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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.
Where the samples came from
Blood samples from 11 locations were sent to IAVI’s Human Immunology Laboratory in London
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
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