Balancing the AIDS vaccine budget

Leading AIDS vaccine researchers gather to discuss priorities in 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. 
The budget for NIAID has remained flat for five years. Without additional money, the question is whether available funds should be shifted away from clinical development—which involves testing vaccine candidates in a series of human trials to determine their safety and efficacy—to basic discovery research, the type that typically takes place in university laboratories or institutes and guides the design of future vaccine candidates. “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 new request for research proposals with the goal of stimulating novel approaches to AIDS vaccine research. “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 NIAID is one of the major recipients. Last year NIAID spent $1.5 billion on all areas of AIDS-related research. 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 also 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.

Responding to a call from one US group to cut government-sponsored funding of AIDS vaccine research altogether, Fauci and the more than 200 researchers who gathered at 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 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, one of the major annual scientific conferences on HIV/AIDS held in the US. They called for 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, MRKAd5, showed no efficacy in either preventing HIV infection or modulating the amount of virus in the blood (viral load) in volunteers who became HIV infected despite vaccination (see VAX October-November 2007 Spotlight article, A STEP back?). 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 modified cold virus used as the vaccine vector—there was a trend toward more HIV infections occurring among vaccine recipients in the STEP trial (see VAX February 2008 Primer onUnderstanding Biostatistics and the STEP Trial). This trial was funded in part by NIAID.

There is still no explanation for the candidate’s failure or the potential effect vaccination had on HIV infection risk. 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.

Following the results of the STEP trial, NIAID postponed the start of a large Phase IIb test-of-concept trial, known as PAVE 100, to evaluate a prime-boost regimen with two candidates developed by researchers at NIAID’s Vaccine Research Center, one of which uses a similar adenovirus serotype-5 (Ad5) vector (see VAX October-November 2007Spotlight article, A STEP back?). Discussions about if or how this trial will proceed are ongoing. “Everything is going to be looked at,” said Fauci. “We need to look much more carefully at these clinical trials, both in their design and their scope.”

One possibility Fauci suggested is moving forward with a scaled-down version of the PAVE 100 trial. This could free up more funding for basic discovery research. “Trials cost more money than grants,” he 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.

Identifying research priorities

Throughout the summit researchers discussed several of the still largely uncharted territories in AIDS vaccine discovery. Among these, were the need to more fully understand mucosal immunity and its role in protecting against HIV infection (see VAX January 2008 Primer on Understanding HIV Transmission); the ability of certain nonhuman primate species to effectively control infection with the related monkey version of HIV, known as simian immunodeficiency virus (SIV); the early events in HIV/SIV transmission and infection; and how to induce broadly neutralizing antibodies against HIV (see VAX February 2007 Primer on Understanding Neutralizing Antibodies).

“The biggest challenge is what is a promising vaccine,” said Rafi Ahmed, an immunologist from Emory University. He emphasized the importance of developing vaccine candidates that can stimulate neutralizing antibodies against HIV, a task that has stumped researchers for many years. Candidates like MRKAd5 and those developed by the VRC induce primarily, if not exclusively, T-cell responses against HIV (see Primer, this issue). Ahmed suggests that only candidates that induce both T-cell and neutralizing antibody responses should be advanced into efficacy trials. “Vaccine concepts that test only one arm of the immune system are doomed for failure,” he added.

But this does not mean that clinical development should be stopped entirely. Almost everyone agreed that Phase I and II clinical trials are 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. “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.

Some researchers called for extensive pre-clinical testing of AIDS vaccine candidates using SIV in nonhuman primates to prioritize the best candidates for advancement into clinical trials (see VAX October 2006 Primer onUnderstanding AIDS Vaccine Pre-clinical Development). But others were reluctant to endorse the nonhuman primate model as the “gatekeeper.” Julie Overbaugh of the Fred Hutchinson Cancer Research Center argued that none of the monkey 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 on which there was almost unanimous agreement, it was 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 scientists into AIDS vaccine research and also collaborating with researchers 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 between discovery and clinical research would be an iterative process. “We’re just getting started,” added Hoxie.