Experts worry infection fears might keep participants from trials
MONDAY, Nov. 12 (HealthDay News) -- An experimental AIDS vaccine used in a recent trial may have placed participants at higher risk of infection with HIV -- although whether or not that was truly the case remains unclear.
What is clear is the concern among experts that the news will keep would-be trial participants away from future AIDS vaccine studies.
"That's always a possibility, and that's the reason why we have to be very transparent and open and honest, and be very energetic to educate people to understand just what went on here," said Dr. Anthony Fauci, an AIDS research pioneer and director of the U.S. National Institute of Allergy and Infectious Diseases (NIAID). The institute was a partner in the trial.
"Already we have a lot of people misinterpreting that the vaccine itself actually gave [recipients] HIV infection -- that's impossible," he said. "We have a lot of education to do, and there's always a danger that this could sour people on getting involved in vaccine trials."
Another expert agreed that the collapse of the large, phase II trial of Merck & Co.'s V520 vaccine could send the wrong message.
"It's a blow to the HIV prevention field," said Rowena Johnston, vice president of research at the Foundation for AIDS Research (amfAR) in New York City. "Clearly, we want to be very careful that people aren't thinking that AIDS researchers are going to be putting them at risk."
The V520 vaccine was the first of the so-called "viral vector" HIV vaccines to make it all the way to such a large, phase II trial, after showing much promise in smaller, earlier studies.
The vaccine used a harmless adenovirus -- a type of cold virus -- as a "vector" to deliver a set of three synthetically derived HIV genes. The hope was those genes would help prime the immune system against the virus that causes AIDS.
The virus vector approach is a common one in vaccine research generally, and HIV/AIDS experts had high hopes for the Merck vaccine, which was meant to be tested in more than 3,000 volunteers uninfected with HIV.
Unfortunately, the vaccine failed to deliver. In September, a preliminary analysis of the data showed no statistical difference between those who got the shot and those who got a placebo, in terms of new infections. The trial was halted at that time.
Reporting last Wednesday at a scientific meeting in Seattle, the research team said an updated review of the numbers had since revealed a widening gap in infections that actually favored the placebo.
So far, the researchers said, 49 of 914 men vaccinated have tested positive for HIV, compared to 33 of 922 men who got the placebo shot.
And in a puzzling twist, individuals who had higher levels of preexisting immunity to the adenovirus before vaccination were actually much more prone to developing HIV infection, compared to participants with low levels of immunity, the researchers said.
Among 778 male volunteers with a high level of preexisting adenovirus immunity, 21 of those vaccinated are now HIV-positive, versus nine in the placebo arm of the trial.
In terms of vaccine's effectiveness at slowing progression from HIV infection to AIDS, the trial was also a bust. Among participants infected with HIV, researchers have so far seen no difference in "viral load" -- HIV levels in the blood -- between those who received a shot and those who did not.
The vaccine's failure comes as a disappointment to AIDS researchers, the experts said. However, the notion that the vaccine actually heightened users' risk for infection is still far from certain, they added.
First of all, the numbers of cases of new infection recorded in the trial simply didn't reach statistical significance, Fauci said. However, the trend "is noticeable enough that you have to pay attention to it," he added.
Fauci and Johnston stressed that it's impossible for the vaccine itself to directly infect a person with HIV, because the adenovirus was the only pathogen included in the shot.
However, there is the possibility that vaccination might have spurred changes in the immune systems of individuals whose immune systems were already primed to fight the adenovirus. Theoretically, those immune-system changes could have made HIV infection more likely in these people if they were exposed to the virus.
"HIV replicates much better in [immune] cells that are activated," Fauci explained. For certain trial participants with a high preexisting immunity to the adenovirus, vaccination could have put their immune system on a kind of "high alert" -- activating exactly the type of CD4+ T-cells that HIV is attracted to, he said.
"Those CD4+ T-cells are then going to be very vulnerable targets for HIV when you become exposed to HIV," Fauci theorized.
But he also stressed that this only remains a theory. Research is continuing to see if the vaccine did, in fact, leave participants more vulnerable to contracting HIV.
"What we are trying to do now is to mine the data to see if we can find out any mechanistic or other circumstantial information that could help us decipher that out, and determine whether this is 'really real,'" Fauci said. That research could take up to a year to yield results, he noted.
In the meantime, Fauci and Johnston agreed that vaccine research using viral vectors should continue to go forward, albeit with an added note of caution.
If the trend seen in the study is confirmed, it could mean changes in the way the organizers of vaccine trials recruit participants in the future, they said.
"If it turns out to be biologically significant, then we will have to be very careful when using a viral vector to which people have underlying immunity, because that [could lead] to a significant activation of their immune responses," Fauci said.
Trial organizers would become more selective as they recruit participants, he said, "to make sure that we don't have people who have underlying immunity to the vector in question."
Both experts stressed that trial participants should always do their best to prevent exposure to HIV and not assume that an experimental vaccine gives them added protection.
"The counseling that people in trials get is really very thorough," Johnston said, "and yet I think that as trial participants, many people really do come away with the perception that they are being given a product that might protect them."
Safe behaviors -- especially condom use -- remain the surest way to prevent infection with HIV, whether you are in a trial or not, Johnston said. "To protect yourself, you really need to assume that the vaccine won't work, and then keep on protecting yourself in every way possible."
In the meantime, an estimated 39 million people remain infected with HIV worldwide, and the hope for a safe, effective vaccine delivered by a viral vector remains high, she said.
"The viral vector is really a very good idea -- it's still one of the best ideas that's out there," Johnston said. "I don't think the failure of one candidate from one company should signal the end of this as a concept."
Find out more about the fight against HIV/AIDS at amfAR.
SOURCES: Anthony Fauci, M.D., director, U.S. National Institute of Allergy and Infectious Diseases, Bethesda, Md.; Rowena Johnston, Ph.D., vice president, research, Foundation for AIDS Research, New York City; Nov. 7, 2007, statement, Merck & Co.
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