of people. Of course,

the more deliberate pace of research possible with

most vaccines does not ensure that all risks will be

discovered before marketing. But the more a vaccine is studied, the more likely it is that adverse

reactions will be discovered.

Wyeth Laboratories ceased DPT vaccine production in 1984, reportedly because of claims

filed asserting adverse reactions to the pertussis

component of DPT. It is entirely plausible that

Wyeth could have decided that vaccine production

would not be profitable enough to justify defending additional lawsuits. At the same time, Wyeth

reportedly faced replacing its old vaccine production facilities if it were to continue selling the vaccine. If the company wanted to get out of the vaccine business, this would have been the time to do

it, before it invested heavily in an expensive new

plant. Wyeth did continue to produce the vaccine,

but sold it to Lederle for distribution.

Also in 1984, Connaught Laboratories announced that it would stop producing DPT because it was having difficulty getting liability insurance at a reasonable price. The Centers for

Disease Control and Prevention (CDC) recommended vaccinating only older children to conserve diminishing vaccine supplies. Connaught

soon found acceptable insurance and continued to

produce DPT. In 1986, prices for childhood vaccines rose dramatically.

CURRENT VACCINE RESEARCH AND

DEVELOPMENT

Companies have few business incentives to produce vaccines at all. The number of U.S. vaccine

makers has declined since the early 1970s. At that

time, many vaccines were “me-too” vaccines, produced much like generic products and sold in high

volume at very low prices (121). In the mid-1970s,

the FDA began to require evidence of effectiveness of vaccines as a condition for continued marketing. Many vaccine makers may have dropped

out of the business rather than conduct the expensive clinical trials necessary to demonstrate their

vaccines’ efficacy. The U.S. market for children’s

vaccines may not be large enough to support several competitors. The percentage of research and

development (R&D) expenditures devoted to biologics (as opposed to pharmaceuticals) in the industry declined from 4 percent in 1973 to 2.1 percent in 1983 (121).45 During that period, sales of

biologics represented between 2.7 and 3.6 percent

of total sales, including pharmaceuticals, of members of the Pharmaceutical Manufacturers

Association (since renamed the Pharmaceutical

Research and Manufacturers Association). Between 1973 and 1980, R&D expenditures for biologics ranged unevenly (between 12.9 and 23.1

percent of sales of biologics alone). In 1981, that

percentage was 9.2 (121).

In recent years, however, vaccine research and

development has increased in the United States. A

recent report by the Institute of Medicine concludes that “the worldwide vaccine industry appears to be entering a new era of activity and innovation” (121). Applications submitted to the

FDA to study new biologics rose from 66 in 1980

to 558 in 1992 (212). Most have been for thera45 Total research and development for both pharmaceuticals and biologics increased gradually from 12.57 percent in 1973 to 15.32 percent

of total sales in 1983 (121). Total R&D for 1990 was 17.4 percent of total sales.
100 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

peutics, but Investigational New Drug applications for vaccines have been increasing since 1990

(67 in 1990, 81 in 1992). Some established pharmaceutical companies in the United States have

begun new investments in vaccine research.46

Several U.S. companies are joining with foreign

firms to develop or license vaccines.

The past four years have seen the introduction

of a dozen new vaccines, including a new acellular

pertussis component of the combination vaccine

(DTaP) with diphtheria and tetanus toxoids by

Lederle-Praxis and Connaught Laboratories, several new Haemophilus influenzae type b (Hib)

vaccines, Japanese encephalitis virus vaccine, and

a new typhoid vaccine. Other new or improved

vaccines, including one to prevent chicken pox,

are in clinical trials or expected to be approved by

the FDA in the near future. It is possible that the

industry went through a shaking-out period in the

1980s and is being restructured to meet the new

scientific challenges posed by infectious diseases

more efficiently.

The growth in biotechnology companies may

have helped this trend. Biotechnology researchers

are likely to be an important source of innovative

products in the next few years (77). More than 75

biotechnology companies around the world were

conducting vaccine research and development in

1992. Small companies may be able to invest in

risky products because they have less to lose in the

event of catastrophe.

At the same time, the biotechnology industry

may experience a shake-out in the near future,

with many of the estimated 1,300 companies going out of business. Few small companies have

any FDA-approved products on the market, and

thus have no product revenue. Most companies reportedly do not have enough financing to operate

for more than two years (67, 77). The investment

community may be wary of investing further in

companies that face a low probability of producing a commercial product within the next several

years, especially after news reports of the failure

of eight companies’ pharmaceutical products in

clinical trials in 1994 (47). Small firms that are

short of operating capital may sell or license their

product rights or the entire company. Most are expected to be acquired by large pharmaceutical

companies, including foreign companies.47

Other biotechnology companies may survive

by concentrating on only one or two products, by

licensing new products to large domestic or foreign companies, or by limiting themselves to one

phase of product development and conducting

joint ventures with other companies that specialize in clinical trials, manufacturing, or marketing

(77). If the pharmaceutical industry scales back its

investment in research and development, the biotechnology industry may fill the gap in research.

Which companies will do so remains to be seen.

The modern vaccine industry looks more like

the pharmaceutical industry and less like the earlier vaccine industry. The trend appears to be toward developing sophisticated products, often the

result of recombinant DNA technology, that can

be sold at prices approaching the higher prices of

pharmaceuticals. Often the technology used influences the attractiveness of vaccine production.

Technologies that can be used to produce other

marketable products, such as diagnostic tests, are

more likely to be pursued than technologies that

have only one use. In view of the fact that only a

small proportion of potential products are ultimately approved by the FDA and successfully

46 For example, Merck & Co., Inc., maker of measles vaccine, created its Merck Vaccine Division in 1991, has invested in a new biotechnology facility in Pennsylvania, and has entered into joint or cooperative ventures with other companies, such as MedImmune. Lederle Laboratories, the target of DPT vaccine lawsuits, acquired Praxis Biologics, developer of a conjugate Haemophilus influenzae type b vaccine (Hib-CV).

American Cyanamid made the resulting Lederle-Praxis Biologicals a regular business unit in 1992, giving it greater corporate weight (121).

47 For example, Ciba-Geigy, Ltd. of Switzerland is reported to have agreed to buy 49.9% of Chiron Corporation, a profitable independent

company and provide it with new financial and technical assistance (57). Ciba-Geigy and Chiron are also partners in Biocine which developed a

candidate HIV vaccine.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 101

marketed, companies may be reluctant to gamble

a large investment on a single long-shot vaccine.

The National Childhood Vaccine Injury Act of

198648 may also have encouraged vaccine research because it limits producers’ liability to a

predictable amount (paid as a tax on vaccine sales)

and frees them from defending claims. As originally enacted, however, the Act did not apply to

investigational or newly approved vaccines. It

was to cover only vaccines that children were required by law to take. A 1993 amendment permits

the Secretary of Health and Human Services to extend coverage to new vaccines that are recommended for children; Hib and HBV vaccines are

expected to be added soon. Vaccine makers may

anticipate that other vaccines will be added. Most

of the recently approved vaccines had been under

development before the act took effect in 1988. If

it does further encourage research, then an even

larger increase in vaccine development should be

expected in the future.

Research initiatives for HIV vaccine development are also encouraging. At least twelve companies are actively engaged in HIV vaccine research

and development, and others are developing adjuvants and other supporting products.49 This exceeds the number of companies developing a vaccine for any other disease. Almost 30 candidate

vaccines are now in clinical trials (207). The debate over phase III field trials centers on scientific

issues whether any of the candidate vaccines that

have been tested show sufficient promise of effectiveness to warrant large=scale testing in human

beings. Potential liability for adverse reactions

does not appear to be a factor in these debates.

There is a possibility that subjects injured in a foreign field trial might try to sue a U.S. vaccine maker in the United States (173). But the rarity of injuries in clinical trials in general (140) and the even

greater rarity of claims arising out of such trials

suggests that liability has not much influenced decision-making about whether to conduct field

trials abroad.

❚ Conclusion:

There is evidence that vaccine research and development is increasing and that a surprising number

of companies are engaged in HIV vaccine research. Indeed, more companies are developing

vaccines for HIV infection than for any other

single disease. Potential liability may have concerned a few companies, but it has not prevented

a strong research effort and appears unlikely to

halt HIV vaccine development. The major stumbling blocks remain scientific. Even if new vaccine candidates show more promise than those

currently in clinical trials, the likely market for an

HIV vaccine is uncertain. Given the business disincentives to producing an HIV vaccine, the vigor

of research is encouraging.

Decisions about HIV vaccine research and marketing are likely to vary from company to company and from product to product, as they have with

other vaccines and drugs in the past. Fear of liability may influence a few companies’ choice of vaccine type, so that they may avoid killed or live attenuated vaccines in favor of recombinant

vaccines that are believed to pose little or no safety

risk. If so, the array of possible vaccines could be

limited to the more expensive recombinant types.

TORT LIABILITY FOR ADVERSE

REACTIONS TO VACCINES

❚ Overview of Product Liability

Like manufacturers of all products, vaccine makers are responsible under state law for personal injuries caused by their own negligence or by a de48The National Childhood Vaccine Injury Act of 1986 is discussed below under Public Compensation Systems.

49See chapter 2 for a discussion on the current state of HIV vaccine development.
102 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

fect in their products.50 Tort law provides two

categories of legal responsibility for personal injuries caused by products: negligence and strict liability (94).51

Negligence is conduct by the product maker

that deviates from standards of acceptable conduct

adhered to by the ordinary manufacturer of similar

products and that results in harm to the product

user. To succeed on a negligence claim, a plaintiff

must prove that: 1) the manufacturer had a duty to

the plaintiff, 2) the manufacturer breached that

duty, 3) the plaintiff suffered an injury for which

damages may be awarded by law, and 4) the injury

was caused by the manufacturer’s breach of duty

(94).

Few cases for vaccine-related injury are

brought in negligence alone. Before 1960, plaintiffs were generally unable to prove that a

manufacturer had been negligent or that a vaccine

had caused an injury (228, 295, 314). Strict liability developed in part because consumers were frequently unable to obtain the evidence that a

manufacturer of consumer products had acted

negligently.52 By the mid 1960s, when more vaccines were being marketed widely in the United

States, the state had begun to adopt the doctrine of

strict liability for injuries caused by defective

products, so that plaintiffs were able to apply that

theory to vaccines as well as other consumer products (13, 168).

The concept of strict liability generally applied

in the United States is summarized in Section

402A of the Restatement (Second) of Torts and

holds “[o]ne who sells any product in a defective

condition unreasonably dangerous to the user or

consumer or to his property [liable] for physical

harm thereby caused to the ultimate user or consumer....” (4).53 Thus, strict liability is said to focus on the condition of the product itself, while

negligence focuses on the behavior of the

manufacturer (206). Because the manufacturer’s

actions or knowledge are often at issue in deciding

whether a product is defective, however, the strict

liability concept has increasingly mimicked aspects of ordinary negligence (72).

These rules would also apply in some cases involving adverse reactions to U.S. products that occur in developing countries and are ligated in the

United States (see box 4-1).

PRODUCT DEFECTS

Traditionally, product defects have been divided

into three categories: 1) manufacturing flaws, 2)

defects in product design, and 3) errors or omissions in directions and warnings accompanying

the product. Least controversial are manufacturing flaws or errors in the manufacturing process.54

These produce something other than the product

intended by the manufacturer, since the manufac50 Although state laws vary to some degree, the basic principles are sufficiently similar to permit generalization for purposes of this report.

There is no general federal tort law, although supporters of tort reform have sought enactment of a federal law governing product liability for

many years. For a description of the National Vaccine Injury Compensation Program, see discussion below.

51 Causes of action also exist for breach of express or implied warranty of fitness for a particular purpose, but because they are not based in

tort law, tend to cover the same facts and duties as strict liability and are usually superseded by strict liability or negligence claims, they are not

discussed herein.

52 Strict liability combines elements of traditional actions in negligence (which do not require privity of contract) and warranty (which do

not require proof of negligence). Warranty claims were available only to those who had purchased a product directly from a seller and were

therefore in contractual privity (51, 52).

53 Section 402A also specifies that the seller is liable if engaged in the business of selling the product and “it is expected to and does reach the

user or consumer without substantial change in the condition in which it is sold.” This rule “applies although (a) the seller has exercised all

possible care in the preparation and sale of his product, and (b) the user or consumer has not bought the product from or entered into any contractual relation with the seller” (4).

54 Liability for manufacturing errors dates back from the thirteenth century when those who supplied contaminated food were subject to

criminal liability (4).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines 103

Although the NIH has postponed Phase Ill clinical efficacy trials of HIV vaccines in the United States,

some U.S. pharmaceutical manufacturers have begun large-scale clinical trials of HIV vaccines in developing countries. These U.S. pharmaceutical manufacturers are thus exposed to liability for adverse

reactions to HIV vaccines that occur among trial participants in developing countries.

Plaintiffs may seek to bring a legal proceeding to the place of manufacture if they believe there is an

opportunity for a larger recovery. Foreign trial participants who are injured by HIV vaccines manufactured in the United States may prefer to bring suit in U.S. courts, because U.S. product liability law is

considered more favorable to plaintiffs than product liability laws of most developing countries. For

instance, U.S. law allows plaintiffs to hire attorneys on a contingency fee basis, so that the plaintiff’s

attorney is not paid unless there is a recovery. U.S. law allows for the award of punitive damages in

product liability cases, whereas the laws of many developing countries do not. And unlike most countries, U.S. law permits jury trials in product liability cases; awards by juries have the reputation of being

more generous.

The legal doctrine of forum non convenient, however, substantially limits the ability of foreign plaintiffs to bring suit in U.S. courts. One of the original intents of this doctrine was to prevent “forum shopping” by plaintiffs, but the doctrine has increasingly been used as a means for “reverse” forum shopping by defendants who wish to dismiss cases brought by foreign plaintiffs in U.S. courts. In analyzing

whether to grant a forum non convenient motion, courts considers a three-part test. The court first determines whether an appropriate alternative forum exists where the plaintiff can receive redress (usually

the home country of the plaintiff, or the place where the injury occurred). In determining whether there is

another suitable forum, the court is not to consider which forum would be more or less favorable to

either of the parties. 1

If the court finds that an acceptable alternative forum exists, then it determines whether the greater

“convenience” of the alternative forum would warrant dismissal. In determining whether it is more appropriate to bring the suit in an alternative forum, the court is to balance the various public and private

interests in the location of the suit.

In considering forum non conveniens motions, courts have emphasized the administrative burden of

the case on U.S. courts. This concern was important in the courts decision to grant a forum non conveniens motion to dismiss in In re Union Carbide Corporation, (268), which followed an explosion at a

chemical plant in Bhopal, India, with a large number of deaths and injuries. U.S. lawyers who were representing a number of injured individuals and their families in a tort action against Union Carbide

sought to try the case in a United States Federal court. The court decided that India’s legal system

could provide an adequate forum. The court also decided that India’s courts were the most appropriate

forum, considering the location of the witnesses, the evidence, and the documentation for this case.

The court weighed the public and private interests involved, and, in dismissing the case, placed the

greatest emphasis on administrative concerns. The court reasoned that “the American interests are relatively minor. Indeed, a longer trial . would unduly burden an already burdened court, involve both

injury and hardship and heavy expense. ” Ibid.

(continued)

1 In Piper Aircraft Co. v. Reyno, (287) the Supreme Court held that the doctrine of form non conveniens applied despite the possibility that the plaintiff may face less favorable product liability laws in foreign courts. The court reasoned that U.S. courts, with their strict

liability theory, potential choice of fifty jurisdictions, availability of jury trials, contingent attorney’s fees, and rules allowing extensive

discovery, are especially attractive to foreign plaintiffs, further congesting crowded U.S. dockets.
104 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

The doctrine of forum non convenient has been raised in a number of cases involving injuries from

U.S. pharmaceutical products marketed abroad.2 In some cases, especially involving injuries that may

also have occurred to a large number of other persons as well, courts have granted forum non conveniens motions to dismiss the case. In Dowling v. Hyland Therapeutics, (237), the plaintiff, an Irish hemophiliac, brought suit in a Federal court in New York City against the U.S. manufacturer of HIV-infected

blood clotting factor that he received. The blood product was manufactured in the United States, and

the blood product was administered to the plaintiff in Ireland. The court dismissed the case, reasoning

that “[t]he public interest in AIDS prevention is equally important in New York as in Ireland. However, in

all other respects, the public interest clearly favors trial in Ireland. Irish law would apply since Dowling

received treatment, allegedly contracted HIV, and at all times resided in Ireland. ” ibid.3

However, in other cases involving individual injuries that were unlikely to have occurred to many others, courts have permitted foreigners injured by U.S. drugs and vaccines to bring their case into U.S.

courts, See, e.g., Cadenstope v. Merck, (227); Chan Tse Ming v. Cordis Corp., (230); Corrigan v. Bjork

Shiley Corp., (233); Haddad v. Richardson-Merrell, Inc. (256); Hodson v. A./-f. Robins Co., Inc., (261)

Given that the U.S. judicial system is overburdened, courts are expected to continue to use the doctrine of forum non conveniens to limit access of foreign plaintiffs to U.S. courts.

SOURCE: R.E. Stein, Blicker & Stein, Washington, DC, “Selected Issues of AIDS Vaccine Liability, ” unpublished contractor report

prepared for the Office of Technology Assessment, U.S. Congress, Washington, DC, Sept. 30, 1994

2 All of the cases cited here involve drugs that have been approved and marketed. To date, there are no cases where a foreign

plaintiff has been permitted to sue in the United States for injuries that occurred during a foreign trial of a U S.-manufactured drug or

vaccine,

3 See also De Melo v. Lederle Laboratories, (236) (Eighth Circuit Court of Appeals upheld the dismissal by a federal district court Of

a lawsuit brought by a Brazilian woman permanently blinded in Brazil by a drug manufactured in the United States. While the U.S.

labeling for the drug warned of permanent blindness, the Brazilian labeling warned only of temporary blindness).

turing process failed to conform to the manufac- Defects in design are problems with the product

turer’s own specifications, and are generally limited to particular units or batches of the product.

Examples include adulterated or contaminated

products and products in which a toxic element

was not removed or rendered harmless by the

manufacturing or quality control process. Claims

based on manufacturing defects in vaccines are

extremely rare, probably because such defects

themselves are so rare.55

specifications themselves, not an isolated

manufacturing error. A design is defective if the

product could have been developed so as to reduce

its inherent danger to the user without significantly decreasing its effectiveness. Whether a design

is defective depends upon a manufacturer’s behavior in its research and testing activities and the

state of scientific knowledge at the time of product

development. Thus, although liability for design

55 The so-called Cutter incident occurred when the manufacturing process for the Salk killed-virus polio vaccine failed to “kill” particles of

live polio virus, the vaccine was used in a mass immunization program, and almost 100 people developed poliomyelitis (15). More than 60

lawsuits were filed. Plaintiffs in the lead case (250) ultimately won their action on the theory that the manufacturer had breached its implied

warranty (302). Most of the remaining lawsuits were settled thereafter.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 105

defects is theoretically part of strict liability, it is

understood to apply in essentially the same way as

liability for negligence. Few cases claiming that

vaccines were defectively designed were brought

until the 1980s (117).56 More recently, several

courts have rejected such claims and granted vaccine manufacturers effective immunity from strict

liability for design defects, absent fraudulent conduct.

The vast majority of litigated claims involving

vaccines are based on warning defects.57 These

are of two types: 1) a failure to provide warnings

of risks inherent in the use of the product (failure

to warn),58 and 2) providing directions and warnings that fail to adequately describe product risks

(inadequate warning). A defect in the warning is

independent of any flaw in the product itself. A

properly produced vaccine that is not accompanied by adequate warnings of possible side effects

is a product that is defective as marketed.

❚ Liability for Defectively Designed

Vaccines

Most vaccine manufacturers and some commentators argue that drug and vaccine makers should

be exempt from liability for defectively designed

products (as long as they meet FDA requirements

for approval) because of the benefits their products confer (159). Others argue that no exception

should be made because not all drugs provide a

significant social benefit and, because consumers

are especially vulnerable to undetectable risks in

pharmaceutical and biological products, their

makers should be held to at least the same standards as manufacturers of ordinary consumer

goods (211).

Courts have upheld both positions, although

the trend appears to be against holding drug and

vaccine makers liable for design defects (156). Almost all courts base their reasoning on Comment k

to Section 402A of the Restatement (Second) of

Torts (American Law Institute, 1977):59

Unavoidably Unsafe Products. There are

some products which, in the present state of human knowledge, are quite incapable of being

made safe for their intended and ordinary use.

These are especially common in the field of

drugs. An outstanding example is the vaccine

for the Pasteur treatment of rabies, which not uncommonly leads to very serious and damaging

consequences when it is injected. Since the disease itself invariably leads to a dreadful death,

both the marketing and use of the vaccine are

fully justified, notwithstanding the unavoidably

high degree of risk which they involve. Such a

product, properly prepared, and accompanied

by proper direction and warning, is not defective, nor is it unreasonably dangerous. The same

is true of many other drugs, vaccines, and the

like, many of which for this very reason cannot

be legally sold except to physicians, or under the

prescription of a physician. It is also true of

many new or experimental drugs as to which,

because of lack of time and opportunity for sufficient medical experience, there can be no assurance of safety, or perhaps even the purity of

ingredients, but such experience as there is justifies the marketing and use of the drug notwithstanding a medically recognizable risk. The

seller of such products, again with a qualifica56 In 1985, a California Court of Appeals found only one case (224) in which strict liability had been applied to a prescription drug (oral

contraceptives in that case) (273). No case involving vaccines was identified. The facts in Brochu may have permitted the plaintiff to recover in

negligence without resorting to strict liability.

57 Plaintiffs often bring claims in strict liability for both defects in design and warning defects, as well as claims in negligence, to ensure that

their claim is not dismissed for failure to correct cause of action.

58 This type of warning includes the failure to provide directions for the proper use of a product whose operation is not apparent to a consumer, but such directions are not relevant to the use of vaccines.

59 The American Law Institute (ALI) prepares treatises that summarize several fields of law. Its Restatement (Second) of Torts is widely

considered by the legal profession to be the most authoritative statement of tort law in the country. Most states have adopted its provisions, albeit

not uniformly, and some states have interpreted its technical requirements slightly differently. In 1993, the ALI began preparing a new (third)

restatement of the law which will include an updated volume on products liability (5).
106 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

tion that they are properly prepared and marketed, and proper warning is given, when the situation calls for it, is not to be held to strict

liability for unfortunate consequences attending

their use, merely because he has undertaken to

supply the public with an apparently useful and

desirable product, attended with a known but apparently reasonable risk.

Comment k describes an exception to strict liability in the case of products that are “unavoidably unsafe.” It was reportedly drafted in response

to an unsuccessful proposal that all prescription

drugs be exempt from Section 402A. The proposal was defeated, but Dean Prosser included language indicating that at least some drugs and vaccines should be exempt from strict liability for

harms that could not be avoided if the product

were to serve its beneficial purpose (132).

Most courts have refused to grant a blanket exemption for all drugs or vaccines (224, 229, 242,

251, 258, 273, 282, 284, 296, 300, 301, 303, 312,

318, 319). Instead they would exempt only those

drugs and vaccines that are unavoidably unsafe,

on a case by case basis.

However, other courts have held that makers of

FDA-approved prescription drugs are entirely exempt from strict liability for defective drug design, regardless of the drug in question, because of

the public interest in drug availability (255, 270,

277).60 The California Supreme Court did so in

1988 in a case involving diethylstil bestrol (DES),

even though the court doubted that DES could not

have been redesigned to reduce its risks or replaced with a safer drug (225).

The American Law Institute is preparing a revised version of its Restatement of Torts, which

will include a volume on products liability that is

expected to become available in 1995. The September 1994 draft of the chapter on liability for defective products includes provisions specifically

delineating and limiting the liability of pharmaceutical and biologics manufacturers for personal

injuries caused by their products (5). In particular,

the draft abandons the use of the term strict liability and instead sets slightly different standards for

“liability” in tort for harm caused by a product defect, depending on whether the defect is a

manufacturing error, a design defect, or a warning

defect. This characterization does not significantly alter existing law with respect to manufacturing

errors and warning defects; it does describe a more

stringent standard of proof for design defects,

however. If these provisions are accepted by the

Institute, they may further support the trend

against holding manufacturers strictly liable for

alleged design defects in prescription drugs and

vaccines. Whether the states adopt all the Institute’s revisions remains to be seen.

Where defective design is a permissible basis

for liability under current law, the plaintiff must

prove that the product is defective because its risks

render it unreasonably dangerous. The product’s

benefit or utility is balanced against the risks it

poses. This requires proving that, on the basis of

scientific knowledge known or available at the

time the product was marketed, the manufacturer

knew or should have known that the risks could

have been avoided or reduced without jeopardizing the product’s effectiveness and losing its benefit. 61 Several courts have described the factors

that should be considered in this calculus in differ60 This does not necessarily preclude liability for claims of negligent design.

61 A few courts have applied a “consumer expectations” test, which required the plaintiff to prove only that the product was more dangerous

than would be contemplated by an ordinary consumer possessing knowledge common in the community. This test appears to have been applied

little outside the area of ordinary consumer products like automobiles and has little, if any, application to product liability claims involving drugs

or vaccines (225). The consumer expectation test was used in the first formulation of a modern strict liability standard in Greenman v. Yuba

Power Products, Inc., (253), and its predecessor, Escola v. Coca Cola Bottling Co. of Fresno, (239) (Traynor, J., concurring). Both cases involved ordinary consumer products (a power tool in Greenman, a Coca Cola bottle in Escola), not drugs or vaccines. The consumer expectations test is also suggested in Comment g (to Section 402A), which defines a “defective condition” as “a condition not contemplated by the

ultimate consumer, which will be unreasonably dangerous to him.” Comment j also notes that Section 402A liability applies “where the product

is...in a condition not contemplated by the ultimate consumer.”
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 107

ent terms, sometimes creating uncertainty as to

the precise evidence needed to prove or disprove a

claim.62 Often, the plaintiff must show that a safer

alternative design was feasible and would have

achieved at least the same benefits. Nonetheless,

in all its formulations, the risk-utility test embodies fundamentally the same concept.

The proposed revision of the Restatement of

Torts, if adopted, would further narrow the

grounds for liability for design defects in prescription drugs, including vaccines, and devices. It

would provide that a drug is not reasonably safe

due to defective design only if its foreseeable risks

of harm are “sufficiently great in relation to its

foreseeable therapeutic benefits so that no reasonable health care provider . . . would prescribe the

drug . . . for any class of patients” (5). This would

limit liability for design defects to drugs that do

not provide any benefit to any group of patients. If

a reasonable, informed health care provider would

prescribe the drug to his or her patients, then the

drug would not be deemed to have a design defect

and no liability would attach. The effect of this restatement appears to be to reduce the grounds for

liability for design defect. It may simply reflect

the practical results in reported cases, however,

since products whose benefits outweigh their risks

are used by reasonable providers and are not found

to have design defects.

Because a design defect case turns on a

manufacturer’s knowledge and conduct, most

courts have found that the cause of action is effectively one of negligence (225). Manufacturers are

held to the knowledge of an expert in the field of

drug or vaccine production. They have a duty to

keep up with advances in scientific knowledge

and to conform to ethical drug industry standards

in research, development, and marketing (242,

255).

In the 1980s, there was some concern that

manufacturers could be held liable for failing to

eliminate a product risk that was unknown or unknowable at the time the product was developed

and marketed (146, 158). The 1982 New Jersey

case that sparked such concerns, Beshada v.

Johns-Manville Products Corp., however, was

largely overruled in 1984 (242).63 The Supreme

Court of California concluded that drug manufacturers are not liable for hazards not foreseeable at

the time of sale (225).

As a practical matter, no drug or vaccine

manufacturer has been found liable for selling a

product with risks that were unknowable when

marketed. A few cases have upheld jury or court

decisions that Quadrigen (a vaccine combining

DPT and polio vaccine marketed between 1959

and 1962) was defective because the preservative

used or combination of vaccines created a known

risk of harm and resulted in more adverse reactions than using the separate vaccines (284, 311).

The requirement that the risk be one that the

manufacturer knew or should have known on the

basis of scientific knowledge at the time the product was produced creates a defense to liability

based on the state of the art or the state of science.64 This is essentially a negligence defense

because it relies on industry standards, not on subsequently detected product risks.

Design defect claims are claims that a different

(safer and at least as effective) product should

62 These variations can add complexity to litigation, primarily for national companies that defend cases in several states.

63 Beshada v. Johns-Manville Products Corp., (223) involved asbestos, and Feldman v. Lederle Laboratories, (242), a failure to warn case,

limited imputing knowledge of product hazards to asbestos cases. Other courts have not made any exception for asbestos, but require a showing

that all manufacturers knew or should have known of the hazard to impose liability for failure to warn of a product’s dangers. (Anderson v.

Owens Corning Fiberglass Corp., (220)) But, in cases involving baby oil and asbestos, one court interpreted Washington’s tort reform statute to

permit liability for design defects and failure to warn of unforeseen risks. (Ayers v. Johnson & Johnson Baby Products Co., (221); Falk v.Keene

Corp., (241)).

64 Some courts consider it an affirmative defense, requiring the manufacturer to carry the burden of proving the unavoidable nature of the

risks and the fact that the benefits outweighed the risks at the time of distribution. (Castrignano v. E.R. Squibb & Sons, Inc., (229); Schackil v.

Lederele Laboratories, (297); Taggart v. Richards Medical Company, Inc., (309); Toner v. Lederle Laboratories, (312).
108 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

have replaced the product that was sold. Some

drug manufacturers have argued that all claims of

liability are preempted by Federal law because

product specifications may not be altered without

FDA approval. Ordinarily, FDA regulation of particular products or classes of products does not bar

states from imposing additional requirements or

providing state law remedies in tort (259).

The vast majority of courts have followed this

principle with respect to vaccines (214, 242, 244,

251, 276, 280, 297, 300, 312, 319).65

The fact that the FDA has approved one vaccine

design does not mean that other vaccine designs

might not be safer or more effective. However,

FDA approval has often provided persuasive evidence that an approved vaccine was not defective.

The Federal National Childhood Vaccine Injury

Act does preempt manufacturer liability for failure to directly warn consumers but does not foreclose other state tort actions (Abbott v. American

Cyanamid Co., 844 F.2d 1108 (4th Cir.), cert. denied, 488 U.S. 908 (1988)).66

In summary, although concerns about design

defect litigation surfaced in the 1980s, there are no

reported decisions after 1969 upholding liability

for a defectively designed vaccine.67 The majority

of states permit a cause of action claiming defective design of a particular vaccine. Such claims are

not generally preempted by federal law, and compliance with FDA requirements is not a legally

conclusive defense. Nonetheless, plaintiffs have

not been able to sustain a claim that a vaccine was

defectively designed.

