Balancing AIDS Vaccine Research

Leading AIDS vaccine researchers gather to discuss balancing AIDS vaccine funding

By Kristen Jill Kresge

The US National Institute of Allergy and Infectious Diseases (NIAID), one of the major financial supporters of AIDS vaccine research and development, is reevaluating its funding allocations in light of the recent failure of Merck’s vaccine candidate in the Phase IIb test-of-concept trial, known as STEP, as well as pressure from scientists.

Without more money, which remains unlikely given the NIAID budget has remained flat for five years, the question is whether available funds should be shifted away from clinical development and directed toward basic discovery research grants. “I think the answer is an overwhelming yes,” said Anthony Fauci, director of NIAID, at the conclusion of a day-long summit on HIV Vaccine Research and Development held March 25 in Bethesda, Maryland. “We will make adjustments to existing resources.”

Fauci said he would likely start by moving US$10 million over to discovery research in 2009 to fund a request for research proposals with the goal of stimulating broad new approaches. “There are so many things we do not know in this field of HIV vaccines,” he said.

The US government is the largest financial backer of AIDS vaccine research and the majority of this funding is funneled through the National Institutes of Health to NIAID. Last year NIAID spent $1.5 billion on all areas of AIDS-related research (see Figure 1). Of this amount, $497 million funded AIDS-vaccine research and development—47% went to basic or discovery research, and 38% funded clinical development. NIAID is providing an additional $300 million over seven years, through a separate funding mechanism, to the Center for HIV/AIDS Vaccine Immunology (CHAVI), a virtual consortium of AIDS vaccine researchers.

Figure 1. Breakdown of NIAID's 2007 AIDS Research Budget

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More funding for discovery research could also be freed up if NIAID chooses to move forward with a scaled-down version of the PAVE 100 trial—a planned Phase IIb test-of-concept trial with a combination regimen of DNA and adenovirus serotype-5 (Ad5) candidates (see What Next?, IAVI Report, September-December 2007). “Trials cost more money than grants,” Fauci said, adding that conducting that trial in 3,000 volunteers, instead of the 8,000 originally planned for, would save between $35 million and $60 million over seven years.

The start of the PAVE 100 trial was postponed following the results of the STEP trial and discussions are still ongoing. “Everything is going to be looked at,” Fauci said. “We need to look much more carefully at these clinical trials, both in their design and their scope.”

Responding to a call from one group to cut government-sponsored funding of AIDS vaccine research all together, Fauci and the more than 200 researchers who gathered for the summit remained steadfast in their commitment to discovering an AIDS vaccine. “Under no circumstances will we stop AIDS vaccine research,” Fauci said. “I’m going to keep fighting like crazy for more money.”

Several researchers echoed these sentiments. “There’s no better health impact on prevention and disease control than vaccines,” said Adel Mahmoud of Princeton University and summit co-chair.

Stepping back

The allocation of funding between discovery and clinical research pillars was called into question recently by a group of outspoken researchers; first in a letter to NIAID and later publicly at the Conference on Retroviruses and Opportunistic Infections (see Clues from CROI, IAVI Report, January-February 2008). This cadre of scientists urged NIAID to place a higher priority on basic discovery research because of the outstanding questions about how best to develop a vaccine against HIV/AIDS.

Some of these questions surfaced when Merck’s vaccine candidate showed no efficacy in either preventing HIV infection or modulating peak viral replication in individuals who became HIV infected despite vaccination (see A STEP back?, IAVI Report, September-December 2007). Things went from bad to worse when researchers later reported that among certain sub-groups of individuals—mainly uncircumcised men with pre-existing immunity to the Ad5 vector—there was a trend toward a higher susceptibility to HIV among vaccine recipients (see Clues from CROI, IAVI Report, January-February 2008).

An explanation for the candidate’s failure or the potential effect vaccination had on HIV acquisition remains elusive. Yet, in light of these results, researchers in the field began looking critically at the current clinical pipeline and the strategies to stimulate protective immunity against HIV. “The field is clearly at a critical crossroads,” said Warner Greene, director of the Gladstone Institute of Virology and Immunology and co-chair of the summit.

Throughout the summit researchers discussed several of the still largely uncharted territories in AIDS vaccine discovery. Among them were the need to more fully understand mucosal immunity and its role in protecting against HIV infection (see The great barrier); the ability of certain nonhuman primate species, including sooty mangabeys and African green monkeys to control simian immunodeficiency virus (SIV) infection; the early events in HIV/SIV transmission and infection; the validation and utilization of the nonhuman primate model; and how to induce broadly neutralizing antibodies against HIV.

