The XIII International AIDS Conference's sessions on HIV vaccines took place in an atmosphere of greater urgency than ever before. Durban, the conference's locale, has an HIV prevalence that exceeds one in five, and treatment for HIV is unaffordable there for all but a tiny elite.

Margaret Liu, Vice-President of Vaccines Research and Gene Therapy, Chiron Corporation, announced in a plenary address on vaccines (Conference presentation ThOr86), "Today the world is well-positioned scientifically to make a successful AIDS vaccine." She nonetheless dodged her assigned topic, "Will We Have an HIV/AIDS Vaccine in Seven Years?," modifying it to "Prospects for an HIV Vaccine."

"We all agree that a vaccine is possible," commented Peggy Johnston when chairing a vaccine debate. Johnston is associate director of the U.S. National Institutes of Health HIV vaccine program. She noted that there are gaps in knowledge about the type and quantity of immune response required for protection and questions about the relevance of HIV subtypes. "We need to do more research to determine the relevance of lab assays to human beings," she said. .

But the challenges posed by the need to develop an HIV vaccine were not presented as solely scientific. The politics of medical research and in particular vaccine research were articulated by Malegapuru William Makgoba, President of South Africa's Medical Research Council (Conference presentation ThOr88). "Because research is to a large extent motivated by scientific objectives such as developing or testing new knowledge, temptations may remain to subordinate the welfare of the volunteers to the objectives of the investigator and treat human beings as a means to an end," Makgoba warned. "Research may also be motivated by financial gains where expediency obscures ethics to the detriment of volunteers and the integrity of science."

Politically Sensitive Science

An issue of key importance to vaccine trial design concerns the role of HIV genetic subtypes (clades) in determining immune response to a candidate vaccine. A vaccine made from a particular clade might be either solely or particularly protective against that specific clade. The current practice is to match the clade of virus used to make the candidate vaccine to the clade that is prevalent in the trial population. But questions were raised at Durban as to whether this is necessarily the best practice.

The clade controversy has both a scientific and political dimension. At the Durban conference, Zambian scientist Rosemary Musonda argued that protective immunity to the HIV in someone's body is not necessarily determined by this HIV's clade (Conference presentation MoOr26). "Clade" (or "subtype") is a categorization arising from an analysis of distinctive viral genetic patterns and may not correspond to a particular isolate's "immunotype," which is based on the types of antibodies and killer T-cells that the isolate elicits when exposed to the immune system. Musonda warned that limiting research to clade vaccines designed to match the dominant local HIV population was holding up vaccine development unnecessarily and leaving unanswered crucial questions about cross-clade immunity.

Margaret Liu said, "We need greater insights into how to induce antibodies that will broadly neutralize viruses both within a clade and between clades. We should not assume that making a vaccine from one clade will be the solution for all the strains within that clade. Likewise, we should not assume that novel immunogens made starting from one clade will not induce antibodies which can neutralize virus from another clade. These decisions must be based upon scientific data, not assumptions."

Liu's speech, "Prospects for an HIV Vaccine," followed Francine McCutcheon's report on the genetic evolution of HIV, which detailed patterns of viral recombination (Conference presentation ThOr85). McCutcheon is chief of the Henry M. Jackson Foundation Global Molecular Epidemiology Program. She pointed out that the map showing which clades and circulating recombinant strains predominate in each part of the globe needs to be redrawn every six months to keep up with viral evolution. If HIV vaccines prove to be protective against only the particular clade from which they are made, or against only particular strains within that clade, then they may prove to be of little use in geographic areas where HIV is endemic and multiple clades are present and recombining.

Discussing the Durban presentations, David Cooper, Director of Australia's National Centre in HIV Epidemiology and Clinical Research, argued that whether a candidate vaccine is likely to confer protection across clades probably depends upon whether it induces cell-mediated immunity or humoral (antibody) immunity. "To generalize, if T-cell immunity is important, clades don't matter because the T-cells recognize short peptides. If antibody is useful-and the jury is still out on that-clades may still be important," he said.

