What About AIDS Vaccines? Four Issues to Watch
A PDF of this document is available here.
September 8, 2011
Next week many AIDS vaccine stakeholders will gather in Bangkok for the annual AIDS Vaccine Conference to share updates and take stock of a field whose recent positive developments have been eclipsed by the headline-making news about PrEP and ARV-based prevention for HIV-positive people.
For many advocates, the main questions are: What about vaccines? Do they matter anymore? Will it be possible to conduct the trials to find one, given the likely expansion of the prevention toolbox? For advocates following the field more closely, one key question is: How will the field maintain its exciting scientific momentum in the context of funding constraints and threatened cuts to the NIH budget?
We hope these questions will get a full and thorough discussion at the upcoming conference. This update is a “score card” of four issues to track, whether you’re attending the conference or following from afar.
Follow-up on antibody breakthroughs
with commitment and clarity
A carefully planned research agenda is yielding exciting results. It would be a grave mistake to underfund or retreat from the path, however long, that lies ahead.
In August, two different groups released new findings on HIV-specific antibodies. These findings are described below—one bottom-line message is that neither of these findings was a lucky break or unplanned. They emerged out of years of diligent research that has taken advantage of emerging cutting-edge technologies. The findings would not have been possible a few years ago, because the technology was not yet there; and yet the work that took place a few years ago is what made these findings possible.
A team of researchers from the NIH’s Vaccine Research Center (VRC), the Center for HIV/AIDS Vaccine Immunology (CHAVI) and the International AIDS Vaccine Initiative (IAVI) mapped how B cells evolve from an immature state to the state in which they produce broadly-neutralizing antibodies against HIV. All antibody-producing B cells start with a basic “germ line” genetic code. This code is altered during a maturation process that takes a B cell from an immature state to a final, mature state in which it triggers production of potent, disease-specific antibodies. The researchers focused on the development of B cells that produce VRC-01, a previously identified broadly neutralizing antibody. They mapped the steps of maturation for B cells producing VRC-01-like antibodies and found that these cells underwent significantly more genetic alterations than matured antibodies against pathogens other than HIV. Having mapped the evolution of B cells that produce broadly neutralizing antibodies against HIV, scientists now aim to develop proteins that could be delivered through a vaccine in order to direct the development of B cell DNA to produce broadly neutralizing antibodies can work to develop vaccine strategies that coax immature B cells down the same pathways. For more on this development, check out Mapping the Long Genetic Road to Broadly Neutralizing Antibodies on the vaccine blog from the Treatment Action Group.
Also in August, a group of researchers at and associated with IAVI, Scripps Research Institute, and the biotech companies Theraclone Sciences and Monogram Biosciences reported the identification of 17 new broadly neutralizing antibodies isolated from the serum of four HIV-positive individuals who had previously been identified as “elite neutralizers”. These individuals were identified through exhaustive screening of samples from around the world; in the follow-on work, the team sought to isolate and better understand the nature of the highly potent, HIV-specific antibodies that can be found in the blood of some people with HIV.
Both of the findings described above built on previous work and suggest concrete next steps. In order for the AIDS vaccine field to maintain this momentum, it is critical that funding for basic scientific research and product development be sustained. As reported last month at the international AIDS conference in Rome, global vaccine funding declined only one percent in 2010, and the US and Europe both saw decreases. Given the primacy of US government funding, these trends could have magnified impacts on HIV vaccine funding when US stimulus funding ends this year.
To learn more about the hope and challenge suggested by findings like these, a perspective piece published September 8 in the New England Journal of Medicine provides an excellent, clear overview of what needs to be done to develop an effective AIDS vaccine. The authors, Dr. Tony Fauci, leader of NIAID, and Peggy Johnston, who led NIAID’s AIDS vaccine efforts for nearly two decades, lay out what’s been learned about the responses to HIV that occur during infection and the “unnatural” responses that a vaccine will need to induce, in order to provide protection.
Now is the wrong time to stint on funds to follow up on basic scientific breakthroughs, and it will be critical for the AIDS vaccine field to prioritize its research agenda to justify the case for continued and even increased funding.
Bring AIDS vaccines into the “real
world” of prevention innovation
AIDS vaccine effectiveness trials cannot function in a vacuum; throughout the biomedical prevention arena, not enough has yet been done to prepare for the era of combination prevention trials.
