Fallout From Failed AIDS Vaccine Could Dampen Research

Fallout From Failed AIDS Vaccine Could Dampen Research
MONDAY, Nov. 12 (HealthDay News) -- An experimental AIDS vaccine usedin a recent trial may have placed participants at higher risk of infectionwith HIV -- although whether or not that was truly the case remainsunclear.
What is clear is the concern among experts that the news willkeep would-be trial participants away from future AIDS vaccinestudies.
"That's always a possibility, and that's the reason why we have to bevery transparent and open and honest, and be very energetic to educatepeople to understand just what went on here," said Dr. Anthony Fauci, anAIDS research pioneer and director of the U.S. National Institute ofAllergy and Infectious Diseases (NIAID). The institute was a partner inthe trial.
"Already we have a lot of people misinterpreting that the vaccineitself actually gave [recipients] HIV infection -- that's impossible," hesaid. "We have a lot of education to do, and there's always a danger thatthis could sour people on getting involved in vaccine trials."
Another expert agreed that the collapse of the large, phase II trial ofMerck & Co.'s V520 vaccine could send the wrong message.
"It's a blow to the HIV prevention field," said Rowena Johnston, vicepresident of research at the Foundation for AIDS Research (amfAR) in NewYork City. "Clearly, we want to be very careful that people aren'tthinking that AIDS researchers are going to be putting them at risk."
The V520 vaccine was the first of the so-called "viral vector" HIVvaccines to make it all the way to such a large, phase II trial, aftershowing 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. Thehope was those genes would help prime the immune system against the virusthat causes AIDS.
The virus vector approach is a common one in vaccine researchgenerally, and HIV/AIDS experts had high hopes for the Merck vaccine,which was meant to be tested in more than 3,000 volunteers uninfected withHIV.
Unfortunately, the vaccine failed to deliver. In September, apreliminary analysis of the data showed no statistical difference betweenthose who got the shot and those who got a placebo, in terms of newinfections. The trial was halted at that time.
Reporting last Wednesday at a scientific meeting in Seattle, theresearch team said an updated review of the numbers had since revealed awidening gap in infections that actually favored the placebo.
So far, the researchers said, 49 of 914 men vaccinated have testedpositive for HIV, compared to 33 of 922 men who got the placebo shot.
And in a puzzling twist, individuals who had higher levels ofpreexisting immunity to the adenovirus before vaccination were actuallymuch more prone to developing HIV infection, compared to participants withlow levels of immunity, the researchers said.
Among 778 male volunteers with a high level of preexisting adenovirusimmunity, 21 of those vaccinated are now HIV-positive, versus nine in theplacebo arm of the trial.
In terms of vaccine's effectiveness at slowing progression from HIVinfection to AIDS, the trial was also a bust. Among participants infectedwith HIV, researchers have so far seen no difference in "viral load" --HIV levels in the blood -- between those who received a shot and thosewho did not.
The vaccine's failure comes as a disappointment to AIDS researchers,the experts said. However, the notion that the vaccine actually heightenedusers' risk for infection is still far from certain, they added.
First of all, the numbers of cases of new infection recorded in thetrial simply didn't reach statistical significance, Fauci said. However,the trend "is noticeable enough that you have to pay attention to it," headded.
Fauci and Johnston stressed that it's impossible for the vaccine itselfto directly infect a person with HIV, because the adenovirus was the onlypathogen included in the shot.
However, there is the possibility that vaccination might have spurredchanges in the immune systems of individuals whose immune systems werealready primed to fight the adenovirus. Theoretically, thoseimmune-system changes could have made HIV infection more likely in thesepeople 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 preexistingimmunity to the adenovirus, vaccination could have put their immune systemon a kind of "high alert" -- activating exactly the type of CD4+ T-cellsthat HIV is attracted to, he said.
"Those CD4+ T-cells are then going to be very vulnerable targets forHIV when you become exposed to HIV," Fauci theorized.
But he also stressed that this only remains a theory. Research iscontinuing to see if the vaccine did, in fact, leave participants morevulnerable to contracting HIV.
"What we are trying to do now is to mine the data to see if we can findout any mechanistic or other circumstantial information that could help usdecipher that out, and determine whether this is 'really real,'" Faucisaid. That research could take up to a year to yield results, henoted.
In the meantime, Fauci and Johnston agreed that vaccine research usingviral vectors should continue to go forward, albeit with an added note ofcaution.
If the trend seen in the study is confirmed, it could mean changes inthe way the organizers of vaccine trials recruit participants in thefuture, they said.
"If it turns out to be biologically significant, then we will have tobe very careful when using a viral vector to which people have underlyingimmunity, because that [could lead] to a significant activation of theirimmune responses," Fauci said.
Trial organizers would become more selective as they recruitparticipants, he said, "to make sure that we don't have people who haveunderlying immunity to the vector in question."
Both experts stressed that trial participants should always do theirbest to prevent exposure to HIV and not assume that an experimentalvaccine 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 peoplereally do come away with the perception that they are being given aproduct that might protect them."
Safe behaviors -- especially condom use -- remain the surest way toprevent infection with HIV, whether you are in a trial or not, Johnstonsaid. "To protect yourself, you really need to assume that the vaccinewon't work, and then keep on protecting yourself in every waypossible."
In the meantime, an estimated 39 million people remain infected withHIV worldwide, and the hope for a safe, effective vaccine delivered by aviral vector remains high, she said.
"The viral vector is really a very good idea -- it's still one of thebest ideas that's out there," Johnston said. "I don't think the failure ofone candidate from one company should signal the end of this as aconcept."