❚ Liability for Errors and Omissions in

Warnings

In view of the impossibility of creating a risk-free

vaccine, tort law imposes an obligation on the

manufacturer to warn of inherent risk. The history

of vaccine warning defects litigation parallels the

history of litigation involving informed consent to

medical care. The two differ, however, in whom

must be warned: a vaccine manufacturer ordinarily has a duty only to warn the physician prescribing its vaccine, not the person taking the vaccine;

a physician has a duty to inform the patient of any

vaccine risks.

In the 1960s, the majority of medical consent

cases involved a failure to warn a patient of the

risk of undergoing a specific medical procedure

(53). Physicians failed to mention even the inherent possibility of death or paralysis, often because they believed that the patients would refuse

the therapy if advised of the risk (91).

Courts uniformly found that the patients’ right

of self-determination entitled them to accept or refuse any treatment, even if their choices were foolish, as long as they were competent to make medical decisions (226, 231, 281, 293). In order to

exercise that right, patients needed information

that only physicians could provide, so the law imposed a duty of disclosure upon physicians that required them to tell patients not only the benefits of

alternative treatments but also their material risks.

Similarly, the first vaccine cases involved the absence of warnings of the risk of contracting poliomyelitis from the oral polio vaccine (235, 290).

65 The proposed revision of the Restatement also continues this rule (5). But see Hurley v. Lederle Laboratories, (264), finding that the Food,

Drug and Cosmetic Act and the Public Health Service Act preempted state claims as to the FDA’s determination of the proper wording of a

warning, provided that the manufacturer has not withheld any relevant information from the FDA.

66 The Medical Devices Act (21 U.S.C. 360g et seq.) expressly preempts state laws affecting most medical devices. Two federal courts have

found the statute’s language precludes strict liability actions under state tort law for medical devices that require premarket FDA approval (274);

Stamps v. Collagen Corp., (306) Other courts have reached different results depending upon the device’s classification and requirements for

premarket approval (58, 275, 278, 279, 304).

67 Design defect causes of action have been used primarily against commercial products, such as asbestos, consumer products, and medical

devices, such as the Dalkon Shield, the Copper-7 IUD, the Bjork-Shiley heart valve, and silicon-gel breast implants (61).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 109

A failure to warn can be prevented by providing

a warning. But, as the next generation of informed

consent cases showed, some warnings failed to

mention material risks. Similarly, more recent

vaccine cases have turned on the adequacy of the

warning given. However, like informed consent

cases, the majority of reported cases have been decided in favor of the defendant manufacturer or

physician (238, 270, 289, 299).68 This is primarily because vaccine makers have been exempted

from the general duty of manufacturers to provide

warnings directly to consumers.69

The exception, known as “the learned intermediary rule,” holds that a manufacturer of prescription drugs or vaccines need only warn the prescribing physician, not the patient who receives

the product (248, 255, 269, 310, 313). Courts have

generally limited the manufacturer’s duty to warn

consumers directly to those circumstances in

which a vaccine is given without the intervention

of a “learned intermediary,” generally a physician

who makes a medical judgment that the vaccine is

appropriate for an individual patient (63, 144).70

Thus, a vaccine manufacturer’s duty to warn

consumers directly applies only in mass immunization or routine public health programs where

physicians are not making “individualized medical judgments” (235, 264, 286, 290). It has been

applied to two vaccinations given in a private physician’s office, where the physician testified that

he acted like a public clinic employee, dispensing

vaccine without evaluating individual recipients

(249, 294). Two of these cases appear to have given rise to the fear in the 1970’s and 1980’s that

manufacturers would have to warn all vaccine recipients directly (235, 290). Recent cases, however, have reiterated that a vaccine manufacturer’s

duty to warn is limited to the prescribing or dispensing physician alone because patients cannot

obtain vaccines except from a physician or medical clinic (258, 285, 288, 292, 301, 307, 322).

To succeed on a claim of inadequate warning,

the plaintiff must prove that an adequate warning

to the physician would have prevented the injury.

This entails proving that the warning would have

persuaded the physician not to give the vaccine to

the patient, as well as proving that the injury

would not have occurred if the vaccine had not

been given (246, 307, 310, 321).

Physicians and other providers do have an independent obligation to warn patients of vaccine

risks as part of their duty to obtain informed consent to any vaccination, regardless of the

manufacturer’s action. Aside from patients with

immunosuppression or allergies, however, it is

often impossible to predict whether an individual

patient is at risk of experiencing an adverse reaction to a vaccine, at least the first time it is given.

Therefore, it is questionable whether an individualized medical evaluation would affect a physician’s recommendation about vaccination in most

cases, and several cases have been decided against

plaintiffs on the ground that the warning did not or

would not alter the physician’s decision.

The National Childhood Vaccine Injury Act

barred any cause of action for a manufacturer’s

failure to directly warn a recipient (or a recipient’s

parent or guardian) about the risks of any childhood vaccine covered by the compensation program. It also created a rebuttable presumption that

warnings approved by FDA are adequate (42

U.S.C. 300aa-22(b), (c)). At the same time, the act

required the Secretary of Health and Human Services to develop new written materials to provide

68 Although the academic literature contains numerous articles debating the merits of the doctrine of informed consent to medical care, the

number of cases actually claiming lack of informed consent remains very small and few such claims succeed.

69 Section 402A of the Restatement imposes liability for inadequate warnings by sellers even if they do not sell directly to consumers. The

duty was imposed on the manufacturer because it, not the retail seller, controlled the condition of the product, assuming it had not been altered

after it left the manufacturer’s hands. The proposed revision of the Restatement retains this general rule and the exception for prescription drugs.

(5)

70 A few cases have found that a nurse acted as a learned intermediary (Rohrburgh v. Wyeth Laboratories, Inc., (292); Walker v. Merck &

Co.,(317) (Mazur v. Merck &Co., Inc., (276)). but others disagree on the grounds that nurses do not ordinarily make medical judgments.
110 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

parents with information about the benefits and

risks of each childhood vaccine. Earlier, the CDC,

which buys about half the domestic supply of pediatric vaccines, had prepared “Important Information Sheets” to serve as warnings, and the

CDC played a primary role in drafting the materials required by the act.

Before the act took effect, most childhood vaccine manufacturers had required the CDC to assume responsibility for providing such warnings

or alternatively to have a learned intermediary dispense the vaccine as a contractual condition of the

sale of vaccines. One federal court of appeals recently held that a vaccine maker fulfilled its duty

to warn by such a contract with the CDC, regardless of whether or not the warning actually

reached the recipient (276). More recently, the Supreme Court of Nevada reached the opposite conclusion where the vaccine was distributed by a

county health district with information sheets prepared by the CDC (219). The court found that the

manufacturer cannot be relieved of ultimate responsibility for an inadequate warning where it

knew that the contractor used warnings that

omitted risk information the manufacturer had

provided with the vaccine.

Liability based on inadequate warnings has

been criticized on the ground that it is too difficult

to describe vaccine risks in terms that patients can

understand.71 The legal doctrine does not require

that patients understand the information included

in the warning, although it is obviously better if

they do. Instead, most courts require only that the

risks be disclosed in ordinary language that is understandable by a reasonable lay person (226,

231). Because the learned intermediary rule applies in most vaccine cases, however, warnings

are directed not to patients, but to physicians, who

are presumed competent to understand technical

information and its implications.

A few cases have found specific warnings inadequate because they failed to apprise physicians of

the vaccine’s known risks (240, 311). In most

cases, warnings have been found adequate in that

they disclosed all reasonably known risks (238,

270, 273, 288, 299). As with all cases alleging design defects, the state of scientific knowledge determines whether a risk should be disclosed (225,

242, 243, 255), and FDA approval of labeling information is often persuasive evidence of the adequacy of a warning (242, 296).

Most lawsuits claiming injury from vaccines

allege several bases for liability, including defective design, inadequate warning, and negligence

in manufacture, design, or risk disclosure. Because, except for manufacturing defects, strict liability requires proof similar to that required to

prove liability for negligence, the specific cause of

action may be less important than the possibility

of any liability.72 This means that where a vaccine

maker is exempted from liability on one basis

(such as design defects), it may be subject to

claims of liability on other grounds. Specifically,

the number of claims against vaccine makers may

not be effectively reduced unless manufacturers

are exempted not only from strict liability but also

from liability for negligence.73

❚ Practical Problems with Litigation

Even if the principles of product liability law are

sensible in theory, there can be practical problems

with product liability litigation. The lengthy and

cumbersome process of discovery, trial, and

sometimes appeal is a perennial subject of legiti71 Similar concerns about the difficulty of describing risks have arisen with respect to informed consent to other medical procedures and

informed consent to experimentation with human subjects. Sometimes such concerns mask a reluctance to disclose the risk at all or professionals’ discomfort with revealing uncertainty about risks (91). Recently, radiation experiments conducted in the 1950s have been denounced primarily because the human subjects of the experiments (including residents at schools for the mentally retarded and terminally ill patients) were

not necessarily told that they were to be part of an experiment or any risks that it might entail (11, 75).

72 The cases finding a defective vaccine were based on an implied warranty of merchantability (284, 311).

73For further discussions about HIV vaccines and product liability see Rosenfeld, 1991 (149); Smith, 1992 (168); Arnold, 1991 (13).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 111

mate complaint. This is true whether the basis for

suit is strict liability or negligence. Determining

whether a particular injury to an individual was

caused by a particular vaccine and whether the risk

could have been avoided is a complex, time-consuming, and expensive process for both sides of a

dispute. Even if it is decided that the plaintiff

should be compensated, determining the amount

of damages has become a similarly complex matter. Although alternative dispute resolution procedures can be somewhat cheaper and faster than

courtroom litigation, they do not eliminate the

need to prepare a case. Thus, the very process of

dispute resolution can discourage both the pursuit

and defense of claims, as well as the thoughtful

application of the law.

Studies of tort claims indicate that ten percent

or less of claims are tried in court (46, 69, 73). The

rest are withdrawn or settled before trial, with

roughly half resulting in some payment to the

plaintiff, although in lower amounts than average

trial awards. This means that defendants have to

deal with many more claims than wind up in court.

There is no publicly available data showing

whether similar figures apply to cases involving

vaccines. If court awards influence settlements, as

they are believed to do, then the low proportion of

court decisions favoring plaintiffs may suggest

that a lower-than-average proportion of claims are

settled with payment to a plaintiff in vaccine

cases.74

It may not be the number of claims, but the possibility of an expensive mistake that worries vaccine makers. One kind of mistake is when a jury

makes an error of fact, reaching a verdict that is not

supported by credible evidence. In principle, such

a mistake can be remedied on appeal, although

additional time and expense can turn even successful appeals into pyrrhic victories. Some factual mistakes are inevitable in any dispute resolution system, whether or not it employs litigation.

Variations in each party’s ability to produce credible evidence and present its case mean that some

cases that ought to be won are lost and others that

ought to be lost are won. Ideally, dispute resolution methods should be designed to minimize both

types of errors but the ideal is not likely to be

achievable without substantial additional expense.

A second type of problem is more difficult to

avoid. These are mistakes arising out of the uncertainty of scientific knowledge that must be used to

identify and categorize the possible risks and

benefits of drugs and vaccines. If the essence of a

defective design is the availability of knowledge

indicating an unreasonable danger, at least in light

of expected benefits, then information indicating

that a drug might produce an adverse reaction is

potential evidence of a design defect or a risk that

should have been disclosed. It is, however, only

potential evidence because it is a matter of knowledgeable interpretation whether and how the risk

might materialize, and whether the possibility is

sufficiently credible to warrant further investigation. A manufacturer might reasonably determine

that the problem was a “fluke.” But in a later lawsuit, the plaintiff might conclude that the

manufacturer ignored an important potential risk.

In some cases, it is impossible to know whether a

drug or vaccine caused a particular injury in an individual or even whether it was capable of causing

such an injury. In those cases, there may be no way

to know whether a mistake was made, whatever

the outcome might be.

If the law is not properly applied, then the process, not the law, stands indicted. But if the law cannot be properly applied at all in some circumstances, then it cannot serve its purpose.

Unfortunately, there is no good information to determine what proportion of cases have been decided correctly or incorrectly, or what proportion

cannot be decided correctly for lack of scientific

74 Most reported court opinions that make final decisions in a case have dismissed a plaintiff’s complaint or granted judgment for the defendant manufacturer (225, 255, 270, 271, 285, 288). However, few reported decisions contain final dispositions of a case. Most determine whether

a plaintiff is entitled to go to trial. The outcome of any such trial or settlement in lieu of trial remains unreported.
112 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

knowledge (60, 153). Thus, we do not know

whether litigation is producing good or bad decisions.

These types of uncertainties can give rise to

fears of unwarranted liability on the part of vaccine makers. They can be compounded by fears of

high damage awards, including punitive damages.

Most punitive damages awards are in cases of

intentional torts (like assault), unfair business

practices, or fraud or bad faith in contracts.75 Because liability for personal injury is rarely based

on intentional or fraudulent conduct, but on negligence or strict liability, there should be little occasion for punitive damages.

The few studies that have been done have concluded that punitive damages are rarely awarded

in personal injury actions and, where inappropriately awarded, are ordinarily reduced or reversed

on appeal (45, 135, 185). The only known punitive damage award in a vaccine case was reversed

on appeal and the vaccine maker found immune

from liability (270). Punitive damages do not appear to be a significant factor in product liability

(104).76 In product liability cases, they are more

likely to be awarded in cases involving defective

automobiles or other consumer products than

drugs or vaccines. Uncertainty surrounding inappropriate damage awards applies to almost all

types of litigation.77 Whether litigation itself is a

necessary form of dispute resolution depends

upon the feasibility of alternatives.

POTENTIAL LIABILITY FOR ADVERSE

REACTIONS TO HIV VACCINES

Vaccines are ordinarily subject to liability for negligence, manufacturing defects, defects in design,

and inadequate warnings of risks. However, liability is rarely found in specific cases. Why, then, is

the perception of excessive liability for adverse

reactions to vaccines so prevalent?

❚ Vaccine Susceptibility to Liability

Claims

Fear of liability may arise from several factors that

distinguish vaccines from pharmaceuticals and

other biologics and that may encourage people to

pursue tort claims. Prophylactic vaccines are taken by healthy people to prevent disease. This

means that adverse reactions are more noticeable

and may be perceived as less tolerable than adverse reactions to a drug that a person takes to relieve the symptoms of illness. Vaccines may also

be taken by sufficiently large numbers of people

to permit the occurrence of a rare side effect that

might not materialize in a smaller group.78 When

a healthy person who takes a vaccine suffers an illness or injury, there may be a natural desire to find

a cause beyond random accident or one’s own behavior. These factors are likely to encourage attributing the injury to the vaccine, correctly or incorrectly, especially when there has been no other

change in the person’s circumstances.

75 The U.S. Supreme Court upheld a state punitive damage law as against a challenge that it was an unconstitutional violation of due process

in Pacific Mutual Life Insurance Company v. Haslip (283). In their brief amicus curiae, the Pharmaceutical Manufacturers Association and the

American Medical Association cited two instances in which punitive damages had been awarded with respect to drugs (an oral contraceptive

and Coumadin) (136).

76 Plaintiffs may include claims for punitive damages in their complaints, but they are rarely awarded. Similarly, the amount a plaintiff may

claim for compensatory damages often bears little relationship to the amount, if any, actually awarded or collected. There is some evidence that,

in cases in which compensatory damages are awarded, the amount of damages correlates with the severity of the injury (46).

77 Physicians and scientists may empathize with vaccine makers’ fear of liability in light of the widespread fear of medical malpractice

litigation among medical practitioners. In both instances, the actual risk of being sued (and of losing a lawsuit) appears to be significantly lower

than is believed by those who might be the target of a lawsuit (25, 109, 182).

78 Of course, some drugs (like Valium and aspirin) are taken by millions of people.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 113

When adverse reactions are suffered by children, the financial consequences can be severe. In

cases of serious permanent injury, inability to

work and the need for expensive rehabilitative or

custodial care over a lifetime generate substantial

costs that may not be covered by private or public

insurance. A lawsuit for substantial damages may

be the only source of payment for needed services.

This may account for relatively more concern

about potential liability for adverse reactions to

vaccines administered to children than for those

given to adults. Of course, the potential for large

damages also exists with most drugs used by children and pregnant women.79

Latent hazards that may not have been detectable before marketing may materialize ten or

twenty years after a vaccine (or drug) is used.

There is a greater chance of discovering such hazards when vaccines are used in children and young

adults with longer subsequent life spans than

those expected for older adults.

Thus, even if tort principles make it difficult for

a plaintiff to win a lawsuit, there may be more

claims brought with respect to vaccines than with

respect to ordinary drugs.

❚ Potential Adverse Reactions to HIV

Vaccines

The risks of HIV vaccines most commonly mentioned are: 1) low levels of effectiveness (so that

not every vaccine recipient is protected); 2) enhanced susceptibility to HIV infection (increased

risk of acquiring infection upon exposure); 3)

more rapid than normal (enhanced) progression of

disease if HIV infection is acquired; 4) the development of cancer many years after vaccination;

and 5) direct vaccine-induced HIV infection from

inadequately attenuated or inactivated virus in

vaccines made from killed or attenuated HIV. In

addition, HIV vaccination may result in social

harms.

Low Levels of Effectiveness

There has been speculation among researchers

that some candidate HIV vaccines now in clinical

trials may ultimately prove effective in less than

half of the vaccinated population.80 If the vaccinated population is at risk for HIV infection, as anticipated, then some proportion may become infected after taking a vaccine of limited efficacy,

even if the vaccine is not defective. Claims based

on low levels (or lack) of effectiveness have not

been brought against existing vaccines. The likelihood of success of a claim of lack of effectiveness

of an HIV vaccine is speculative, but probably

small as long as those who take the vaccine are

warned of its limited efficacy and advised to take

precautions against exposure to HIV infection.

A claim based on defective design would have

to demonstrate either that a more effective vaccine

was feasible or that the level of efficacy was so low

that the vaccine should not have been marketed at

all.81 Given the difficulties of finding a vaccine

that works at all, and the need for a vaccine to prevent any additional HIV infection, neither requirement would be easy to meet. The more likely basis

for a claim would be inadequate warning of the

vaccine’s limited effectiveness and the need for

the recipient to take appropriate precautions. Ordinarily, a plaintiff would have to prove that any

warning to the physician was inadequate and that

an adequate warning would have caused the phy79 This has fueled fears of large claims for contraceptive products and drugs used by pregnant women (31). The number of successful

claims, however, appears to be smaller than the perception (44).

80 For a discussion of effectiveness of current vaccines in development, see chapter 2.

81 The latter theory raised the possibility of a claim against the FDA for approving a vaccine in violation of its own standards of safety and

effectiveness, although it would be difficult to prove that the level of effectiveness was too low in light of the need for a preventive vaccine. The

United States Supreme Court has found that, under the Federal Tort Claims Act, the FDA may be subject to suit if it fails to follow its own governing statute and regulations, unless it is performing a discretionary function (222, 266). In the absence of any statutory or regulatory requirement

for any minimum level of effectiveness, the balancing of risks and benefits in the approval of a new HIV vaccine is likely to be treated as a

discretionary function which is exempt from challenge.
114 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

sician either not to recommend the vaccine or to

warn the plaintiff more strongly against risk behaviors (119). If physicians are properly warned

of a vaccine’s limited effectiveness, the plaintiff

would have no cause of action against the

manufacturer. Rather, any claim would be against

the physician for lack of informed consent.

In addition, a plaintiff would have to prove that

he or she failed to take appropriate precautions

against infection solely because of the inadequate

warning. If the infection were acquired through

sexual contact, the plaintiff would have to prove

that he or she would have abstained from sex or

used barrier protection in most, if not all, relationships. If the transmission occurred through intravenous (IV) drug use, it may be especially hard to

prove that the plaintiff would have abstained or

used precautions, like sterile needles.82 Alternatively, a plaintiff would have to prove that he or

she would not have taken the vaccine had an adequate warning been given, and that not taking the

vaccine would have prevented infection. Both alternatives would entail proving the somewhat implausible: continuous use of precautions against

infection or complete avoidance of exposure to

HIV infection.

Enhanced Susceptibility to Infection or

Disease Progression

Some researchers have theorized that candidate

vaccines might have the potential to increase one’s

susceptibility to infection with HIV or other organisms (24). Others have speculated that a vaccine might increase the rate of disease progression

in people who become infected with HIV in spite

of vaccination.83 Both hypotheses raise the possibility of a claim for defective design if they are not

investigated, or a claim for inadequate warning if

they are not disclosed. Such a claim would face

the same difficulties as a vaccine with low levels

of effectiveness, discussed above. In addition, a

plaintiff would have to prove that the manufacturer knew or should have known that the vaccine

was capable of causing the reaction. The strongest

case against a manufacturer would be one in

which the vaccine was demonstrated to cause the

susceptibility in controlled clinical trials. This

suggests that such hypotheses should be studied,

at least to attempt to determine whether they are

realistic concerns or merely theoretical.84 Potential liability may provide an incentive to vaccine

makers to invest in additional vaccine research,

which may both clarify the vaccine’s safety profile

and increase the eventual cost of development. In

this respect, however, HIV vaccines do not differ

from other vaccines or drugs.

Development of Cancer

There has been speculation that, because HIV is a

retrovirus, an HIV vaccine might cause cancer

many years after vaccination.85 The likelihood of

a claim for vaccine-induced cancer is also similar

to the claims for other potential adverse reactions.

It differs primarily in the length of time it may take

for the reaction to be discovered. This means that,

in the absence of feasible studies that could predict

the risk, if any, of cancer, neither manufacturers

nor vaccine recipients would know whether the

vaccine posed any such risk for perhaps two decades. Although a manufacturer is not liable for

injuries caused by unforeseeable dangers in its

products, there may be some question as to whether a manufacturer adequately investigated a suggested risk. Given the need for an HIV vaccine,

however, it seems unlikely that a manufacturer

would be held responsible for distributing a vaccine with a risk that could not be verified at the

time it was released.

82 As a practical matter, juries may have little sympathy for habitual drug users.

83 For a discussion of vaccine-induced enhancement of disease susceptibility, see chapter 2.

84 Since some subjects who received investigational preventive vaccines have become infected, there is renewed attention to examining

whether the vaccine simply failed to prevent HIV infection or might have enhanced the risk of infection upon exposure.

85 The potential of an HIV vaccine to cause cancer is discussed in chapter 2.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 115

Vaccine-Induced HIV Infection

Non-recombinant vaccines that use killed, inactivated, or attenuated virus have been reported to

hold some promise (124). Concern about such

vaccines arises from the possibility, albeit remote,

that the manufacturing process might inadvertently fail to remove or render harmless part of the virus that could actively infect a person, or that an

attenuated virus could revert to an infectious

state.86 Reports of newborn monkeys that became

ill after inoculation with a live attenuated virus

vaccine to prevent SIV may increase such concerns. A person who became infected with HIV

from such a vaccine would have a claim against

the manufacturer for injury caused by a manufacturing error.

It is unlikely that a claim for design defect

would be possible, except in the unlikely event

that the manufacturer knew or should have known

that its manufacturing process could not render

the virus incapable of infection. Although claims

of vaccine manufacturing errors have been rare in

the past, the consequences of a batch of vaccine

accidentally escaping inactivation are sufficiently

serious to make this type of vaccine unappealing

to many vaccine makers. Thus, potential liability

for manufacturing errors may discourage companies from developing this type of vaccine, and

provide relatively greater incentive to pursue recombinant vaccines. At the same time, companies

may not wish to pursue a type of vaccine that

might produce HIV infection, regardless of exposure to liability, especially if they believe that they

cannot eliminate the risk of manufacturing error.

Social Harms

HIV vaccines may pose risks of social harm that

are not ordinarily linked with other vaccines or

drugs. People who receive HIV vaccines will test

positive on screening tests, making them especially vulnerable to denials of health or life insurance,87 permission to travel abroad,88 loss of employment or housing,89 segregation in

institutions, or rejection by family and friends (2)

(98, 114).90 People institutionalized in prisons or

mental health facilities may be segregated or victimized. Other forms of discrimination and

stigmatization are also possible. The possibilities

remain largely unexamined.

An HIV vaccine may produce an antibody reaction that may be difficult to distinguish from a

positive test for HIV infection, so that vaccine recipients may be mistakenly believed to be HIV

positive. But vaccine recipients (and subjects in

vaccine clinical trials) may be targeted for discrimination on the assumption that they are members of a risk group, regardless of whether they are

shown to have HIV infection. Moreover, most

such harms result from lawful conduct for which

the vaccine recipient would have no legal recourse. Although job loss might violate the Americans with Disabilities Act (42 U.S.C. 12101 et

seq.), most other forms of discrimination would

not, and no law prevents family members, lovers,

and friends from abandoning someone stigmatized as at risk for HIV infection.

Although such risks should be made clear to

anyone who takes a vaccine, there is no precedent

86 The potential for whole killed virus or attenuated virus vaccines to cause infection is discussed in chapter 2.

87 Many health, life, and disability carriers now require an HIV test for individual coverage or extended coverage (173).

88 The Department of State lists 45 countries that have restrictions on entry of HIV-infected individuals to their countries and require HIV

tests of all or some people entering their countries (202).

89 The U.S. armed forces, the Department of State, Job Corps and some other employers either require or urge employees to have HIV tests

as a conditions of employment.

90 These social harms are discussed in further detail in chapter 3.
116 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

for holding a vaccine maker liable for their occurrence, and it is unlikely that a claim would be successful on such grounds. Manufacturers are not responsible for the bigotry of others. Product

liability is intended to impose responsibility for

physical injury caused by defective products, not

personal insults resulting from discriminatory actions. There does not appear to be any basis for

counting social harm as either a manufacturing defect or a design defect.

It might be possible to claim that an adequate

warning should include the risk of social harms.91

A successful cause of action would require the

plaintiff to prove that he or she would not have

been identified as at risk for HIV infection but for

the vaccination. But, ordinarily it would be the act

of vaccination, not the vaccine itself, that confers

any stigma. Moreover, it is unlikely that a vaccine

maker would be responsible for specifying social

risks, since such risks are not necessarily within

the realm of expertise of vaccine manufacturing.

Physicians who administer HIV vaccines may be

the more likely target for any claims that a vaccine

recipient was not adequately warned about possible discrimination.

❚ Different Uses of Vaccines

The same principles of liability apply to manufacturers of all vaccines, regardless of whether they

are preventive (intended to prevent) or therapeutic

(intended to treat or cure infection or disease), and

regardless of whether the vaccines are experimental (investigational) or approved and licensed. The

likelihood of adverse reactions and liability

claims occurring may differ, however, depending

upon the way in which a vaccine is used.

Preventive HIV Vaccines

Preventive HIV vaccines have most of the factors

that make vaccines more susceptible to liability

claims than drugs. They are intended for use by

healthy individuals who may be sensitive to the

appearance of adverse reactions. At the same time,

HIV vaccines are likely to be given to people at

risk for HIV infection for the foreseeable future.

Several risk groups are also at risk for other diseases, such as Hepatitis B and other blood-borne

and sexually transmitted diseases. It may be difficult to distinguish some symptoms or illnesses

from other causes from adverse reactions to vaccination, at least until sufficient years of experience with the vaccine have produced reliable data

identifying vaccine-related risks.

Uncertainty about the cause of illnesses following vaccination may encourage vaccinees to attribute injuries to the vaccine and seek legal redress against manufacturers. On the other hand,

the difficulty of demonstrating that the vaccine

caused the injury is likely to discourage or defeat

product liability claims. In other words, the very

uncertainty that may increase the likelihood of

lawsuits also decreases the probability of plaintiffs’ success on the claims.

The characteristics of the populations that use

an HIV vaccine may influence the potential for liability. Most people at risk of HIV infection are

young adults with a relatively long life expectancy. Potential damages for permanent injury arising from vaccination could be substantial, although less than those for young children. A

growing proportion of people at risk, however, are

IV drug users, many of whom are not working and

may not be able to claim lost income as damages.

However, if the majority of people who actually

take an HIV vaccine are middle-class workers,

then permanent injury that deprives them of the

ability to work will give rise to potential damages

for lost income, as well as medical expenses. If

HIV vaccines are given to newborns and young

children, the potential damages increase proportionately with life expectancy. Pregnant women

who are HIV-positive and take a vaccine to prevent transmission to their children can expect very

limited damages because of their preexisting

condition and shorter life expectancy.

91 Ethical principles would certainly require such warning in careful counseling sessions, but ethical principles go beyond legal duties. For a

discussion of ethical duties to warn about adverse reactions to HIV vaccines, see chapter 3.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 117

The number of vaccinations may also affect potential liability. If an HIV vaccine’s effectiveness

is limited over time and requires several doses and

booster vaccinations, there are more opportunities

per vaccinee for adverse reactions and for injuries

following vaccination to be attributed to the vaccine. The costs involved may be balanced to some

degree by the increased sales generated by a multiple dose vaccine.

In summary, the potential for liability arising

from the use of an approved HIV vaccine appears

to be similar to what might be expected from any

new vaccine intended for use by adults. Although

the possible damages from a successful lawsuit

may be large in the case of a permanently disabled

young adult or child, the probability of a successful lawsuit appears to be quite low. Although an

HIV vaccine might carry unknown latent risks

that portend a DES-like future, that possibility

probably exists for every new drug and vaccine

marketed. HIV vaccines are not unique in this respect. Currently, the most likely basis for liability

claims is an inadequate warning of low levels of

effectiveness or limited protection against HIV infection. Yet it would be very difficult for anyone

who became HIV positive to prove that his or her

infection was caused by either the vaccine or an inadequate warning of the vaccine’s limited protection. Physicians are likely to be more vulnerable

to such claims than vaccine makers.

Investigational HIV Vaccines

The potential for liability for adverse reactions to

investigational preventive HIV vaccines is less

than that for marketed vaccines. The legal grounds

for liability are the same for both investigational

and approved vaccines. But the nature of investigational vaccines and clinical trials reduces both

the likelihood of claims and the probability of successful claims in practice.

It is generally understood that the purpose of

clinical trials is to determine how safe and effective an experimental vaccine may be and whether

unpredictable adverse reactions may occur. There

are more protections for subjects in clinical trials

than for patients in ordinary medical care settings.

Federal regulations governing both federally

funded research with human subjects and research

intended for submission to the FDA require that

subjects’ informed consent be in writing in a document approved by an institutional review board

(21 U.S.C. Parts 50 and 56). Regardless of the

merits of the document itself, prospective subjects

are likely to be made aware that they will be part of

a research experiment and that the vaccine has not

been approved by the FDA. The subject’s consent

has the legal effect of making the subject assume

responsibility for any disclosed risks that materialize. Since most informed consent documents

note that not all risks can be predicted and unknown adverse reactions might occur, there is

little basis for a claim that the subject was not

properly warned.

