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A Glimmer of Hope for HIV Vaccines

A large trial has shown that a vaccine can protect against HIV acquisition. The task now is to figure out how to build on this initial success.

In late September, the U.S. Military HIV Research Program announced that, for the first time ever, an investigational vaccine regimen showed efficacy in preventing HIV acquisition (JW AIDS Clin Care Sep 28 2009). Now, the full results of this community-based trial have been presented at the AIDS Vaccine Conference and published in the New England Journal of Medicine.

As previously described, the trial involved 16,402 healthy volunteers in Thailand (age range, 18–30) who were randomized 1:1 to receive placebo or a prime-boost regimen that involved two vaccines (ALVAC-HIV and AIDSVAX B/E) designed to protect against clades B and E. The trial had two primary endpoints: a decrease in HIV acquisition, and, among those who became infected during the trial, a decrease in viral load. (The vaccine manufacturers provided partial support for the trial, and several members of the trial steering committee were company employees.)

After randomization, seven study participants were found to have been HIV-infected at baseline (PCR positive but EIA negative), leaving 16,395 individuals (39% women) who were truly free of HIV infection at the time of first injection with vaccine or placebo. At baseline, 22% of study participants reported having no sex partners, and another 67% reported having only one partner. Depending on their reported risk behaviors, participants were classified as being at low risk (48%), medium risk (28%), or high risk (24%) for HIV acquisition.

During 3 years of follow-up, HIV infection was diagnosed in 132 study participants overall — 56 in the vaccine group and 76 in the placebo group. The data were analyzed three ways:

• Intent-to-treat (ITT) analysis, involving the 16,402 individuals who were initially randomized
  
• Modified ITT analysis, involving the 16,395 individuals who were not HIV-infected at baseline
  
• Per-protocol analysis, involving the 12,452 individuals who received all injections on schedule and remained free of HIV infection throughout the 6-month vaccination period
  

The results of the study are shown in the table.

In the modified ITT analysis, 75 infections (60%) occurred among men and 50 among women. When the modified ITT population was analyzed by subgroup, vaccine efficacy appeared to be greatest in people aged 21 to 25 and in individuals at low-to-medium risk for infection, although these results were not statistically significant. Vaccination did not appear to reduce viral load among those who became infected.

Comment: For the first time, we have encouraging news that a vaccine can protect against HIV acquisition. However, this achievement has been somewhat lost in the controversy surrounding how the results were released: The modified ITT results — the only ones to show a significant, albeit modest, effect — were released several weeks before the ITT and per-protocol results. Typically, a per-protocol analysis shows greater effect than an ITT analysis, but, in this case, the per-protocol analysis lacked power because it included 39 fewer HIV infections than the modified ITT analysis. (These infections were not included in the per-protocol analysis because they either occurred during the 6-month vaccination period or occurred in volunteers who did not receive all injections on time.) Notably, the ITT and modified ITT analyses trended in the same direction as one another, which suggests that the modest benefit seen is real. All the subgroup analyses should be viewed with caution, including the suggestion of improved efficacy in lower-risk groups; risk was self-reported, and some risk factors, such as same-sex behavior, were most likely underreported.

The real issues for this trial are whether the influence of the two different vaccines can be teased out and whether an immune correlate of protection can be found that will allow for the design of more-robust candidates in the future. The investigators are encouraging all of us to submit ideas for further studies that can be conducted with the banked specimens from the trial. (More information can be obtained at http://www.hivresearch.org.) Although we are all hopeful that these data will lead to a better understanding of the correlates of protection from HIV, the relatively small number of endpoints, the lack of data on potential cofactors (such as male circumcision and herpes simplex virus type 2 infection), and the lack of mucosal specimens will make this an uphill battle.

— Frances H. Priddy, MD, MPH, and Carlos del Rio, MD

Dr. Priddy is a Senior Director of Medical Affairs at the International AIDS Vaccine Initiative in New York.

Published in Journal Watch HIV/AIDS Clinical Care October 22, 2009

Citation(s):

Rerks-Ngarm S et al. Vaccination with ALVAC and AIDSVAX to prevent HIV-1 infection in Thailand. N Engl J Med 2009 Oct 20; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMoa0908492)

Dolin R. HIV vaccine trial results — An opening for further research. N Engl J Med 2009 Oct 20; [e-pub ahead of print]. (http://dx.doi.org/10.1056/NEJMe0909972)