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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 on Understanding 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 2007 Spotlight 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.”

GLOBAL NEWS:

HIV Vaccines: Progress and Prospects

Just a few days after many of the leading researchers in the AIDS vaccine field gathered for the HIV Vaccine Summit (see Spotlight, this issue), they reconvened in vastly different environs for the annual joint Keystone Symposia on HIV Vaccines and HIV Pathogenesis. This year’s meeting took place from March 26 to April 1 in Banff, Canada, and like the field itself, was more focused on fundamental immunology and discovery research.

Many speakers remarked in some way on the results of the STEP trial and its repercussions. Larry Corey of the University of Washington said during his opening keynote presentation that the STEP trial has “recalibrated” the HIV vaccine field, but he dismissed the notion that nothing positive has come out of it and made it clear that in his estimation, the results from the STEP trial do not mark the end for vaccine candidates that stimulate T-cell responses and not neutralizing antibodies (see Primer, this issue). “The ability to make such vaccines may be more approachable than getting effective neutralizing antibody vaccines,” Corey said.

Researchers presented some updated data from the ongoing analyses of the trial. Susan Buchbinder of the San Francisco Department of Public Health, and a principle investigator on the STEP trial, said there was a two- to three-and-a-half-fold increase in risk of HIV infection in the vaccine group as the level of antibodies against adenovirus serotype-5 (Ad5), which was the modified cold virus used as the vaccine vector, increased. Corey and Buchbinder addressed possible explanations for this observation. The majority of volunteers in the trial were men who have sex with men and so one possible mechanism is that more Ad5-specific CD4+ T cells were present in the rectal mucosal tissues, creating more targets for HIV, according to Corey. He also said an indirect biological mechanism could be at play and that perhaps the vaccine candidate interfered with the body’s innate or natural immune responses against HIV. Buchbinder said analyses of other potential confounding factors—including sexual networks, clusters of infections, and changes in sexual behavior—which may also help explain this observation are still ongoing (see VAX February 2008 Primer on Understanding Biostatistics and the STEP Trial).

Efforts to more fully understand mucosal immunology (see VAX January 2008 Primer on Understanding HIV Transmission), the types of T-cell responses a vaccine should induce (see Primer, this issue), and the mysteries of individuals who are HIV infected but are able to control the virus (long-term nonprogressors), all figured prominently at this meeting and remain clear priorities for the field. “There isn’t one way forward or one simple way forward,” said Alan Bernstein, executive director of the Global HIV Vaccine Enterprise. “If anyone says there is they’ve got a crystal ball that I don’t have.”

First Phase I trial of Ad26 vector begins

Dan Barouch and colleagues at the Beth Israel Deaconess Medical Center in Boston began enrolling volunteers in April for a Phase I clinical trial to evaluate the safety of an adenovirus serotype-26 (Ad26) vector-based vaccine candidate compared to an inactive placebo. The trial is being conducted at the Brigham and Women’s Hospital, also in Boston, and will involve 48 volunteers randomly assigned to receive either two or three doses of the vaccine candidate. The Ad26 vector is used to carry an HIV fragment in the hope that it will trigger immune responses against HIV. The vaccine candidate itself can not cause HIV infection.

There are several serotypes of adenovirus, which is one cause of the common cold, and AIDS vaccine candidates based on adenovirus serotype-5 (Ad5) have already been tested in clinical trials. Merck’s vaccine candidate, which was tested in the Phase IIb test-of-concept trial known as STEP, used an Ad5 vector, but this is the first time an Ad26-based vaccine candidate is being analyzed in human volunteers. Ad26 was chosen because fewer people are naturally exposed to this serotype of adenovirus and therefore levels of pre-existing immunity to Ad26 are much lower throughout the world. Pre-existing antibody immunity to the vaccine vector could potentially limit an individual’s immune responses against HIV.

In preclinical studies in nonhuman primates, Barouch and colleagues also found that the Ad26 vaccine candidate was more effective than an Ad5 candidate at protecting against infection with the monkey equivalent of HIV, known as simian immunodeficiency virus (SIV). This Ad26 vector “outperforms Ad5 vectors in rhesus macaques,” said Barouch. The vaccine candidate is manufactured by the Dutch biotechnology company, Crucell.