Historically, there have been no cases of product liability claims involving research, probably

because there has been a very low incidence of observed or reported injury among research subjects

(27, 118, 200).92 Rare adverse reactions may not

materialize in a small cohort of research subjects

and side effects may be reversed or minimized

promptly where the subjects are being monitored

by research investigators. Design defect claims

are also minimized, if not precluded entirely, by

the fact that the trial is being conducted to find out

whether the vaccine works and whether it has dangerous side effects. Not until such trials are concluded and a risk is discovered or confirmed is

there any significant basis for claiming that the

vaccine was defectively designed.

It is possible that a vaccine might be too dangerous to test in human subjects at all. But this

could only be inferred from prior laboratory research which should be reviewed by the FDA and

an institutional review board. Those bodies serve

92 There have been several cases in which people were not told they were being used as human subjects in a research study or that the research could produce serious harm (9, 188, 265, 183).
118 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

as a safeguard against proceeding with unjustifiable research and, although imperfect, they ordinarily should prevent unreasonably dangerous research from going forward.

The most likely risk of a preventive vaccine

trial is that a research subject may believe that the

vaccine is effective to prevent HIV infection, fail

to take precautions, and become infected. (In a

blinded, randomized trial, the subjects are not told

whether they have received the investigational

vaccine or a placebo, although they can find out by

getting tested, even if they are asked not to do so.)

As with marketed vaccines, the subject might

claim that he or she was not adequately cautioned

against risk behaviors, but would probably find

that especially difficult to prove in a research setting. The written informed consent document

would provide evidence that the information was

given. Such documents have proved sufficient to

defeat claims of lack of informed consent by patients in medical settings (320). The best solution

to such a problem is to prevent it, by making clear

the uncertainty about the candidate vaccine before

a subject agrees to participate in the trial.

Another potential, but probably remote, risk is

that use of an early candidate vaccine would preclude a subject from participating in a later investigational study of a newer vaccine, perhaps one

that proved to be more effective. Again, the most

likely basis for a claim would be lack of informed

consent, with results similar to those described

above. It may be more difficult to explain the nature of this type of risk unless there is some laboratory basis for predicting the effectiveness of vaccines that have not yet been fully developed.

Finally, subjects who experience some of the

social risks of participating in a vaccine trial may

claim lack of informed consent to such risks.

Merely volunteering for a vaccine trial can expose

the subject to discrimination. Research subjects

may be more vulnerable to social harms than the

recipient of a marketed vaccine, because participation in a vaccine trial may be discovered more

easily than receipt of a vaccine from a private physician or public clinic. As with physiologic reactions, the precise social risks that may befall a vaccine recipient may not be predictable in advance.

Indeed, vaccine trials may gather as much information about such risks as they do about vaccine safety and effectiveness. Thus, the risk of liability again depends upon the clarity with which

the risk of social harm is presented, and the responsibility for warning prospective research subjects would lie with the investigators rather than

the vaccine manufacturers.

Therapeutic HIV Vaccines

Therapeutic HIV vaccines that are used to treat

people already infected with HIV are comparable

to drugs. The special concerns surrounding the use

of preventive vaccines do not apply. Patients and

research subjects who take therapeutic vaccines

may be willing to accept accompanying risks in

order to receive any benefit the therapeutic vaccine might afford, as they have with drugs like Zidovudine, ddI, ddC, and d4T. Adverse reactions to

the vaccine may be especially difficult to distinguish from other symptoms related to HIV infection and opportunistic infections and illnesses.

Moreover, the potential for damages is quite limited because of the perceived limited life expectancy of people with AIDS. Perhaps this is why

there have been no reports of fear of liability for

adverse reactions to therapeutic vaccines. Even

companies that reported fear of liability for their

preventive vaccines actively pursued clinical

trials of their therapeutic candidate vaccines without mentioning liability as a concern.

❚ Conclusion

Preventive vaccines may be more susceptible to

claims of liability than most drugs and biologics,

primarily because they are ordinarily used in large

numbers of healthy people. Their extensive use

can permit even rare adverse reactions to materialize and people who expected vaccines to prevent

disease may be less tolerant of such reactions than

sick patients. As with drugs, the majority of

claims have been directed against only a few vaccines. Despite the increased probability of claims,

the proportion of reported cases that impose liability on the vaccine maker is very small. There is no

publicly available evidence on the number or result of claims that were withdrawn or settled be-
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 119

fore a court decision. Thus, although the probability of claims of liability may be relatively high, the

probability of actual liability is relatively low.

The main causes of action against a vaccine

maker are claims of a defectively designed vaccine and an inadequate warning of vaccine risks.

Plaintiffs have not succeeded on a claim of defective design, probably because of the improbability

of demonstrating that a safer, equally effective

vaccine could have replaced a vaccine approved

by the FDA.93 Few courts have found a vaccine

maker liable for an inadequate warning of risks.

More extensive and sophisticated warning statements may have improved vaccine makers’

protection against such claims. In addition, a vaccine maker’s duty to warn is ordinarily limited to

the prescribing physician, who bears responsibility for disclosing vaccine risks to patients. Thus,

physicians may now be more vulnerable to claims

(of lack of informed consent) than vaccine makers.

The probability of future claims of adverse

reactions to an HIV vaccine is impossible to predict because it depends upon what, if any, adverse

reactions occur and whether they could be plausibly attributed to the vaccine. The probability of

courts imposing liability in the case of an HIV

vaccine appears to be about the same or lower than

in the case of existing vaccines. This is primarily

because of the difficulty of demonstrating that an

adverse reaction was caused by the vaccine. Also

important is the possibility that the most predictable risk of vaccination is discrimination against

the person vaccinated for which manufacturers are

not likely to be responsible.

Fear of liability for adverse reactions to vaccines may have been based on a perception in the

1970s and early 1980s that courts were expanding

the grounds for liability. That expansion appears

to have halted and, although there is no guarantee

that it could not recur, there is no reason to assume

that it will.94 More important, it is difficult to argue that the principles of product liability are unfair in theory. Rather, the major concern lies with

the time, expense and uncertainty of the litigation

process and the fear that the law will not be applied

correctly, so that a vaccine maker is mistakenly

held liable where it should not be.

Since liability itself is so rarely imposed, fear of

liability may be more accurately described as fear

of having to litigate at all. This is understandable,

but not limited to cases involving HIV vaccines.

Therefore, there appears to be little, if any, basis

for claiming that HIV vaccines present a special or

increased risk of liability. This does not mean that

an alternative means of allocating responsibility

for injury and compensation is not warranted for

other reasons. It does mean that any alternative

that is intended to remedy tort litigation’s inefficiencies would have application beyond HIV vaccines.

ALTERNATIVE COMPENSATION POLICY

OPTIONS

People who are injured as a result of vaccination

with an HIV vaccine could receive compensation

in a variety of ways. Currently, their only option,

apart from private health and disability insurance,

is likely to be a product liability claim against the

vaccine maker, or a claim of professional negligence (medical malpractice) against the physician

or other health care provider who vaccinated the

individual, if the circumstances support a legal

cause of action95

This section summarizes several major policy

options for compensating HIV vaccine-related injury—reforms in tort liability, voluntary contrac93 The only reported decisions (in 1969) finding a vaccine (Quadrigen) defective were based on warranty, not tort law (284, 311). Whether

any vaccine maker has settled any claims with payment to the plaintiff on this basis is unknown.

94 If the revised version of the Restatement of Torts volume on product liability is accepted, the grounds for liability for design defects will be

narrower than current legal principles in states that permit the cause of the action at all (5).

95 Some recourse may be available with respect to California vaccines under a California statute, described below.
120 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

tual arrangements, government-financed insurance systems, and public no-fault compensation

programs—and their advantages and disadvantages.96 It also considers several alternative approaches to encouraging HIV vaccine development that focus on overcoming financial and

scientific difficulties. Which option is best depends upon the goals to be achieved by compensation and how alternative approaches affect the

achievement of other important goals like prevention of disease, deterrence of injury, and the just

distribution of resources.

TORT LIABILITY REFORM

Tort liability functions as a compensation system

by imposing legal responsibility for compensating certain specified injuries. It is also justified as

a means of retributive justice or risk deterrence

(51, 59, 210). Whether or not it serves adequately

as a deterrent to risk, it is widely criticized as either ineffective or inefficient in providing equitable compensation. The tort system does not provide compensation to all victims of injury. In

theory, compensation is allowed only in cases in

which a plaintiff can prove another party’s legal

responsibility for an injury. In practice, many

people who might have a valid cause of action in

tort do not file a claim or receive compensation,

and others who may not have a legitimate claim

may pursue a cause of action and receive compensation (69, 74, 109).

The most common criticisms are that tort litigation is unreasonably time-consuming and expensive and often unpredictable or inconsistent, with

some plaintiffs seeming to receive undeserved

windfalls and others receiving nothing in spite of a

legitimate claim (82, 131). Even those who do not

support specific tort reform proposals often voice

these criticisms (156).

Others argue that product liability principles

make manufacturers responsible for injuries that

are unavoidable (80, 158, 203). Sometimes the

objection is that the law itself grants plaintiffs a

cause of action where, it is argued, it should not be

permitted, such as for an injury caused by a design

defect. More often, perhaps, the objection is that,

in practice, judges and juries apply the law incorrectly, so that a defendant is mistakenly found liable. Of course, judges and juries make mistakes

that operate in favor of, as well as against, defendants. But it is the prospect of mistaken liability,

not mistaken absence of liability, that most often

gives rise to calls for tort reform.

Almost all tort reform proposals seek to limit

the liability of potential defendants. Limitations

on liability, however, are cost control measures,

not compensation mechanisms. Such limitations

are ordinarily intended to decrease the number of

people who seek and obtain compensation

through litigation or the amount of compensation

they receive. Such proposals may be justifiable if

the goal is to save defendants money and if providing compensation to those who would not qualify

under the reformed system is not relevant or desirable. If other goals are important, however, the

specific limitations must be analyzed to see

whether there is good reason to restrict compensation to a smaller population.

❚ Reforms Granting Immunity from Strict

Liability

Some vaccine manufacturers and legal commentators have argued that manufacturers should not

be held strictly liable for a defectively designed

vaccine. Several jurisdictions have, by court decision, already granted manufacturers immunity

from strict liability for all vaccines (and drugs)

(225, 255, 270, 277). The trend in other jurisdictions, while not granting complete immunity from

liability, is for courts to reject claims for drug and

vaccine design defects on a case-by-case basis,

generally because the product is not found to be

defective or the claimed defect was not avoidable

(156).

One may draw conflicting conclusions from

this trend. One is that the courts that have rejected

96 Similar policy options have been reviewed by several groups (82, 95, 191, 201).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 121

strict liability claims are applying the law correctly and as intended to sort out good products from

bad ones, and good products are not being found

defective. Another is that the courts have applied

the law incorrectly, and companies are not being

held liable for defective products. Finally, it could

be argued that if most reported cases are being

found correctly in favor of the defendant, then liability is not needed; drug and vaccine makers

should be granted complete immunity from all

strict liability, at least for defective design. This

assumes that tort law has no deterrent effect.

While everyone hopes that no drug or vaccine

could ever be defective, it is probably an unrealistic assumption.

The argument for exempting all vaccines from

strict liability is basically an argument that drugs

and vaccines are special or differ from other products in significant ways that warrant protecting

their producers from responsibility for injuries.97

The California Supreme Court, for example, distinguished between drugs and ordinary consumer

products on the grounds that the latter are used to

“make work easier or to provide pleasure, while

the . . . former . . . may be necessary to alleviate

pain and suffering or to sustain life” (225). Of

course, not all drugs have such valuable purposes,98 and many ordinary consumer products

provide important benefits.99 If drugs and vaccines deserve immunity from strict liability, then

they must be distinguished from other products on

more precise grounds. In the absence of any such

distinction, this argument requires exempting not

just drugs and vaccines, but all equally beneficial

products from strict liability. The alternative is to

exempt only those particular drugs and vaccines,

as well as other products, that confer special benefits on humankind. This is the kind of risk-benefit

analysis adopted by courts that require case-bycase evaluation of strict liability claims.

A second argument for exempting drugs and

vaccines from strict liability (again, excluding

manufacturing errors) is that federal regulations

provide sufficient incentives to ensure safe and effective products. One reason for the adoption of

strict liability was to deter manufacturers from

marketing products that are unsafe. Here, the fact

that most, if not all, drugs and vaccines are intended to prevent or alleviate suffering is not advanced as a reason to dispense with liability. The

importance of drugs and vaccines does not explain

why their manufacturers should not be deterred

from marketing unsafe products. Rather, drugs

and vaccines differ from ordinary consumer products because they cannot be marketed without

FDA approval based on substantial evidence of

safety and effectiveness.

Federal regulation is said to serve the deterrence function of tort liability, so that liability is

superfluous and unnecessarily costly. This is a

practical argument with considerable basis in fact.

Although FDA approval has not generally been

sufficient to preempt a claim, it has often provided

convincing evidence to reject a claim that a product could have been made safer. Thus, even if it is

appropriate to permit strict liability claims against

specific drugs or vaccines, few can be successful

where the manufacturer has complied with FDA

testing requirements and the product remains approved. If FDA requirements for approval are diluted or its standards for evaluating the safety and

effectiveness of vaccines are reduced in order to

speed up the availability of an HIV vaccine, the argument loses some of its force. Expedited review

by the FDA thus may undermine reliance on regulatory standards. In any event, in reviewing new

97 This would leave manufacturers responsible for product injuries that, in theory at least, they could not prevent, while exempting them

from liability for errors in design that, again in theory, could have been corrected. In practice, the argument is advanced selectively to seek

immunity from liability for design defects and inadequate warnings, not from liability for manufacturing errors.

98 Aspirin is intended to relieve pain, but its importance to the public may diminish when it is used to relieve a slight headache.

99 Automatic electrical current shut-off devices or furnaces to heat homes, for example, provide important safety benefits and relief from

suffering.
122 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

drugs and vaccines for approval, the FDA does not

explicitly examine whether they might be made

safer.

❚ Reforms Limiting Liability

Where liability should not be removed entirely,

numerous reform proposals are intended to reduce

the number (frequency) of claims made, the number of claims in which a plaintiff can succeed

(awards), or the amount of compensation payable

to a successful plaintiff. Other reforms are intended to expedite the litigation process or make

it more accurate or less expensive. A growing

number of studies have begun to evaluate tort reforms adopted by the states, primarily those directed to reducing medical malpractice insurance

premiums by reducing malpractice litigation (20,

185, 186).100 In many cases, the generalizability

of research results has been hampered by limitations on the data available and variations in study

design (193). The studies show that reforms have

had somewhat mixed results to date. Few reforms

have had a significant effect on the price of insurance, the frequency of claims, or the amount of

awards.

A limitation or cap on the amount of damages

that can be awarded to a successful plaintiff has

been the most effective type of reform to date. As

might be expected, caps have been found to reduce

the average amount of awards in successful cases

in several studies (193). But they have not been

found to affect the frequency of claims consistently (46, 213), perhaps because they apply to only a

small proportion of claims made. Caps have been

enacted to limit either non-economic damages

(pain and suffering) or total damages (including

incurred medical expenses and lost income).

Different studies have reached different conclusions with respect to the effect of different

types of caps. One study of reforms and malpractice insurance premiums found that premiums

were reduced most successfully by a cap on total

damages (213). This is consistent with conventional wisdom that insurers are best able to set premiums when they have a fixed ceiling on future

expenditures. Caps on total damages, however,

have been criticized as disadvantaging the most

severely injured plaintiffs with the largest losses.

One study found that an increased proportion of

awards granted the maximum amount after a damage cap was enacted (66).

Limitations on the amount of plaintiffs’ attorneys’ fees, usually by placing a ceiling on the percentage of an award that can be paid as a contingency fee, are intended to limit claims made by

discouraging attorneys from accepting cases, and

to increase the proportion of the award that the

plaintiff can keep.101 Danzon found such contingency fee limits had no effect on the number of

malpractice claims made or the amount paid per

claim (46), while another study found that they increased the amount paid per claim (213). Fee limits may have little effect where they are about the

same as the prevailing customary percentage of

awards.

Shortening the statute of limitations (the time

within which a claim must be filed) to bar claims

submitted long after an injury occurs also produced mixed results, with several studies finding

no significant effect (193). Shorter statutes of limitations may encourage claims to be filed earlier

(193).

Pretrial screening panels are intended to screen

out nonmeritorious claims, expedite settlement,

and reduce the costs of litigation. They have been

difficult to evaluate because panel types vary from

state to state and voluntary panels are not used frequently. Studies have found both increased pay100 The Robert Wood Johnson Foundation and the Agency for Health Care Policy and Research, for example, support ongoing studies, of

medical malpractice and the US General Accounting Office has conducted several studies (184). The Office of Technology Assessment summarized much of the published research in a 1993 report (193).

101 There has been little interest in limiting the amount of defendants’ attorneys’ fees, presumably because they do not affect plaintiffs’

decisions to make claims. Legal defense costs do contribute to total litigation expenses.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 123

ments for successful claims using mandatory panels (213), and decreased payments per claim using

voluntary panels (193). Another study found that

panels had no effect on the probability that a plaintiff would be awarded payment (166). Some may

increase costs by adding another layer of procedure. One study found that panels were associated

with reduced malpractice insurance premiums for

obstetrics/gynecology but not for general surgery

or general practice (213).

Collateral source offsets are intended to reduce

the amount of awards and, indirectly, the number

of claims, by prohibiting plaintiffs from collecting

payment for insured losses, such as medical expenses.102 Again, study results are mixed, with

two studies finding no significant effect on the frequency of claims in the case of mandatory offsets,

one finding a significant reduction in claim frequency when discretionary offsets were included,

and both finding a significant reduction in amount

of payment in successful cases (46, 213).

Requiring the losing party to pay the successful

party’s attorneys’ fees and costs also has had little

demonstrable effect on claim frequency, payment

per claim, or premium prices. This may be explained by the fact that this type of reform has generally been limited to rare cases in which a court

finds the claim to be frivolous or fraudulent, and

few cases have been found to fall into that category (193).

In summary, tort reforms intended to reduce

claims and payments have had spotty success to

date. Most types of reform adopted in the past are

unlikely to make a dramatic difference in the frequency of future claims. Since most such reforms

are intended to reduce litigation and the amount

paid to plaintiffs, without improving the probability of “correct” results, they do little to make compensation more equitable. Studies of product liability claims have not yet been able to determine

whether the distribution of claims and payments

comports with actual legal responsibility for injury (60). Thus, there has been no way to determine

whether the number of claims and number and

amount of awards are “correct.” In the absence of

any baseline knowledge of how many claims and

awards would be warranted in an error-free system, it is impossible to know whether there are

currently too many, too few, or about the right

number of claims and awards (153).

❚ Reforms Favoring Compensation

Four different types of tort reform may address the

goal of equitable compensation. The first is to

change the substantive law governing compensatory damages to make them more consistent

across plaintiffs with similar injuries. This might

be accomplished by a schedule of injuries, ranked

by severity, loss of function, or other criteria, each

with an assigned dollar value or range of values.

The amounts of compensation could be determined by calculating appropriate medical expenses for each injury and adding expected lost income or expenses for continuing care. It may be

difficult to reach agreement on what values should

be used in each category. For example, should lost

income be calculated by reference to the individual’s own income (which awards more to those with

higher incomes, as is done now), or should the

same rate, such as average non-farm wages, be applied to everyone? How, if at all, should the

amounts be adjusted for inflation or geographic

area? Such technical problems should not be minimized.103 In addition, there is the question of the

whether the amount of awards can be set at a level

that is sufficiently high to meet the reasonable

102 A health or disability insurer may require the insured/plaintiff to reimburse it for health care and other expenses paid by the insurer if the

insured receives compensation covering such expenses.

103 Officials in the Division of Vaccine Injury Compensation note that children with neurological injuries have such different needs that it

may be impossible to establish a schedule that would be fair to all. However, it may be possible to schedule non-economic damages more easily

(20).
124 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

needs of injured people, but still affordable by

those who have to pay.104

If such problems are surmountable, a schedule

would offer some measure of consistency in compensation for the same type of injury. The schedule could be enacted by state legislatures, although a regulatory agency might be delegated

responsibility for updating the award amounts periodically. Alternatively, courts could adopt the

schedule to guide jury deliberations.

One advantage of scheduling compensation is

that it makes defendants’ exposure more predictable, and probably more insurable. Some counsel

for vaccine makers have noted that it is not routine

litigation, but the possibility of one multimillion

dollar judgment that makes their employers nervous. If potential or maximum awards could be estimated on the basis of a schedule, they could

more easily be accounted for in pricing. Of course,

this does not eliminate the need for predicting the

number of possible claims in the future; but that is

true for all products.

A second type of reform is alternative dispute

resolution, which is intended to expedite settlements in litigated cases and reduce expenditures.

Although such procedures hold some promise for

speeding up the resolution of disputes, they do not

alter the law governing the cases they resolve.

Their advantage is that they can be used with almost any type of dispute, regardless of how compensation is calculated. They may also produce

more consistent decisions, especially if they are

inexpensive enough to be used by more potential

claimants and defendants.

A third type of reform would expand potential

plaintiffs’ opportunities to recover compensation;

for example, by granting them a cause of action in

instances that tort law currently forbids or by easing standards of proof for existing causes of action. This option would be unattractive to defendants. It is directly contrary to the current trend

among courts to limit defendants’ liability (50).

Some countries in the European Union, however,

are moving in the opposite direction from the

United States, toward strict liability for product

injuries, in their harmonization of laws effort

(175). Some countries may not allow a “state of

the art” defense, called developmental risk, but

would make companies liable for risks that were

not discovered or foreseen. The justification appears to be that drugs and vaccines are too important to people’s health to permit anything less than

the most stringent safeguards against product

risks. Japan is considering replacing negligence

with strict liability for defective products, although opposition has reduced the likelihood of

reform (43).

Some Northern European countries have patient compensation funds to assist those with adverse reactions to drugs and vaccines (23, 165).

Others have compensation funds specific to adverse reactions to vaccines recommended for children (112). These countries have a longer tradition

of government provision of social assistance to

their residents than the United States. Their relatively more extensive programs of health and disability insurance leave injured people with fewer

unreimbursed expenses, so there may be less need

for other sources of compensation than in the

United States.

A fourth type of reform would encourage more

people to bring claims under existing law. Several

studies have found that only a small proportion of

people who are injured as the result of another’s

negligence actually file tort claims, and an even

smaller proportion (perhaps half of those who file

claims) eventually recover any compensation (46,

69, 74). The Harvard Medical Practice Study, for

example, estimated that about 28 percent of all adverse events experienced by hospitalized patients

in New York in 1984 were attributable to medical

negligence (one percent of all patients discharged)

104 The workers compensation system has been criticized for offering too little compensation, and this has been thought to encourage product liability claims as an alternative source of compensation, as in the litigation involving asbestos.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 125

(109). Yet for every eight negligently injured patients, only one patient filed any claim of medical

malpractice.105 Tort reform designed to provide

equitable compensation would encourage more,

not fewer claims, as well as more accurate claims

determination.

❚ Summary

If the goal of reform is to minimize costs to government and vaccine makers, then tort reforms

limiting the liability of vaccine makers would be

the best choice. It does have disadvantages, however. Most important, it is difficult to justify withdrawing a legal remedy from one class of injured

people (those with adverse reactions to HIV vaccines) while it is preserved for other classes. In the

past, when liability has been limited, those injured

have sometimes been provided an alternative

compensation system, such as workers compensation or the National Vaccine Injury Compensation

Program. Other reforms, such as most of those intended to limit medical malpractice liability, have

not included any alternative compensation system.

As a practical matter, however, even granting

vaccine makers immunity from strict liability for

design defects may not change the litigation climate significantly. Such claims are effectively litigated like negligence claims and would not be

eliminated without granting vaccine makers immunity from liability for their own negligence.106

Protection against liability, whether in strict liability or negligence, for design defects would not

foreclose claims for inadequate warnings of product risks.107 Elimination of product liability may

result in shifting claims that would have been

brought against vaccine makers to physicians and

clinics that administer vaccines.108 Such actions

would probably be limited to claims of lack of informed consent, which may be difficult to prove.

Nonetheless, physicians are not likely to welcome

becoming a more visible target of complaints.

Tort reforms limiting liability are not likely to

improve compensation for injured persons or

make it more equitable. If the goal is to provide

compensation within the tort arena to a larger proportion of people with injuries, then mechanisms

to increase the number who file claims are needed.

Few reforms have the potential to correct the

most pressing problems of tort litigation—its time

and expense, and the possibility of inconsistent results. Of course, those problems are not unique to

litigation involving vaccines. If tort reform is considered for vaccine-related injuries, it may have to

be considered for all other types of injuries. This

raises the question whether a Federal tort law

should preempt state tort law. Although the advantages and disadvantages of such a change are

beyond the scope of this paper, they should be studied if tort reform is thought to be an otherwise desirable option for HIV vaccines.

VOLUNTARY CONTRACTUAL

ARRANGEMENTS

Private companies are free to reduce the time and

expense of resolving claims by voluntarily agreeing to provide compensation without the necessity

of litigation or legislation. The voluntary contract

105 Patients who filed claims were not necessarily among those that the study identified as negligently injured (109). It is not known whether

such cases involved negligence that was outside the scope of the study (such as outpatient incidents or incidents in years not studied) or whether

such cases did not involve negligence at all, or both.

106 See “Tort Liability for Adverse Reactions to Vaccines,” above. Connecticut enacted a statute limiting HIV vaccine makers and researchers’ liability for product defects and ordinarily negligence to encourage testing candidate HIV vaccines in human subjects.

107 The revised Restatement of Torts on product liability, if adopted, may effectively eliminate most causes of action for design defects in the

case of prescription drugs and vaccines (See “Tort Liability for Adverse Reactions to Vaccines,” above). One justification for reducing the scope

of liability for design defects is to permit physicians to decide whether to use a specific vaccine. Warnings then become an important source of

information about the vaccine’s risks and benefits that affect the decision whether to recommend the vaccine (5).

108 For manufacturers that are owned by foreign companies, some part of any financial savings to the manufacturer is likely to accrue to the

foreign owner.
126 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

model, such as that developed by Professor Jeffrey O’Connell and used by some schools with respect to football injuries, encourages such private

agreements (130). A variant has been introduced

in Congress, but never passed, in the Moore-Gephardt bill (99th Cong., 1st Sess., 1985). Applied

to HIV vaccine use, it would have a vaccine maker

or administrator contractually agree, at the time of

vaccination, to promptly pay the vaccine recipient

compensation for medical care and other specified

financial losses in the event of an adverse reaction

to the vaccine. Ordinarily, the vaccine maker or

physician would agree to make an offer of compensation within a specified period of time, perhaps two to six months, following notification of

injury. If the recipient agreed to accept the offer,

he or she would ordinarily waive any right to pursue a tort claim. If a qualifying offer were refused,

the recipient would forfeit certain tort remedies or

be entitled to limited damages.

The advantage to the injured person is that a

reasonable amount of compensation could be provided promptly following injury. The vaccine

maker could limit its payments to actual out-ofpocket expenses (compensation for pain and suffering and for insured expenses is generally excluded) and incur few transaction costs, thereby

improving the predictability and limiting the

amount of liability expenses.

By itself, the contract approach does not affect

tort law, and could be used voluntarily with or

without tort reform. It could also be required by

state or Federal legislation. A contract could be offered voluntarily by any vaccine maker, or any

physician or clinic that administers vaccinations.

It may be most attractive to companies that believe that they are likely to receive a substantial

number of claims that would be successful under

existing tort law. Companies that expect few such

claims probably have little incentive to assume a

voluntary burden of compensation, unless the

contract can effectively limit claims to cases in

which the company would have legal liability for

the injury.

The contract model may work reasonably well

in circumstances in which the payor and payee

agree to the arrangement before any injury occurs

and where causation is relatively easy to establish.

It may be attractive to physicians who administer

vaccines to their patients and to investigators who

give investigational vaccines to subjects in clinical trials. Physicians and researchers are better

able to monitor adverse reactions among people

who take vaccines, although it may be difficult to

identify the cause of many adverse reactions, especially when the vaccine is investigational.

Vaccine makers have no personal relationship

to those who take their vaccines. It is doubtful that

a standard form contract offered by a vaccine maker prior to vaccination would work as well. Vaccine recipients may reject the contract as self-serving on the part of the vaccine maker, or they might

agree to it on the mistaken assumption that it was

required in order to receive the vaccine. The utility

of the contract depends upon whether vaccine

makers could produce a realistic offer in a limited

amount of time. Deciding whether to offer compensation requires investigating the merits of a

claim that a vaccine caused injury, a complex undertaking. This process is similar to that used in

deciding whether to settle a tort claim. The most

salient obstacle to using the contract approach

with a new HIV vaccine would be the difficulty in

determining whether the vaccine caused the injury

and, therefore, whether an offer should be made.

Some hospitals have adopted similar compensation programs for injuries resulting from

medical research, although there are few reports of

their use. Whether this is attributable to lack of

knowledge of the availability of compensation or

lack of injuries or both is not known. Where the

program is voluntary, compensation is not assured

to all injured persons. Those institutions and companies that do adopt a program may have different

policies that produce inconsistent results.

GOVERNMENT-FUNDED INSURANCE

ARRANGEMENTS

Government-financed insurance programs could

fund compensation for injuries, with or without

any change in tort law, in several ways.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 127

❚ Government-Funded Excess Insurance

If the only problem with relying on tort compensation were its cost, and that cost dissuaded vaccine

makers from pursuing vaccine development, then

one alternative would be to shift at least some

costs to government by having government assume the obligation for liability costs in excess of

a fixed amount. A state or the Federal government

could purchase excess insurance or reinsurance

policies or use government funds to pay excess

amounts out of general or special revenues. Such

a program could be adopted whether or not tort liability were altered. If government wished to

change the number and amount or distribution of

its payments, however, it could modify tort law either to increase or decrease the number or amount

of awards to claimants. In the absence of any

change in the way damages awards are calculated,

it would not affect the possibility of inconsistent

awards for similar injuries. Although individual

states could adopt a reinsurance or excess insurance program, consistency could not be achieved

unless all states adopted a substantially similar

system.

The primary disadvantage of creating such a

program for HIV vaccine injuries is that it may be

impossible to predict the amount of excess insurance needed until there have been many years of

experience with the vaccine. It is unlikely that the

federal (or any state) government would commit

to expenditures with no ceiling. It will also be especially difficult to determine the amount at

which liability costs to vaccine makers should be

deemed excessive. That question involves complex social policy decisions about the degree to

which government and private industry should be

responsible for HIV vaccine-related injuries, as

well as the fairness of liability determinations.

Other more practical questions would have to

be resolved. For example, should such costs be

limited to awards to plaintiffs, or should they also

include the costs of defending claims? If defense

costs are included, how would they be verified?

