When the outcome of the vaccine combination trial was first announced last month, the news sent shockwaves through a research community that had never seen an HIV vaccine trial end with a promising result — although questions lingered on the far-reaching impact of the study’s findings.
The collaborative team behind the recent trial, which includes the U.S. Army and the Thai Ministry of Health, said Tuesday the results of the Thailand-based study hold up under continued examination and serve as a “landmark” for the future direction of HIV vaccine research.
“This was the first successful demonstration that a vaccine, all-be-it modestly, protects people from HIV infection,” said Col. Jerome Kim, the deputy director of science for the U.S. Military HIV Research Program who co-led the study. While the trial won’t reap a public health benefit yet since the protection provided was too low, “As a scientific event it has critical importance for us,” Kim said.
The full analysis of the results was released this week at the 2009 AIDS Vaccine conference in Paris and on Tuesday in the New England Journal of Medicine.
Alan Bernstein, co-chair of the conference and head of the Global HIV Vaccine Enterprise, agreed that the trial has implications beyond the initial study.
“We are learning so much about the interaction of that vaccine with the immune system that will be invaluable for future vaccine research,” he said.
The primary analysis of the trial showed the vaccine provided a 31 percent level of protection from HIV. The study tracked more than 16,000 Thai volunteers. Of the 8,197 people given the test vaccine, 51 became infected with HIV; of 8,198 who got dummy shots, 74 became infected.
But in the weeks that followed the release of the initial findings on Sept. 24, a secondary analysis by the team was circulated among independent scientists that excluded trial participants who did not complete all the vaccinations in the trial or those who became infected with HIV early in the process.
That analysis showed a 26 percent level of protection from HIV that was not statistically significant, leading some scientists to question the trial and whether it was a research fluke. All of the analyses were included in the full results.
Science Magazine first reported on its blog on Oct. 5 that an anonymous leading HIV investigator and several other researchers criticized study leaders for not giving a fuller picture when they held a news conference announcing the initial results, and that the secondary analysis undermines the claims of success.
Col. Nelson Michael, director of the U.S. Military HIV Research Program, said the trial was designed from the start to look at the population featured in the primary analysis and that it is the “most clinically relevant,” an assessment that was backed by Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, which was the study’s main sponsor.
With the full results available, Michael said “the debate can continue in a very rich way … which is the scientific process.”
Over the years, researchers have run into numerous challenges in HIV vaccine trials. Nicole Frahm of the HIV Vaccine Trial Network worked on a Merck vaccine trial that was shut down in 2007, and was later shown to actually increase some participants’ risk of contracting the virus. She said the Thai result is a much-needed boost for efforts to develop a vaccine.
“We had two years of a trial that failed … so having a positive signal, even if it is weak and even if we are still debating if it’s real or if it’s not, is a good sign,” said Frahm.
“It’s a proof of concept that a vaccine against HIV can work,” she said, which gives researchers something to build on. “But this was not effective enough to be the one and only [vaccine] pursued.
Eric Hunter, co-director of the Emory Center for AIDS Research, said after seeing the full analysis he is “sufficiently convinced” the result was real.
“From my perspective there is good evidence from the data that there was some protection conferred by this vaccine,” said Hunter, who was one of 22 prominent scientists who signed on to a criticism of the trial in Science Magazine in 2004 when it was slated to begin.
The vaccine trial tested a combination of two weak vaccine candidates, Sanofi-Pasteur’s ALVAC canary pox/HIV vaccine and an AIDSVAX booster, neither of which had previously shown promising results in solo tests. Hunter said there were many reasons to think the trial would not be successful.
One of the problems cited in 2004 was that it would be unclear at the conclusion of the trial which of the components in the study caused the result, positive or negative. Researchers are now wrangling with that very problem, said Michael.
“”We have no idea why this series of vaccinations worked,” he said, so future investigation will need to isolate some of the elements of the trial to gather more information.
A scientific steering committee created by the U.S. Army and Thai Health Ministry team will consult with outside researchers and institutions to determine how to make the best use of the trial’s valuable samples and what future research should be pursued.
Hunter said if similar research could be done with the same vaccines in primates, that could help researchers draw missing links between animals and humans and more closely correlate HIV research.
One of the big questions the full data raises is whether the treatment provided an early, but not long-lasting, protection as some of the results seemed to suggest, Michael said.
The study has led researchers to rethink how immune response should be measured in HIV vaccine trials, as the Thai trial showed lower levels of some markers that registered relatively high in the failed 2007 Merck trial. Kim said the indicators used for measurement need to be reexamined.
Questions also remain as to why the vaccines showed no impact on viral load – the severity of an infection — of test participants that became infected. Hunter said the most that can be concluded at this point is that the vaccines are blocking an initial stage of infection, but more research will be needed to narrow the possibilities.
Bernstein said it is still too early to know the full impact the trial will have on the field, and that a vaccine that can be administered to the general population is not imminent, but that it is an important moment nonetheless.
“Today, HIV vaccine research is moving faster than any time in the last 26 years,” he said. “We still have a long way to go.”