“The biggest challenge is what is a promising vaccine,” said Rafi Ahmed, an immunologist from Emory University. He emphasized the importance of research into developing vaccine candidates that can stimulate neutralizing antibodies, a task that has stumped the field for many years. “I know something about T cells,” he said, “CD4+ T cells on their own have great limitations. Vaccine concepts that test only one arm of the immune system are doomed for failure,” added Ahmed. “Let’s remember what we learned in immunology 101.” This idea was repeated a week later when many of the same researchers gathered for the annual Keystone Symposium on HIV Vaccines: Progress and Prospects (see Down, but not out).

A recurring theme at the summit was the need for more checks and balances before candidates advance into clinical trials. Ahmed proposed a clear, yet stringent, requirement for late-stage trials, saying that a vaccine candidate should not enter efficacy trials unless it induces responses from both arms of the immune system.

But this does not mean that clinical development should be stopped entirely. Almost everyone agreed that clinical research, in the form of Phase I and II trials, was still necessary. “We have a lot to learn from clinical investigation,” said Alan Bernstein, who was recently appointed executive director of the Global HIV Vaccine Enterprise. Several participants spoke instead about more carefully bridging discovery and clinical research to ensure that each was informing the other. To achieve this, Scott Hammer of Columbia University, said a “nimble, collaborative clinical trial system” is required. Others proposed using the already-established clinical trial infrastructure to explore research questions that could inform the design of future vaccine candidates. “There needs to be more emphasis on discovery,” said Ahmed, but “this should not come at the expense of jeopardizing the clinical infrastructure.”

Between mice and men

In a session devoted to the strength and limitations of the current animal models for HIV infection and their role in vaccine discovery, Louis Picker of Oregon Health and Sciences University said any rational approach to AIDS vaccine development would have to involve full exploitation of the nonhuman primate model.

But to fully exploit this model, more consistency is required. Jeffrey Lifson of the National Cancer Institute called for more standardization among nonhuman primate models, including the strains of challenge viruses used when evaluating candidates. The failure of MRKAd5 ignited some discussion among researchers about the utility of the SHIV model, a hybrid simian/human immunodeficiency virus (see Getting it right early, IAVI Report, September-December 2007). Talk about the utility of the SHIV model continued, but many researchers overwhelmingly spoke in favor of using the SIV challenge model to prioritize pre-clinical vaccine candidates. “The SIV system has many problems, but there are many aspects of it that are highly reminiscent of HIV,” said Malcolm Martin of NIAID.

Ronald Desrosiers of New England Primate Research Center called for extensive pre-clinical testing of viral vector-based vaccine candidates in nonhuman primates, although he admitted he had a hard time imagining any viral vector used to deliver HIV immunogens being successful against HIV, “without some breakthrough discovery that I just don’t see coming right now.” Instead, he touted more creative approaches, including the use of viral vectors to deliver HIV monoclonal antibodies.

Overall there was little dissent about the role of nonhuman primate models in preclinical development, but some participants were reluctant to endorse the model as the “gatekeeper” by which decisions are made about which vaccine candidates should be advanced into clinical trials. Julie Overbaugh of the Fred Hutchinson Cancer Research Center argued that none of the nonhuman primate models have been validated in their ability to predict vaccine efficacy in humans. “It [the nonhuman primate model] shouldn’t be used solely as a go no-go,” said Seth Berkley, president and chief executive officer of IAVI.

Influx of ideas

If there was one point where there was almost unanimous agreement, it was on the need for more creative approaches to vaccine discovery. Carl Dieffenbach, director of the Division of AIDS at NIAID, said that in 2007, NIAID funded all “meritorious” discovery grants on HIV vaccine research that were solicited. He said this was not a comment on the amount of funding available, but rather the “dearth of ideas.”

“The easy things have been done,” said James Hoxie of the University of Pennsylvania. There are several innovation programs currently operating in the field, including those from IAVI and the Bill & Melinda Gates Foundation, but other mechanisms for supporting novel research are still required, according to many summit attendees. Bruce Walker of Harvard University said coming up with innovative ideas isn’t the problem, it is actually having the money to test them.

Some ideas for encouraging innovation were recruiting young researchers into the AIDS vaccine field and also collaborating with scientists from outside, but related, disciplines. The hope is that young scientists would bring fresh perspective to this now 25-year-old problem. “The real next step is going to come from outside this room,” said Mahmoud.

And although this point was mentioned repeatedly throughout the day, the question of just how to recruit young researchers remained largely unanswered. “We have to find mechanisms to recruit young people into the field and not just talk about it,” said Dennis Burton of the Scripps Research Institute. More guidance on this issue may come from future sessions—Fauci said this meeting was just the initial step and that finding the right balance in AIDS vaccine research would be an iterative process. “We’re just getting started,” added Hoxie.