Would companies be willing to allow government

to audit their records? Should government accept

cost certification as sufficient proof of expenditures? Such questions are not insoluble. A more

sensitive question is whether an excess insurance

program would set a precedent for government reinsurance of liability expenses for other tort

claims, from medical malpractice to automobile

injuries.

❚ Government-Funded Disability Benefits

Vaccine-related injuries could be compensated

through a state or Federal disability insurance program that covers only adverse reactions to HIV

vaccines or one that covers many or all injuries.

For example, the Social Security program could

be amended to specifically include coverage of injuries resulting from HIV vaccines. A more general expansion of disability insurance to cover injuries regardless of cause would be more in keeping

with the purpose of Social Security, however,

which bases eligibility on disability and age and

already covers AIDS-related disabilities.

The only compensation mechanism that avoids

serious questions of horizontal justice is a program that compensates all injuries regardless of

their cause. This is because every program that

provides compensation only for injuries from one

cause requires a justification why those injuries

deserve special compensation when injuries from

other causes do not. The need for financial assistance is not a sufficient reason to provide compensation to some injured persons but not others

with similar needs. The desire to encourage the

production of important products by protecting

them from liability is also not a sufficient justification when the makers of equally important

products are not similarly protected. The cost and

inefficiency of the tort system is not a sufficient

reason to replace it with a special compensation

program for only some people but not others. Other reasons specific to injuries from one cause are

required to justify a special compensation system

for those injuries. Although justifications may exist, they are often complex and difficult to identify.

Other countries, like Germany, have had general disability insurance programs in place for decades. The New Zealand Accidental Injury pro-
128 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

gram provides compensation for injuries from

almost all causes (62). The Commission established to study accidental injuries concluded that

limiting the program to injuries from particular

causes was both illogical and unfair and recommended universal coverage as the only defensible

approach (1).

In the United States, a federal general disability

insurance program may be more feasible if future

health care reform achieves universal coverage of

health insurance. Health insurance takes care of

one significant cost of injuries. The remaining expenses are those needed to replace lost income to

pay for living expenses and, in cases of permanent

disability, rehabilitation or long-term care. These

latter expenses can be paid for with disability

benefits funded by insurance or general revenues.

Establishing such a program would require answering many of the questions raised for a causebased compensation program, such as the seriousness of injuries covered, how much and what type

of compensation would be available, and whether

those responsible for certain injuries should contribute to financing the system.109 The cost of

such a program may require new government revenues, although it could be financed in part by

taxes on products and services that caused injury.

The existence of a compensation program may encourage a larger proportion of injured people to

seek compensation. Because the costs of disability for the entire national population are relatively

consistent over time, unlike the costs of injuries

from specific products, they are likely to be more

predictable than the cost of compensating injuries

caused by new HIV vaccines. Moreover, a general

disability insurance system would avoid the administrative expenses of resolving disputes over

causation. There would be no need for separate administrative programs for injuries from different

causes, each with its own fixed costs.

A general disability benefits program could exist with or without tort liability. A program that

provided only compensation, however, could not

purport to serve any deterrence function. If deterring unsafe products and services continued to be

an important social goal, additional mechanisms

would be needed, such as regulation of products

and services, or requiring providers of products

and services to help finance the program in accordance with the proportion of injuries attributed

to their products.

PUBLIC COMPENSATION SYSTEMS

Federal and state governments have created several publicly administered injury compensation programs. Examples include state workers compensation programs, Virginia’s Birth-Related

Neurological Injury Compensation Act (Va. Code

Ann. 38.2-5001 et seq.), Florida’s Birth-Related

Neurological Injury Compensation Act (Fla. Stat.

766.301 et seq.), the Federal National Vaccine Injury Compensation Program (42 U.S.C. 300aa-10

et seq.), the Federal Black Lung Benefits Act (30

U.S.C. 901 et seq.), and, most recently, the Radiation Exposure Compensation Act (42 U.S.C.

2210 et seq.).

Most such compensation programs are limited

to specific injuries from specific causes (causebased), but provide compensation on a no-fault

basis. As long as the injury is demonstrated to result from the specified cause, compensation can

be granted without the need to prove negligence or

other traditional legal responsibility for the injury.

No-fault compensation systems have advantages over tort litigation. The most salient is that a

larger proportion of injured people are entitled to

compensation. There are ordinarily no defendants, so that parties that might otherwise be liable

for injury need not participate in the claims deter109 See Elements of a Compensation Program, below.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 129

mination process or pay compensation.110 The

costs of administering the compensation system

can be less that the total costs of litigation so that a

larger proportion of funds go to injured people.

Costs are ordinarily spread over a large population

or society as a whole, rather than falling on individual companies or organizations. Compensation can be funded from different sources to

achieve different goals. General tax revenues can

be used where the program benefits society. Special taxes on entities that create the risk (such as

employers in workers compensation, or vaccine

makers in the National Vaccine Injury Compensation Program) can be used to link the benefits and

risks of specific products or actions.

No-fault compensation systems have two main

disadvantages. A cause-based system must satisfy

the requirements of horizontal justice by justifying different or special treatment for one class of

people or injuries. The more compensation programs that exist for specific causes, the more difficult it becomes to defend excluding other injuries

from a no-fault system. This can be seen in the tendency to call for a special compensation program

to remedy social problems.111

No-fault systems (whether or not cause-based)

may also generate more, rather than less, cost, either in compensation awards or administrative expenses. Because no-fault systems compensate

more people than would receive compensation (or

even file a claim) in tort law, a system’s cost depends upon who is eligible for compensation and

the level of compensation awarded.112 Per-capita

compensation at the level of average tort awards

would generate higher costs. Very low levels of

compensation may be inadequate or unfair and

generate dissatisfaction, as seen in some worker

compensation programs. In the absence of reliable

estimates of the number of compensable injuries,

it is difficult to predict system costs.

Most important, no cause-based system can

avoid disputes over the cause of injuries. Determining causation is often difficult and time-consuming, especially where the scientific and medical evidence is uncertain or conflicting (115).113

Yet no-fault systems are often recommended in order to provide needed compensation in circumstances where causation is unclear or controversial. Thus, the same complexities that make

litigation frustrating and expensive are often necessarily part of no-fault compensation proceedings.

Health care reform proposals debated in the

103rd Congress included provisions affecting

compensation and liability for adverse reactions

to HIV vaccines (see box 4-2).

❚ The National Vaccine Injury

Compensation Program

The National Vaccine Injury Compensation Program (42 U.S.C. 300aa-10 et seq.) was enacted in

1986 as part of the National Childhood Vaccine

Injury Act in response to concerns that vaccine

makers would not continue to produce childhood

vaccines or to develop new ones if the pressure of

liability for adverse reactions were not abated and

the need for financial assistance to families whose

children suffered permanent injury or death following vaccination (115). In August, 1992, Con110 Most systems provide that the compensation program is subrogated to the rights of the claimant so that it may seek reimbursement for

compensation paid from anyone who is legally liable for the injury. This is most often provided with respect to injuries caused by negligence.

111 In 1986, Congressman Edward Markey called for compensating human subjects in radiation experiments sponsored by the Department

of Energy’s predecessors (190). Recent publicity has renewed interest in the proposal.

112 The Harvard Medical Practice Study estimated that a compensation system for medical malpractice in New York State could be financed

for approximately the same amount as current malpractice insurance premiums if it limited compensation to serious permanent injury or death,

and excluded injuries lasting less than six months and medical expenses covered by Medicaid (70).

113 For example, in workers compensation cases, it is generally far more difficult to determine the cause of a worker’s chronic disease than

the cause of a traumatic injury.
130 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Health care reform proposals that were debated in the 103rd Congress and ultimately defeated

would have had implications on compensation for adverse reactions to HIV vaccines. Each of the proposals, to the extent that they expanded access to health insurance coverage, would have better ensured access to medical care for HIV vaccine trial participants. However, none of the proposals addressed needs for long-term care

President Clinton’s Health Security Act provided for coverage for investigative medical treatments.1

Decisions about which investigative medical treatments to cover, however, were left to the discretion of

the individual health plans. In addition, coverage only applied to investigative treatments that are qualifying, meaning that investigational treatment has been given as part of an approved clinical trial, and

that another treatment would have been provided as routine care if the participant were not receiving

the Investigational treatment. Approved clinical trials were those sponsored by government agencies

such as the National Institutes of Health, the Food and Drug Administration, the Department of Veterans

Affairs, the Department of Defense, or a qualified nongovernmental research entity or a peer reviewed

and approved program

Other proposals that were presented to Congress did not specifically address these issues. The

“single payor” approach (Wellstone) would provide universal coverage for medical care, Including medical care for adverse reactions to HIV vaccines 2 The plan did not detail whether the costs of experimental therapies would be covered under the plan.

HIV vaccine Iiability would also have been affected by health reform proposals that included provisions reforming medical malpractice Iiability. Clinton’s Health Security Act included provisions reforming

medical malpractice and strict Iiability for injuries from pharmaceuticals, Including vaccines (Health Security Act, sees 5501 et seq. ) However, the Act left in place current product liability rules for injuries

from pharmaceuticals due to negligence.

SOURCE: R.E. Stem, Blicker & Stem, Washington, DC, “Selected Issues of AIDS Vaccine Liability, ” unpublished contractor report

prepared for the Office of Technology Assessment, U S Congress, Washington, DC, Sept. 30, 1994

1U.S. Congress, Senate, S. 1757, Health Security Act, Sec. 1128 (Washington, DC U S Government Printing Office, 1993).

2 U.S. Congress, Senate, S. 491, American Health Security Act of 1993 (Washington, DC: U.S. Government Printing Office, 1993).

gressman Fortney “Pete” Stark introduced the Na- The program, which took effect October 1,

tional Vaccine Development and Compensation

Act, patterned after the National Childhood Injury

Compensation Act, which would create a compensation program for injuries occurring in the development and marketing of an HIV vaccine

(170). Because the National Childhood Vaccine

Injury Act has been suggested as a model for compensating injuries following future vaccination

with HIV vaccines, (Stark) it is described in some

detail here.

1988, provides compensation on a “no-fault” basis for injuries resulting from vaccines to prevent

poliomyelitis, diphtheria, pertussis (whooping

cough), tetanus, measles, mumps, and rubella.

These were the vaccinations then ordinarily required in all states to permit children to enter

114 The program is a “no-fault” school or day care.

system because it does not condition eligibility for

compensation on any party’s legal liability for the

114 The Act was amended in 1993 to permit coverage of vaccines recommended by the CDC for routine administration to children. (42

U.S.C. 300aa- 14(e))
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 131

injury. Claimants (called petitioners) are entitled

to compensation if they demonstrate either that

the injury is listed in a statutory Vaccine Injury

Table or that the injury was actually caused by a

covered vaccine, and also meet other eligibility requirements.115 There is no requirement that the

vaccine be shown to have been defective or negligently administered or warnings inadequate. Neither vaccine makers nor health care providers are

parties to the proceedings.

The program has been lauded for reducing tort

claims against vaccine makers. This is undoubtedly because the act postpones and effectively precludes most lawsuits in two ways. First, it forbids

tort claims against vaccine makers unless a petitioner has filed a claim with the Program. Only if a

petitioner rejects the Program’s decision may he

or she commence a lawsuit.116 The likelihood of

succeeding in court on a claim that has been rejected by the program is probably too small to encourage petitioners to proceed. Only if a petitioner

has a very strong claim and believes that a court

would award much more than the program would

a lawsuit be worth the effort.

Second, the act also bars liability on the part of

vaccine manufacturers for failure to issue a direct

warning of risks to the petitioner (42 U.S.C.

300aa-22(c)). However, most courts have reached

the same result by finding that the manufacturer

has no duty to warn the vaccine recipient. This

leaves petitioners with a possible claim that the

manufacturer’s warning to the prescribing physician was inadequate, but the act provides that the

warning shall be presumed adequate if the vaccine

maker complied with all FDA requirements (42

U.S.C. 300aa-22(b)(2)). This represents a nominal change in the law; however, few cases have

found FDA-approved labeling to be inadequate.

Although petitioners may prefer the compensation system to litigation, in effect, they have little

alternative. It should not be surprising that there

are few liability claims against manufacturers for

adverse reactions to the covered vaccines.

Parents or guardians of injured children117 file

petitions for compensation with the United States

Court of Federal Claims (formerly the United

States Claims Court) in Washington, DC. A special master in the Court’s Office of Special Masters118 reviews the petition and makes two determinations: whether the petitioner is eligible for

compensation and, if so, how much compensation

is to be awarded. The Secretary of Health and Human Services is named Respondent in the proceedings. The Department’s Division of Vaccine

Injury Compensation119 reviews petitions and offers its opinion on whether the injury was in fact

caused by a vaccine. Compensation may be denied if the Special Master determines that, on the

115 Petitioners have the burden of proving entitlement to compensation. The vaccine must have been received in the United States or as a

U.S. government employee or dependent overseas; the injury must last more than 6 months and result in more than $1000 in unreimbursable

expenses, or death; the petition must be filed within a specified time period; and the petitioner must not have collected an award or settlement for

the injury.

116 Petitioners with retrospective claims who have recovered compensation in an earlier lawsuit are not eligible for the program. Those who

had commenced a lawsuit before the Program took effect were not permitted to file a petition unless their lawsuit was suspended pending the

Program’s determination. A recent decision by the federal court of appeals for the First Circuit, however, held that the husband and daughter of a

woman who received compensation from the Program (for contact polio) were entitled to commence a tort action for their own loss of the

woman’s consortium, because the husband and daughter were not eligible for compensation from the Program (54, 298). The Court of Federal

Claims has also held that a prior tort recovery by a parent for her own losses did not bar a petition on behalf of the child for compensation from the

program (215).

117 Eligibility is not limited to children, and specifically includes polio contracted from someone who was vaccinated with OPV.

118 There are currently seven Special Masters who work exclusively for the program.

119 The division is part of the Bureau of Health Professions, Health Resources and Services Administration, U.S. Department of Health and

Human Services.
132 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

basis of a preponderance of the evidence, the injury was not the result of the vaccine in question.120

There are actually two programs, one for vaccinations that occurred before October 1, 1988

(retrospective cases), and another for vaccinations

on or after October 1, 1988 (prospective cases).

All petitions for retrospective cases had to be filed

by January 31, 1991. Compensation for permanent injury in retrospective cases is limited to unreimbursed medical and rehabilitation expenses

incurred after judgment; past expenses are not

covered.121 Awards in retrospective cases are paid

from general revenues appropriated by Congress.

Until 1993, appropriations were $80 million per

year; for FY 1993, they were $110 million and are

authorized to continue at that level for future years.

Prospective cases may be filed within three

years after the injury materializes,122 and have no

limit on the amount of compensation payable, except that compensation for death is fixed at

$250,000 as in retrospective cases, and non-economic compensation may not exceed $250,000.123

Awards are paid from a trust fund financed by excise taxes on sales of the covered vaccines.124 The

fund had approximately $700 million in unallocated, unawarded funds as of March 30, 1994.

Like most compensation systems in the United

States, the program is cause-based. Only injuries

or deaths caused or aggravated by a covered vaccine are compensable. Congress sought to avoid

litigation-like disputes over causation by providing a list of medical conditions that are statutorily

presumed to be caused by a covered vaccine in a

Vaccine Injury Table, shown in table 4-1 (42

U.S.C. 300aa-15). The table lists conditions, such

as anaphylaxis and residual seizure disorder, and

the time period following vaccination within

which the injury must have occurred to be presumptively compensable. However, in the majority of cases, causation has been disputed.

Many disputes, especially those involving the

pertussis component of DPT,125 were disagreements over whether a child actually experienced a

condition listed in the table 4-1. These included

disputes over whether the medical evidence demonstrated an injury covered in the table or whether

factors unrelated to vaccination caused the injury.

In addition, there were disagreements about

whether a death resulted from a qualifying injury.

The table did not eliminate difficult, time-consuming disputes over eligibility for compensation.

120 Determinations may be made with or without a hearing including petitioners, their attorneys and witnesses, and medical reviewers from

the Division of Vaccine Injury Compensation, which is represented by attorneys from the Department of Justice. The majority of cases to date

have involved hearings, either in person or by telephone conference call.

121 In the case of death, compensation is fixed at $250,000. A maximum of $30,000 may be awarded for the combined cost of lost income,

pain and suffering, and attorneys’ fees and costs.

122 In the case of death, the period is two years after the date of death, but not later than four years after the initial injury.

123 Compensation for injury may include past and future medical expenses and rehabilitative and custodial care (to the extent not paid for by

insurance, other than Medicaid), lost income, pain and suffering (up to $250,000), and reasonable attorneys’ fees and costs.

124 The excise taxes per dose of vaccine currently in effect are: DPT- $4.56; MMR (measles-mumps-rubella)- $4.44; polio- $0.29; and DT

(diphtheria-tetanus)- $0.06.

125 Which, if any, adverse reactions to the pertussis component result in permanent neurological damage or death has been at the center of

controversy for decades (85). Parents of children who suffered serious injuries or death following DPT vaccination were instrumental in initially

advocating a compensation Program. (They also pressed for the adverse reaction monitoring Program and efforts to improve the safety of vaccines, which were provided for in companion legislation creating the National Vaccine Program. That Program, however, may soon be phased

out). Not surprisingly, pertussis is the cited vaccine in the majority of petitions filed with the Program. But the Program has not settled the scientific controversy over the cause of many adverse reactions; nor was it designed to do so. The Secretary of Health and Human Services proposed

revising the Vaccine Injury Table to add, modify, and remove several conditions presumed to result from rubella and pertussis vaccines. After

publication of a follow-up study of the National Childhood Encephalopathy Study (111, 120) and the Institute of Medicine’s analysis of the new

data (87), however, the Secretary postponed action on the regulations in order to allow time for additional public comment. (59 Fed. Reg. 13916,

Mar. 24, 1994).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines 133

Illness, disability, Injury, or condition covered and time period for first symptom or manifestation of onset or of significant aggravation after vaccine administration, by vaccine.

Diphtheria-tetanus-pertussis (DPT); pertussis; DTP/polio combination; or any other vaccine containing whole

cell pertussis bacteria, extracted or partial cell bacteria, or specific pertussis antigen(s)

■ Anaphylaxis or anaphylactic shock, within 24 hours

■ Encephalopathy (or encephalitis), within 24 hours

■ Shock-collapse or hypotonic-hyporesponsive collapse, within 3 days

■ Residual seizure disorder in accordance with subsection (b)(2), within 3 days

■ Any acute complication or sequela (including death) of an illness, disability, injury, or condition referred to above

which illness, disability injury, or condition arose within the time period prescribed

Measles, mumps, rubella, or any vaccine containing the foregoing as a component; DT; Td;

or texan us toxoid

■

■

■

■

Anaphylaxis or anaphylactic shock, within 24 hours

Encephalopathy (or encephalitis), within 15 days for mumps, rubella, measles, or any vaccine containing any of

the foregoing as a component, within 3 days for DT, Td, or tetanus toxoid

Residual seizure disorder in accordance with subsection (b)(2), within 15 days for mumps, rubella, measles, or

any vaccine containing any of the foregoing as a component, within 3 days for DT, Td, or tetanus toxoid

Any acute complication or sequela (including death) of an illness, disability, injury, or condition referred to above

which illness, disability, injury, or condition arose within the time period prescribed

Polio vaccines (other than inactivated polio vaccine)

■ Paralytic polio: in a nonimmunodeficient recipient, within 30 days, in an immunodeficient recipient, within 6

months, in a vaccine-associated community case, no time Iimit

■ Any acute complication or sequela (including death) of an illness, ability, injury, or condition referred to above

which illness, disability injury, or condition arose within the time period prescribed

Inactivated polio vaccine

■ Anaphylaxis or anaphylactic shock

■ Any acute complication or sequela (including death) of an illness, disability, injury, or condition referred to above

which illness, disability injury, or condition arose within the time period prescribed — ————— -—..——.———

SOURCE :42 U.S.C. 300aa-14(1)(a).

In its early years, the program suffered from inadequate funding and had difficulty developing an

efficient mode of operating (115). The statute has

been amended almost every year to correct technical problems. Now, however, the Program appears

to be functioning relatively smoothly (198) and

has been reauthorized as a permanent program.

As of September 7, 1994, the Program had received 4,069 petitions for retrospective injuries

and 574 petitions for prospective injuries (table

4-2). Since retrospective petitions cover any injury or death resulting from a vaccination before

1988, they may indicate the number of adverse

reactions that were believed by parents to be vaccine-related for each covered vaccine since it was

first introduced, beginning with IPV (injected polio vaccine) in the mid- 1950s. The number of petitions exceeds the number of lawsuits involving

DPT brought against vaccine makers during the

same period reported to the CDC. Some petitioners who did not file lawsuits may have believed

that they did not have a cause of action in tort law.

Others may not have been aware of the possibility

that their children injuries might be connected to

vaccination until publicity about the program

reached them.
134 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

1988 24

1989 146

1990 3,060

1991 839a

1992 0

b

1993 0

1994 0

0 24

1 147

31 3,091

19 958

91 191

37 137

95 95

Totals 4,069 574 4,643

aAn additional 26 petitions filed were not accepted as timely filings.

b

The deadline for filing retrospective petitions was Jan, 31, 1991. No retrospective petitions may be filed after that date

SOURCE: Division of Vaccine Injury Compensation U S Department of Health and Human Services, 1994.

About 45 percent of the retrospective petitions

filed between October 1, 1988 (when the Program

became effective) and January 31,1991 (the deadline for filing retrospective claims) had been finally decided by the United States Court of Federal

Claims by September 7, 1994 (table 4-3). Of

these, only 32 percent were determined to be entitled to compensation.

126 Payments totaling

$417.2 million have been made to petitioners in

about two-thirds (67 percent) of the adjudicated

cases.

127 In fiscal year 1992, many awards could

not be paid on a timely basis because the revenues

appropriated to fund them were not sufficient. The

average award in a retrospective case involving

permanent injury is about $1 million, although

awards in 1994 average $750,749. 128

Prospective petitions are more representative

of the number and type of claims that could be

made annually on an ongoing basis. An average of

96 prospective petitions per year were filed during

the six-year period 1989 through 1994 (table 4-2).

More than a third (38 percent) of the 574 prospective petitions have been decided (table 4-4). Of decided cases, 44 percent have been determined to

be compensable. Awards (including attorneys’

fees in noncompensable cases) have been paid out

to petitioners in 145 (67 percent) of the 217 adjudicated cases for a total of $53.8 million (table

4-5).129 Awards for permanent injury are highly

variable, but tend to exceed awards in retrospective cases because the children are younger and are

eligible for past as well as future losses, and higher

lost wages and pain and suffering awards.130 The

trust fund for prospective awards has always had a

surplus. If prospective petitions continue to be

filed and compensation awarded at the same rate

126 This contrasts with the Program’s experience during its first two years of operation ( 1989 and 1990), in which 73 percent of retrospective

claims were awarded compensation. Since the majority of the retrospective claims were filed in late 1990 and January 1991, the earlier claims

may have involved different or stronger facts.

127 Award amounts also include “reasonable attorneys’ fees” for petitioners’ attorneys, which may be awarded in cases brought in good 

faith even if the petitioner is determined to not be eligible for compensation.

128 Awards in the case of death are limited to $250,000. About 12 percent of all petitions filed have involved death. Awards in cases of 

permanent injury have ranged from $120 to $4,000,000 (Division of Vaccine Injury Compensation).

129 An Institute of Medicine informal survey in 1984 found that the four responding vaccine makers had paid a total of about $2 million for 

 all liability claims closed or settled in the previous ten years and an additional $1.8 million in defense costs (82). Even adjusting for inflation, the

Program appears to provide substantially more compensation than did tort litigation.

130 As of Mrach 1, 1994, 51 percent of awards (34 out of 67) were for the death of a vaccine recipient, totaling $8.6 million. Awards for

injuries totaled $32.8 million for 33 cases, or just under $1 million per compensable claim.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines 1135

Fiscal year Award granted # (%) Claim denied # (%) Claim dismissed # (o/o) Total

1989 9 (41) o 13 (59) 22

1990 98 (79) 10 (8) 16 (13) 124

1991 132 (29) 65 (14) 256 (56) 453

1992 135 (29) 51 (11) 280 (60) 466

1993 102 (21 ) 63 (13) 316 (66) 481

1994 102 (36) 36 (13) 147 (52) 285

Totals 578 (32) 225 (12) 1,028 (56) 1,831

SOURCE: Division of Vaccine Injury Compensation, U S Department of Health and Human Services, 1994

as they have been during the last six years, the trust

fund will continue to accumulate surplus funds.

This would suggest that the surtax on vaccines is

set at too high a level and could be reduced.131

The program’s major advantages are the relative speed with which it can make decisions

(compared with litigation) and the fact that it compensates a much larger proportion of children than

would receive any recovery otherwise. The Program’s ability to make speedy decisions was hampered by an unexpected influx of retrospective

petitions in late 1990 and January 1991, as well as

by funding disruptions; many retrospective cases

have taken years to resolve. Prospective cases

have generally been decided within the statutory

period of 14 months.

Administrative costs appear reasonable for the

services rendered. The Court of Federal Claims

and its Office of Special Masters, the Division of

Vaccine Injury Compensation, and the Vaccine Injury Claims Division of the Department of Justice

have received a total of between $4.5 and $9 million annually in appropriations to pay for staff and

resources.

132

Although the program was not originally intended to be a model for replacing tort liability

with no-fault compensation, it has been suggested

as one for HIV vaccine-related injury. Congressman Stark circulated a proposal for legislation to

create a no-fault compensation program for such

injuries patterned after the legislation creating the

program (170). The major technical difficulty

with developing a compensation program for HIV

vaccines lies in determining what types of injuries

should be deemed compensable before sufficient

experience with a vaccine permits causation to be

reasonably determined. 133

It may not be necessary to create another independent compensation system. HIV vaccines

might be added to the vaccines covered by the existing program. The statute now provides for covering new vaccines when they are recommended

for routine administration to children. In the near

future, the Secretary of Health and Human Ser131 It may also suggest that the estimates for liability, which were higher than the surtax amounts, were too high. The Public Health Service is

contemplating recommending changing the amount of the excise tax to generate only about $60 million per year, which should be adequate to

fund prospective awards.

132 Over the five-year period 1989-1993, $7.5 million per year would total $37.5 million to decide 1,768 cases yielding total awards of

$424.6 million. This represents about 8% of total awards plus administrative costs. In the future, a smaller number of petitions are likely to be

filed and decided.

133Another important technical difficulty with the proposal involved the manufacturer’s bond, the mechanism used to provide indemnity

during the clinical trials stage. Some manufacturers objected that a bond would be difficult for a small company to raise. In addition, some

manufacturers did not want their bond to be used to pay for adverse reactions attributable to other companies’ vaccine candidates (173).
136 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Fiscal year Award granted # (%) Claim denied # (o/o) Claim dismissed # (o/o) Total

1989 0 (o) o 0 (o) o

1990 2 (67) o (o) 1 (33) 3

1991 10 (37) 4 (15) 13 (48) 27

1992 28 (42) 6 (9) 33 (49) 67

1993 22 (35) 10 (16) 30 (48) 62

1994 33 (57) 7 (12) 18 (31) 58

Totals 95 (44) 27 (12) 95 (44) 217

SOURCE: Division of Vaccine Injury Compensation, U S Department of Health and Human Services,1994

vices is likely to recommend adding Hepatitis B

vaccine and hemophilus influenza type b vaccine

to the list of covered vaccines. These additions

would be consistent with the purpose of covering

vaccines that are recommended, if not required,

for children. It is unlikely that an HIV vaccine

would be required for children or adults, although

it might be recommended for people at high risk of

HIV infection, including newborns whose mothers are HIV positive. Adding HIV vaccines to the

program would represent a larger break with the

origina purpose of the program than adding vaccines recommended for children. It raises the

question why other vaccines taken primarily by

adults should not be covered.

Beyond the program itself, attention to the larger question of horizontal justice may require asking why injuries from other causes should not be

covered. If the most anticipated adverse reaction

to an HIV vaccine is HIV infection, covering adverse reactions to HIV vaccines would treat

people differently depending upon how they became infected. People who became infected as a

result of vaccination would be eligible for special

compensation, but those who became infected in

other ways would not. This is true for any causebased compensation program, of course, but it

may be particularly sensitive in view of the limited resources often available to people living with

HIV infection and AIDS.

❚ State Compensation Programs

Two states, California and Connecticut, have

adopted special measures pertaining to HIV vaccines that are described briefly below. In addition,

Virginia and Florida have operated compensation

programs for birth-related injuries that may suggest some lessons for the creation of cause-based

compensation programs.

California

In 1986, California created the AIDS Vaccine Victims Compensation Fund as a source of future nofault compensation (Cal. Health & Safety Code,

Ch. 1.14, s. 199.50). The program is limited to

people who suffer personal injury caused by an

HIV vaccine that is developed by a California

company and approved by the FDA or the state. It

does not cover research-related injuries or injuries

resulting from vaccines from non-California companies. Compensation (for medical expenses, lost

earnings, and up to $550,000 in non-economic

damages) is to be awarded by the California Board

of Control out of funds collected from a surcharge

on future HIV vaccine sales. Claimants remain

free to pursue any tort claim they may have for the

injury, but the state is entitled to recoup any damages that duplicate a program award. Since no vaccine has yet been approved for marketing, the program has not become operational. The authorizing

legislation is relatively general, leaving details to

be worked out by a task force.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines 137

For Vaccinations Before October 1988

Fiscal year Number Amount ($millions)

1990 91 $71.9

1991 149 75,4

1992 215 84,5

1993 390 110.4

1994 396 75,0

Subtotals 1,241 $417,2

For Vaccinations After October 1988

Fiscal year Number Amount ($millions)

1990 0 0

-

1991 14 $4,2

1992 33 13.1

1993 40 15,0

1994 58 21.5

Subtotals 145 53.8

Totals 1,386 $471.0

SOURCE: Division of Vaccine Injury Compensation, U S Department of Health and Human Services, 1994

The AIDS Vaccine Victims Compensation

Fund was part of legislation that was intended to

remove three obstacles to AIDS vaccine development identified by California vaccine companies

to the legislature: the high cost of testing investigational vaccines, an uncertain market, and strict

liability for adverse reactions to vaccines. The legislation provides for grants to California vaccine

makers for research and testing investigational

vaccines and guaranteed state purchases of up to

500,000 units of an approved vaccine (at up to $20

per dose if fewer than 500,000 doses are sold within three years after FDA approval) (Calif. Health

& Safety Code, s.199.45-51, 199.55-60). The

state has provided almost $2 million dollars in research grants to two California companies. Under

the statute, grants are to be repaid from sales of an

approved HIV vaccine; California is also to receive royalties from such sales after the grant is repaid, with the royalty to be negotiated at the time

of the grant award. In the absence of any licensed

HIV vaccine, the state has not had to appropriate

any funds to fulfill its purchase commitment. Because the statute gives the state discretion to

choose among competing vaccines on the basis of

their safety, effectiveness, and cost, it is not clear

whether the guaranteed purchase is sufficiently

precise to offer manufacturers a reliable market.

