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Reprinted with permission from Stanford Medicine, Vol. 16,
No. 1, Fall 1998
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by Reprinted with permission from Stanford Medicine, Vol. 16, |
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Abstract
The author argues for rapid movement of potential HIV vaccines into clinical trials, because even vaccines that might be considered a failure by traditional standards would still save many lives and dollars.
Today, about 16,000 people worldwide will become infected with the human immunodeficiency virus (HIV). Last year, 1.8 million adults and 460,000 children died from HIV/AIDS. Since the beginning of the epidemic, 8.2 million children have lost either a mother or both parents to HIV. All told, approximately 30 million people are living with HIV, and another 12 million people have already died from the acquired immunodeficiency syndrome (AIDS), caused by HIV. In just 20 years, the HIV pandemic has become one of the most devastating infectious disease epidemics in history.
Although recent therapeutic advances, especially the introduction of combination antiretroviral therapy, have reduced mortality dramatically in the developed world, these therapies are far too expensive for the developing world. Combination antiretroviral therapy that includes a protease inhibitor, a new and highly effective class of drugs, may cost $10,000 to $15,000 per patient per year. Yet 90 percent of people who have HIV live in developing countries, where per capita spending on all health care may be as low as $10 annually. With antiretroviral treatment currently out of reach economically, the alternatives for most of the developing world are to prevent further spread of HIV, with interventions to reduce risk behavior or with an HIV vaccine. Because the HIV epidemic is still rapidly growing worldwide, an effective HIV vaccine that is widely available could save millions of lives. Indeed, another 6 million people may have become infected in 1998 alone.
For many reasons, the development of HIV vaccines has proven difficult. Unlike many other diseases, researchers do not understand the biological mechanisms that provide immunity to HIV. In addition, there are many different strains of HIV that vary geographically and change over time. Whether a vaccine that is protective against one strain would also be protective against other strains is uncertain. These factors suggest that an HIV vaccine may be only partly protective; a vaccine might reduce but not eliminate the probability of infection, given an exposure.
What factors determine whether a vaccine should be tested in trials? Should a partially effective vaccine be tested in clinical trials? How good must a candidate vaccine be before it is tested? The question of when a vaccine should be tested in clinical trials has divided scientists.
Recently, the Food and Drug Administration approved the first large-scale trial of the efficacy of an HIV vaccine in the United States, but the decision was controversial. If a vaccine is tested prematurely, trial recipients may be exposed to risks (from the vaccine or from false reassurance) without any real benefit. Also, clinical trials are expensive, and the number of people willing to participate is not unlimited. Thus, premature testing of vaccines that do not have potential efficacy could actually delay introduction of an effective vaccine.
One important factor in the decision to test an imperfect vaccine is whether such a vaccine would be useful in the population at large. If so, then evaluation by clinical trials seems warranted. Suppose clinical trials suggest that a vaccine reduces the chance of HIV infection by 50 percent, or 75 percent. Would such a vaccine be useful?
To investigate this question, about four years ago my colleagues and I began using mathematical modeling to evaluate how a preventive HIV vaccine would affect the course of the epidemic. Sandia National Laboratories systems researcher Donna Edwards, a Stanford University
doctoral student at the time; and Ross Shachter, in the university's Department of Engineering-Economic Systems; and Operations Research, and I developed a mathematical simulation
of a population of homosexual men, designed to reflect the population in San
Francisco, California. The model used epidemiological data about risk behaviors
and the infectivity of HIV to simulate the spread of the epidemic in this
population. We also used an economic model to evaluate the costs (or savings)
associated with a hypothetical vaccine program. We evaluated the health benefits
associated with a variety of hypothetical vaccines, including perfect and
imperfect vaccines.
The results of our study were clear. Even substantially imperfect vaccines can provide enormous health benefits to our model population. For example, a vaccine that reduced the chance of infection by 75 percent would avert 2,950 HIV infections in the population we studied (about 55,000 people) over a 20-year period. The economic findings were also impressive; even if the vaccine cost $1,000, it would reduce health care expenditures by almost $10 million. A vaccine that reduced the chance of infection by only 25 percent would still provide significant health benefits at an acceptable cost-effectiveness for the United States.
Our
study shows that vaccines that might be considered a failure by traditional
standards still provide sizable benefits and are highly cost-effective.
Mortality and morbidity from HIV are high; therefore, a vaccine that prevents
only a portion of infections is useful. For a vaccine to be practical in the
developing world, however, it must be inexpensive, or the costs of the program
must be borne in part by the developed world.
Given that imperfect vaccines could provide substantial benefit, are the candidate vaccines under development sufficiently promising to start effectiveness trials? One viewpoint is that the tools of molecular biology are now sufficiently sophisticated that we should test only vaccines that appear promising based on a detailed understanding of the molecular pathogenesis of HIV. The contrary view is that we cannot wait for a complete understanding of molecular biology of HIV or of the mechanisms of HIV immunity. Proponents of this argument can point to history: highly successful vaccines, such as those for polio and measles, were introduced without a detailed understanding of how they worked. Thus, scientists disagree, in part based on philosophy, about the promise of candidate vaccines.
How good is good enough
for a vaccine to enter effectiveness trials? Of course, a fully effective HIV
vaccine is the goal researchers should continue to pursue. In the meantime,
however, I argue for rapid movement of candidate HIV vaccines into clinical
effectiveness trials, even if the vaccines are not likely to provide perfect
protection. The decision to test a vaccine in a large-scale trial must balance
costs, availability of participants, risks, and potential benefit to the
participants, as well as the number of participants required to provide
statistically valid results. But we should not wait for a vaccine that is
perfect or nearly so. The cost of delay is extremely high, and imperfect
vaccines can provide great benefit.
Douglas K. Owens is a senior research associate at the VA Palo Alto Health Care System and an associate professor of medicine and of health research and policy at Stanford University School of Medicine.
Caleb Brown is an illustrator and biologist living in Montana. By day he drives a delivery van, and by night he draws pictures with his computer.
Endlinks
Obstacles and Progress Toward Development of a Preventive HIV Vaccine - a brief summary of progress to date in HIV vaccine development, the obstacles and controversies that impede its progress, and future directions. From the Web site of the International Association of Physicians in AIDS Care.
HIV InfoWeb: AIDS Vaccine Development - an in-depth look at the issues and policies related to vaccine development.
International AIDS Vaccine Initiative - comprehesive news and information.
National Institute of Allergy and Infectious Diseases: Division of Acquired Immunodeficiency Syndrome - provides an overview of research, conferences, and resources on vaccine development.
Vaccines- a collection of reports and publications. From the United Nations Programme on HIV/AIDS.
The Global View of EvolutionWhat is Lamarck's Signature?: NeoplasiaDefend Only the Defenseless: Genetic Variation and VaccinationReprieve for a Killer: Saving SmallpoxThe Future of Evolutionary Biology