The difficult and inefficient search for vaccines
The quest for an AIDS vaccine is a compelling story. Pronouncements on the subject have emanated from sources that ordinarily do not address public-health issues: international economic organizations, geopolitical conferences, even a presidential State of the Union address. The topic has spawned at least two full-length books, most recen tly Big Shot: Passion, Politics, and the Struggle for an AIDS Vaccine, by Patricia Thomas. Thomas, a medical writer and journalist, was formerly an editor of the Harvard Health Letter. We are told on the book jacket that she participated in an early clinical trial of one candidate AIDS vaccine, but her experience is not discussed further within. This is a pity, because her perspective on this aspect of AIDS vaccine research might have been particularly illuminating.
The need for an AIDS vaccine is indeed urgent. The HIV pandemic has now reached numbers so staggering they almost defy comprehension: worldwide, an estimated 40 million individuals are infected with HIV, and 16,000 new infections occur daily. In some areas of southern Africa, the epicenter of the pandemic, nearly one-half of all adults of procreative age are infected with HIV. The vast majority of public-health and biomedical leadership in the field believes that the development and utilization of an effective AIDS vaccine is the only genuine hope to control the pandemic, or at least to avert a human and social catastrophe of even greater proportion.
Against this background, Big Shot describes the initial attempts to develop candidate AIDS vaccines. It focuses on researchers from biotechnology companies large and small, particularly Genentech and Chiron. Thomas traces the frequently tortuous path developers of vaccines have to tread--with government regulatory bodies, with public-advocacy groups, with university-based scientists, and within labyrinthine corporate halls of power. Participants in this drama are described in colorful, if not readily verifiable, terms. The gung-ho attitude--or hubris--of a major biotech firm is char-acterized as "Are we not men? We are Genentech." A female scientist states that "she was used to being surrounded by men who never lost sleep wondering whether they were wrong about anything." Many of these characterizations are sprinkled with heavy doses of pop psychology, such as the description of a top administrator at the National Institute of Allergy and Infectious Diseases (NIAID--which sponsors most of the basic and clinical research in the field) as a "productive narcissist."
Big Shot, understandably, is a work of journalism rather than a traditional history of a scientific field. Yet Thomas confronts the same challenge that historians of science face: to impart sufficient knowledge of the relevant science so that readers may understand the evidence upon which decisions are intended to be based. This is, after all, a defining principle in science--that data rather than passion, politics, ambition, or other motives will ultimately carry the day. In this regard, Thomas performs admirably. Large sections of the book are devoted to a layperson's explanation of the science behind the development of vaccines in general and of an HIV vaccine in particular. Biomedical scientists may quibble with some of her attempts to popularize scientific concepts in their field, but overall, I believe that hers is a simple and useful presentation for general readers. (Of note: A review of Big Shot in the Washington Post referred to even this rudimentary discussion of science as "mind numbing.")
After all, it is the science which lies at the core of the search for an AIDS vaccine, and some understanding of that science is a prerequisite for making sense of the "struggle," let alone assessing its progress. The scientific challenges to developing an effective AIDS vaccine are formidable. The virus is highly mutable. There is no naturally occurring immunity (like that seen after most virus infections, such as the measles or chicken pox), which vaccines can be designed to mimic. Virtually all vaccines rely on experiments in animal models to address critical questions of efficacy before they are evaluated in humans, yet there is no fully satisfactory animal model for HIV. (Primate models of simian immunodeficiency virus [SIV] or of chimeric [hybrid] SIV-HIV viruses in rhesus monkeys have been significantly refined, however, and are now yielding important information in the search for a vaccine.) In addition, clinical trials of promising vaccines in humans face important ethical and public-health issues, in both the developed and the developing worlds. And finally, there are major problems surrounding large-scale production and utili-zation of vaccines, particularly in areas of the world with insufficient infrastructure to support public-health initiatives.
According to Thomas, a biotech firm needs to invest more than $100 million to develop a candidate AIDS vaccine, merely to reach the first small clinical trials of safety and immune responses in humans (Phase I trials), and drug-company executives have recently quoted even higher figures. The National Institutes of Health (NIH) has estimated that a large-scale clinical trial of efficacy (Phase III) involving 10,000 subjects would cost upwards of $60 million--considerably more than reported in Thomas's book. The search for an AIDS vaccine is very "big science," indeed.
For any particular vaccine, the decision to proceed from small Phase I/II clinical trials to a large-scale efficacy trial cannot be taken lightly. The controversy surrounding such a decision by the NIH with respect to the candidate AIDS vaccines generated by Chiron and Genentech is the centerpiece in Big Shot's narrative. Both companies had developed similar vaccine candidates, consisting of part of the outer protein coat--gp120--of HIV. These had undergone Phase I/II testing in humans and appeared to be safe and immunogenic. But whether the immune responses they generated were likely to protect humans against HIV infection, or AIDS, was the subject of much disagreement, and studies in primate models did not settle the issue. The NIH had conducted the initial Phase I/II trials, and now was being asked to conduct (and pay for) the Phase III trials.