The 1986 legislation also limited the liability of

manufacturers, in effect, to liability for negligence. In 1988, the California Supreme Court issued its decision in Brown v. Superior Court (225)

which effectively precluded strict liability based

on design defects caused by FDA-approved prescription drugs. The decision, which is considered

to apply to FDA-approved vaccines as well as

drugs, provided more protection against liability

than the legislation, and the provisions limiting li-
138 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

ability were repealed the same year (Calif. Statutes 1988, ch. 1555 s.3).134

California had already adopted a limited compensation program for severe adverse reactions to

mandatory childhood vaccines in 1977 (Calif.

Health & Safety Code, s. 429.35-.36, 1977;

(112)). That program, however, provided compensation only for medical and institutional care

up to a maximum of $25,000. California’s MediCal and other programs for disabled children were

expected to provide other assistance. Children

with severe injuries requiring extensive medical

care could seek compensation from the fund in addition to pursuing any tort remedy they might

have against a vaccine manufacturer. The legislation provided immunity from liability for physicians and others who administered the required

vaccines. Perhaps because of its narrow scope, the

program has received only a handful of claims. It

was created in the aftermath of the swine flu program in the hope of encouraging continued vaccine development and marketing, but it was not

considered an adequate model for the later AIDS

Vaccine Victims Compensation Fund or the National Vaccine Injury Compensation Program,

and has had little, if any, influence on vaccine development or compensation policy.

Connecticut

Connecticut adopted a statute protecting

manufacturers, research institutions and researchers from liability for personal injury resulting

from the administration of any HIV vaccine to a

research subject (Conn. Gen. Stat. ss. 19a-591-

591b) (172). The law exempts those involved in

clinical trials of an HIV vaccine from all liability,

including liability for negligence, unless the person provided false information to the FDA in connection with an Investigational New Drug application, or caused injury by gross negligence or

reckless, willful or wanton misconduct. It was enacted after MicroGeneSys said it would not test its

vaccine to prevent maternal-fetal HIV transmission in HIV-positive pregnant women. The trial

was closed when it failed to enroll enough subjects to permit conclusions about the effect of vaccination to be drawn. MicroGeneSys is no longer

pursuing those trials.

Virginia

The Virginia Birth-Related Neurological Injury

Compensation Act (Va. Code Ann. 38.2-5001 et

seq.) was enacted in 1987 in an attempt to reduce

the cost of medical malpractice insurance on the

theory that tort claims against obstetricians for

birth-related injuries were driving up the price of

insurance, limiting available coverage, and threatening the availability of obstetric services. It protects participating physicians from tort liability

for medical malpractice for specific, narrowly defined birth-related injuries to newborns, and offers

compensation in very restricted circumstances.

The Virginia program is limited to severe neurological injuries to a newborn that are caused by a

physician who participated in the program and

which render the infant “permanently in need of

assistance in all activities of daily living.” (Va.

Code Ann. s. 38.2-5001 (emphasis added)).135

Given the narrow definition, it should not be surprising that the program had received only ten

134 In 1992, California enacted a law limiting the liability of HIV vaccine manufacturers, research institutions, and researchers participating

in clinical trials of vaccines intended to prevent HIV transmission from a pregnant woman to her baby. (Calif. Health & Safety Code, s. 199.89)

Liability is expressly limited as in the Brown decision. The law does not preclude liability for negligence, gross negligence, or reckless, willful or

wanton misconduct, or for providing false information to the FDA.

135 Birth-related neurological injury was redefined in 1990 as “injury to the brain or spinal cord of an infant caused by the deprivation of

oxygen or mechanical injury occurring in the course of labor, delivery or resuscitation in the immediate post-delivery period in a hospital which

renders the infant permanently motorically disabled and (i) developmentally disabled or (ii) for infants sufficiently developed to be cognitively

evaluated, cognitively disabled. In order to constitute a ‘birth-related neurological injury’ ..., such disability shall cause the infant to be permanently in need of assistance in all activities of daily living. This definition shall apply to live births only and shall not include disability or death

caused by genetic or congenital abnormality, degenerative neurological disease, or maternal substance abuse.” Va. Code Ann. s. 38.2-5001.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 139

claims by mid-1994,136 although the Virginia

State Medical Society had predicted at least 40

claims per year (118). Of these claims, seven were

awarded compensation, two were denied and one

was pending in August 1994.137

Claims against participating physicians and

hospitals must be brought to the program exclusively. Physicians are protected against liability

for the injuries covered by the program (Va. Code

Ann. 38.2-508). The Virginia Worker Compensation Commission makes decisions on claims.

Physicians (primarily obstetricians) and hospitals

elect to participate in the program and pay an

annual assessment. Assessments on non-participating physicians have been suspended because of

surplus revenues in the compensation fund.

Florida

The Florida Birth-Related Neurological Injury

Compensation Act (Fla. Stat. 766.301 et seq.) was

modeled after the Virginia program. It has received more claims, presumably because it defines a compensable injury slightly more broadly.138 The Neurological Injury Compensation

Association (NICA) had received 108 claims

through fiscal year 1993.139 Of these claims, 31

received an award, 42 were denied as noncompensable by a judge (of which 4 were on appeal),

and 22 were denied by the NICA and pending judicial determination. Total awards, which are paid

throughout the child’s lifetime as expenses as incurred, are estimated to be about $73 million, with

about $5 million having been paid out.

It is not known whether either the Virginia or

the Florida program has had any effect on malpractice claims or insurance rates for obstetricians

in those states. In its recent report on defensive

medicine, the Office of Technology Assessment

speculated that the “subset of injuries is so small

and the link between these injuries and physician

practices so unclear, removing personal liability

for the specified birth-related injuries probably

has very little impact on defensive medicine and . .

. impact on malpractice premiums is unclear”

(195). No study has documented increased access

to obstetrical care, one of the goals of the Virginia

and Florida statutes.

ELEMENTS OF A NO-FAULT

COMPENSATION PROGRAM

If a no-fault compensation program for HIV vaccine-related injuries is desirable, it can be

constructed in different ways to suit different purposes. If the choices made are already part of an

ongoing program, HIV vaccine-related injuries

might be added to that program. The following

pages summarize key elements of a no-fault compensation program and how they might be adapted

to adverse reactions to HIV vaccines.

❚ Eligibility

The first question to be decided is who should be

eligible for compensation. Should the program be

limited to United States citizens or residents, or

should anyone who receives an HIV vaccine be eligible? In the National Vaccine Injury Compensation Program, people who are employed by the

Federal government, such as diplomats and military personnel and their dependents, are covered

if they receive a U.S.-made vaccine abroad, like

all individuals who receive a vaccine in the United

States. Should the program cover foreign citizens

residing in their own countries who receive vaccine made by a U.S. manufacturer? Obviously, the

136 Eleanor Pyles, Virginia Office of Birth-Related Compensation Claims, Richmond, VA personal communication, Aug. 8, 1994.

137 Ibid.

138 “ ‘Birth-related neurological injury’ means injury to the brain or spinal cord of a live infant weighing at least 2,500 grams at birth caused

by oxygen deprivation or mechanical injury occurring in the course of labor, delivery, or resuscitation in the immediate post-delivery period in a

hospital, which renders the infant permanently and substantially mentally and physically impaired. This definition shall apply to live births only

and shall not include disability or death caused by genetic or congenital abnormality.” (Fla. Stat. 766.302(2)). Florida’s definition does not require that an infant require assistance in all activities of daily living.

139 NICA claims office, Tallahassee, FL personal communication, Aug. 8, 1994.
140 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

broader the eligible population, the more expensive the program. But if the program is to encourage HIV vaccine development for overseas use, as

in Africa and Asia, it may wish to include foreign

vaccinees, although potential liability claims

from foreign vaccinees does not appear to threaten

vaccine development. A different question may

arise as to what counts as a U.S. vaccine if the

company that makes it is owned or controlled by

a foreign company.

It is customary to fix a time within which

claims must be filed (a statute of limitations). Ordinarily, this would be several years after an injury

manifests itself. If adverse reactions to HIV vaccines are not expected to occur for many years after vaccination and if they are difficult to identify,

the first claims might not be expected for many

years after the program begins.

Programs have often distinguished between investigational and marketed products, reserving

compensation to those injured as a result of a marketed product. If a compensation program is to encourage research, as well as provide compensation, it may wish to cover injuries to research

subjects. However, research-related injuries raise

special questions in most of the categories discussed below.

The National Vaccine Injury Compensation

Program was originally justified because it covered childhood vaccines required by law. An HIV

vaccine is not likely to be required for any specific

population, at least not in the near future. If a compensation program covers vaccines that are recommended or voluntary, then it may set a precedent for expanding the program to cover all

recommended or voluntary vaccines.

❚ Compensable Injuries

The question of what injuries to cover may be the

most difficult and the least capable of resolution

before an HIV vaccine acquires several years of

experience. Three threshold questions could be

answered sooner, however. The first is whether all

injuries should be covered, regardless of seriousness, or whether there should be a minimum level

of severity, defined in either physical or financial

terms. If the compensation program is to make

compensation more equitable, then, arguably,

even transient injuries should be covered. After

all, the less serious the injury, the less likely it is

to be compensated in the tort system. If resources

for compensation are limited, however, it may be

necessary to restrict compensable injuries to those

for which people are unlikely to be able to pay

themselves. This could be done by specifying the

particular injuries, by requiring injuries to be permanent or last more than six months, for example,

by covering only uninsured or unreimbursed expenses, or by requiring that the injury cost more

than a minimum amount in medical expenses or

lost earnings or both. The particular choice might

be balanced with the amount of compensation

payable. More injuries could be compensated if

the amount of compensation per injury were limited. It should be recognized, however, that if insured expenses are not covered, those costs remain with the health or accident insurer.

The second threshold question is whether to include HIV infection as a compensable injury. The

possibility that vaccine recipients might become

infected as a result of vaccination (because of enhanced susceptibility to infection, limited efficacy

of the vaccine, or a manufacturing defect) poses an

initial difficulty. If it is impossible to determine

whether a person’s HIV infection resulted from a

vaccine or from other causes, it might be impractical to include HIV infection as a compensable injury. In many cases, it is likely to be quite difficult

to attribute HIV infection to lack of vaccine efficacy rather than risk behavior. On the other hand, if

HIV infection is the most common injury among

vaccine recipients, then a compensation program

that excludes HIV infection will compensate very

few people.

A third question is whether social harms, such

as discrimination in housing, employment, insurance, and personal relationships, should count as

compensable injuries. Although compensation

systems have traditionally been limited to cases

involving physical injury for which someone

could be legally liable, social harms, including

lawful discrimination, may injure many HIV vac-
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 141

cine recipients. Social harm also serves to distinguish HIV vaccines from other vaccines. It may be

difficult to determine whether discrimination resulted from taking an HIV vaccine or from other

factors. At the same time, the cost of compensating lost earnings, housing, insurance, and even

personal relationships, may be no higher than

compensating similar losses resulting from permanent physical injuries.

Finally, injuries do not always appear in a

single episode. Thus, it will be necessary to determine whether adverse reactions that aggravate or

worsen existing health conditions should be compensable. Some adverse reactions result in death,

although death may not be immediate. It may be

impossible to determine whether death resulted

from another compensable injury until more is

known about adverse reactions to HIV vaccines.

❚ Causation

If a compensation program is limited to injuries

that are caused by an HIV vaccine, then causation

must be determined. In the absence of a list of

compensable injuries (and no complete list will be

available immediately) and for injuries that do not

appear on such a list, a procedure for deciding

causation in individual cases is needed. Like tort

law, most compensation programs place the burden of proving causation on the injured person. As

a practical matter, however, the injured person is

the least likely to be able to find the evidence needed to prove causation. The same factors that make

a list of compensable injuries impossible may preclude proving causation. Some presumptions

could be used to overcome this difficulty, such as

presuming causation for any injury that cannot be

explained by credible scientific or medical evidence as caused by something other than the vaccine. Alternatively, a reduced amount of compensation might be provided in some circumstances in which causation cannot be established.

The standard of proof, applicable to all requirements for compensation, affects decision making

about causation in particular. Most programs use

the preponderance of the evidence standard,

which may be the standard most favorable to

claimants. More stringent standards, like clear and

convincing evidence, may be too difficult to meet,

at least for many years. The standard of beyond a

reasonable doubt, ordinarily reserved for criminal

prosecutions and, in some states, for civil commitment, seems inappropriate and probably would be

met very rarely whether one was trying to prove or

disprove causation.

The type of evidence that should be admissible

to prove or disprove causation may create problems. How much weight should be given to the

opinion of individual treating physicians? Should

epidemiological studies be admitted and, if so,

how might they inform individual cases? Should

the testimony of the injured person be sufficient to

prove causation or must it be corroborated? What

type of evidence should be required, permitted,

and excluded to prove causation of social harms?

❚ Compensation Benefits

The type and amount of compensation available

affect both the program’s attractiveness to potential claimants and its overall cost. If claimants retain the option to file lawsuits as an alternative to

using the compensation program, then awards

may have to be reasonably comparable to those

available after litigation in order to attract claimants away from court. Of course, other program

features, such as expeditious decisions, may offer

sufficient attractions, but they may not be fully operational in the early years of a program.

Compensation may be provided for several

types of losses. Medical expenses are the most

common. These may include hospital and physician expenses, rehabilitative expenses, special

education, vocational training, behavioral therapy, case management, residential and custodial

care, medical and special equipment, adaptive

construction to refit a home, and travel expenses

related to obtaining care. It is difficult to justify

limiting most of these expenses, especially those

paid out of pocket. Many compensation programs

do not compensate expenses that are paid for by
142 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

health or accident insurance.140 Whether such reimbursed expenses should be compensated depends upon who should bear the ultimate loss, the

compensation program or the health or accident

insurer. If it is appropriate for the health insurer to

bear the loss, then the program might enroll the injured person in a health insurance program (if not

already enrolled) rather than attempt to estimate

and compensate future medical expenses.

If any health care reform succeeded in providing universal health insurance coverage, then a

compensation program that did not cover insured

expenses would be able to minimize payments in

this category. It should be noted, however, that no

health reform proposal contemplates covering

long term care for permanent disabilities, so that

the compensation program might be expected to

do so.

Compensation for lost earnings is intended to

enable an injured person to pay daily living expenses. Lost earnings can be calculated on the basis of an individual’s actual losses, which pays

high income people more than low wage earners,

or on the basis of a standard formula independent

of actual income. The use of actual losses is consistent with tort litigation practice but generally

fails to compensate those who have no earnings,

especially women with children who are not in the

paid workforce. Standard formulas have been

used in the case of young disabled children who

will never be able to work, and could be applied to

others.

In the case of death, many compensation systems pay a fixed dollar benefit in lieu of other

forms of compensation. The size of the benefit varies with the nature of the program, although it is

ordinarily less than the amount payable in the case

of permanent injury which is intended to provide

for living expenses. If the benefit were intended to

replace the earnings that would have supported the

decedent’s family, however, it might be calculated

in the same manner as lost earnings. If an injured

person who has received compensation for the injury later dies, a death benefit could be paid or not,

depending upon the purpose of the payment.

Compensation for social harms could be limited to actual losses, such as lost earnings, medical

expenses that would have been covered by lost

health insurance (or the amount of a more expensive policy, if obtainable), the increased cost of

housing, and similar expenses. Additional

amounts to compensate for any damage to one’s

reputation might also be considered, although

these could be included in non-economic damages.

Noneconomic damages are intended to provide

some compensation for the pain and suffering occasioned by injury. In tort practice, such compensation is often used to pay attorneys’ fees in

contingency fee arrangements, so that a plaintiff

can at least be reimbursed for out-of-pocket expenses (although some fees can exceed the

amount of noneconomic damages). If attorneys’

fees are separately compensated, there may be less

financial need for non-economic damages. But

there may be reasons to compensate for pain and

suffering, especially in cases of permanent injury

and if the program intends to compete with litigation. Programs like the National Vaccine Injury

Compensation Program limit noneconomic damages to a maximum amount, presumably to control at least one program cost.

It is also possible to provide fixed-dollar benefit payments in lieu of itemized compensation for

losses and expenses, as does the Radiation Exposure Compensation Act (42 U.S.C. 2210 et seq.)

and the United Kingdom’s Vaccine Damage Payments Act (Current Law Statutes Anno. 1979,

Ch.17). Fixing awards at a uniform amount obviously simplifies decision making and reduces

administrative costs, but it does not purport to

compensate for actual individual losses.

140Currently, some health insurance plans cover treatment for adverse reactions from investigative treatments. Other insurance plans, however, do not cover ordinary and necessary care that is required as a result of participating in an experimental activity such as a vaccine trial,

reasoning that the care would not have been required but for the experimental procedure (173).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 143

If claimants are permitted to be represented by

attorneys, then the program will have to pay something toward their attorneys’ fees, at least in the

case of those who cannot afford to hire an attorney.

Attorneys may be seen as necessary by claimants

who are unfamiliar with the system and unprepared to prove causation. It may be cheaper to

grant attorneys’ fees to all claimants than to implement an income or means test to determine

who can and cannot afford to pay themselves. The

amount payable for attorneys’ fees affects the

willingness of attorneys to represent claimants.

The amount can be determined on a case-by-case

basis by the decisionmaker. Although this requires additional administrative time, there is precedent for determining what is reasonable. Alternatively, a fee schedule could be used if one could

be developed that was sufficiently flexible to account for variations in the type of cases expected

under the program.

❚ Mode of Payment

Traditionally, payments have been made in lump

sums which require predicting future losses and

reducing them to a present value. More recently,

periodic payments have been used to spread out

payments, reduce immediate costs, and minimize

the chance that the recipient will use or invest the

whole amount unwisely and be left indigent. An

alternative is for the compensation program to

purchase an annuity or pension that provides periodic income to cover anticipated expenses. This

approach is generally less expensive than periodic

payments because the premiums are often less

than the total payouts. If annuities are used and the

injured person later dies, a decision will have to be

made concerning who—the program or the injured person’s survivors—should be entitled to

any death benefit. As noted above, an alternative

to making payments for medical expenses would

be to purchase health or long term care insurance

for the injured person, which would function in

much the same way as annuities, although future

premiums would not necessarily be fixed at the

time of purchase.

❚ Decisionmaking Authority

A compensation program can be organized and

operated in many different ways. The most important administrative decisions are who has the authority to make decisions about claimant eligibility and awards, and how it is exercised. In the

administrative agency model, such as Social Security, the authority to make decisions is vested

with an administrative agency. Proceedings are

often informal and recourse is limited. An independent agency or review board can perform the

same functions, as do some worker compensation

commissions. This may be preferred when there

is a reason to avoid linking compensation decisions to a particular government agency.

Alternatively, decisionmaking authority can be

exercised by one or more federal or state courts.

Federal courts created under Article III of the U.S.

Constitution require a “case or controversy” as a

condition of jurisdiction, so that the decision making process may have to have both a claimant and a

respondent or defendant, increasing the likelihood

of creating a litigation-like atmosphere. An Article I court, like the U.S. Court of Federal Claims

that hears National Vaccine Injury Compensation

cases, does not necessarily require an identified

defendant; the federal government is identified as

the respondent and is presumed to be the target of a

claim for payment. Special masters, like those

who decide cases in the National Vaccine Injury

Compensation Program, could be used to expedite

decision making in proceedings that are less formal that court hearings. With respect to HIV vaccine related injuries, the simplest means of creating a compensation program may be to add HIV

vaccines to the list of vaccines covered by the National Vaccine Injury Compensation Program.

The degree of discretion granted to decision

makers can affect the efficiency of the program.

The more specific the legislation governing the

program, the less freedom decision makers have.

Specificity is often used to prevent arbitrariness.

But it may also require frequent amendments to

the legislation to adjust to unanticipated problems

or changing conditions. If the administering
144 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

agency has the confidence of those who participate in the program, it might be granted the authority to make regulations governing many administrative procedures in order to reduce the

rigidity that detailed legislation can produce.

Many compensation programs specify time

limits for deciding claims in order to promote expeditious decisionmaking. Speed and informality

may be a program’s main advantages over litigation. Realistic time limits depend upon the complexity of the decisions to be made. More time is

required to establish causation where there is

scientific uncertainty than where there is clear evidence. More time is required to prove what is

needed to compensate an individual when compensation is calculated on the basis of actual

losses than when it is computed according to a

schedule. If time limits are imposed, then the program should specify the consequences of exceeding a time limit, such as automatic payment or denial of compensation. Both alternatives can create

incentives to delay dispute resolution and can operate unfairly in circumstances of unavoidable

delay.

Not everyone will agree with the decisions of a

compensation program. Should determinations of

eligibility and compensation be appealable? Administrative programs ordinarily have an internal

review mechanism, with appeals possible in at

least some cases to the courts. The availability and

extent of appeals may take into account the

amount of compensation permitted by the program and whether claimants have the option of

taking their case to court instead of the compensation program.

❚ Relationship to Tort Law

A compensation program can be an exclusive

source of compensation or an optional alternative

to tort litigation. If the program’s major goal is to

eliminate tort litigation, then exclusivity may be

preferred. If the program intends to make compensation more equitable and also retain any deterrent effect, then making the program optional

may be preferable. The program could still be

made a required “first resort” that must be used before proceeding in tort.

Many compensation programs have a right of

subrogation that grants to the program any rights

that a successful claimant might have against a

third party who would be legally liable for the

claimant’s injuries. The program is then entitled to

sue the third party for reimbursement of the compensation paid to the claimant. This both replenishes the program’s funds for awards (although

the cost of litigation may increase other expenditures) and shifts the cost of compensation (but not

administration) to the responsible party. This is

useful where it is beneficial to retain the link between responsibility for injury and financial loss.

As a practical matter, however, proving that a third

party is liable is difficult in vaccine cases, and is

likely to be especially difficult in HIV vaccine

cases, so the opportunities for subrogation may be

limited.

❚ Conditions on Program Operation

When the effects of a new program are uncertain,

the authorizing legislation sometimes limits its

period of operation with a sunset clause. If at the

end of the time period the program is operating

successfully, it may be reauthorized; if not, it may

expire without doing further damage. Continued

authorization may be contingent on the occurrence of certain conditions, such as the initial or

continued marketing of an HIV vaccine or pricing.

For example, the program might be continued

only if an acceptable vaccine remains on the market and its price does not exceed a specified

amount, or only if vaccines are sold to government

at below-market prices for distribution to indigent

persons.

If the costs of the program are not reasonably

predictable when it begins operation, the continuation of the program may be made conditional on

the availability of funds for either administration

or compensation or both. A program that risks termination, however, may be unable to attract sufficient support to achieve its goals.
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 145

❚ Financing

A compensation program may be financed by society as a whole, by those who produce, sell or administer the vaccines that result in injury, or by

those who purchase or benefit from the vaccines.

Compensation may be funded from the same or

different sources as administrative expenses. Financing by society generally means government

funding from general tax revenues. The feasibility

of such funding may depend upon budget limitations. If the program wishes to incorporate an element of risk deterrence, then it may prefer to have

those who produce vaccines fund the program.

This can be done by levying a tax on each dose of

vaccine sold or distributed or by assessing vaccine

makers according to the awards paid that involve

their vaccines. In this way, vaccine makers retain

some financial responsibility for the injuries

caused by their vaccines, but are relieved of the

burden of litigation. Of course, some or all of the

assessments or taxes will be passed on to vaccine

purchasers as part of the vaccine price. Where

government buys significant quantities of the vaccine, government will bear a significant share of

the ultimate cost of the compensation program.

❚ Supplements to Compensation

Programs

Compensation programs deal only with compensating injuries. They do not prevent injuries.

Thus, if a no-fault compensation system supplants

all or part of tort liability, other mechanisms must

be in place to prevent or deter avoidable risks.

ALTERNATIVE INCENTIVES FOR HIV

VACCINE DEVELOPMENT

Compensation programs deal with the consequences of vaccine use after a vaccine is developed. By themselves, they cannot guarantee that

any vaccine is developed. Thus, if HIV vaccines

are insufficiently attractive to private industry for

reasons of the difficulty and expense of research

or an unrewarding market, other initiatives will be

necessary to encourage vaccine development

(100).

An Institute of Medicine committee, formed to

study ways to foster U.S. industry participation in

vaccine development for the Children’s Vaccine

Initiative, concluded that the most significant disincentives to producing new and better vaccines

primarily for use in the developing world were the

cost of research and clinical trials and the expected

limitations on the price at which vaccines could be

sold (121).141

The Committee recommended that the fderal

government create a National Vaccine Authority

to support new vaccine product development

(121). This type of initiative could be used to foster research and development of HIV vaccines. A

National Vaccine Authority or similar entity could

provide grants to private industry to develop HIV

vaccines. It could also reduce the risks and costs to

industry by establishing product development

programs, production facilities to make investigational vaccines for clinical trials, and assistance in

complying with FDA regulations. In addition, the

authority might arrange procurement contracts to

create a guaranteed market for approved vaccines.

Estimates of the annual operating costs of a National Vaccine Authority ($55 to $75 million) for

all vaccines, including HIV vaccines, are about

the same as estimates of annual future compensation awards for the National Vaccine Injury Compensation Program (about $60 million).

California created a research assistance program to provide grants to California vaccine makers to test candidate HIV vaccines in clinical

trials.142 In order to ensure a market, the state also

agreed to purchase a minimum number of doses of

an approved HIV vaccine from a California HIV

vaccine maker and to subsidize the price of vaccines to guarantee a price of $20 per dose. Establishing a purchase price before a vaccine has even

141 The author served as a member of that committee.

142 See State Compensation Programs above.
146 Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Mechanisms for Increased collaboration and Information sharing among vaccine researchers to increase productivity

and expedite research.

Simplification of collaborative arrangements between government and industry researchers.

Expanded access to preclinical nonhuman animal models for testing investigational vaccines.

■ Tax deductions or credits for Investments in vaccine development,

■ Expedited review by the FDA of applications for vaccine licenses.

■ International harmonization of national vaccine Iicensing standards.

■ Expanded patent protection for approved vaccines.

■ Guaranteed purchases of vaccine supplies by government,

■ National coordination of vaccine research and distribution policies. —

SOURCE: Office of Technology Assessment, 1995

been tested in field trials is difficult. A future licensed HIV vaccine might be sold at a more than

$20 per dose, and vaccine companies may be unable or unwilling to agree to any specific price before a vaccine is approved. Nonetheless, such efforts are examples of policy innovations that

might be considered, with appropriate modifications, at the national level.

Other actions, such as those listed in Table 4-6,

may facilitate scientific research or encourage

HIV vaccine development. Although beyond the

scope of this report, they target specific points in

the vaccine research and development process and

are likely to have a more direct effect on HIV vaccine development than future compensation programs.

❚ Conclusion

The initiatives supporting vaccine research and

development recognize that neither limitations on

liability nor compensation for injury can produce

new HIV vaccines. It is not clear that a new compensation program is needed to abate fears of liability on the part of most companies engaged in

HIV vaccine research. A compensation program

cannot guarantee that important research will be

done, that new products will be brought to market,

or that any new products will be affordable to

those who need them.

This is not to suggest that a compensation system should not be considered. But a compensation

program can and should be adopted on its own

merits. Society might feel an ethical obligation to

compensate those who take an HIV vaccine in an

effort to abate the epidemic. Even if society does

not feel an ethical obligation itself, it might conclude that compensation is nonetheless desirable

as a means of rewarding those who suffer adverse

reactions in an effort to prevent the continuing

spread of HIV infection and the tragic toll of

AIDS. The reasons for providing compensation,

however, should be carefully considered in light

of their application to other types of injuries.

It will be especially important to consider why

people who have adverse reactions to a vaccine to

prevent HIV infection or progression to AIDS

should receive special compensation when people

who have adverse reactions to drugs like Zidovudine, ddI and ddC, do not. Special compensation

for HIV-negative people may give the appearance

of social indifference to the needs of people living

with HIV infection. A public debate about the justification for compensating specific injuries may

offer a valuable opportunity to reconsider the

ways in which responsibility for injuries and illnesses of all kinds should be allocated.

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Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 157

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238. Dunn v. Lederle Laboratories, 121 Mich.

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240. Ezagui v. Dow Chemical Corp., 598 F.2d

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249. Givens v. Lederle, 556 F.2d 1341 (5th Cir.

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250. Gottsdanker v. Cutter Laboratories, 182

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251. Graham v. Wyeth Laboratories, 906 F.2d

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252. Grant v. Parke-Davis & Co., 544 F.2d 521

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253. Greenman v. Yuba Power Products, Inc., 59

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255. Grundberg v. Upjohn Co., 813 P.2d 89 (Utah

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271. Jones v. Lederle Laboratories, 785 F.Supp.

1123 (S.D.N.Y. 1992).

272. Keane v. Lederle Laboratories, 1994 U.S.

Dist. LEXIS 4305 (1994).
158 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

273. Kearl v. Lederle Laboratories, 172 Cal.

App. 3d 827, 218 Cal. Rptr. 453 (1985).

274. King v. Collagen Corp., 983 F.2d 1130 (5th

Cir. 1993), cert. denied, 114 S.Ct. 84 (1993).

275. Larsen v. Pacesetter Systems, Inc., 837 P.2d

1273 (Haw. 1992).

276. Mazur v. Merck & Co., Inc., 742 F. Supp. 239

(E.D. Pa. 1990) (Mazur I), 767 F. Supp. 697,

aff’d, 964 F.2d 1348 (3d Cir. 1992) (Mazur

II).

277. McKee v. Moore, 648 P.2d 21 (Okla. 1982).

278. Mitchell v. Iolab Corp., 700 F. Supp. 877

(E.D. La. 1988).

279. Moore v. Kimberly-Clark, 867 F.2d 243 (5th

Cir. 1989).

280. Morris v. Parke-Davis & Co., 667 F.Supp.

1332 (C.D. Cal. 1987).

281. Natanson v. Kline, 186 Kan. 393, opinion on

denial of motion for rehearing, 187 Kan. 186

(1960).

282. Oresman v. Searle & Co., 321 F. Supp. 449

(R.I. 1971).

283. Pacific Mutual Life Insurance Company v.

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284. Parke-Davis & Co. v. Stromsodt, 411 F.2d

1390 (8th Cir. 1969).

285. Pease v. American Cyanamid Co., 795 F.

Supp. 755 (D. Md. 1992).

286. Petty v. United States, 740 F.2d 1428 (8th

Cir. 1984).

