Vaccine development moves to front burner

Critics say president’s vaccine plan inadequate

Three years after the National Institutes of Health nixed the first large human trial for an AIDS vaccine, the government is jump-starting a stalled vaccine initiative that has fallen behind the development of new AIDS treatments. While the new effort has been lauded, many scientists and AIDS advocate groups say more support is needed than what President Clinton proposed in his AIDS agenda in December.

The most supported aspect of the initiative is the announcement that Nobel laureate David Baltimore, MD, a microbiologist at the Boston-based Massachusetts Institute of Technology, would head the government’s vaccine research. But while Baltimore brings his considerable knowledge and prestige to the effort, Clinton’s plan mentions nothing about funding vaccine research or setting time lines for human trials.

In fact, the one paragraph concerning vaccines in the White House’s national AIDS strategy is not much different from the government’s past position, says Gary Rose, treatment and research coordinator for AIDS Action Council in Washington, DC.

"David is terrific," Rose says. "The problem is that he has to sit down with all the stakeholders, all the researchers, and government agencies to form a coherent and cost-effective strategy to develop a vaccine. But does this government have any idea how much this is going to cost?"

Treatment unavailable to most HIV+ people

To date, less than 5% of the $4 billion spent on worldwide AIDS research has been dedicated to vaccines, according to the Rockefeller Foundation, which has become a key player in the new vaccine initiative. Of the estimated 18 million people who will become infected with HIV in the next five years, 90% will live in the developing world, where the high cost of protease inhibitors and other antiretrovirals makes treatment largely unavailable, say Rockefeller Foundation officials.

With no market incentive to develop AIDS vaccines and the correlates of protective immunity to HIV still eluding scientists, all but a few pharmaceutical manufacturers have curtailed vaccine research. Many dropped out of the race entirely in 1994 when NIH shocked the scientific community by not going ahead with a Phase III trial of the most promising vaccine candidate, gp-120.

"So far, very few companies have made any sort of commitment in this area," says Bill Heyward, MD, vaccine coordinator for the National Center for Infectious Disease at the Centers for Disease Control and Prevention. "It’s complicated — socially, politically, financially, and scientifically — and a lot of companies are just sitting back and waiting for some clarity."

In the past six months, amid new insights into protective immunity against HIV and criticism that NIH’s vaccine research structure was inadequate, vaccine research has moved off the back burner in the United States. At the same time, the World Health Organization, along with the International AIDS Vaccine Initiative, has moved ahead with plans for Phase III trials of gp-120, as well as development of HIV-DNA vaccines and live-attenuated HIV vaccines.

‘Some people think there is plenty of time’

Heyward, who recently returned to the CDC after spending five years at WHO working on vaccine development, says other countries attach more importance to an AIDS vaccine than the United States does, and saw the 1994 decision as a big step backward.

"Some people think there is plenty of time to continue basic research and turn over every molecule before developing a vaccine to go forward with," he says. "Generally, that is not how vaccines have developed in the past."

While the gp-120 trial was halted in the United States, WHO chose to forge ahead with it. This likely will be the first large vaccine trial that will not begin in the United States, but rather in Thailand, he says. Up and running with a new name (Vacsgen) and new financial commitments, gp-120’s manufacturer, Genentech of San Francisco, is modifying its vaccine antigen to fit the subtype-e strain prevalent in that country. A safety and immunogenicity trial of the product is expected to proceed this year, and a Phase III trial could begin in 1998, he adds.

Meanwhile, NIH has decided to start a Phase II trial of the ALVAC vaccine, developed by France’s Pasteur Merieux Connaught, later this spring. The multicenter trial will study the vaccine’s safety and efficacy in 400 volunteers. The only other vaccine candidates are still in the Phase I stage, including a DNA vaccine in HIV-negative people and an HIV immunotherapeutic vaccine developed by Immune Response of Carlsbad, CA.

What makes AIDS vaccine research so much more difficult than, say, a polio vaccine, is the diversity of genetic differences in the various HIV subtypes and not knowing if these differences affect immunity, Heywood says. "With HIV we can’t see the forest from the trees," he says.

Heywood and many other researchers argue that the only way scientists will discover the correlates of immunity to HIV is by going forward with one or possibly several Phase III trials to see what works and what doesn’t.

In the past year, however, scientists have explored another route through identifying those lucky few patients whose bodies naturally protect them against the virus. The recent discovery of chemokines, and their important role as receptors for HIV, has opened a new door for vaccine research. The findings suggest that without a chemokine receptor, the virus cannot infect cells, leading researchers to speculate that HIV infection can be thwarted by a vaccine that blocks the chemokine receptors. It is these very same receptors that have been found to be mutated in the 1% of white male HIV-positive patients who are naturally immune to HIV disease.

Structure of agencies a barrier

Even with the restructured NIH vaccine initiative, such leading virologists as Max Essex, MD, professor of virology at Harvard University, argue that the effort won’t succeed under NIH and that a separate organization should be created solely for AIDS vaccine research.

In the history of vaccine development, the CDC has played a prominent role, particularly in eradicating smallpox and malaria. Yet the agency has no budget for AIDS vaccine research, says Heywood.

"It’s a bit difficult to come back from WHO to find that CDC is nowhere on the map in this effort, especially if you consider that the CDC has had a lot of experience in Phase III trial evaluation," he says.

Part of Heywood’s new job is to enlarge the CDC’s role, but once again, funding is the crucial factor and Clinton’s AIDS agenda doesn’t address it, Rose says.