COMMENTARY Ethics of vaccine research Christine Grady Vaccination has attracted controversy at every stage of its development and use. Ethical debates should consider its basic goal, which is to benefit the community at large rather than the individual. accines truly represent one of the mira- include value, validity, fair subject selection, the context in which it will be used and Vcles of modern science. Responsible for favorable risk/benefit ratio, independent acceptable to those who will use it. This reducing morbidity and mortality from sev- review, informed consent and respect for assessment considers details about the pub- eral formidable diseases, vaccines have made enrolled participants. Applying these princi- lic health need (such as the prevalence, bur- substantial contributions to global public ples to vaccine research allows consideration den and natural history of the disease, as health. Generally very safe and effective, vac- of some of the particular challenges inherent well as existing strategies to prevent or con- cines are also an efficient and cost-effective in testing vaccines (Box 1). trol it), the scientific data and possibilities way of preventing disease. Yet, despite their Ethically salient features of clinical vac- (preclinical and clinical data, expected brilliant successes, vaccines have always been cine research include the fact that it involves mechanism of action and immune corre- controversial. Concerns about the safety and healthy subjects, often (or ultimately) chil- lates) and the likely use of the vaccine (who untoward effects of vaccines, about disturb- dren and usually (at least when testing effi- will use and benefit from it, safety, cost, dis- ing the natural order, about compelling indi- cacy) in very large numbers. Furthermore, tribution, political will, acceptability and so viduals to be vaccinated for the public good in vaccine research, individuals are asked to on). An important consideration is the and the injustices of uneven access to the accept risk for the public good and the value of the research for those participating http://www.nature.com/natureimmunology benefits of vaccines have been interwoven prospect of ‘provisional’ benefit. Finding in the vaccine testing and how it will be throughout the history of vaccines and safe and effective vaccines benefits the pub- maximized through dissemination of remain controversial today1–3. Such contro- lic health through reducing the burden of knowledge gained, product development, versies and the scientific complexities and disease among individual members of the long-term research collaboration and/or successes that fuel them raise considerable public and indirectly protecting unvacci- health system improvements. No judgment of ethical challenges in the development, public nated members of the public through ‘herd value is straightforward or immune from crit- health use and social acceptability of vac- immunity’. Individual benefit is ‘provi- icism, however, as illustrated by the following cines. This commentary will broadly con- sional’, however, because individuals benefit example in which the value of vaccine sider one aspect of these ethical challenges in directly from investigational vaccines only if research was in dispute. An effective rotavirus the clinical testing of vaccines. they are sufficiently exposed to the infec- vaccine was pulled from the US market Vaccine development is a lengthy, expen- tious agent at some future time, had because of a high incidence of intussuscep- sive and multifaceted process of basic and received the active vaccine and had been tion in vaccinated children. Consequently, clinical research, production, licensing and sufficiently protected. debates ensued about proceeding with large © 2004 Nature Publishing Group marketing. Clinical testing, usually with large trials planned in developing countries numbers of healthy subjects, is an integral Value where disease burden and vaccine efficacy and essential part of the process. Principles, According to the framework, the first ethi- might differ. Debates highlighted differing codes and norms of ethics guiding the ethical cal requirement is that the research ques- risk-benefit calculations in developing conduct of all clinical research apply to vac- tion have potential social or scientific value countries in which childhood deaths from cine research, yet most such guidance con- to justify exposing individuals to research rotavirus were high, as well as how accep- centrates on therapeutic clinical trials of risks and inconvenience. Research that can tance of vaccine might be compromised by interventions for individuals seeking treat- improve health or increase useful knowl- the US decision6,7. Assessing the value of ment. Little specific attention has been given edge has value. Determining the value of a this research was clearly, and appropriately, to how the ethics of vaccine trials differ. vaccine trial calls for an understanding that context dependent. “…the major purpose is to determine Applying a framework for ethical research whether a vaccine is of use as a public Validity One framework for ethical clinical research health tool. This is in contrast to the many A valuable research question ethically synthesizes and simplifies guidance found in large scale therapeutic trials where the requires a valid research design and imple- existing codes and regulations and describes objective is to determine what is best for mentation. Carefully chosen and rigorous seven principles universally applicable to eth- individuals. Yet, our ethical system is built study design, methodology and implemen- ical clinical research4. The seven principles around individuality…”5. tation strategies appropriate to the research Although vaccines have considerable question, and likely to provide interpretable public health value, it does not necessarily generalizable data, also are balanced by con- Christine Grady is in the Department of Clinical follow that every vaccine research proposal siderations of fairness and minimizing risk. Bioethics, Warren Grant Magnuson Clinical Center, has social or scientific value. A specific vac- In ensuring that the scientific design of a National Institutes of Health, Building 10/1C118, cine study or program’s value depends on its vaccine trial realizes social value for the pri- Bethesda, Maryland 20892-1156, USA. contribution to the goal of finding a safe, mary beneficiaries, several controversial e-mail: [email protected] effective and available vaccine useful within design and methodological issues can arise. NATURE IMMUNOLOGY VOLUME 5 NUMBER 5 MAY 2004 465 COMMENTARY BOX 1 FRAMEWORK APPLIED TO VACCINE RESEARCH is used in some places but not others, the jus- tification for and choice of a control can be Elements of ethical research Specific considerations more difficult. The use of placebo controls Value • Public health need in one arm of National Institutes of •Scientific possibility Health–sponsored acellular pertussis vac- • Social acceptability cine trials in Sweden and Italy, for example, • Political will was criticized despite a previous decision by Validity • Endpoints and measurement of efficacy the Swedish and Italian governments not to • Choice of control (such as placebo) routinely use the available whole killed per- • Randomization tussis vaccine10. These trials could not have •Feasibility of recruitment and follow-up been done in the US, where pertussis vaccine Fair subject selection • Large numbers of healthy subjects, is required for children to go to school. often including children Randomization, a powerful research tool • Participants in developing countries used to balance comparison groups, is a common feature of vaccine trials. Favorable risk/benefit ratio • Risks to individuals: physical, social, Randomization raises ethical questions confidentiality, future trials about participant autonomy, especially as • Risk of no protection empirical data show that randomization is •Provisional benefit to individual • Benefits to community and public good poorly understood by research subjects. • Fair benefit evaluations Although most phase 3 vaccine efficacy trials randomize individuals to demonstrate the Independent review • Familiarity with vaccine research direct protective effects of vaccine, some • International settings studies use cluster randomization or ran- Informed consent • Misconceptions about vaccines domization by community or group. http://www.nature.com/natureimmunology • Cultural and social differences Although often justified by the need to eval- • Community permission uate herd immunity and indirect as well as Respect for enrolled participants • Monitoring welfare direct protection from a vaccine, community • Right to withdraw randomization could be seen as jeopardizing •Treatment and/or compensation for the autonomy rights of individuals within vaccine-induced injury randomized communities. Ethically, it is necessary to ensure that a research study is feasible given the social, polit- Carefully defined endpoints, for example, serve many important scientific and public ical and cultural environment. In this regard, a are essential for high-quality science as well health purposes, addressing questions about feasible strategy for recruiting a large sample as ethical science. Although some vaccines etiology, pathogenicity, pathogenesis, and following them over time is essential. prevent infection, many alter the course of immune response and protection9. Although infection and have their protective effect