287. Piper Aircraft Co., v. Reyno, 454 U.S. 235

(1981), rev’g 630 F.2d 149 (3rd Cir. 1980)

rev’g 479 F. Supp. 727 (M.D. Pa. 1979).

288. Plummer v. Lederle Laboratories, 819 F.2d

349 (2d Cir.) cert. denied, 484 U.S. 898

(1987).

289. Pollard v. Ashby, 793 S.W.2d 394 (Mo. Ct.

App. 1990).

290. Reyes v. Wyeth Laboratories, 498 F.2d 1264

(5th Cir.), cert. denied, 419 U.S. 1096 (1974).

291. Roberts v. Patel, 620 F. Supp. 323 (N.D. Ill.

1985).

292. Rohrburgh v. Wyeth Laboratories, Inc., 719

F. Supp. 470 (N.D.W. Va. 1989), aff’d, 916

F.2d 970 (4th Cir. 1990).

293. Salgo v. Leland Stanford Jr. University, 317

P.2d 170 (Cal. Ct. App. 1957).

294. Samuels v. American Cyanamid Co., 130

Misc.2d 175, 495 N.Y.S.2d 1006 (1985).

295. Sandel v. State, 126 S.C.1, 119 S.E. 776, appeal dismissed, 269 U.S. 532 (1922).

296. Savina v. Sterling Drug, Inc., 247 Kan. 105,

795 P.2d 915 (1990).

297. Schackil v. Lederle Laboratories, 116 N.J.

155, 561, A.2d 511 (1989).

298. Schafer v. American Cyanimid Co., 1994

U.S. App. LEXIS 5477 (1st Cir. 1994).

299. Schindler v. Lederle Laboratories, 725 F.2d

1036 (6th Cir. 1984).

300. Senn v. Merrill-Dow Pharmaceuticals, Inc.

850 F.2d 611 (9th Cir. 1988).

301. Shanks v. Upjohn Co., 835 P.2d 1189 (Alaska

1992).

302. Sheffield v. Eli Lilly & Co., No. A013100,

Cal. Ct. App. 1st Dist. 1983 .

303. Singer v. Sterling Drug, Inc., 461 F.2d 288

(7th Cir. 1972).

304. Slater v. Optical Radiation Corp., 961 F.2d

1330 (7th Cir.), cert. denied, 113 S.Ct. 327

(1992).

305. Spencer v. United States, 569 F. Supp. 325

(W.D. Mo. 1983).

306. Stamps v. Collagen Corp., 1993 U.S.App.

LEXIS 2745 (1st Cir. 1993), cert. denied,

114 S.Ct. 86 (1993).

307. Stanback v. Parke, Davis & Co., 657 F.2d

642 (4th Cir. 1981).

308. Sulesky v. United States, 545 F. Supp. 426

(S.D. W. Va. 1982).

309. Taggart v. Richards Medical Company, Inc.,

677 F. Supp. 1102 (Col. 1988).

310. Thomas v. Hoffman La-Roche, Inc., 949 F.2d

806 (5th Cir. 1992).

311. Tinnerholm v. Parke-Davis & Co., 411 F.2d

48 (2d Cir. 1969).

312. Toner v. Lederle Laboratories, 112 Idaho

328, 732 P.2d 297 (1987).

313. Tracey v. Merrell Dow Pharmaceuticals,

Inc. 569 N.E.2d 875 (Ohio 1991).
Chapter 4 Liability and Compensation for Adverse Reactions to HIV Vaccines | 159

314. Tremaine v. H.K. Mulford Co., 317 Pa. 97,

176 A.2d 212 (1935).

315. Unthank v. United States, 732 F.2d 1517

(10th Cir. 1984).

316. Vincent v. Thompson, 79 Misc.2d 1029, 361

N.Y.S.2d 282 (1974), rev’d in part, 50 App.

Div. 211, 377 N.Y.S.2d 118 (1975).

317. Walker v. Merck & Co., 648 F. Supp. 931

(M.D.Ga. 1986), aff’d without opinion, 831

F.2d 1069 (11th Cir. 1987).

318. West v. G.D. Searle & Co., 305 Ark. 33, 806

S.W.2d 608 (1991).

319. White v. Wyeth Laboratories, 40 Ohio St. 3d

390, 533 N.E.2d 748 (1988).

320. Whitlock v. Duke University, 637 F. Supp.

1463 (M.D.N.C. 1986), aff’d, 829 F.2d 1340

(4th Cir. 1987).

321. Williams v. Lederle, 591 F. Supp. 381 (S.D.

Ohio 1984).

322. Wyeth Labs, Inc. v. Fortenberry, 530 So.2d

688 (Miss. 1988).
Appendix A

A Technical Review of the

Evidence for Adverse Reactions

to HIV Vaccines

his appendix reviews the various theoretical risks that have

been proposed by various investigators to be potentially

associated with HIV vaccines for prophylactic and/or therapeutic use. The theoretical basis for these risks, as well as

their proposed mechanisms and experimental support are also examined. As is explained below, some of the risks reviewed here

are unlikely or are entirely theoretical (i.e., are currently without

experimental support). Suggestions for research initiatives to uncover clues to potential adverse reactions from HIV vaccines are

provided.

A key point to remember throughout this analysis is the high

rate of genetic mutation of HIV (2, 5, 7, 25, 32, 58); these mutations may allow the virus to become resistant to antiviral drugs

and to escape immune surveillance. On average, the virus makes

one genetic “mistake” every time it replicates. This is because the

unique enzyme that allows the virus to turn RNA genetic information into DNA genetic informationa process called reverse transcriptionis a low fidelity enzyme that makes many errors. Such errors are called mutations, and may be lethal (i.e., incompatible

with viral replication) or may be tolerated.

Unfortunately, HIV appears to tolerate an extraordinary number of mutations throughout the length of its genome. Under certain conditions these mutations even confer a selective advantage

to the virus. This is the basis for the high rate of evolution of new

viral mutants (or quasispecies). For example, if the mutation interferes with the ability to bind active metabolites of the antiviral

drug AZT (zidovudine), the resulting mutant virus may be resistant to AZT. If the infected patient (the host) is treated with AZT,

the mutant virus will have a selective advantage and over a period | 161

by

David Schwartz

Johns Hopkins University

School of Hygiene and

 Public Health,

Baltimore, MD
162 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

of months to years become the predominant type

of virus in the patient (the dominant quasispecies)

(12, 56).

Similarly, if a mutation occurs at a site previously recognized by the patient’s neutralizing

antibodies, the virus carrying this mutation (the

escape mutant) may evade immune detection and

emerge as the dominant quasispeciesat least until

a new set of antibodies are formed that can recognize and block the mutant virus (20, 46). Thus,

HIV is continually evolving under the selective

pressure from the host’s immune response and

from antiviral drugs. This evolution occurs not

only at the level of the overall population of infected people, but also within a single infected individual over the course of disease.

Enhancing Antibodies

The possibility that HIV vaccination could induce

antibodies that facilitate viral entry into immune

phagocytic cells has been studied in the laboratory

using a variety of cell types143. Results have been

inconsistent among studies, and the evidence for

this phenomenon has recently been comprehensively reviewed by a study group sponsored by the

National Institutes of Health (NIH) (39). Some

have suggested that anti-HIV antibodies that are

protective or inactive at one concentration may be

enhancing at a lower concentration (50). To date,

there has been little laboratory evidence of antibody dependent enhancement in the sera of HIV

vaccine recipients, but this may be due to the limited number of laboratories that are examining this

potential problem. More importantly, the activity

of HIV in humans may not be adequately approximated by laboratory studies. Investigators have

presented evidence that macaques that were vaccinated with SIV protein subunit vaccine (17) or

transfused with anti-SIV antibodies (26) showed

enhanced rates of infection and disease progression when subsequently exposed at mucosal

membranes to SIV.

Original Antigenic Sin

HIV infection induces an abundance of antibodies, including neutralizing antibodies; however

several groups have shown that the generation of

neutralizing antibodies tends to lag behind the

generation of viral escape mutants by several

months or even years. One explanation for this observation involves the phenomenon of original

antigenic sin (OAS), the fixing of an immune response in a nonadaptive pattern.

OAS was first observed in immune responses

to sequential influenza A virus infections. Investigators observed that, in some instances, exposure

of an individual to one strain of influenza A virus

triggered the production of antibodies that were

predominantly directed at another strain of influenza A virus that had infected the individual in

the past. The antibodies that were produced had

weak affinity for the newly encountered strain of

influenza A virus. OAS is a particularly important

problem with organisms that mutate frequently.

OAS has also been observed in some bacterial infections as well, but its mechanism has never been

fully elucidated.

Some investigators have argued that, during the

course of HIV infection, an OAS pattern occurs

with respect to antibodies recognizing the V3 loop

and other variable regions of HIV envelope proteins (31, 44).

In infected individuals, there may emerge a predominance of neutralizing antibodies directed

against HIV species present at some earlier time

of infection, but not to the contemporaneous HIV

species.144 While this may simply reflect a delay

in the development of measurable titers of anti143 This antibody dependent enhancement may occur in the presence (50) or absence (15) of complement.

144 The mechanism by which OAS occurs has been investigated. The current hypothesis is that previously stimulated B lymphocyte clones

bearing surface receptors with high affinity for previously circulating strains of virus may be sufficiently cross-reactive (due to membrane surface-arrayed multivalent binding) to be triggered by new viral strains; but the B lymphocytes secrete antibody that, in soluble monomeric form,

have only low affinity for the new strains.
Appendix A A Technical Review of the Evidence for Adverse Reactions to HIV Vaccines | 163

body directed against the more recent circulating

strain of HIV, this delay may have potentially significant immunologic consequences, and its

mechanism remains unclear. There is also some

recent laboratory evidence that an OAS pattern

can be observed in B and T lymphocytes from

uninfected volunteers following vaccination with

recombinant HIV protein subunit vaccines (54).

Related to the observation of a lagging antibody response to HIV escape mutants is that of a

limited and relatively fixed diversity of antigenic

specificity seen among antibodies created in response to HIV antigens (14, 31, 43, 44, 45, 61).

Whether this is a cause or effect of the delayed antibody response to emergence of new strains of virus is unclear. In either case, this low diversity antibody response to HIV is probably detrimental to

the host’s ability to suppress infection.

It should be emphasized, however, that the evidence supporting the view that there is a limited

diversity in antibody response to HIV rests largely

on the finding that certain antibody variable region genes, the genes that code for an antibody’s

antigenic specificity, are used disproportionately

for the immune response to the dominant antigenic regions of the virus. This still allows for greater

diversity to be generated during the course of the

immune response by a process called somatic

mutation, as demonstrated by Andris and colleagues (1). Thus, studies showing that only a restricted number of variable region genes are used

for the production of anti-HIV antibodies probably underestimate the true diversity of the antibody response.

Vaccine-induced OAS may occur when a vaccinated individual is exposed to a noncross reactive

strain of HIV that induces the production of antibodies specific for the vaccine strain that are unable to neutralize the newly encountered strain.

When exposed to HIV, however, vaccinated individuals exhibiting OAS may be no worse off than

unvaccinated individuals because unvaccinated

individuals also have a lag in generation of antibody to HIV because their immune response has

not been “primed” by vaccination. It is not known

whether the lag in antibody production in unvaccinated individuals is greater than the lag in the production of antibody directed to contemporaneous

HIV strains in vaccinated individuals exhibiting

OAS.

Expansion of V3H family or other families of

B lymphocytes

Investigators have found that certain genes for a

particular family of antigen receptors on B lymphocytes (the V3H family) are expressed much

more frequently among HIV-infected individuals

than uninfected individuals. Because more than

half of all HIV-infected individuals express these

antibodies, which bind to viral proteins, we know

that the virus induces their expression (43, 61).

Muller and colleagues have shown that such antibodies were even further elevated in 40 of the 44

HIV-infected patients with B cell lymphomas

(24). Because these antibodies are not necessarily

protective and seem to be associated with lymphomas, their presence may not be desirable.

Recently Schwartz and colleagues examined

the sera of vaccinees receiving various HIV envelope-based vaccines for the presence of these antibodies. They found that many vaccinees made

them at some point after immunization, generally

at times of peak total antibody response (unpublished data). Thus, envelope based-vaccines are,

at least transiently, inducing antibodies that mimic this aspect of the host response to HIV infection.

Recently, a group of investigators presented evidence that HIV-envelope (gp120) protein can

function as a superantigen for B lymphocytes carrying another family of antigen receptors (4). By

binding to a common portion of the surface immunoglobulin receptors of B lymphocytes, gp120 -

envelope protein initially induces stimulation and

then exhaustive depletion of those B lymphocytes

carrying surface receptors from that family of

genes. Other investigators (34) believe such B

lymphocytes can support infectious replication of

HIV and also may contribute to B cell lymphomas

in HIV-infected patients. Hence, a concern that
164 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

most HIV envelope vaccines in development

could expand this pool of B lymphocytes and induce B cell lymphomas exists.

Expansion of “Double Jeopardized” CD4+

(T Helper) Cells, Leading to Increased HIV

Replication

There may be subsets of CD4+ T lymphocytes

that are particularly susceptible to HIV infection

early in disease. All CD4+ T lymphocytes can be

infected by HIV by virtue of their surface membrane CD4 molecules, which serves as the site of

attachment of the virus. However, it has long been

appreciated that immune-activated CD4+ lymphocytes are better hosts for HIV entry, integration, and replication than are resting CD4+ cells.

Further, cells cannot become infected unless they

are brought into proximity either with infected

cells or virus. At the earliest stages of HIV infection, the number of infected cells limits the cellto-cell spread of the virus, and therefore there is a

low likelihood that a random CD4+ lymphocyte

will come into contact with an infected cell. By

contrast, CD4+ lymphocytes with specificity for

HIV are constantly “searching” for HIV infected

cells to bind to, and thus are at increased risk of

coming into close proximity to virus and becoming infected. If HIV undergoes a burst of replication in such cells, this would contribute to early

dissemination of virus and poorer long-term prognosis.

Circumstantial evidence supporting the early

destruction of HIV-specific CD4+ lymphocytes

comes from the results of in vitro lymphoproliferation assays, which measure the magnitude of

the proliferative response of lymphocytes to a series of recall antigens to which the lymphocytes

have previously been exposed. These experiments

have shown that HIV envelope protein was unable

to induce the proliferation of CD4+ lymphocytes

obtained from asymptomatic HIV-infected individuals, even though the responses of these CD4+

lymphocytes to other recall antigens were intact.

Experimental evidence also exist for the special

ability of antigen-presenting immune cells pulsed

with HIV to activate and destroy CD4+ lymphocytes with which they come in contact (8, 38). At

the same time, these activated cells can become

infected with HIV and support a burst of HIV replication prior to destruction of the infected cells.

This might be expected to happen with vaccineinduced CD4+ lymphocytes, which would seek

out and proliferate in response to HIV at the earliest stages of infection. A mathematical model this

scenario has recently been published (55).

Priming for T Helper 2 (TH2) and T Helper 1

(TH1) Patterns of Cytokine Response

Cytokines are cell-to-cell communication and

growth molecules, which can be thought of as

short-range hormones. The distinct and to some

degree antagonistic cytokine profiles of TH1 and

TH2 responses have received increasing attention

from HIV researchers. TH1 responses are characterized by the production of the cytokines interleukin-2 (IL-2), IL-12, and Interferon gamma.

These cytokines are important in the induction of

cytotoxic T lymphocytes. TH2 responses produce

IL-4, IL-5, and IL-10—cytokines crucial for the

induction and amplification of various antibody

responses. Furthermore, the cytokine IL-12, produced by the TH1 response, suppresses TH2 cytokine production, while IL-10, produced by the

TH2 response, suppresses TH1 cytokine production. This negative feedback inhibition between

TH2 and TH1 responses can accentuate the differences between them.

Although TH1 and TH2 responses were first

described in mice, similar though less clearly distinct cytokine profiles have been demonstrated in

human cells in vitro, with mitogens (cytokines

that induce cell division) and recall antigens inducing predominantly TH1 responses in PBMCs

of normal donors and a TH2 profile in PBMCs of

HIV-infected individuals (10, 11, 41).

To the extent that TH2 responses in HIV-infected individuals are not protective and are antagonistic to desirable TH1 responses, some researchers have argued that priming for TH2

responses is an inappropriate, counterproductive

goal for vaccination, and a likely consequence of

recombinant protein subunit vaccines (51).
Appendix A A Technical Review of the Evidence for Adverse Reactions to HIV Vaccines | 165

Schwartz and colleagues at Johns Hopkins University are currently testing the cytokine profiles

of vaccinees’ PBMCs restimulated in vitro with

HIV or HIV antigen. Unpublished preliminary results suggest that the TH1 response remains dominant, thus assuaging some of the concerns that

vaccines may prime for TH2 responses.

Induction of Autoimmunity

Any pathogen that binds to or mimics the structure

of self-antigens is capable of inducing antibodies

directed against the self (autoantibodies). HIV

both binds to CD4 receptors of T lymphocytes via

it’s gp120 -envelope protein and bears sequence

homology with several human antigens. There

have been several autoantibodies among HIV-infected and envelope vaccinated individuals found,

albeit of questionable significance (13, 18, 19, 33,

47, 52). Most intriguing has been the transient,

episodic appearance of anti-CD4 antibodies in

HIV-infected individuals and in uninfected recipients of rgp160- or rgp120-envelope vaccines (28,

29, 30). Originally a concern because of the potentially immune suppressive effects of such antibodies on CD4+ lymphocytes, the transient appearance of anti-CD4 antibodies has not had

detectable effects on healthy vaccinees as judged

by their CD4+ lymphocyte counts and the results

of in vitro lymphoproliferation assays against recall antigens. Furthermore, Neurath and colleagues have recently demonstrated that hyperimmune rabbit anti-gp120/gp160 antisera had

negligible binding activity against a variety of

CD4, HLA-I and HLA-II cell surface antigens

(30). These authors concluded that detrimental effects from envelope vaccines are improbable.

Interestingly, Letvin and colleagues have

shown that the purposeful induction of anti-CD4

antibodies in chimpanzees (63) or administration

of anti-CD4 monoclonal antibodies in macaques

(48) can protect their cells in vitro from infection

with HIV or SIV upon subsequent challenge. Furthermore, immunization of SIV-infected macaques with soluble recombinant RCD4 receptors

resulted in both an anti-CD4 and an antiviral response (63). The significance of the low and intermittent anti-CD4 antibody titers seen in the sera

of HIV-infected patients is unknown. The possibility of autoimmunity is frequently invoked in

discussions of HIV immunosuppression and the

destruction of uninfected CD4+ lymphocytes, but

there is presently no evidence that anti-CD4 antibodies play a role.

Induction of Endogenous Retroviruses or

Oncogenes by HIV Genes or Proteins

In mice, various mammary tumor viruses encode

superantigens that can activate dysfunctional

lymphocyte proliferation (see discussions of clonal expansion above). Gallo and colleagues were

able to induce Kaposi sarcoma-like lesions in

male mice transgenically engineered to express

only the HIV tat gene (16). Recently, Sekaly and

colleagues have shown that transfection of only

the HIV gag gene into mice carrying latent mouse

mammary tumor virus (MMTV) can cause the induction of active expression of the MMTV viruses, with detrimental MMTV-induced immune

consequences. Humans may also carry latent endogenous retroviruses or retrovirus related cellular oncogenes with pathogenic potential. It is possible that introduction of even partial HIV

genomes in live vectors carrying, for example, the

gag and tat genes, could activate harmful endogenous retroviral genes.

There is a high frequency of tumors in HIV-infected individuals, and in most cases these cells do

not harbor HIV. Therefore, secondary effects of

HIV infection must be invoked, and these effects

may not be dependent on the presence of the complete viral genome. Recently, McGrath and colleagues have identified the HIV genome at

constant chromosomal location in the genome of

non-B cell lymphoma cells obtained from several

unrelated patients with this cancer (57). This further supports the notion that HIV genes may have

oncogenic potential.

Induction of Short-Term Immunosuppression

Luban and colleagues have shown that HIV gag

proteins bind to cyclophilins (37). These cyclophilins are also targeted by the potent immuno-
166 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

suppressive drugs cyclosporin A and FK506.

Thus, production of significant amounts of gag

gene product for any extended length of time,

which may occur as a result of vaccination with a

live vector coding for HIV gag gene, might induce

immune suppression by the same mechanism as

cyclosporin A. Presumably, the vaccine-induced

immune response would then eliminate this

source of gag.

Cross-linking of CD4 by HIV envelope gp120

or gp160 proteins sends an incomplete signal

leading to immune exhaustion (anergy) or subsequent programmed cell suicide (apoptosis) (3, 35,

41, 62). This is thought by some to be a major

mechanism of immunosuppression in HIV disease. It is unlikely that the amounts of gp120 used

or produced by HIV vaccines would be sufficient

to induce any serious immunosuppression, but

subtle short-term effects might be induced, especially if anti-gp120 antibodies have also been induced by vaccination (36). Similarly, while apparently not a long-term problem, it is possible that

the vaccine-induced production of anti-CD4 antibodies, as described above, could also cause transient immunosuppression.

Short-term immunosuppression following

vaccination may occur due to temporary dysregulation of cytokine responses. This is observed

after measles vaccination (21) and mimics the

more severe immunosuppression accompanying

measles infection (22).

The detrimental consequences of transient

acute post-vaccination immunosuppression may

be much greater in developing countries and other

settings where there are high pathogenic burdens

(due to other viruses, bacteria, and parasites)

found in many third world countries. Subtle immunosuppression of selected T lymphocyte

clones—even some HIV specific clones—may

not be detected on current routine tests of immune

function. Limited data on the course of HIV infection is acquired from several volunteers who became infected during or following immunization

with experimental vaccines. It is too soon to know

if disease progression will be accelerated in these

individuals.

Recombination in HIV Infected Vaccinees: Retroviruses are capable of genetically recombining

with themselves, other viruses, and with host-cell

genes (27, 59). This raises the possibility that even

multiply deleted, replication incompetent, live

vector or naked DNA vaccines might conceivably

recombine in the vaccinated host with preexisting

or newly acquired HIV or other viruses. There is

also the possibility of integration of the HIV genome at a site that has oncogenic (cancer inducing) potential, as is noted above. This is likely to

be a rare event, and not readily predicted by preclinical studies.

Activation of HIV from Latently Infected Cells

It has been a goal of HIV vaccine developers to

generate protective cytotoxic T lymphocyte responses to HIV. Many other viral infections are

thought to be controlled by the constant surveillance and appropriate activation of cytotoxic T

lymphocytes recognizing viral antigens in the

context of histocompatibility antigens on the surface of infected cells. Recently, however, some

studies have raised the possibility that, at least under some conditions, activated cytotoxic T lymphocytes may release cytokines such as TNF-alpha and GM-CSF that can stimulate HIV

production in infected cells (6, 23). This concern

has caused at least one biotechnology company to

discontinue a program of ex vivo expanded autologous anti-HIV cytotoxic T lymphocyte reinfusion, following what they perceived to be a downhill course during treatment of their first patient.

However, similar Phase I clinical trials under the

direction of Dr. Judy Lieberman at Boston University/New England Medical Center appear to be

moving forward with encouraging results.

Possible Adverse Immunological

Consequences At The Population Level

There is a possibility that widespread immunization with vaccines could select for more virulent

strains of HIV at the population level. Some of the

same mutations that permit HIV to avoid neutralization by the immune system may also select for
Appendix A A Technical Review of the Evidence for Adverse Reactions to HIV Vaccines | 167

greater virulence. There is some evidence for this

occurring naturally during the course of HIV infection in individuals, in that HIV recovered from

patients in later stages of infection is generally

more rapidly growing, has a more pathogenic effect, and attacks a wider variety of cells, than HIV

isolated from patients in early stages of infection

(9, 53, 60). Empirical evidence exists, as well as

theoretical reason, to consider these late stage viruses as mutants that escaped host immune defenses. If the effect of vaccination programs were

to select for the these late stage viruses early in disease, they might become the dominant circulating

strains in the population, leading to more acute

disease progression among infected individuals.

It is also theoretically possible that large scale vaccination could select for the most infectious

strains of HIV145.

Current studies of early seroconverting cohorts

suggest that macrophage tropic, non-syncytium

inducing (NSI) HIV strains are the most readily

transmitted (40, 65, 64). These also tend to be the

strains associated with better health and longer

term survival. By contrast, syncytium-inducing

(SI) strain emergence is correlated with a downhill

course in the host (49). Because of the apparent

role of NSI strains in HIV transmission, there has

been discussion of focusing vaccine efforts

against such strains. If this selective pressure favors transmissible SI strains, it might result in increased prevalence of those more pathogenic

strains.

No firm evidence has developed that HIV has

evolved toward greater pathogenicity at the population level since the onset of the global pandemic.

One reason for this may be the relatively early

stage of worldwide host-virus equilibrium in a

plague that is still spreading exponentially

through many populations. Also because of the

high rate of mutation intrinsic to HIV, only the

most strongly and consistently selected mutations

will remain constant, with reversions occurring as

soon as specific selective pressures are removed.

Some evidence for population-based selective

pressure has come from the reported recovery of

AZT-resistant strains in recently infected individuals who had never received AZT, but lived in

areas where the use of AZT in infected individuals

was high.

Vaccination for particular HIV strains or epitopes would create the conditions for constant and

widespread selective pressures that may affect the

genotype and phenotype of HIV in the population.

If enough members of a population were vaccinated, selection pressures would favor the predominance of escape mutants in the population,

resistant to vaccine-induced immune responses.

Because of the long-lived nature of successful immunizations, and the fact that a large percentage

of uninfected high-risk individuals may have been

vaccinated within a given community, the longterm selective effects of vaccination on the circulating strains of HIV may be more difficult to reverse than those of an antiviral drug such as AZT,

which can be stopped completely, allowing for

rapid reversion to drug sensitivity in the circulating strains of virus.

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54. Schwartz, D., et al., “Antibody Responses to

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67:171-177, 1993.

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Appendix B

Acknowledgments

Arthur J. Ammann

Pediatric AIDS Foundation

Novato, CA

Larry Arthur

Program Resources Incorporated

Frederick, MD

Alberto Avendano

National Association of People

with AIDS

Washington, DC

Nancy K. Bannon

American Medical Association

Chicago, IL

Lewellys F. Barker

Division of AIDS

National Institute of Allergy and

Infectious Diseases

National Institutes of Health

Bethesda, MD

Ronald Bayer

School of Public Health

Columbia University

New York, NY

David Beier

Genentech, Inc.

Washington, DC

Robert Belshi

Infectious Diseases Division

St. Louis University Health

Sciences Center

St. Louis, MO

David Benor

Office of the General Counsel

U.S. Department of Health and

Human Services

Rockville, MD

Raoul E. Benveniste

Division of Cancer Etiology

National Cancer Institute

National Institutes of Health

Bethesda, MD

Robert C. Bollinger

Division of Infectious Diseases

School of Medicine

Johns Hopkins University

Baltimore, MD

Dani P. Bolognesi

Department of Surgery

Duke University Medical Center

Durham, NC

Randall Bovbjerg

The Urban Institute

Washington, DC

Kenneth Bridbord

International Studies Branch

Fogarty International Center

National Institutes of Health

Bethesda, MD

Baruch Brody

Center for Ethics

Baylor College of Medicine

Houston, TX

Colonel Donald S. Burke

Division of Retrovirology

Walter Reed Army Institute of

Research

Rockville, MD

| 173
174 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Margaret A. Chesney

Prevention Sciences Group

University of California at

San Francisco

San Francisco, CA

Thomas Christoffel

School of Public Health

University of Illinois at Chicago

Chicago, IL

Mary Lou Clements

School of Hygiene and Public

Health

Johns Hopkins University

Baltimore, MD

John Coffin

Department of Molecular

Biology and Microbiology

School of Medicine

Tufts University

Boston, MA

James D. Cross

The Travelers Insurance

Company

Hartford, CT

John G. Curd

Genentech, Inc.

South San Francisco, CA

James Curran

Division of HIV/AIDS

National Center for Infectious

Diseases

Centers for Disease Control and

Prevention

Atlanta, GA

Suzanne Dandoy

Virginia Department of Health

Richmond, VA

Paul De Stefano

Pennie & Edmunds

Menlo Park, CA

Abby P. Dilley

The Keystone Center

Washington, DC

Linda Distlerath

Merck & Company, Inc.

Whitehouse Station, NJ

Lynda Doll

Division of HIV/AIDS

National Center for Infectious

Diseases

Centers for Disease Control and

Prevention

Atlanta, GA

Gordon Douglas

Merck Vaccine Division

Merck & Company, Inc.

Whitehouse Station, NJ

Gary B. Ebbert

Connaught Laboratories Inc.

Swiftwater, PA

Emilio Emini

Research Laboratories

Merck & Company, Inc.

West Point, PA

Patricia Fast

Division of AIDS

National Institute of Allergy and

Infectious Diseases

National Institutes of Health

Bethesda, MD

Genoveffa Franchini

Division of Cancer Etiology

National Cancer Institute

National Institutes of Health

Bethesda, MD

Donna Freeman

Division of Antiviral Drugs

Center for Drug Evaluation and

Research

Food and Drug Administration

Rockville, MD

L. Patrick Gage

Genetics Institute, Inc.

Cambridge, MA

Murray B. Gardner

Department of Pathology

School of Medicine

University of California at Davis

Davis, CA

Helene Gayle

Office of the Director

Centers for Disease Control and

Prevention

Washington, DC

Karen L. Goldenthal

Office of Vaccine Research and

Review

Division of Vaccines and Related

Products Application

Food and Drug Administration

Rockville, MD

Allan L. Goldstein

Department of Biochemistry and

Molecular Biology

George Washington University

Medical Center

Washington, DC

Barney S. Graham

Department of Infectious

Diseases

School of Medicine

Vanderbilt University

Nashville, TN
Appendix B Acknowledgments | 175

Olga A. Grinstead

Preventive Sciences Group

University of California at

San Francisco

San Francisco, CA

Ronald W. Hansen

School of Business

Administration

University of Rochester

Rochester, NY

Deborah Harnesberger

Wunder, Diefenderfer

Washington, DC

Leslie Hardy

Institute of Medicine

Washington, DC

John Hoff

Swidler and Berlin

Washington, DC

Harold Jaffe

National Center for Infectious

Diseases

Centers for Disease Control and

Prevention

Atlanta, GA

Michael Jacobs

School of Law

DePaul University

Chicago, IL

Edward Kantongole-Mbidde

Uganda Cancer Institute

Kampala, Uganda

Ted Kirsch

Wyeth-Ayerst Laboratories

Radnor, PA

Wayne C. Koff

United Biomedical, Inc.