One of the greatest challenges facing the AIDS vaccine field today is also its greatest opportunity. By the time the next efficacy trial starts—the earliest date would be 2013 for a follow-on trial based on the candidates evaluated in RV144—the prevention options available in national programs may look quite different. Recent developments in ARV-based prevention clearly show that initiation of treatment at 350 CD4 cells and above slashes risk of transmission to sexual partners and has some clinical benefit for the HIV-positive individual. There are also data showing an HIV prevention benefit from trials of pre-exposure prophylaxis (PrEP) using daily oral TDF/FTC in gay men and transgender women, and in heterosexual men and women. One percent tenofovir gel also reduced women’s risk of HIV via vaginal sex in CAPRISA 004 and confirmatory research on this is also underway.
The timelines and options for and feasibility of implementing each of these strategies are distinct. But as advocates, we will have failed if there is not progress on all fronts by the time the next vaccine efficacy trial starts. It is critical for AIDS vaccine researchers and trial planners to address the design questions related to the next efficacy trials head-on.
A recent community call on the revised protocol for the HVTN 505 trial gave a flavor of this discussion. As previously reported by AVAC, HVTN 505 has revised its protocol in order to evaluate whether the vaccine strategy reduces risk of HIV infection. In the original version of the protocol, the primary endpoint was reduction in post-infection viral load. The protocol has also been revised to gather more information on PrEP use among the 2,200 gay men and transgender women in the US who will enroll in the trial.
On the call with the HVTN 505 principal investigators, advocates asked about how the trial would evaluate the potential contributions of PrEP use to vaccine protection—i.e., will the trial be able to tell whether people who received the vaccine plus PrEP had different, perhaps more potent, immune responses compared to vaccine recipients who only used PrEP. Other questions focused on how the trial was planning for success—i.e., what follow-on steps would be taken if there was evidence of efficacy, and on the types of information participants would receive about PrEP from the study team.
The answers, at this stage, are relatively simple. The trial will collect blood samples and be able to look at immune responses in participants who receive the vaccine and report PrEP use, but this kind of analysis will only provide hints about what might be happening. Because PrEP wasn’t added to trial protocol itself, the study doesn’t have the ability pre-specified questions related to vaccine plus PrEP versus PrEP alone.
Keep up with
The Thai prime-boost trial (RV144) has the potential to provide clues to guide future research; the field has to have clear plans and messages for what to do if these clues emerge...and if they don’t.
In September 2009, the leaders of the RV144 vaccine trial announced that the prime-boost strategy studied in Thailand provided modest protection. One of the most important questions was whether researchers would be able to identify immune responses linked to the observed protection. Almost exactly two years later, initial results of the extensive analysis of samples from RV144 are due to be presented in Bangkok at the AIDS Vaccine Conference.
Any association between protection and specific immune responses will be a great boon to the field—and will also trigger a range of questions. Because the analyses were post-hoc (i.e., not part of the original trial protocol), no firm conclusions about protection—or lack thereof—can be drawn. Any positive findings would need to be further explored, while a report that the team found no link between immune responses and protection might throw the trial’s original conclusion—of a modest, time-bound protective effect—into question. It is therefore critical that the field work collaboratively to develop clear messages around any results, good or disappointing, and also have clear answers about the most critical next steps.
Develop and strengthen leadership
and cooperation to meet the needs of changing
To capitalize on breakthroughs in a changing and increasingly complex environment, the field needs innovation and clarity from current, new and yet-to-be identified leaders and institutions.
Finally, this AIDS Vaccine Conference will be the first one since leading figures in the field have left their organizations. Seth Berkley of IAVI, Peggy Johnston of NIAID and Alan Bernstein of the Global HIV Vaccine Enterprise have all stepped down in the past nine months. These organizational transitions, coupled with the scientific advances and challenges, present an important opportunity to re-energize and advance the field.
AVAC has been an active member of the Enterprise and our executive director, Mitchell Warren, is a member of the Enterprise board, which is now reviewing the Enterprise mission, role and structure with the goal of ensuring that the Enterprise is best aligned to support the current and future needs of a rapidly evolving field.
Now, perhaps more than ever before, the science tells us a vaccine can be an invaluable prevention tool, as part of an expanding combination prevention package. In each of the areas described above, there is need for innovation, collaboration and leadership. In Bangkok, and in the months to come, AVAC will continue to track the scientific and organizational efforts to address the field’s most pressing opportunities and challenges.