HIV Vaccine Reduces Infection Risk
September 24, 2009
For the first time, an investigational HIV vaccine has shown it can protect people from the virus -- a giant step forward in a field that has been humbled by repeated failure, experts said.
Scientists involved in the so-called RV-144 study, a large proof-of-concept trial conducted in Thailand, released some details early today.
The key finding: In a large population of everyday people at relatively low risk for HIV, the vaccine reduced the chances of infection by 31.2% compared with placebo, according to Col. Jerome Kim, MD, deputy director of science for the U.S. Military HIV Research Program.
"This is the first evidence that a safe and effective HIV vaccine is possible," Kim said.
Although the effect was repeatedly described as "modest," the finding was also called a major scientific achievement that paves the way for better vaccines.
"We now know that this is a doable objective," said Alan Bernstein, PhD, executive director of the New York-based Global HIV Vaccine Enterprise, which was not involved in the study.
Bernstein said there were many who, after repeated failures, considered an HIV vaccine impossible. Most recently, a closely watched vaccine candidate failed dramatically, and even seemed to increase the risk of getting HIV. (See CROI: HIV Vaccine's Mysterious Failure Leads to Call for New Directions)
Given previous failures, the latest finding is "incredibly important," said Harriet Robinson, PhD, of Atlanta-based GeoVax, which is developing its own HIV vaccine candidates.
"This is a ground-breaking demonstration that an HIV/AIDS vaccine can prevent infection, something that the scientific community had begun to doubt," she said.
But Bernstein and others cautioned that the result is only proof that a vaccine can be made to work. It is likely to take years of additional research to get a drug on the market, they said.
"I'm incredibly optimistic about it -- it made me smile this morning," said Jill Gilmour, PhD, of the New York-based International AIDS Vaccine Initiative, which did not have a role in the research.
The trial results will "re-energize the field," she said.
But Gilmour said she and other researchers will now want to drill down into the data collected in the study to see how a more effective vaccine can be developed.
"We're out of the blocks," she said. "Now can we get to the finish line?"
The researchers involved in the trial, too, said they need more time to digest all the data.
For one thing, despite the success in preventing infection, Kim said, there was no effect on the other main goal of the trial -- to see if the vaccine could lower the amount of virus in the bloodstream of infected people. When volunteers were tested between three and six months after their infection, levels among those in the placebo and vaccine arms were the same.
Side effects were the same in both arms of the trial and more information is expected in October, at a Paris conference sponsored by the vaccine initiative.
The Army was one of the partners in the $105-million trial, along with the Thai Ministry of Public Health, the National Institute of Allergy and Infectious Diseases (NIAID), Sanofi Pasteur, and Global Solutions for Infectious Diseases.
A host of questions remains to be answered, according to Anthony Fauci, MD, director of the NIAID.
The key one, he said, is what caused the result.
"We have a positive signal," Fauci told reporters. But "what immunological parameters gave us this result" remains a mystery.
Fauci and other experts have, in a sense, been working blind for years because they didn't know what a positive immune response to HIV would look like on a biological level.
Now, with a vaccine that has demonstrated at least some protection, they hope to be able to tease out the so-called "correlates of immunity" -- biological changes that signal an immune response.
"There's nothing like a positive result to help us focus on some critical questions," he said.
Fauci said a central scientific question is why there was a discordant effect on the two study endpoints -- some protection against infection but no apparent effect on viral load.
The finding "strongly suggests" that the immune mechanisms that block infection and those that control the virus after infection are different, he said.
Among the other questions that need answers, Fauci said:
* How long does the benefit of the vaccine last?
* Will booster shots be needed?
* Can the efficacy be boosted above the 30% level?
* How well will the approach work in high-risk groups, such as men who have sex with men, or injection drug users?
* Will the approach work against all subtypes of HIV?
"We have a great deal of work ahead of us," Fauci said.
"But today I have a renewed sense of optimism -- cautious optimism -- at the possibility of improving on these encouraging results," he said, "and ultimately developing a highly effective vaccine to protect against HIV infection."
It's unlikely, however, that this vaccine candidate will go to the FDA for licensing, if only because the trial itself was not set up to provide the kind of data the agency requires, according to Col. Nelson Michael, MD, PhD, director of the U.S. Military HIV Research Program.
Also -- even in places where the incidence of HIV is high -- a 31% benefit is not enough to justify using a vaccine, Bernstein said.
The trial randomized 16,395 community volunteers from the central Thai provinces of Chon Buri and Rayong, rather than high-risk groups, as many other vaccine studies have done.
In the final analysis, there were 74 infections in the placebo arm, compared with 51 in the vaccine arm, a difference that was significant at P=0.039 with a 95% confidence interval from 1.1% to 52.1%.
The trial tested a so-called "prime-boost strategy" using two different medications.
The first, dubbed ALVAC-HIV, was a canarypox virus, engineered so it could not cause disease, and modified to carry synthetic versions of three HIV genes, known as gag, env, and pro.
Volunteers were given four injections of ALVAC-HIV over six months or a matching placebo.
At the last two injections, they were also given a shot of AIDSVAX B/E (or placebo) -- a vaccine candidate that had been tested on its own and found to be safe, but without benefit. After the six-month vaccination phase, the volunteers were followed for three years, with HIV testing every six months.
The AIDSVAX B/E contains an HIV protein known as gp120.
The idea was to prime the immune system with the first vaccine and then boost it with the second. Researchers hoped to elicit both antibodies to HIV and killer T cells that would destroy the virus.
Both medications contained HIV fragments from subtype B -- common in Europe and North America -- and subtype E, found in Thailand and Southeast Asia.
It does not contain elements of the so-called clade C HIV strain, which is the main subtype found in Africa, where an estimated 22 million people are living with HIV -- 67% of the global total.
The trial was controversial when it started, largely because of the previous failure of the AIDSVAX component.
"There were many prominent scientists who thought this trial should not go forward," Bernstein said, and even supporters could not have predicted the outcome, especially the discordant results of the two endpoints.
"Like all good experiments, (the trial) raises more questions than it answers," he said.