Hauppauge, NY

Peter Lamptey

The AIDS Project

Family Health International

Arlington, VA

Jeffrey Laurence

Department of Medicine

The New York Hospital-Cornell

Medical Center

New York, NY

Carol Levine

The Orphan Project

New York, NY

Robert J. Levine

Department of Internal Medicine

School of Medicine

Yale University

New Haven, CT

Peter Lurie

Institute for Health Policy

Studies

Center for AIDS Prevention

Studies

University of California at San

Francisco

San Francisco, CA

Mary Lyons

MicroGeneSys, Inc.

Meriden, CT

William Lyons

Ciba-Geigy Corporation

Washington, DC

Jonathan Mann

Center for Health and Human

Rights

Harvard University

Cambridge, MA

Bonnie J. Mathieson

Division of AIDS

National Institute of Allergy and

Infectious Diseases

National Institutes of Health

Bethesda, MD

Captain Douglas L. Mayers

Division of Retrovirology

Walter Reed Army Institute of

Research

Rockville, MD

Janet W. McGrath

Department of Anthropology

Case Western Reserve University

Cleveland, OH

Richard P. McGuire

Merck & Company Inc.

Whitehouse Station, NJ

Lieutenant Colonel John McNeil

HIV Prevention Program

Walter Reed Army Institute of

Research

Rockville, MD

Donald N. Medearis

Children’s Service

Massachusetts General Hospital

Cambridge, MA

Peter Nara

National Cancer Institute

National Institutes of Health

Frederick, MD

Phillip Nieburg

Division of HIV/AIDS

National Center for Infectious

Diseases

Centers for Disease Control and

Prevention

Atlanta, GA
176 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Jeffrey O’Connell

School of Law

University of Virginia

Charlottesville, VA

June E. Osborn

School of Public Health

University of Michigan

Ann Arbor, MI

Jean W. Pape

Cornell University Medical

College,

New York, NY

and Medical School of Haiti

Port Au Prince, Haiti

Paul Parkman

Parkman Associates

Kensington, MD

William Paul

Office of AIDS Research

National Institutes of Health

Bethesda, MD

Sallie Perryman

AIDS Institute

New York State Department of

Health

New York, NY

John C. Petricciani

Genetics Institute

Cambridge, MA

Jane Pitt

Department of Pediatrics

College of Physicians and

Surgeons

Columbia University

New York, NY

Philip A. Pizzo

National Cancer Institute

National Institutes of Health

Bethesda, MD

Stanley A. Plotkin

Pasteur-Merieux Serums and

Vaccines

Marnes-La Coquette, France

Joan Porter

Office for Protection from

Research Risks

National Institutes of Health

Bethesda, MD

Moses Pounds

Office of Science and

Epidemiology

Bureau of Health Resources

Development

Health Resources and Services

Administration

Rockville, MD

Albert T. Profy

Procept, Inc.

Cambridge, MA

William Randolph

Bethesda, MD

Richard Reisberg

Office of General Counsel

Public Health Division

Department of Health and

Human Services

Rockville, MD

Jerry M. Rice

Division of Cancer Etiology

National Cancer Institute

National Institutes of Health

Bethesda, MD

H. Alexander Robinson

American Civil Liberties Union

Washington, DC

Helen Rodriguez-Trias

Brookdale, CA

Martin Rose

Alpha 1 Biomedicals, Inc.

Bethesda, MD

Philip Russell

School of Hygiene and Public

Health

Johns Hopkins University

Baltimore, MD

Gerald Schochetman

Division of HIV/AIDS

National Center for Infectious

Diseases

Centers for Disease Control and

Prevention

Atlanta, GA

Teresa Schwartz

School of Law

George Washington University

Washington, DC

Belinda Seto

Office of Extramural Research

National Institutes of Health

Bethesda, MD

Amy R. Sheon

Division of AIDS

National Institute of Allergy and

Infectious Diseases

National Institutes of Health

Bethesda, MD

Merrill Singer

Hispanic Health Council

Hartford, CT
Appendix B Acknowledgments | 177

Jane E. Sisk

School of Public Health

Columbia University

New York, NY

Herbert B. Slade

Rhone-Poulenc Rorer Central

Research

Children’s Hospital of

Philadelphia

Collegeville, PA

William Snow

ACT UP Golden Gate

San Francisco, CA

Joy Stevens

Office of Legislative Affairs

Food and Drug Administration

Rockville, MD

Jeff Stryker

Center for AIDS Prevention

Studies

University of California at San

Francisco

San Francisco, CA

Jeremy Sugarman

Division of General Internal

Medicine

Duke University Medical Center

Durham, NC

Martin Teicher

Ciba-Geigy Corporation

Ardsley, NY

Eugene A. Timm

Rochester Hills, MI

Ramon A. Torres

St. Vincent Hospital and Medical

Center

New York, NY

Beth L. P. Ungar

Vaccine Trials and Epidemiology

Branch

National Institute of Allergy and

Infectious Diseases

National Institutes of Health

Bethesda, MD

Robert Vasquz-Pacheco

The National Latino/a Lesbian &

Gay Organization

Washington, DC

David Vlahov

School of Hygiene and Public

Health

Johns Hopkins University

Baltimore, MD

Paul A. Volberding

AIDS Program and Department

of Clinical Oncology

San Francisco General Hospital

San Francisco, CA

Franklin Volvovitz

MicroGeneSys, Inc.

Meriden, CT

Catherine M. Wilfert

Department of Pediatrics

Duke University Medical Center

Durham, NC

Ann Wion

Office of the General Counsel

U.S. Department of Health and

Human Services

Rockville, MD

Kathryn Zoon

Center for Biologics, Evaluation,

and Research

Food and Drug Administration

Bethesda, MD
References

and

Glossary

ABBREVIATIONS

ADR alternative dispute resolution

AIDS acquired immunodeficiency syndrome

ALI American Law Institute

ARAC AIDS Research Advisory Committee

(NIAID)

AVCTN AIDS Vaccine Clinical Trials Network

AVEU AIDS Vaccine Evaluation Unit (NIH)

AVEG AIDS Vaccine Evaulation Group

(NIH)

AZT Zidovudine

CDC Centers for Disease Control and

Prevention, (PHS)

CIOMS Council for International

Organizations of Medical Sciences

CTL cytotoxic T lymphocytes

DAIDS Division of AIDS (NIAID)

DES diethylstilbestrol

DHHS U.S. Department of Health and Human

Services

DNA deoxyribonucleic acid

DOD U.S. Department of Defense

DTP diphtheria, tetanus, and pertussis

ELISA enzyme-linked immunosorbent assay

EIA enzyme immunoassay

FDA Food and Drug Administration, U.S.

(PHS)

GPA Global Programme on AIDS (WHO)

HAV hepatitis A virus

HBV hepatitis B virus

Hib Haemophilus influenza type B

HIV human immunodeficiency virus

HIV-1 human immunodeficiency virus, type 1

HIV-2 human immunodeficiency virus, type 2

HIVIG human immunodeficiency virus

immune globulin

HIVNET HIV Trial Network (NIH)

IND investigational new drug

IOM Institute of Medicine

IPV injected polio vaccine

NCI National Cancer Institute (NIH)

NIAID National Institute of Allergy and

Infectious Diseases (NIH)

NIH National Institutes of Health, (PHS)

OIG Office of the Inspector General

(DHHS)

OPV oral polio vaccine

PAHO Pan American Health Organization

PCR polymerase chain reaction

PHS Public Health Service (DHHS)

R&D research and development

RNA ribonucleic acid

SIV simian immunodeficiency virus

UNICEF United Nations Children’s Emergency

Fund

WHO World Health Organization

| 179
180 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

GLOSSARY

Acquired immunodeficiency syndrome

see AIDS.

Adenovirus

Any of a group of DNA-containing viruses originally

identified in human adenoid tissue, causing respiratory diseases, and including some capable of inducing

malignant tumors in experimental animals. See also

virus; compare reovirus and retrovirus.

Adjuvant

A substance or treatment given in conjunction with

another treatment. In immunology, a substance, such

as alum, added to a vaccine which non-specifically enhances its antigenicity.

ADR

See alternative dispute resolution.

AIDS (acquired immunodeficiency syndrome)

A disease caused by infection with HIV (human immunodeficiency virus) and characterized by impaired

immune function. The primary defect in AIDS is an

acquired, persistent, quantitative functional depression within the T4 subset of lymphocytes. This depression often leads to infections caused by microorganisms that usually do not produce infections in

individuals with normal immunity. HIV infection can

be transmitted from one infected individual to another

by means that include the sharing of contaminated, intravenous needles and engaging in unprotected sexual

intercourse (i.e., intercourse without condoms), as

well as transmission from infected mother to newborn

(vertical transmission).

Alternative dispute resolution (ADR)

A process outside the judicial system for resolving legal claims. Decisions are made by dispute resolution

professionals. ADR can be binding or nonbinding. See

arbitration.

Amino acid

Any of a group of 20 molecules that join together in

various combinations to form proteins. A protein’s

shape, properties, and biological functions are determined in part by the specific sequence of its constituent amino acids.

Anaphylaxis

An uncommon potentially life-threatening allergic

reaction that occurs immediately (within minutes) following exposure to a previously encountered antigen,

such as from an insect bite or vaccine injection. It can

be manifested as either a localized response (an allergic attack) or as an extreme and generalized reaction

(anaphylactic shock) in which difficult breathing, pallor, hypotension, loss of consciousness, and possibly

heart failure may result if untreated. Anaphylaxis is

has not been observed with HIV vaccine candidates

studied.

Annuity

A set sum is paid at maturity.

Antibiotic

A chemical substance that is administered to inhibit

the growth of bacterial and fungal infections in humans or animals. Examples are penicillin, tetracycline, erythromycin, and cephalosporins.

Antibody

A blood protein (immunoglobulin) produced by B

lymphocytes, a type of white blood cell, in response to

the introduction of a specific antigen (e.g., vaccine antigen, invading bacteria, incompatible red blood cells,

inhaled pollen grains, or foreign tissue grafts). Once

produced, the antibody has the ability to combine, a

process called neutralization with the specific antigen

that stimulated antibody production, and thereby render the antigen harmless. This reaction to foreign substances is part of the immune response. The production of neutralizing antibody is one important

biological measure of vaccine protection.

Appeasement

Assuaging the victim’s desire for vengeance through

compensation.

Antigen

A substance that elicits an immune response. Vaccine

antigen is protein, derived from a microbe, which can

induce a protective immune response when administered to a recipient.

Arbitration

A form of alternative dispute resolution in which the

parties agree to have one or more trained arbitrators

hear the evidence of the case and make a determination on liability or damages. The rules of evidence and

other procedural matters may often be specified by the

parties. There are two types of arbitration: binding and

nonbinding. In binding arbitration the arbitration decision is subject to every limited judicial review. If arbitration is nonbinding, the parties may proceed to

trial if they are not satisfied with the outcome of the
Appendix C References and Glossary | 181

arbitration. Some states require paries to submit a

claim to nonbinding arbitration before trial.

Assumption of risk 

A person is aware of risks of harm inherent in a decision, and accepts responsibility for the consequences

of the decision.

Attenuated vaccine 

A vaccine derived from pathogenic organisms that has

been altered or weakened so that it is incapable of producing disease, but still capable of causing an inapparent infection and inducing immunity.

Attorney fee limits

Legislation that either limits a plaintiff’s attorney fees

to a set percentage of the award or allows for court review of the proposed fee and approval of what it considers to be a “reasonable fee.”

Autoantibody

An antibody that is formed by an individual against the

individual’s own tissues. See antibody.

Autoimmune

Referring to an abberent response of the immune system directed against an individual’s own tissues, an

abnormal reaction (the immune system is designed to

respond to foreign tissue) believed to contribute to a

number of chronic diseases (e.g., rheumatoid arthritis,

diabetes mellitus type I). Some traditional vaccines

may cause diseate by this mechanism

Autonomous choice 

Refers to an individual’s ability to independently

make choices in his or her own interests.

Avirulent

Lacking virulence (the ability to produce a significant

infection or disease); used to refer to mutant strains of

ordinarily pathogenic organisms.

Awarding costs, expenses, and fees 

Statutes that provide that the losing party in a frivolous

suit may be required to pay the other party’s reasonable attorney and expert witness fees and court costs.

These provisions are designed to deter the pursuit of

frivolous medical injury claims.

AZT 

See Zidovudine.

B lymphocytes (or B cells) 

An immune lymphocyte that can produce antibody in

response to an antigen. B indicates its bone marrow

origin. See lymphocyte.

Beneficence 

Mercy, kindness, or charity. In ethics, it is the principle

that one has a duty to confer benefits or to help others

to further their legitimate interests.

Beyond a reasonable doubt 

A standard of evidence typically used in criminal

cases, that means fully satisfied, entirely convinced,

satisfied to a moral certainty; and phrase is the equivalent of the words clear, precise, and indubitable.

Biologics

Drug products made from living organisms and their

products, including viruses, serums, vaccines, antigens, antitoxins, allergenic, or analogous products.

Biotechnology

Commercial techniques that use living organisms or

substances from those organisms to make or modify a

product for use in medicine and industry. Biotechnology includes the use of novel biological techniques

such as recombinant DNA and cell fusion.

Blinded trial 

Clinical trial in which the investigator and/or the subjects are not made aware of whether the subject has

been assigned to the treatment group or a comparison

group. In a single-blind trial, only the investigator

knows to which group the subject has been assigned.

In a double-blind trial, both the investigator and the

subject are not aware of which group the subject has

been assigned. The investigator and/or the subject is

kept unaware of which group the subject has been assigned in order to minimize bias.

Blood cells

Cells found in whole blood, including red blood cells

(erythrocytes) and various types of white blood cells

(such as granulocytes, monocytes, and lymphocytes).

Blood plasma

See plasma.

Blood serum

The clear liquid that separates from blood after the red

blood cells, fibrin, and clotting factors are removed by

centrifugation or vigorous stirring.
182 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Blood

A liquid (plasma) containing red blood cells (erythrocytes), white blood cells (leukocytes), and platelets

(thrombocytes) that circulates through the heart, arteries, veins, and capillaries, carrying oxygen and nutrients to body tissues, removing carbon dioxide and other wastes, transferring hormonal messages between

organs, carrying substances that prevent excessive

bleeding and protect injury sites with clots, and transporting antibodies and infection-fighting cells to sites

of infection.

Caps on damages 

Legislative limits on the amount of money that can be

awarded to the plaintiff for economic or noneconomic

damages in a personal injury claim, such as medical

malpractice or product liability. The limit is imposed

regardless of the actual amount of economic and noneconomic damages.

Cause-based compensation 

A system of compensation where one’s entitlement to

compensation for injury depends on its cause.

CDH-receptor

The target receptor for HIV infection.

CD4+ binding site

Domain on the HIV-1 envelope protein that attaches to

the CD4+ cell receptor. See CD4+ cell.

CD4+ cell

A type of helper T lymphocyte that bears CD4 receptors on its surface. The CD4+ cell is a target for HIV

infection. The virus binds to the CD4 receptor in the

process of cell entry.

CD8+ cell

A type of cytotoxic T lymphocyte that bears CD8 receptors on its surface; CD8+ lymphocytes are able to

lyse infected cells that are otherwise hidden from antibody. See cytotoxic T lymphocytes.

Cell-mediated immunity 

Immune protection provided by a network of white

blood cells in the blood and tissues; immune protection provided directly by the direct action of immune

cells, without the intermediation of antibodies.

Cell-mediated immunity

Immunity resulting from an increase of activity by living cells in the blood and other tissues (e.g., T lymphocytes, cytotoxic T lymphocytes) that directly and nonspecifically destroys infected cells and other foreign

material. Compare humoral immunity.

Challenge

In immunology, administration of an antigen to assess

the state of immunity. In vaccine testing, a vaccinated

animal or person is challenged with an infectious

agent or antigen to determine whether the vaccine has

increased the animal or person’s ability to fight infection.

Children’s Vaccine Initiative 

See National Vaccine Injury Compensation Program.

Clade 

A major subgroup of viral strains; for HIV, at least five

clades have been identified. Clade B is predominant in

the Americas and Western Europe.

Claimant 

Person who is requesting compensation for injury.

Classic prophylactic vaccination 

Vaccination of uninfected individuals to prevent infection or disease. Compare second order prophylactic vaccination.

Clear and convincing proof 

Proof beyond a reasonable (i.e., well founded) doubt.

Clinical trial

Experimental research in which preventive, diagnostic, or therapeutic agents, devices, regimes, and procedures are given to human subjects under controlled

conditions in order to define their safety and effectiveness. In a randomized clinical trial, subjects are assigned at random to one or more treatment groups or to

a control group that is given a placebo or a comparison

treatment. See phase I, II, III, and IV studies.

Collateral source offsets 

Reduce the amount of awards to the plaintiffs by prohibiting plaintiffs from collecting payment for insured

losses, such as medical expenses.

Compensation 

In personal injury, refers to replacing a victim’s losses.

Compensatory damages 

In personal injury, refers to money awarded to the

plaintiff to compensate the plaintiff for losses incurred

as a result of an injury.
Appendix C References and Glossary | 183

Compensatory justice 

Principle of fairness in compensation for harms.

Confidentiality (of the physician/patient

relationship) 

The state or quality of being confidential, that is intended to be held in confidence or kept secret. Courts

and legislatures have established a physician-patient

privilege to protect the confidentiality of communications between physicians and their patients and have

established similar privileges to ensure the confidentiality of communications between other types of

health care providers and their patients or clients.

Contingency fee 

Legal fees that are dependent on the plaintiff’s recovery.

Contract

A legally binding agreement between two or more parties.

Contractors 

A person entering a contract, often seen as a businessperson striking a bargain. As long as the bargaining

process is fair, contractors may be entitled to no more

than what they bargained for, and may be seen as seeking an unfair advantage if they later demand more.

Control group

In a randomized clinical trial, the group receiving no

treatment or some treatment with which the group receiving experimental treatment is compared. The control treatment is generally a standard treatment, a placebo, or no treatment. Compare experimental group.

Core antigens

Proteins that make up the internal structure or core of a

virus. The core proteins of HIV are the products of the

genes gag and pol. Compare envelope antigens.

Cross-protection

The ability of immunization for one strain of virus to

provide protection against infection against another

strain of virus.

Cross-reactivity

The property of an organism to be able to provoke an

immunological reaction against a different organism.

The tuberculosis vaccine BCG, for example, is an attenuated strain of Mycobacterium bovis (a bovine tuberculosis) that provokes the immune reaction against M.

tuberculosis, the cause of human tuberculosis.

CTL 

See cytotoxic T lymphocytes.

Cyclophilins 

Proteins that function in immune modulation; acted on

by Cyclosporin A, a potent immunosuppressant drug.

Cytokines 

Molecules secreted from cells that affect growth or

other activity in closely proximate cells. Cytokines are

often thought of as short-range hormone, accomplishing cell to cell communications.

Cytotoxic T lymphocytes (CTL)

T lymphocyte characterized by its ability to recognize

and destroy cells producing HIV-1; see CD8+ lymphocytes.

ddC (zalcitabine)

An inhibitor of HIV replication by interfering with viral DNA synthesis, indicated in combination with Zidovudine, is used in patients with advanced HIV infection and immunosuppression.

ddI (didanosine) 

An inhibitor of the replication of HIV, used in HIV infected patients who are intolerant or nonresponsive to

Zidovudine. Also known by its brand name Videx

(Bristol-Myers).

Damages

In personal injury litigation, refers to money that is

awarded by the court to the plaintiff for injuries for

which the defendant is legally responsible.

Defendant

In personal injury litigation, refers to the party that is

alleged to be responsible for the injury.

Denaturation

The separation of double-stranded DNA into its single

strands or of protein into its constituent peptides

through treatment with chemicals, heat, or extremes of

pH. Denaturation also results in loss or reduction of

the biological properties of the substance.

Deoxyribonucleic acid

See DNA.

Design defect

When an object is lacking in some particular that is essential to its completeness, rendering it not fit for the

purpose for which it was sold and used. A design is defective if the product could have been developed so as
184 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

to reduce its inherent danger to the user without significantly decreasing its effectiveness.

Deterrence 

The creation of disincentives for socially undesirable

activities.

Developmental risk

The danger or hazard of incurring financial losses

through litigious action resultant from research, development, and trials of a vaccine.

Diagnostic test 

A medical test administered to those asymptomatic

but high-risk individuals identified by a screening test,

or a test used to identify the cause of abnormal physical signs or symptoms. Compare predictive test and

screening test.

Diethylstilbestrol (DES)

A white, crystalline, synthetic non-steroidal estrogen

having estrogenic activity similar to but greater than

that of estrone. Diethylstilbestrol is one of several

drugs that have been withdrawn from the market in the

United States because of adverse reactions.

Diphtheria

An acute infectious disease affecting primarily the

membranes of the nose, throat, or larynx, characterized by the formation of a gray white pseudomembrane; attended by fever and pain of varying degree

and aphonia and respiratory obstruction in the laryngeal form; caused by the toxigenic gram-positive bacillus Corynebacterium diphtheriae.

Diphtheria, tetanus, pertussis (DTP) vaccine

A combination vaccine composed of two toxoids

(diphtheria and tetanus) and one inactivated wholecell bacterial vaccine (pertussis). Included among

vaccines recommended in childhood.

Disability insurance

Insurance that provides payments to insured people

should they be unable to work due to physical or mental incapacitation.

Disease

Any deviation from or interruption of the normal

structure or function of any part, organ, or system (or

combination thereof) of the body that is manifested by

a characteristic set of symptoms and signs whose etiology, pathology, and prognosis may be known or unknown.

Distributive justice

Fairness in the distribution of benefits and burdens

among members of society.

DNA

(deoxyribonucleic acid) The genetic material of most

living things (exceptions include some RNA viruses,

such as HIV) that determines the hereditary characteristics by directing protein synthesis in the cells. DNA

is composed of two strands of nucleotide bases that are

linked and wound around each other to form a spiralshaped molecule. Compare RNA.

Double-jeopardized CD4+ T cells

Vaccine-activated CD4+ T cells with specificity for

HIV. One theoretical risk is that vaccination may facilitate HIV infection by “activating” CD4+ T cells. Active CD4+ T cells are better hosts for HIV entry, integration, and replication. In addition, CD4+ T cells

activated by HIV vaccine will search for HIV-infected

cells to bind to, increasing the rate of dissemination of

HIV infection among CD4+ T cells.

DT vaccine

Combined vaccine against diphtheria and tetanus.

DTP vaccine

See diphtheria, tetanus, pertussis vaccine.

Economic damages 

Monetary damages that compensate the plaintiff for

his or her actual economic losses—i.e., past and future

medical expenses, lost wages, rehabilitation expenses,

and other tangible losses.

Economic efficiency

The state in which the greatest direct and indirect

gains (benefits) are derived from the resources expended (costs) to achieve a stated objective.

Effectiveness

Same as efficacy (see below) except that it refers to

“...average or actual conditions of use.” Compare efficacy.

Efficacy

The probability of benefit to individuals in a defined

population from a medical technology applied for a

given medical problem under ideal conditions of use.

Efficacy is generally evaluated in controlled trials of

an experimental therapy and a control condition.

Compare to effectiveness.
Appendix C References and Glossary | 185

Efficiency

See economic efficiency.

Encephalitis 

Inflammation of the brain.

Encephalopathy 

Any degenerative disease of the brain.

Endogenous retroviruses 

Genes present in the host genome that code for retroviruses. One theoretical risk is that HIV vaccines could

activate latent disease-causing retroviruses present in

the host genome.

env gene 

Gene coding for HIV env envelope protein.

Envelope (env) antigens

Proteins that constitute the envelope or surface of a virus. For HIV, these include the gp 160, gp 120, and gp

41 proteins. Compare core antigens.

Enzyme immunoassay (EIA)

An assay based on antigen-antibody interactions,

which uses enzymes to measure the reaction.

Enzyme-linked immunosorbent assay (ELISA)

A type of enzyme immunoassay for determining the

amount of protein or other antigen in a given sample

by means of an enzyme-catalyzed color change. ELISA is used as a screening test to detect the presence of

antibodies to HIV in human sera. ELISA tests that are

positive for HIV are confirmed by the Western blot

test. See enzyme immunoassay.

Enzymes 

Proteins that are produced by living cells and that

mediate and promote the chemical processes of life

without themselves being altered or destroyed.

Episome 

The genome of a virus that remains free in the nucleus

of the host cell. Compare provirus.

Epitope

A structural part of an antigen that is responsible for an

antibody response against that antigen. Also known as

an “antigenic determinant.”

Equity

The concept of fairness or justice.

Erythrocytes

Red blood cells. These cells contain hemoglobin and

are adapted for the transport of oxygen in the blood.

Excise tax

A tax imposed on the performance of an act, the engaging in an occupation, or the enjoyment of a privilege.

Experimental group

In a randomized clinical trial, the group receiving the

treatment being evaluated for safety and efficacy.

Federal Tort Claims Act (FTCA)

Enacted in 1946 (28 U.S.C.A. sec. 1346(b)(Supp.

1988)), the FTCA allows an injured party to sue the

U.S. government.

forum non conveniens 

Motion to dismiss a case brought by foreign plaintiffs

in U.S. courts on the basis that a more suitable alternative forum exists (usually the home country of the victim, or the place where the injury occurred).

Fraud

An intentional perversion of truth for the purpose of

inducing another in reliance upon it to part with some

valuable thing belonging to him or to surrender a legal

right.

Free virus

Virus that resides outside of cells.

gag gene 

A gene that codes for HIV structural core (internal)

proteins p18, p24, and p15. See core antigens.

Gene

The basic unit of genetic information. Each gene

codes for a specific antigen.

Genome

The total genetic information or collection of genes in

an organism, composed of RNA or DNA subunits.

gp 120

An HIV surface glycoprotein that bears the principle

sites for induction of neutralizing antibody and binding to the host CD4 receptor. These are sites where

vaccine-induced antibody can block viral replication.
186 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

gp 160

A membrane-bound surface glycoprotein that projects

through the virus envelope surface. Also termed “envelope” or env protein, the gp160 protein is comprised

of an external portion (gp120) protein, and a transmembrane region (gp 41 protein).

Gross negligence

The intentional failure to perform a manifest duty in

reckless disregard of the consequences as affecting the

life or property of another.

Haemophilus influenzae type b (Hib)

A parasitic bacterium that occurs in an encapsulated

form. In children and debilitated older adults, infection may result in destructive inflammation of the larynx, trachea, and bronchi, and may also cause subacute bacterial endocarditis and purulent meningitis.

Immunization against Hib is available through inoculation with anti-Haemophilus influenzae serum.

Haemophilus influenzae type B (Hib) vaccine

Vaccine included among those recommended in childhood. See Haemophilus influenzae type b.

Hepatitis A

Viral hepatitis, type A. An acute inflammation of the

liver caused by infection with hepatitis A virus, which

is transmitted by fecal contamination of food or water

(e.g., through infected people handling food), or

through parenteral infection (by contaminated needles

or administration of blood products). Formerly known

as “infectious hepatitis.”

Hepatitis B

Viral hepatitis, type B. An acute inflammation of the

liver caused by infection with hepatitis B virus, which

is transmitted mainly by sexual contact, parenteral exposure (contaminated needles or administration of

blood products), and from carrier mother to baby. In

some cases, infection may be severe and result in prolonged illness, destruction of liver cells, cirrhosis, and

death. Formerly known as “serum hepatitis.”

Herd immunity 

Resistance of a population to spread of infection. Vaccines can induce herd immunity by decreasing the

transmission of infection among members of the population. The immunity to infection of some members

of the population may reduce the likelihood of spread

of infection to other members of the population, including spread to members who are not immune. Models for herd immunity include the worldwide smallpox

vaccination program and the U.S. childhood vaccination program. Compare individual immunity.

Heroes 

Willing volunteers who assume risks in order to accomplish a goal, ordinarily for someone else’s sake.

HIV-1 

Human immunodeficiency virus, type 1; a virus found

in most of the world that causes the immune deficiency leading to AIDS; a member of the retrovirus subfamily that includes HIV-2 and SIV.

HIV-2

Human immunodeficiency virus, type 2; a retrovirus

that is found in West Africa; in the same virus subfamily as HIV-1 and SIV.

HIV

See human immunodeficiency virus.

HIV-related diseases 

Diseases that occur more frequently in persons who

are infected with the human immunodeficiency virus

(HIV).

Horizontal justice

The concept that similarly situated individuals should

be treated in a like manner.

Host

In virology, the organism used for growth and reproduction of viruses.

Human immunodeficiency virus (HIV)

A retrovirus that is the etiologic agent of AIDS and

whose infection has been associated with depression

of the immune system and various opportunistic diseases. HIV infects and disables the CD4+ subset of T

lymphocytes, which are key elements of the immune

system. See AIDS.

Humoral immunity

Immunity associated with antibodies that circulate in

the blood.

Hypersensitivity

In immunology, a state of heightened reactivity to a

previously encountered antigen; may cause mild allergy or severe anaphylactic shock.

Idiotype (or idiotope)

An antigenic determinant specific for an individual

immunoglobulin molecule; idiotypes are regions near

the antigen binding site of an antibody that act as anti-
Appendix C References and Glossary | 187

gens themselves by stimulating the production of antibodies.

Immediate post-exposure vaccination

Vaccination of individuals immediately after infection

to prevent the infection from becoming permanently

established. An example is rabies vaccine, which is

administered immediately after being bitten by a rabies-infected animal.

Immune deficiencies

Any number of disorders, including AIDS, resulting

from a failure or malfunction of the bodily defense

mechanisms, or immune system.

Immune enhancement 

The facilitation of infection and disease progression

by the immune system. One theoretical risk of an HIV

vaccine is that vaccination may induce the production

of antibodies that may facilitate entry of HIV into

phagocytic cells (cells such as macrophages that ingest microorganisms or other substances), and thereby

increase dissemination of HIV infection in those cells.

Immune response

A defensive reaction of the body in response to exposure to certain substances not recognized as normal

body components (pathogenic microorganisms, transplanted tissue, etc.). Immune responses may involve

the production of antibodies that react with antigens

on the surface of the foreign substances to render them

harmless, as well as a variety of physical and chemical

responses from other cells of the immune system.

Immune system

The group of organs, specialized cells, and cell products that protect the body from harmful microorganisms, contribute to allergy and hypersensitivity reactions, are involved in the rejection of transplanted

tissue and organs, and may play a role in the development of cancer.

Immune

Protected against disease by innate or acquired resistance to specific foreign or pathogenic substances or

organisms. See immunity.

Immunity

The condition of being immune, or being protected

against disease by the action of the immune system.

Immunity may be either innate or acquired; innate

immunity is present from birth having been passed to

the baby from the mother during pregnancy; acquired

immunity may be active (resulting from either previous exposure to the disease-causing agent or vaccination) or passive (resulting from the injection of

preformed antibodies derived from an individual already immune to a particular antigen).

Immunization

The deliberate introduction of an antigenic substance

(vaccination, or active immunization) or antibodies

(passive immunization) into an individual, with the

aim of inducting immunity or resistance to disease.

