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On the Brink of a Watershed Moment for HIV Vaccine R&D

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BUILDING BRIDGES, DISMANTLING WALLS

Seth Berkley

The development of a vaccine to prevent HIV infection is one of the most daunting scientific challenges of our time. Yet, for all its complexity, this field of research seeks to answer a relatively simple question: how do you get the immune system to detect and disable HIV before it has a chance to insert itself into the human genome and establish an intractable infection? Most vaccines against viruses, such as those that prevent measles and polio, do so by teaching the immune system's B cells to generate neutralizing antibodies - exquisitely targeted protein missiles that bind to invading pathogens and tag them for destruction. HIV, however, is no ordinary adversary. It has evolved multiple strategies to flummox the immune response. Not least among these is a nearly unparalleled mutability that has vexed vaccine designers for the better part of three decades.

Any vaccine devised to seriously curb the AIDS pandemic will, at a minimum, have to protect against those HIV subtypes that predominate in developing countries, where some 90 percent of new infections occur. It should also thwart multiple variants of those viruses. This poses extraordinary scientific and logistical challenges. But it also has significant implications for the policies that guide and shape AIDS vaccine research and development. First, it requires that candidate HIV vaccines be tested in developing countries, which entails the establishment of the requisite human resources and technical capacity in such places. Second, in light of the unique scientific challenges of AIDS vaccine development, funders and policymakers need to find ways to encourage innovation and the application of hitherto untapped technologies to solve the toughest problems in the field. Finally, global efforts to develop AIDS vaccines would benefit from greater participation from the private sector. The market disincentives and risks - most prominently high failure rates and opportunity costs - inherent to HIV vaccine development have traditionally discouraged industrial participation. But appropriate incentives and funding policies could do much to change that.

This is especially true today. Following the failure of two AIDS vaccine candidates over the past decade, some commentators had begun to suspect that AIDS vaccine researchers might be tilting at windmills. But significant breakthroughs in the past year have countered such doubts. Late last year, a clinical trial in Thailand demonstrated - for the first time ever in humans - that a vaccine can prevent HIV infection (though this particular vaccine candidate provided only modest protection). A few weeks prior to that, researchers at the International AIDS Vaccine Initiative (IAVI) and in the Neutralizing Antibody Consortium (NAC) it oversees reported in the journal Science that a highly collaborative effort involving some 1,800 HIV-positive volunteers in eleven countries on four continents had resulted in the isolation, from a single African volunteer, of a pair of novel antibodies capable of neutralizing a wide spectrum of HIV variants. The two broadly neutralizing antibodies (bNAbs) - PG9 and PG16 - were found to be exceptionally potent neutralizers of HIV. This discovery was closely followed by the isolation of equally potent bNAbs by the Vaccine Research Center (VRC) of the U.S. National Institutes of Health, and several others from IAVI's antibody project.

Why should these findings matter? In short, because they clear a path to solving one of the most pressing problems of AIDS vaccine development - the elicitation of sufficiently potent antibodies against many of the subtypes of HIV in circulation.

Most of the experimental AIDS vaccines that have been put into clinical trials in recent years have been devised to primarily harness cell-mediated immunity (CMI). This is the branch of the immune response that depends on the recruitment of specialized soldiers known as T lymphocytes to detect and destroy cells already infected by HIV. But most researchers believe that an effective vaccine will also need to activate a neutralizing antibody response. In this view, the ideal vaccine would first deploy antibodies to prevent HIV from infiltrating cells, and would then mobilize the CMI response to mop up any viruses that slip past that biologic barrier. One of the major difficulties with this strategy has been in designing immunogens - the active ingredients of vaccines - that can teach B cells to produce broadly and potently neutralizing antibodies.

Researchers have long known that some HIV positive people produce just such antibodies. And animal experiments suggest that these bNAbs, if elicited by a vaccine, would block HIV from establishing an infection in the first place. This is why researchers had exhaustively studied four particularly versatile - though not especially potent - bNAbs that were isolated more than a decade ago. But it was clear that more such antibodies were sorely needed to inform vaccine design.

Antibodies attach with exquisite precision to unique folds and surfaces on large molecules. These shapes are known as epitopes. The careful study of purified bNAbs, and the epitopes they target, is the first step to devising strategies to elicit similar antibodies via vaccination. One approach to the neutralizing antibody problem - known as reverse vaccinology, the driving objective of the NAC - is to study these shapes in atomic detail, recreate them in the lab (or at least find similar structures) and use the synthetic epitopes as immunogens. Of course, the more such antibodies researchers have to scrutinize, the more likely they are to find an epitope that can be replicated to make a broadly effective vaccine.

