Special Coverage: 11th Retroviruses Conference

Early HIV vaccine setbacks dim prospects for near term but possibilities exist

Research pipeline is full of potential solutions

The first potential HIV vaccine heading down the track has been derailed, but vaccine experts are optimistic that success still may be possible with some competing approaches, including some that are just getting started.

Vaccine research presented at the 11th Conference on Retroviruses and Opportunistic Infections, held in February in San Francisco, shows unequivocally that the AIDSVAX vaccine, sponsored by VaxGen Inc. of Brisbane, CA, provided no protection against HIV for injection drug users who were enrolled in a phase III trial in Thailand.1

AIDSVAX was found to be ineffective in earlier U.S. clinical trials, and a new analysis of that earlier study also found the vaccine had no impact on vaccine efficacy to prevent infection and had no impact on disease progression in subjects who became infected.2

Although these first findings are discouraging, vaccine experts say there are many novel approaches being explored, so it still is too early to give up on the idea of a successful HIV-1 vaccine.

"The first two phase III studies on an HIV sub-unit vaccine were not successful, and the challenge now is to find other vaccine candidates that might be successful," says Kenneth H. Mayer, MD, an infectious disease physician with Miriam Hospital in Providence, RI, a professor of medicine and community health at Brown University, and a medical research director at Fenway Community Health.

There are some exciting and novel vaccine approaches being studied, but it’s difficult to predict which approach may work, he says.

"There are a lot of things in the pipeline that will take time," Mayer adds.

Making the best use of limited resources

The vaccine research field has had some controversy over what is the best use of limited resources.

"Are we ready to spend huge sums of money for clinical trials when the basic research results suggest an approach may not work, or should we spend more money on basic research?" asks Michael Cho, PhD, an assistant professor in the Department of Medicine at Case Western Reserve University in Cleveland.

"There are arguments to both sides, and both are good and it’s an ongoing debate," he adds. "Personally, having done nonhuman primate vaccine studies and having looked at the data, I’m not too optimistic with our current plans for phase III clinical trials."

The level of immune response and the type of immune responses elicited by vaccine candidates now being prepared for phase III trials are not potent and not the right type, Cho explains.

One of the studies that is furthest along is the AIDS vaccine trial in Africa, which is sponsored by the National Institutes of Allergy and Infectious Diseases (NIAID). This Phase I study uses the experimental canarypox vector vaccine that incorporates genes from clade B viruses.

If it turns out that the most advanced vaccine approaches prove unsuccessful, it might be a decade or longer before one of the pre-clinical novel approaches reaches this stage.

However, it’s only a guess at this point, the experts say.

"I think we don’t really know how long it will take before we have a vaccine that’s available," says Susan Buchbinder, MD, director of the HIV Research Section of the San Francisco Department of Public Health.

"There’s a wonderful quote from a polio investigator 10 years before there was a licensed Salk vaccine; and the investigator said, We don’t understand the basics of polio and might not see a vaccine in our lifetime,’" she says. "So we don’t really ever know how far away we are."

The good news about the VaxGen studies is that these demonstrated the feasibility of the mechanics of doing clinical vaccine trials, Mayer explains.

Subjects in both the United States and Thailand had high rates of retention; and with the education offered as part of the trials, there was a general tendency toward reducing risk taking, he notes.

Also, investigators have been using AIDSVAX data to help improve phase III trial design for future vaccine trials.

"We’re trying to think about how to evaluate vaccines that impact viral load during efficacy trials," says Peter B. Gilbert, PhD, associate member of the Fred Hutchinson Cancer Research Center in Seattle. Gilbert was an investigator involved in the study of the AIDVAX vaccine’s effects on preventing infection and delaying disease.

Controversial subset

While there was some controversy over the racial subset in the U.S. AIDSVAX trial, a subsequent analysis presented at the retroviruses conference suggested that there isn’t a good reason to think there was a major difference by racial subgroups, Mayer adds.

The U.S. AIDSVAX study found that among a small subset of African-Americans, there appeared to be efficacy and increasing efficacy with increasing risk. But these numbers were small, and an independent analysis found that these differences did not suggest any sort of protection from the vaccine among certain ethnic groups.

National Institutes of Health investigators and others concluded that analyses of HIV risk behavior, antibody response, and type of infecting strain did not support a biologic explanation for a different vaccine efficacy by racial/ethnic subgroups.3

Despite this interpretation, the vaccine research field should take a closer look at the AIDSVAX studies and see if there are some clues to what may work in a future vaccine, suggests Marc Gurwith, MD, senior vice president for medical affairs with VaxGen.

"I think people are ignoring what might be clues from our trials," he says.

Buchbinder points out that the AIDSVAX data regarding minority subgroups will never tell researchers definitively whether the findings were due to chance or effect.

"If we found a vaccine that found efficacy in a subgroup, particularly one that was so heavily impacted by the epidemic, then that would be incredibly good news," she says.

However, the AIDSVAX study’s data on the minority subgroup was not significant statistically because there were not enough African-Americans enrolled in the trial, Buchbinder continues.

"The lessons here are that you have to be very careful when you report results to the public, so people are clear about what you know," she says. "You don’t put out results before you do appropriate statistical analyses and hypotheses."

VaxGen earlier had been criticized for offering false hopes to African-Americans by releasing their data regarding that subgroup.

"I don’t want to create any false hopes," says Gurwith. "It’s hard to imagine a vaccine that you give only to certain racial groups, but the only reason I think there’s something there is because it’s a statistical issue."

However, researchers should not dismiss the AIDSVAX results entirely, especially since it may be years before the HIV vaccine field has any validated approaches, he adds.

VaxGen will not be pursuing further vaccine research until the company receives outside support, Gurwith says.

Meantime, there are a number of promising vaccine approaches at various stages of development.

The key is that government funding is needed at all levels of vaccine research, the experts say.

"I’m optimistic in the long haul," Mayer says. "In the short haul, it’s very clear that with a lack of success in the VaxGen trials and because that vaccine wasn’t shown to be beneficial, we’re years away from a successful vaccine."

References

1. Pitisutithum P. Efficacy of AIDSVAX B/E vaccines in injecting drug use. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract: 107.

2. Gilbert PB, Cai T, Self SG, et al. Joint assessment of HIV vaccine effects on preventing infection and delaying disease in the first phase 3 trial of AIDSVAX B/B. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract: 283.

3. Follmann D; Gilbert P; Self S, et al. An independent analysis of the effect of race in VAX004. Presented at the 11th Conference on Retroviruses and Opportunistic Infections. San Francisco; February 2004. Abstract: 106.