The Road to a Correlate

Earlier today, AIDS Vaccine 2010 came to a close in Atlanta. The feeling of optimism that has been palpable in the field over the past year was sustained through the four-day meeting and many new, incremental scientific advances were reported.

Progress with antibody-based vaccine approaches were showcased, including the isolation of new broadly neutralizing antibodies, more structural details of some of the recently discovered antibodies, and progress in engineering immunogens based on the HIV epitopes targeted by these antibodies.

In the final session, Nelson Michael, director of the US Military HIV Research Program (MHRP), gave an update on the status of the search for correlates from the RV144 trial in Thailand. He reported that case-control studies should begin in January and be concluded by April next year. The correlates analysis is being conducted by 35 investigators at 20 institutions.

In the meantime, analyses conducted by MHRP of 60 vaccinated volunteers have shown that T-cell responses induced in these volunteers target two peptides, 44 and 49, on the V2 loop of HIV envelope. Peptide 44 contains the alpha4 beta7 site, which was previously shown to be an alternative receptor for HIV on the surface of CD4+ T cells by Anthony Fauci, director of the US National Institute of Allergy and Infectious Diseases. The integrin alpha4 beta7 is a gut mucosal homing receptor. Work from Fauci’s lab has shown that recently transmitted virus is more likely to bind to alpha4 beta7 than chronically circulating virus that is more heavily glycosylated.

CD4+ T-cell responses to these two distinct peptides were not seen in breakthrough infections in RV144 participants, and were only found in one HIV-infected individual in Thailand that has been studied. However, Michael cautioned that the responses to these peptides may have existed in RV144 volunteers with breakthrough infections but just been eradicated once the infection occurred. "We’re developing interest in V2 and those assays will probably be included in the case-control studies," said Michael. "That may be on the pathway to a correlate."

Michael also presented the plans for RV144 follow-up trials, including a Phase IIb trial of men who have sex with men in Thailand, which he called a - top priority - because if found to be effective it could lead to licensure of the vaccine regimen for use in Thailand.

Michael’s talk was followed by a presentation from Larry Corey, director of the HIV Vaccine Trials Network, on plans for how best to conduct future clinical trials. Corey said the AIDS vaccine field suffers from two conflicting neuroses: the fear of failure and the fear of success. To combat this, he is advocating for adaptive clinical trial designs that allow for multiple vaccine candidates to be tested simultaneously with more frequent interim analyses so that investigators can more quickly identify the weak or strong candidates and adapt the trial accordingly. This new approach to clinical testing was one of the main talking points throughout the conference. When asked if there were enough candidates in the pipeline to support these adaptive designs, without hesitation, Corey said yes.