Compare vaccination.

Immunocompetence

The capacity to respond immunologically to an antigen.

Immunodeficient 

A defect in the host’s ability to mount an effective immune response.

Immunogenic

Able to cause an immune response.

Immunogenicity

The ability to generate an immune response in the host.

Immunoglobulin

Any of a group of specific proteins (produced by white

blood cells) that react to the presence of a foreign antigen, react more quickly to a previously encountered

antigen than to a new one, and under normal circumstances, do not respond to components of its own body.

They are found in the blood plasma and lymph and in

other body tissues and fluids. There are five basic

classes of immunoglobulins—IgA, IgD, IgE, IgG, and

IgM. See antibody.

Immunology

The scientific study of the ability of organisms to identify and attack foreign substances, to distinguish self

from nonself, to form antibodies and antigen-reactive

lymphocytes, and to become hypersensitive to common allergens.

Immunopathogenesis 

A process in which the course of a disease is altered or

affected by an immune response (either the cellular (Tcell) or humoral (B-cell) response) or by products of

an immune reaction, such as the antigen-antibodycomplement complexes deposited in renal glomeruli.
188 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Immunosuppression

Inhibition or suppression of the immunologic response (e.g., by infection, as in AIDS, or by the administration of drugs to prevent rejection of tissue grafts or

transplanted organs, or by irradiation or biochemical

agents).

Immunosuppressive

Pertaining to or inducing the artificial prevention or

diminution of the immune response. See immunosuppression.

Implied warranty of merchantability 

An implied contract between seller and purchaser of

consumer goods that the goods meet each of the following: 1) pass without objection in the trade under

the contract description; 2) are fit for the ordinary purposes for which such goods are used; 3) are adequately

contained, packaged, and labeled; 4) conform to the

promises or affirmations of fact made on the container

or label.

Influenza

A viral disease that is characterized by prominent systemic symptoms, such as weakness, fever, and malaise; usually occurs in epidemics.

In vitro test

Experimentation using cells, tissues, or explants

grown in a nutritive medium rather than using living

animals or human subjects.

In vivo

Literally, “in the living,” pertaining to a biological

process or reaction taking place in a living organism.

In biomedical research, used to describe the experiments or processes in whole animals (e.g., mice, rats,

humans), as opposed to those in a test tube or other experimental system.

Individual immunity 

A person’s ability to resist infection and disease.

Compare herd immunity.

Infectivity 

The ability or propensity to transmit infection.

Informed consent

As applied to human research, the agreement of a person (or his/her legally authorized representative) to

serve as a research subject, in full knowledge of all anticipated risks and benefits of the experiment. Informed consent requires that the researcher impart to

the prospective subject any information that might influence the subject’s decision to participate or not participate in the research, including an explanation of

the methodology to be used, the availability of alternative therapies, and the prospective subject’s freedom

to withdraw from the experiment at any time, without

prejudice.

Informed consent 

As applied to clinical care, a patient’s agreement to allow a medical procedure based on full disclosure of

the material facts needed to make an informed decision. The required elements of disclosure differ from

state to state, but generally include the duty of health

care providers to inform patients of the risks and benefits of medical tests or treatments, and to the patient’s

right to refuse medical care.

Institutional Review Board (IRB)

A group established by an institution conducting medical research to assess the legal, ethical, and scientific

aspects of that research on human subjects. IRB approval is required by the Department of Health and

Human Services before proposals can receive federal

funding. IRBs must review research protocols on a

regular basis, but not less than once a year.

Internal protein 

Protein found inside the cell.

Investigational New Drug (IND) application 

An application submitted by a sponsor to the Food and

Drug Administration (FDA) before beginning human

testing on an unapproved drug or on an approved drug

for an unapproved use.

Joint and several liability 

A rule under which each of the defendants in a tort suit

can be held liable for the total amount of damages, regardless of his or her individual responsibility. In other

words, even if a defendant was only 20 percent responsible, he or she could be held liable for 100 percent

damages if other defendants are unable to pay. Several

states have eliminated joint and several liability so that

defendants are liable only in proportion to their responsibility.

Jurisdiction

In law, refers to the authority of a court to decide the

case that is before it.

Justice

In liability for personal injury, refers to imposing the

costs of injury on the one who causes it.
Appendix C References and Glossary | 189

Learned intermediary Rule

A manufacturer of prescription drugs or vaccines need

only provide product warnings to the prescribing physician, not the patient receiving the product.

Leukocyte

White blood cells (WBCs), including lymphocytes,

monocytes, neutrophils, basophils, and eosinophils.

WBCs are formed in lymph nodes and bone marrow

and are present in the blood and lymphatic circulation.

Their main function is to protect the body against infection and to fight infection when it occurs.

Liability

Legal responsibility.

Litigation 

A lawsuit. Legal action, including all proceedings

therein.

Lump sum payment 

In tort, refers to an award, the entirety of which is to be

made in a single payment.

Lymphocytes

Specialized white blood cells involved in one type of

immune response that does not depend directly on antibody attack (cell-mediated immunity). Lymphocytes originate from fetal stem cells and develop in the

bone marrow. They normally comprise about 25 percent of the total white blood cell count and increase in

number in response to infection. They occur in two

forms: B cells and T cells. B cells, which circulate in

an immature form and secrete antibodies that are carried on their surface membranes, search out, identify,

and bind with specific antigens. T cells mature in the

thymus gland and differentiate into thymocytes when

exposed to an antigen; they divide rapidly and produce

large numbers of new T cells sensitized to that antigen.

Lymphoma 

A neoplastic disorder of the lymphoid tissue. Malignant lymphomas are classified based on their predominant cell type. B cell lymphomas have predominantly

B-lymphocyte-type cells.

Lyse 

To damage or rupture a cell membrane, allowing the

release of cell contents into the extracellular medium.

Macrophage

A large, specialized immune cell in the circulation or

tissues that is an important intermediary in many

stages of the immune response, including engulfing

bacteria and other foreign particles; the macrophage is

one target of HIV infection.

Manufacturing defects

Something other that the product intended by the

manufacturer is produced; the manufacturing process

fails to conform to the manufacturer’s own specifications; generally limited to particular units or batches

of the product.

Maternal-fetal HIV transmission 

Transmission of the human immunodeficiency virus

across the placenta from the mother to the fetus.

Measles, mumps, rubella (MMR) vaccine

A combination vaccine composed of the three live, attenuated virus vaccines providing long-term immunity against measles, mumps, and rubella; given by injection in a two-dose schedule, usually at 15 months of

age and again at school entry.

Measles

A highly contagious viral disease involving primarily

a hacking cough with steadily mounting fever followed by the eruption of red papules on the skin. It is

spread by respiratory contact, primarily airborne droplets of nasal secretions containing the virus.

Microbe

A minute living organism; the term especially applies

to those minute forms of life that are capable of causing disease in animals and man, including bacteria,

protozoa, viruses, and fungi.

Model 

A disease in animals used to study an analogous disease in man. SIV infection of chimpanzees and Asian

monkeys has been used as a model for HIV infection

and disease progression in man.

Molecular biology 

The study of biology at the level of individual molecules, such as proteins and DNA.

Mucosa

The thin membrane lining various tubular structures of

the body, including the colon, small and large intestine, mouth, nasal cavity, pharynx, and esophagus.

The mucosal surfaces of the vagina, anus, and rectum

are common sites of sexual transmission of HIV.

Mucosal immunity 

Immune protection provided by antibody and immune

cells located in the surface of mucous membranes.
190 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Mumps

An acute, viral infection that produces painful inflammation and swelling of the salivary glands in the

face and neck; occurs most commonly in school-aged

children.

Mutation

A change in the structure or amount of genetic material (DNA, or in RNA viruses, RNA), either by changes

in the base sequence of DNA or RNA, by changes affecting larger portions of a chromosome, or by the loss

or addition of an entire chromosome. Mutations can be

induced (e.g., caused by exposure of genetic material

to a physical or chemical agent), spontaneous (occurring in the absence of any known causative agent), or

heritable (changes in genetic material passed from

parent to offspring). The human immunodeficiency

virus (HIV) is characterized by frequent spontaneous

mutations. This, in combination with selection, allows

HIV to evade immune control.

National Childhood Vaccine Injury Act 

Enacted by Congress in 1986 (42 U.S.C. SCCS.

3000aa et seq.), this Act sets up a program of administrative hearings to review claims for adverse reactions

resulting in injury or death from taking a childhood

vaccine. The amount of compensation for adverse

reactions to these vaccines is determined by reference

to a vaccine injury table. Currently, MMR, DPT and

polio vaccines are covered under the Program.

National Vaccine Development and Compensation

Act of 1992 

Introduced by Congressman Fourtney (Pete) Stark,

This Act (H.R. 5893)sought to provide the framework,

based on the 1986 National Childhood Vaccine Injury

Act, for dealing with AIDS vaccine liability concerns

both during the period of research and development

phase, as well as in the marketing phase.

National Vaccine Injury Compensation Program

This program sets up administrative hearings to review claims that injuries or deaths resulted from adverse reactions to approved childhood vaccines.

Natural killer cell

A type of lymphocyte that attacks cancerous or virusinfected cells without previous exposure to the antigen.

Natural selection

The process by which simpler ancestral species of animals and plants evolve into new species, based on

variations among traits in populations and differential

reproductive success that selects for certain of those

traits; described by Charles Darwin in 1858 in On the

Origin of Species.

Negligence 

The doing of some act that a person of ordinary prudence would not have done under similar circumstances or failure to do what a person of ordinary prudence would have done under similar circumstances.

In product liability law, negligence is conduct by the

product maker that deviates from standards of acceptable conduct adhered to by the ordinary manufacturer

of similar products and that results in harm to the product user.

Neutralizing antibody

Antibody with capacity to inactivate virus directly.

The capacity of antibody to neutrialize virus is tested

in vitro by mixing the antibodyand virus, and then assaying residual viable virus in sensitive cells. It is a biologically significant measure of protection, i.e.,

when compared to antibody that can physically bind

viral antigen but cannot neutralize.

New Drug Application

An application to the FDA for approval to market a

new chemical (non-biological) drug for human use in

U.S. interstate commerce.

NK cell 

See natural killer cell.

No-fault compensation 

A system of compensation where one’s entitlement to

compensation is not contingent upon establishing who

is at fault for an injury; claimants must merely establish that they were injured and that the injury arose

from a specified cause.

Non-economic damages

In personal injury litigation, refers to claims for harms

from the injury that cannot be expressed in sums certain of money, such as pain and suffering.

Nucleic acid 

Macromolecules composed of sequences of nucleotides that carry genetic information. Two kinds of nucleic acids exist, occurring as double-or singlestranded molecules DNA, which contains the coded

instructions for an organism’s development in the

chromosomes and is transferred to daughter cells; and

RNA, which helps transport, translate, and implement
Appendix C References and Glossary | 191

the DNA instructions, particularly the biosynthesis of

proteins.

Nucleotide 

A subunit of DNA or RNA, consisting of a nitrogenous

base (adenine, guanine, thymine, cytosine, or uracil),

a phosphate molecule, and a sugar molecule (deoxyribose in DNA or ribose in RNA). The linkage of thousands of these subunits forms the DNA or RNA molecule.

Nucleus 

The membrane-enclosed structure in eukaryotic cells

that contains the genetic material (DNA).

Oncogenes 

Genes present in the host genome that, if activated,

have the potential to cause cancer. One theoretical risk

is that HIV vaccines could, upon integration into the

host genome, activate latent oncogenes.

Oncogenic 

Cancer inducing.

Original antigenic sin 

Fixing of an immune response in a non-adaptive pattern. One theory is that HIV vaccination may induce a

non-adaptive immune response that, in response to infection with a closely related strain of HIV, produces

antibodies that are directed to the vaccine strain of

HIV, but that weakly bind to the infecting strain of

HIV.

Peptide 

A compound consisting of two or more amino acids

linked together by chemical bonds. Peptides are the

building blocks of proteins.

Per capita

According to the number of individuals; in the law of

descent and distribution, that method of dividing an

intestate estate by which an equal share is given to

each of a number of persons, all of whom stand in

equal degree to the decedent, without reference to

their stocks or the right of representation.

Periodic payment 

In tort, refers to an award of damages that are to be paid

in portions over a specified time interval; contrast

lump sum payment.

Personal injury action

A suit brought in court based on a hurt or damage done

to a man or woman’s person, such as a cut or bruise, a

broken limb or the like, as distinguished from an injury

to property or reputation. In statutes the term “personal injury” is also used in a much wider sense, including

any injury that is an invasion of personal rights, and in

this signification it may include such injuries to the

person as libel or slander, criminal conversation, malicious prosecution, false imprisonment, and mental

suffering.

Pertussis 

An acute, infectious inflammatory respiratory disease

of children caused by the bacterium Bordetella pertussis. The disease is characterized by explosive attacks

of coughing ending in an inspiratory whoop or choking on mucus and occurs in infants and children who

have not been immunized against the disease. Also

known as “whooping cough.”

Petition

A written request to a court officer, legislature, or other body for the exercise of its authority in the redress of

some wrong, or the grant of some favor, privilege, or

license.

Petitioner

One who presents a petition to a court, officer, or legislative body.

Phase I, II, III, IV studies 

Specific phases of the clinical (human) testing of new

drug or vaccine products. Phase I studies of vaccines

are small trials usually involving only healthy uninfected volunteers to document the safety and immune

response it produces. Phase II studies further test the

vaccine’s safety and immunogencityand note any adverse reactions in vaccinated individuals. Phase III

studies assess the vaccines effectiveness and risks

among a large number of volunteers under conditions

of ordinary use. These trials are randomized, placebocontrolled, and double-blind in design. Phase IV studies refer to surveilllance conducted after a vaccine is

already approved for marketing, to further determine

its safety and efficacy.

Placebo 

A drug or procedure with no intrinsic therapeutic value. In a randomized clinical trial, a placebo is given to

patients in control groups as a means to blind investigators and patients as to whether the patient is receiving the experimental or control treatment.

Plaintiff 

In personal injury litigation, refers to the injured party.
192 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Plasma

The liquid portion of blood, excluding blood cells but

including a large number of dissolved substances (e.g.,

salts, hormones, glucose, amino acids, fats, vitamins,

and waste products). Compare blood serum.

pol gene 

In HIV, a gene coding for three enzymes, including

polymerase reverse transcriptase. See core antigens,

reverse transcriptase.

Poliomyelitis

An acute, infectious, viral disease, occurring sporadically and in epidemics. The disease is caused by three

strains of poliovirus, which attack the central nervous

system, leading to the selective destruction of motor

neurons of the spinal cord and brain stem, followed by

extensive paralysis. The disease is preventable

through use of the oral polio vaccine.

Polymerase chain reaction (PCR)

A very sensitive laboratory test to detect the presence

of HIV RNA or DNA in the circulating blood.

Postmarketing surveillance 

Surveillance for adverse reactions occurring after the

drug or biologic has been approved by the FDA and

placed on the market.

Preclinical research

Laboratory and animal research conducted prior to the

clinical testing of a new chemical entity. Preclinical

research may include basic research and applied nonclinical research.

Predictive test

A medical test generally applied to asymptomatic individuals to provide information regarding the future

occurrence of disease. Compare diagnostic test and

screening test.

Preemption

Doctrine adopted by U.S. Supreme Court holding that

certain matters are of such a national, as opposed to local, character that federal laws preempt or take precedence over state laws. As such, a state may not pass a

law inconsistent with federal law.

Premarket testing

Testing of pharmaceuticals and medical devices that

occurs before a product can be introduced into the

market. The FDA requires clinical evidence of safety

and efficacy before a drug or medical device can be

sold in the United States.

Premium

A reward for an act done.

Preponderance of the evidence

Standard of evidence, typically used in civil litigation,

that means more likely than not, or a majority of the

evidence.

Presumption

A rule of law, statutory or judicial, by which finding of

a basic fact gives rise to existence of presumed fact,

until presumption is rebutted.

Product liability

Refers to the legal liability of manufacturers and sellers to compensate buyers, users, and even bystanders,

for damages or injuries suffered because of defects in

goods purchased.

Prophylactic vaccine

Vaccine to prevent infection or disease in uninfected

individuals (classic prophylaxis), or to reduce their infectivity should they subsequently become infected

(second order prophylaxis).

Prophylaxis

The prevention of disease and preservation of health.

Protein

A molecule composed of many linked amino acids in a

specific sequence, which is, in turn, determined by the

sequence of nucleotides in DNA in the gene coding for

the particular protein. Proteins are required for the

structure, function, and regulation of the various cells,

tissues, and organs in the body.

Provirus 

The genome of a virus integrated into the chromosome

of the host cell, and thereby replicated in all of the

host’s daughter cells. Compare episome.

Punitive damages 

Money that is awarded to the plaintiff to punish the defendant for wrongful (usually intentional) activity.

Quasispecies

New viral mutants that have evolved from initial infecting strains of virus.
Appendix C References and Glossary | 193

Randomized clinical trial (RCT) 

An experiment designed to test the safety and efficacy

of a medical technology in which people are randomly

allocated to experimental or control groups, and outcomes are compared.

Rebuttable presumption 

A legal presumption that can be rebutted upon presentation of sufficient evidence. See presumption.

Recklessness

The state of mind accompanying an act, which either

pays no regard to its probably or possibly injurious

consequences, or which, though foreseeing such consequences, persists in spite of such knowledge.

Recombinant DNA (rDNA) technology

Techniques involving the incorporation of DNA fragments, generated with the use of restriction enzymes,

into a suitable host organism’s DNA (a vector). The

host is then grown in culture to produce clones with

multiple copies of the incorporated DNA fragment.

The clones containing this particular DNA fragment

can then be selected and harvested. Also called genetic

engineering.

Recombinant DNA 

Genetic material that contains DNA from different

sources that have been combined by genetic engineering methods. Rearrangement of the genes is artificially induced using enzymes to break DNA into fragments, allowing recombination in different sequences.

Recombinant technology

Scientific knowledge of the process of forming new

combinations of genes as a result of crossing over between homologous chromosomes.

Recombination 

In genetics, the formation of new combinations of

genes as a result of crossing over between homologous

chromosomes. One theoretical risk is that genetic material from a live vector or naked DNA HIV vaccine

could recombine in the vaccinated host with preexisting or newly acquired HIV or other viruses.

Red blood cells

see erythrocytes.

Reovirus 

Any group of relatively large, widely distributed, and

possibly tumor-causing viruses with double-stranded

RNA. Unlike retroviruses, which also contain RNA,

reoviruses replicate in the cytoplasm of the cells they

invade and do not produce DNA analogs to their RNA

for incorporation into the host cell’s genome. The genus name “reovirus” is derived from the term respiratory enteric orphan virus, to denote both respiratory

and enteric trophism and isolation of the virus in the

absence of known disease. See also virus; and

compare adenovirus and retrovirus.

Replication 

In genetics, the synthesis of new DNA from existing

DNA.

Respondent 

In equity practice, the party who makes an answer to a

bill or other proceeding in equity. In appellate practice, the party who contends against an appeal (i.e., the

appellee). In the civil law, one who answers or is security for another.

Restatement of Torts

American Law Institute’s treaties that summarize several fields of law. Widely considered to be the most authoritative statement of tort law in the country. Most

states have adopted its provisions, albeit not uniformly, and some states have interpreted its technical requirements somewhat differently.

Retributive justice 

Assuaging the victim’s and society’s desire for vengeance or retribution through punishment.

Retrovirus

A familly of viruses with an RNA genome and an intermediary DNA stage, which is persistently integrated into the genome of the host cell chromosome. A

retrovirus contains two identical single strands of

RNA, not DNA, and that reproduces by making a

double-stranded DNA transcription of itself in a process catalyzed by a virally encoded enzyme known as a

“reverse transcriptase.” The resulting DNA product

may integrate into the cell genome (as a provirus) or

may remain free in the nucleus (as an episome). Either

way, it remains as a latent infection to be activated later (by a variety of factors) to a virus-producing form.

Retroviruses are found widely in nature and are

associated with a variety of diseases, including cancer,

neurologic disorders, and immune deficiency syndromes, notably AIDS. Four well-characterized retroviruses are HIV-1 and HIV-2 (major causative agents

of AIDS), and HTLV-I and HTLV-II (associated with

T-cell leukemia and lymphoma). See also provirus and

virus; and compare adenovirus and retrovirus.
194 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Reverse transcriptase

Also called RNA-dependent DNA polymerase. Enzyme present in HIV and other retroviruses that allows

the virus to turn RNA genetic information into DNA

genetic information. See retrovirus and reverse transcription.

Reverse transcription 

The creation of DNA genetic information using RNA

genetic information as a template. HIV and other retroviruses are unique in their RNA genetic information into DNA, which is subsequently integrated into

the DNA genome of the host. This process is accomplished by the enzyme “reverse transcriptase.”

RGB

Purified recombinant glycoprotein expressed in a host

cell.

Ribonucleic acid

See RNA.

Right of subrogation

A provision typically found in health and disability insurance contracts that requires a plaintiff to reimburse

the insurance company for any payments received

from the tort system that were for services reimbursed

by the insurer.

Risk-benefit analysis

A determination of whether the risks to health and the

environment of using a chemical, drug, or vaccine exceed the economic benefits that accrue from its use. In

the case of drugs and vaccines, benefits are measured

in terms of therapeutic efficacy.

Risk deterrence 

The prevention or deterrence of avoidable risk.

RNA

Ribonucleic acid. A type of nucleic acid that carries

genetic instructions and assists in the assembly of proteins. RNA is a single-stranded chain of repeating

units of adenine, cytosine, guanine, and uracil. Specialized types of RNA include: messenger RNA

(mRNA), which carries a transcript of a DNA sequence to be used as a template for protein synthesis;

transfer RNA (tRNA), which attaches the correct amino acid to the protein chain being synthesized at a ribosome; and ribosomal RNA (rRNA), a structural constituent of ribosomes. In some viruses, RNA contains

the instructions for viral replication. The HIV-1 genome is composed of RNA. However, HIV-1 assmes a

DNA form when persistantly integrated into host cell

(e.g. CD4+ lymphocytes) genetic material as part of

its replication cycle.

Rubella (German measles)

An acute viral illness that causes a diffuse reddish rash

and swollen lymph glands. Infection during pregnancy, especially in early stages, can cause miscarriage or

congenital rubella syndrome, a potentially fatal disorder involving deafness, cataracts, mental retardation,

and/or heart lesions (depending on when infection occurred in gestation). The disease is preventable

through vaccination.

Schedule of damages 

A set of guidelines for juries to use in deciding appropriate awards for noneconomic damages in malpractice cases.

Screening test 

Generally, a test used to sort out apparently well persons who probably have disease from those who probably do not. A screening test is not intended to be diagnostic. Compare diagnostic test and predictive test.

Second order prophylactic vaccination 

Vaccination of uninfected individuals to reduce their

ability to transmit subsequently acquired infections.

Compare classic prophylactic vaccination.

Section 402A liability

Section 402A of the Restatement of Torts (2nd) makes

manufacturers of drugs and vaccines strictly liable for

adverse reactions in the absence of warnings.

Selection

In combination with mutation, a source of rapid genetic change of HIV. See Natural selection.

Selective advantage 

In biology, an organism’s increased probability of reproduction and producing offspring, conferred by its

genetic characteristics.

Selective pressure

In biology, the influence of factors extrinsic to an organism (i.e., environmental factors) on its ability to

compete with other organisms for reproductive success.

Sequelae 

Aftereffects or secondary consequences of a disease,

disorder, or injury.
Appendix C References and Glossary | 195

Seroconversion

The initial development of antibodies specific to a particular agent.

Seropositive 

In the context of HIV, the condition in which antibodies to the virus are found in the blood.

Serum 

See blood serum.

Settlement 

In the context of a civil suit, refers to a private agreement of a plaintiff not to further pursue a court judgment in return for compensation from the defendant.

Simian immune deficiency virus (SIV)

A retrovirus from the same virus subfamily as HIV-1

and HIV-2 that infects chimpanzees and Asian monkeys; SIV infection of chimpanzees and Asian monkeys has been used as a model for HIV infection in

man.

SIV 

See Simian immunodeficiency virus.

Spontaneous mutation 

In the absence of any known causative agent, a change

in the structure DNA or in the number of chromosomes. Also called a “background” mutation. HIV is

characterized by frequent spontaneous mutations. See

mutation.

Statute of limitations 

A statute prescribing limitations to the right of action

on certain described causes of action or criminal prosecutions; that is, declaring that no suit shall be maintained on such causes of action, nor any criminal

charge be made, unless brought within a specified period of time after the right accrued.

Strain 

A group of organisms of the same species having a distinctive quality or characteristic (biochemical, pathogenic, or other) that can be differentiated, but is not

different enough to constitute a separate species.

Strict liability 

A legal concept that states liability lies with the party

best able to prevent injury or absorb its costs even if

that party was not responsible for causing the specific

injury in question through negligence or intent. See

malpractice.

Subrogation

See right of subrogation.

Subunit vaccine 

A vaccine that contains only portions of an antigenic

molecule from a pathogen. Subunit vaccines can be

prepared by using recombinant DNA technology to

produce all or part of the antigenic molecule or by artificial (chemical) synthesis of short peptides.

Sunset clause

Clause that provides for the automatic expiration of

legislation.

Swine Flu Act 

Enacted in 1976, the Act held harmless manufacturers

of the swine flu vaccine from claims of individuals injured by the vaccine. The Act also permitted claimants

to file suit against the U.S. government under the Federal Tort Claims Act for compensation for injuries

from the swine flu vaccine.

Swine flu vaccine

Vaccine against the swine flu, an especially virulent

strain of influenza that spread throughout the United

States during the fall and winter of 1976.

Systemic

Pertaining to or affecting the body as a whole.

T4 cell 

See CD4+ cell.

T8 cell

See cytotoxic T lymphocyte.

T helper cell 

See CD4+ cell.

T lymphocyte (T cell) 

A lymphocyte produced in the bone marrow that matures in the thymus and is integral to cell-mediated immunity. T cells regulate the growth and differentiation

of other lymphocytes and are involved in antibody

production. See lymphocytes.

Teratogen 

Physical or chemical agents, (e.g. thalidomide, radiation, alcohol, and certain viruses) that act on the fetus

in utero to cause congenital malformations.

Teratogenic 

Capable of inducing the formation of developmental

abnormalities in a fetus.
196 | Adverse Reactions to HIV Vaccines: Medical, Ethical, and Legal Issues

Tetanus 

An acute, potentially fatal disease of the central nervous system caused by infection of a wound with

spores of the bacterium Clostridium tetani; these

spores release a poisonous neurotoxin (tetanus toxoid)

that causes trismus (”lockjaw”), generalized muscle

spasm, arching of the back, glottal spasm, seizures, respiratory spasms, and paralysis. Short-term immunity

can be derived through vaccination. Tetanus vaccine is

among vaccines recommended for children. See DTP

vaccine.

Therapeutic vaccine

Vaccine to prevent or reduce disease progression in infected individuals, or to reduce disease transmission to

persons who come in contact with infected individuals.

Tort law 

A body of law that provides citizens a private, judicially enforced, remedy for injuries caused by another person. Legal actions based in tort have three elements:

existence of a legal duty from defendant to plaintiff,

breach of that duty, and injury to the plaintiff as a result

of that breach.

Tort liability 

Liability imposed by a court for breach of a duty implied by law, contrasted with contractual liability,

which is breach of duty arising from an agreement. A

legal basis for compensation when property has been

damaged or a person has been injured. The tort liability system determines fault and awards compensation

for civil wrongs, including medical malpractice and

product liability.

Tort reform 

A legal reform that changes the way tort claims are

handled in the legal system or removes claims from

the civil judicial system.

Transaction costs

In personal injury, refers to the administrative costs

associated with transferring compensation to the injured.

Transcription 

In genetics, the process by which RNA is formed from

a DNA template during protein synthesis. Compare

translation, reverse transcription.

Translation 

The process in which the genetic code contained in the

nucleotide base sequence of messenger RNA directs

the synthesis of a specific order of amino acids to produce a protein. Compare transcription.

Transmission 

In infectious disease, the passage of a pathogen from

one host to another host or from vector to host.

Vaccination 

The deliberate introduction of an antigenic substance

(vaccine) into an individual, with the aim of producing

active immunity to a disease. Compare immunization.

Vaccine 

A preparation of living, attenuated, or killed bacteria

or viruses, fractions thereof, or synthesized antigens

identical or similar to those found in the disease-causing organisms that is administered to produce or increase immunity to a particular disease.

Vaccinia virus 

The organism that causes cowpox; its injection into

humans results in immunity to the related smallpox virus.

Varicella 

Virus that causes chickenpox.

Vector 

In HIV vaccines, refers to a live attenuated virus or

bacterum carrying selected HIV genes, which produces desired antigenic proteins when administered to

a recipient. Proteins produced in a living microorganism are generally capable of inducing cytotoxic T

lymphocyle responses in addition to antibody.

Victims

Persons misused or injured without their consent.

Virology 

The study of viruses and the diseases they cause; also,

the isolation and identification of viruses associated

with specific infection.

Virus 

Any of a large group of submicroscopic agents infecting plants, animals, and bacteria and characterized by

a total dependence on living cells for reproduction and

by a lack of independent metabolism. A fully formed
Appendix C References and Glossary | 197

virus consists of nucleic acid (DNA or RNA) surrounded by a protein or protein and lipid coat. See also

adenovirus, provirus, reovirus, and retrovirus.

Warning defects

There are two types of warning defects: 1) a failure to

provide warnings of risks inherent in the use of the

product (failure to warn); and 2) providing directions

and warnings that fail to adequately describe product

risks (inadequate warning).

Western Blot

A laboratory technique used to detect the presence of

antibodies to specific antigens, including those specific for HIV infection. The method is often used to check

the validity of a positive ELISA screening test for HIV.

It is also used to clinical trials to detect vaccine induced antibody. Electrophoresis is used to separate

proteins by their molecular weights, and each protein

is identified through combining with its respective antibody or antigen. For example, in Western Blot testing for HIV antibodies, the protein components of HIV

are first separated electrophoretically, transferred to

blots, then mixed with sera suspected of containing

HIV antibodies. The presence of antibodies to specific

proteins of HIV is revealed by the combination of antibodies with their specific protein components of HIV.

White blood cells 

Cells in the blood stream and tissues, including lymphocytes, macrophages, and neutrophils, that provide

immune protection. See leukocyte.

Whole, killed-virus vaccine

Vaccine formed from virulent virus that has been altered so that the virus is no longer able to replicate.

Workers compensation 

System that provides compensation for work-related

injuries, regardless of the fault of the employer.

Zidovudine (AZT) 

An inhibitor of the replication of some retrovirses including HIV, used in the treatment of persons with

HIV infection who have evidence of impaired immunity. Also known by its brand name, Retrovir (Burroughs Wellcome).