NIH's typical process for a decision of this magnitude is to convene a panel of experts who examine the question, listen to presentations and testimony, and then make a recommendation to the relevant administrative heads--in this case, the director of NIAID. The committee's recommendations are not binding upon NIH, though for obvious reasons an advisory committee's recommendations are rarely contradicted by government decisionmakers. The AIDS Research Advisory Committee (ARAC) of NIAID was typical. Such committees are staffed by NIH administrators and are intended to have broad representation from the scientific community and public advisory groups, and often receive input from other interested parties as well. Nonetheless, they are typically led and dominated by university scientists who are considered impartial experts in the field.
Most leading academic scientists were not impressed by the gp120 vaccines and therefore felt that they were unlikely to be efficacious in a Phase III trial. AIDS activists expressed concern that an efficacy trial of an ineffective vaccine would give a false sense of protection and might encourage "high-risk" behavior, as well as divert resources needed to support other types of worthwhile AIDS initiatives. At the end of a tumultuous meeting on June 17, 1994, ARAC recommended against a Phase III trial of the gp120 vaccines at that time, and the director of NIAID accepted the recommendation.
Thomas's chronicles of the presentations before the committee and of the deliberations of its members provide interesting and useful insights into both the process and the issues being addressed. But her suggestion that senior staff at NIAID tried to manipulate ARAC's decision by leaking to the press misleading and potentially unfavorable data from early Phase I/II trials is unsubstantiated and seems highly unlikely.
As a result of the decision, neither Chiron or Genentech chose to proceed with further development of their AIDS vaccine candidates. Don Francis, one of the strongest advocates of the gp120 vaccines at Genentech, eventually formed a separate company, VaxGen, to further develop the vaccine. In an extraordinary feat of fundraising and organization, he and some colleagues raised sufficient capital and other resources to undertake on their own two Phase III trials of the gp120 vaccines. These trials, involving some 7,900 subjects, are currently underway in the United States and Thailand and should be finished during the next two to three years. The significance of these trials to HIV vaccinology obviously depends on their ultimate outcome; even so, valuable lessons have already been learned about what is needed to conduct such trials--a substantial achievement by Francis and his colleagues.
The search for an AIDS vaccine, as reported by Thomas, illustrates the difficult and highly inefficient process by which vaccines are developed in this country. By and large, the fundamental laboratory or clinical observations from which vaccines emanate are usually made by academic researchers in universities. These scientists are extraordinarily proficient at what they do, but notoriously inefficient at the development process--that is, taking a scientific finding and turning it into a product which can be used in humans. For this part of the process, academic researchers usually seek an industry sponsor or partner to take the concept through the manufacturing and regulatory maze, from which will emerge a product that can be tested in clinical trials. Of course, vaccine candidates that originate within industry, or for which industry partners with academe, need to navigate corporate requirements for economic justification as well. The NIH now has elaborate clinical-trial networks capable of conducting various trials without added costs to the vaccine sponsors or developers. Although these networks are intended to accelerate the development process, they frequently have their own formidable bureaucratic complexities, as Thomas clearly reports.
Vaccine development would certainly benefit from engaging the three major players--academe, industry, and the federal government--in an earlier, more interactive, and better coordinated manner. Academic researchers might derive particular benefit from this, and a number of universities, including Harvard, are discussing ways to make the process more effective. Clearly the impetus for vaccine development, not only for AIDS but also for other diseases, has never been greater.
Historians and journalists of science always run the risk that their observations will quickly be out of date. This is particularly true of fast-moving areas of research, such as AIDS vaccines, where much of the field has moved beyond what is described in Big Shot. New techniques to measure immune responses more precisely, multiple novel candidate vaccines, different approaches to augmentation of immunity, and expansion of the infrastructure to conduct clinical trials, have imbued the field with a vitality and even a sense of optimism that may not be present in Thomas's narrative. Until an effective AIDS vaccine is developed, it is difficult to conclude who will turn out to be the heroes or villains in this quest, which remains, like Thomas's book, an unfinished story. As a work of journalism, Big Shot does not provide analysis or recommendations. But it does present an interesting description of that quest so far.
Raphael Dolin '63, M.D. '67, is Finland professor of medicine and dean for clinical programs at Harvard Medical School. He is principal investigator of the NIH-sponsored Harvard HIV Vaccine Unit and helped to found the school's new Division of AIDS, which coordinates and spurs research on the disease.
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