In contrast, the status of HIV as a global emergency was also used to insist on the importance of clade-matching, notably by Carolyn Williamson of South Africa (Conference presentation MoOr25) and Malegapuru Makgoba. Given the unknowns regarding the correlates of immunity, Williamson said that it was logical to try to limit one of the variables by matching vaccine clade to the local population's clade in the hope of expediting the process. Similarly, Makgoba told a Durban press conference that, with regard to southern Africa, "The epidemic is 96% clade C. That is the strain we should make." He is now directing a South African vaccine initiative that focuses on a clade C vaccine for that country. Clade-matching fits his agenda because it may increase the likelihood that the research outcome is relevant to the population participating in the research.

South African senior scientist Eftyhia Vardas, who is also from the Medical Research Council, noted, "We have long been the target of 'imperialistic' research and we all obviously feel that this should not continue." Regardless of whether HIV clades are really relevant, testing a candidate vaccine based on one clade in an area where another predominates is bad public relations. With respect to the science, Vardas situates herself somewhere between Makgoba's hard line on matching clades and what she describes as the "laxness" of completely discounting clades at this time.

"We need to balance somewhere in between these two extremes. Phase I and II HIV vaccine trials have been substantially delayed in Africa because of this HIV subtype preoccupation. I don't think that it's that important and it is more likely that there will be some common responses to vaccine candidates that will obviate the need to make specific subtype vaccines.

"However, the pressing issue remains that vaccine development, especially in Africa, needs to move really quickly in order to implement our last real chance of controlling the HIV pandemic."

Australian scientist Stephen Kent, pointing out that it would be more appropriate to design vaccines that addressed immunotypes, if they were known, rather than clades, said, "It is reasonable to use subtypes predominating in the country of testing in most cases." This view is not incompatible with Margaret Liu's. Although Liu urged in her plenary speech that decisions about which strains to use in a vaccine must be based upon science, "not upon biases or politics," she later agreed that, given the lack of data, "matching may be a good place to start."

"But there are several issues," she warned. "We should not raise hope unless supported by the data that a clade-specific vaccine will necessarily be broadly effective within a clade."

Vardas commented that it appears more likely that HIV resembles the hepatitis B virus in terms of vaccine strategy. The HBV vaccine is broadly effective despite genetic diversity, unlike the vaccine for influenza, which requires frequent re-construction to take account of the way the virus varies over time. Large portions of HBV's immunologically targeted regions are conserved, whereas influenza viruses have very few conserved regions. Despite HIV's mutability, significant parts of HIV surface antigen are conserved, too. The problem for vaccine design is that the host immune response to the conserved parts of the envelope is not very strong.

"In fact, neutralizing antibodies have not been shown to occur after exposure to these HIV antigens," Vardas said.

Using the example of a study by John McNeill of the Walter Reed Army Institute of Research, Liu explained that vaccines based on certain clades might confer broader immunity than others.

"[The study] demonstrated that using a recombinant gp120 vaccine from a clade E isolate (CM235) induced antibodies which could neutralize both clade E and B viruses, whereas clade B constructs induced only antibodies effective for neutralizing clade B but not clade E. So there might be a particular virus or clade that is for some reason better for a vaccine," she said.

The incidence and speed at which recombination of different clades occurs in areas where HIV is endemic and different clades proliferate-particularly sub-Saharan Africa-is the other reason Liu cited for diversifying research away from clade-matched vaccines.

"Not everyone can afford to make all their expensive clinical lots of vaccine in duplicate or triplicate for early phase testing. So the field can suffer if people are dogmatic up front [about remaking the construct with different clades] unless the data truly support the clade specificity," Liu said.

The point is not necessarily to discourage clade-matching but to ensure that the focus remains on the data. Remaking a vaccine just to change the clade may result in unnecessary loss of time and resources, she argued. The existing construct may have broader immunity either because it is based on cellular responses or because there is something about the way it induces antibody responses that confers broader protection.

Because of the history of exploitation of resource-poor countries by the developed world, trials that might prove cross-clade immunity are politically sensitive. With this in mind, David Cooper asked, "Why not test an African clade in a European population for immunogenicity, or an Asian clade in an Australian population to explore that? You would not be putting anyone at risk."