NAC researchers have found that the newly discovered bNAbs, PG9 and PG16, have several potentially valuable traits. They latch on to a relatively unchanging patch on its endlessly mutable spike - a roughly toadstool-shaped scrum of proteins on its surface that HIV uses to invade its target cells. This epitope may prove an Achilles heel on HIV, given that it appears to be relatively accessible compared to the target sites of previously isolated bNAbs. This means scientists might have an easier time devising immunogens to elicit similar antibodies. Finally, the antibodies are notable for their potency. This is of great practical significance because candidate HIV vaccines have historically failed to elicit vigorous antibody responses, and the more potent an antibody the less of it is needed to block infection.

Beyond the elegance of the science, IAVI's antibody project provides a lesson in how well-conceived policies can drive the development of drugs and vaccines that may have questionable market prospects but are of critical significance to global health. For one thing, it confirms the value of cultivating biomedical research capacity in developing countries and working in partnership with local scientists and institutions to conduct vaccine trials and HIV research. A network of clinical research centers IAVI supports in five southern African countries played an indispensible role in the antibody project. The network, along with a half-dozen other research centers worldwide, provided the NAC with well-characterized cohorts of HIV positive volunteers who could be studied for the project. And it allowed IAVI to cast a wide net in the antibody hunt: there's no guarantee that a single, small cohort of volunteers would have yielded even a single antibody of interest.

The IAVI-supported clinical trials network continues to contribute to the antibody project, especially through cohorts participating in Protocol C, an IAVI study of HIV positive volunteers that tracks how the virus and the immune response to it evolve from the earliest phases of infection. Thanks in part to their access to these cohorts, IAVI researchers recently received a major grant from the NIH to explore why it is that only some HIV-positive people make potent bNAbs.

The antibody project also illustrates how practices that promote partnerships with the private sector can advance science in the public interest. The detection and isolation of bNAbs were accomplished through close collaboration between IAVI and affiliated scientists and researchers at two biotech companies - Monogram Biosciences in San Francisco, and Theraclone Sciences in Seattle. The former adapted its existing screening technology to evaluate hundreds of blood serum samples for their ability to neutralize a panel of HIV variants selected by IAVI researchers.

Theraclone, one of four laboratories charged with isolating antibodies from IAVI's blood samples, was the first to succeed, successfully isolating PG9 and PG16. It was the recipient of a grant from the Innovation Fund, which IAVI supports in partnership with the Bill & Melinda Gates Foundation to underwrite the novel application of existing technologies to AIDS vaccine development. Until it became involved in the antibody project, the company had applied its technology primarily to discover drugs for autoimmune disorders. By participating in the project, it got to showcase the versatility and power of its technology, which is just the sort of thing a start-up needs to generate new streams of revenue. In fact, Theraclone's success with PG9 and PG16 helped it win new business from a Japanese drug company.

IAVI continues to work with Theraclone and Monogram to isolate new bNAbs from several other serum samples collected in the antibody project, and has engaged other biotechs in vaccine design through the Innovation Fund. Other policy approaches that might draw more private sector participation in AIDS vaccine development include the fashioning of better incentives, advance market commitments and even public sector support to lessen the financial risk of tackling such a formidable problem.

Finally, policies that support long-term rather than project-by-project financing for research would benefit AIDS vaccine design. The NAC, for example, funds labs that have a long track record of success and a demonstrated ability to innovate. This not only gives researchers the time they need to pursue the painstaking business of designing vaccines. It also frees them to adapt their strategies to respond to advances in the swiftly evolving fields of HIV pathogenesis and immunology. It is noteworthy that the NAC and the VRC, which takes a similar approach to funding, have both made several significant contributions to AIDS vaccine design. By providing a measure of financial and professional security, such policies also create a space for young HIV researchers to hone their skills in vaccine-related research, and ready the best of them for future scientific leadership.

Thanks to the recent renaissance in R&D, the outlook for an AIDS vaccine is more promising today than ever. The progress was achieved in laboratories and in clinical testing centers, but was made possible by policies and practices, beyond the domain of pure science, that encourage collaboration, capacity-building, innovation and private-sector engagement. Those practices must be extended and expanded if we are to reach the goal of making an AIDS vaccine a reality.

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Dr. Seth Berkley is president, CEO and founder of the International AIDS Vaccine Initiative.