The failure of Merck & Co.'s once-promising AIDS vaccine has cast a pall over research efforts and forced delays in trials of other experimental vaccines as scientists ponder what went wrong.
After more than two decades of work, vaccine researchers were hoping to be further along. Even if other vaccine initiatives eventually succeed, the arduous process of development and testing means that there won't be an immunization to prevent HIV for at least another decade, one top federal researcher says.
The Merck vaccine not only failed to protect participants in the trial, it also might have put them at a greater risk of contracting the virus, company officials said last week.
"The recent Merck trial results were a big blow to the field," said Dr. Gary Nabel, director of the National Institutes of Health's Vaccine Research Center in Bethesda.
He said few in the field believed that the vaccine would provide total immunity, but "it had absolutely no effect. We thought maybe it would have a little effect and maybe that would point us in some direction we could follow up on."
Instead of looking forward to the next vaccine candidate, scientists at the NIH and elsewhere must first look back to make sure that mistakes are not repeated. A large clinical trial involving human subjects being done by Nabel's center has been pushed back to mid-2008 while a half-dozen smaller trials in earlier testing phases have been paused.
The Merck results don't mean researchers are at a dead-end, several insisted. In the 1930s, two major vaccines for preventing the polio virus failed "miserably," said Mitchell Warren, executive director of the nonprofit AIDS Vaccine Advocacy Coalition.
"The world didn't say, let's abandon the search," he said. Two decades later, two vaccines were developed that led to the eradication of polio in the United States.
Merck was the only pharmaceutical company developing a vaccine - spending 10 years, untold millions of dollars and some top scientific talent toward that end - and a company official said last week that it has no other vaccine candidate in development. That removes a major player, though government money and foundation dollars are likely to keep flowing to others doing vaccine research.
The Merck failure also raises important scientific questions. In analyzing the results, the company said 49 cases of HIV infection were seen among 914 male volunteers after they got the vaccine, compared with 33 cases of HIV infection among the 922 male volunteers who got a placebo.
The vaccine used a disabled form of a common cold virus to carry three synthetic fragments of HIV genetic material into the body's cells. The cold virus was believed to be the perfect vector because it replicates very quickly inside the cells it infects.
But because some people already have some immunity to the common cold, the vector might have led to the vaccine's failure. If the immune system failed to respond when the cold virus arrived carrying the vaccine, then it might not have known that the vaccine was there at all. In the Merck trial, those vaccine recipients with the highest immunity to the cold virus were some of the most likely to get HIV.
"It's unequivocal that the vaccine cannot cause infection," Dr. Keith Gottesdiener, vice president for clinical research at Merck, said last week. "But it raises the possibility of increased susceptibility of the volunteers. We don't yet understand the reasons."
There are two dozen groups around the world actively pursuing an AIDS vaccine. Only two major clinical trials have taken place and neither has succeeded.
Scientists have taken two basic paths toward an AIDS vaccine. Some researchers have taken a more traditional route by trying to prompt the body to make neutralizing antibodies to fight off the virus before infection can take hold. Others take a tack similar to Merck's in trying to trigger a cellular response to HIV once it has invaded, forestalling disease at that point. Many researchers agree that a combination of both will probably be needed to create a successful vaccine.
A vaccine in the pre-clinical trial stage at the University of Maryland School of Medicine's Institute of Human Virology, which received a $15 million grant this summer from the Bill & Melinda Gates Foundation, is based on antibodies, an approach considered the more difficult of the two. Officials there declined to comment on the impact of the Merck failure.
Each approach uses a different methodology to get there. Some are similar to the one employed by Merck, raising questions about whether those will also raise the risk of infection in volunteers who receive them. But scientists say many of the cellular-based vaccines should be different enough to be able to move forward safely.