On the Brink of a Watershed Moment for HIV Vaccine R&D
By: Margaret McGlynn and David Cook
In late 2009, researchers from Thailand’s Ministry of Health and the United States Military HIV Research Program caused quite a stir when they announced that a vaccine regimen they evaluated in a large clinical trial in Thailand was modestly effective in preventing HIV. It was the first experimental demonstration that a vaccine can protect people from HIV, but it wasn’t at all clear why the regimen tested in that trial, known as RV144, had worked. So a global team of researchers was quickly convened to find the answer.
Their efforts were not in vain. In September, the team revealed at the international AIDS Vaccine 2011 Conference in Bangkok what it had learned from its analysis of the blood samples collected in the RV144 trial. The conclusion of their analysis capped another year of extraordinary productivity in a number of areas of AIDS vaccine research. From antibody discovery to the evaluation of new methods to deliver HIV vaccine candidates, researchers have lately made remarkable headway against some of the toughest scientific challenges the virus has presented – generating unprecedented momentum and optimism in the field.
Vaccinologists know very little about how exactly an AIDS vaccine should engage the immune system to prevent infection by HIV. Of course, a truly preventive HIV vaccine will probably have to activate both a broadly effective antibody response, which stops viruses from slipping into their target cells, and the cell-mediated response, which destroys cells that have already been commandeered by the virus. But the devil, as always, is in the details – what are the particular identities and roles of the scores of molecular and cellular supporting actors essential to this response? Vaccinologists call those details the correlates of protection, and they remain in large measure a mystery even for existing vaccines. The slightest hint about what they might be for HIV would be a big help to AIDS vaccine designers.
That the global RV144 research team – led by Barton Haynes, director of the Duke Human Vaccine Institute at Duke University School of Medicine – found anything at all of value in their correlates analysis came as a pleasant surprise. The correlates analysis was hindered by the fact that it was a retrospective, case-controlled analysis and not a prospective, randomized study. Further, due to the limited number of appropriate samples available to researchers and the small number of people who contracted HIV, there was a possibility that the analysis would lack statistical power. The study design in RV144, for want of funds, had not been designed to reveal such information. Still, Haynes and his colleagues discovered that two distinct types of antibodies that bind HIV in roughly the same place corresponded with different outcomes of vaccination. Specifically, those who produced an antibody known as Immunoglobulin G (IgG) at the peak of their immune response to vaccination were 43 percent less likely to contract HIV than those vaccinated volunteers who did not produce the antibody. Conversely, those who had another type of antibody in their blood, known as IgA, that similarly targeted HIV, had a higher risk of subsequently becoming HIV-positive. This risk was roughly equal to that of unvaccinated RV144 volunteers – which is to say that vaccination did not increase the risk of HIV infection but did decrease the protection afforded by the vaccine. It isn’t clear why this was the case, but the phenomenon isn’t entirely strange. Haynes and his team point out that the presence of IgA has been known to similarly compromise the immune response to tumors.
To stress the limitations of its findings, the team referred to their markers as “correlates of risk,” rather than protection. Still, these are the first such markers to have been found in an HIV vaccine trial, and their discovery has buttressed the credibility of the trial result. Researchers are planning studies to test various hypotheses to explain the phenomenon. The discovery also will influence the design of future vaccine candidates and the clinical trials in which those candidates are evaluated. Trials slated to be conducted in Thailand and South Africa are already being planned in the hope of improving upon the results of RV144.
There have also been major successes on the vaccine design front over the past year. HIV researchers have made important breakthroughs in approaches to designing both immunogens – the active agents of vaccines – as well as vectors, the genetic vehicles in which HIV immunogens are delivered. One such approach seeks to devise vectors that are safe, yet capable of replicating like a naturally occurring virus after they are introduced into the body. All vectors currently used to make HIV vaccine candidates are, for safety reasons, engineered to be incapable of replication. The hope is that replicating vectors, by more closely mimicking a natural infection, will elicit more sophisticated and enduring immune responses to HIV immunogens.
That notion found support in the results of a study done on an animal model of HIV that was published in the journal Nature this summer. In that study, led by Louis Picker, associate director of the Oregon Health & Science University's Vaccine and Gene Therapy Institute, rhesus macaques were given an experimental vaccine based on a novel replicating viral vector bearing immunogens derived from simian immunodeficiency virus (SIV), the monkey analogue of HIV. When the macaques were later exposed to SIV, all of them went on to develop infection. But, one year later, while the unvaccinated ones had developed simian AIDS, more than half of the vaccinated primates had suppressed SIV so effectively that the virus could not be detected in their bodies. In fact, they showed no sign of ever having been infected. Picker and his colleagues are now studying ways to adapt this vector to human use.