Cooper suggests inverting the historical pattern by mobilizing an altruistic first-world population to test a concept of major significance to the developing world. "[If it's] more comfortable to do it in reverse, let's do it, let's push the envelope," he said.

Drafting Ethical Guidelines for Trials

This reversal echoes the position taken by ethicist Soloman Benatar (Conference presentation TuOr44) in the debate on whether research participants in developed and developing countries should receive the same standard of care. Benatar advocated a higher standard of care for research participants from developing countries in recognition of their vulnerabilities, and he interpreted "standard of care" much more broadly than just the provision of drugs. Benatar's complex argument resisted reduction to the questions of using placebo controls where proven therapy exists or the provision of highly active antiretroviral therapy (HAART) to seroconverters in vaccine trials. It focused instead on the principles of respect for human dignity and the equitable distribution of benefits and burdens.

The raging controversy over attempts to change existing ethical guidelines to accommodate the agendas of HIV vaccine researchers revolves around precisely the issue of whether participants in HIV vaccine trials should be given access to the best-proven anti-HIV treatment if the vaccine fails to protect them during the trial. Under the current Declaration of Helsinki, research participants must be assured of access to therapeutic and diagnostic services at the highest international level of care. This provision implies that participants in HIV vaccine trials who become infected must be able to access HAART and appropriate viral load testing regardless of where they live.

Breaches of the Declaration's mandate have been increasingly frequent, particularly with regard to researching cheaper therapies in resource-poor countries. As of last summer, proposed changes to the Declaration would permit this practice, and vaccine trial participants who contract HIV could be offered the "highest attainable" therapy available in a particular setting. At the most extreme, infected participants might receive no treatment at all.

Robert Levine of Yale University produced the 1999 draft revision of the Declaration of Helsinki. (When finally adopted in October 2000, the reference to "highest attainable" therapy had been changed to "best proven therapy," but it is not clear that vaccine trials have to follow this requirement. See accompanying article by Emily Bass.) Levine represented the guidelines debate as being between "ethical universalists" and "cultural pluralists" (Conference presentation ThOr95). In his taxonomy, the "universalists" advocate the best proven standard of care for all trial participants whereas the "pluralists" view the issues within cultural contexts where variation is deemed inevitable and acceptable.

Levine's framing of the debate in these terms caused real consternation. Dirceu Greco from the Federal University of Minas Gerais, Brazil (Conference presentation ThOrE651) rebutted Levine by stating that "the pressure to lower the established ethical standards is based on economics and not on ethical or scientific grounds." But conference attendees were denied a voice in this discussion-quite forcibly, in one instance, when a microphone was turned off. If the Durban conference was successful in any respect, it was in bringing to the fore the unacceptable injustices that determine who lives with and who dies of HIV disease. "The struggle for social and economic rights for the poor must become central to every aspect of AIDS research and treatment," said Paul Farmer in his speech "Prevention without Treatment Is Not Sustainable" (Conference presentation MoOr5).

000110
AM010106

Copyright © 2001 by the American Foundation for AIDS Research (amfAR) and first displayed on amfAR's Treatment Directory web site (http://www.amfar.org/gl). They appear on AEGIS with amfAR's permission. Organizations wishing to reprint or redistribute these materials should request authorization from amfAR's Department of Treatment Information Services (212/806-1600).

AEGiS is made possible through unrestricted grants from Boehringer Ingelheim, iMetrikus, Inc., the National Library of Medicine, and donations from users like you. Always watch for outdated information. This article first appeared in 2001. This material is designed to support, not replace, the relationship that exists between you and your doctor.

AEGiS presents published material, reprinted with permission and neither endorses nor opposes any material. All information contained on this website, including information relating to health conditions, products, and treatments, is for informational purposes only. It is often presented in summary or aggregate form. It is not meant to be a substitute for the advice provided by your own physician or other medical professionals. Always discuss treatment options with a doctor who specializes in treating HIV.

Copyright ©1990, 2001. AEGiS & the Sisters of Saint Elizabeth of Hungary. All materials appearing on AEGiS are protected by copyright as a collective work or compilation under U.S. copyright and other laws and are the property of AEGiS and the Sisters of Saint. Elizabeth of Hungary, or the party credited as the provider of the content.