There has been a flurry of activity in immunogen design as well. Researchers at and affiliated with IAVI and The Scripps Research Institute, as well as a separate team working at the Vaccine Research Center of the U.S. National Institutes of Health (VRC), have made notable progress in the study of antibodies that target a broad spectrum of circulating HIV variants. The hope is that these antibodies will yield clues to the design of immunogens that elicit similarly broadly neutralizing antibodies.
All of the antibodies isolated by the VRC-led team target the part of the virus that makes direct contact with its docking station on HIV’s target cell, known as the CD4-binding site. The VRC team recently published an important paper in the journal Science that parsed the genetic origins of these kinds of antibodies. Their analysis reveals that the CD4-binding broadly neutralizing antibodies, despite having been isolated from different and unrelated people, share a very similar genetic lineage. All of them also go through an exceptionally extended process of change and refinement at the genetic level as they mature into potently neutralizing antibodies. This information could someday be applied to vaccine design, allowing researchers to create immunogens that sequentially direct the generation of increasingly potent broadly neutralizing antibodies. More immediately, however, it could help vaccine developers devise methods to quickly assess whether candidate immunogens in trials are inducing the CD4-binding broadly neutralizing antibodies likely to protect people from HIV.
But the CD4-binding site isn’t the only viable target for antibodies. Indeed, researchers at the IAVI Neutralizing Antibody Center at The Scripps Research Institute, which serves as the headquarters of the Neutralizing Antibody Consortium (NAC), published in Science earlier this year a report on the isolation and characterization of 17 novel broadly neutralizing antibodies that target a variety of different sites on HIV. This brings to 20 the number isolated through a hunt for such antibodies that was launched by IAVI in 2006 in partnership with research centers in a dozen countries on four continents.
Some of the broadly neutralizing antibodies are 10 to 100 times as potent as previously isolated ones. This is of interest because, in theory, a vaccine would only need to induce relatively low levels of a similarly potent antibody to confer protection from HIV. This matters because there is no guarantee that people will produce high levels of antibody in response to an AIDS vaccine candidate. Studies of the neutralizing breadth and potency of the newly isolated antibodies also revealed information of potential value to vaccine design. Based on their analysis, the NAC team suggested that a vaccine devised to elicit broadly neutralizing antibodies will probably need to elicit multiple combinations of such antibodies to provide comprehensive protection from HIV.
That insight might be put to the test within a few years: immunogen design based on the close study of broadly neutralizing antibodies has recently begun to gather pace. Researchers at a variety of laboratories, including those of the VRC and the NAC, have made significant headway in capturing, at an atomic scale, the molecular structures targeted by some of the major broadly neutralizing antibodies. They have even made significant progress in their attempts to recreate those structures for evaluation as candidate immunogens.
The one thing that could stall this renaissance in AIDS vaccine design and development is a shortage of resources. Global funding for the effort has so far held relatively steady – $859 million was invested last year, a $9 million decline from 2009, according to the HIV Vaccines and Microbicides Resource Tracking Working Group, in which IAVI participates. But a sudden decline in funding remains a looming possibility due to the economic troubles that have beset traditional donor nations.
That would be a pity. AIDS vaccine research is advancing at a rate that would have been unimaginable just a few years ago. Success in this endeavor likely will stretch far beyond HIV, as the strategies, tools and technologies that are being developed to solve the most stubborn problems of HIV vaccine design are likely to find useful application in the prevention and treatment of a variety of human diseases. But most of all, the successful creation of a broadly preventive HIV vaccine would have a major impact on curbing the HIV pandemic, which has so far taken approximately 30 million lives and devastated communities and economies across the globe.
And that’s a goal worth supporting – through thick as well as thin.
Margaret McGlynn is president and CEO, and David Cook is COO of the International AIDS Vaccine Initiative.
The prospect of HIV Vaccine becoming available in the foresable future is an encouraging news. This is especiALLY so especially for those of us working with orphans, people living with HIV, clergy, women and youths in developing Countries. Keep on the research as we keep on with care and support. God will make it a reality.
— Rev. Moses J. K. Thliza on 2012-01-03