In 2009, the results of an HIV vaccine clinical trial sponsored by the Thai Ministry of Health and U.S. Military HIV Research Program galvanized the worldwide HIV vaccine community. This 3-year trial, referred to as RV144, showed for the first time it is in fact possible to reduce the incidence of HIV infection via a vaccine regimen. While the vaccine afforded modest efficacy, 31% protection from HIV acquisition, it also provided a wealth of information and resources for understanding why this particular vaccine regimen was successful and how to improve upon it.
VIDD scientists have been spending the last several years analyzing a plethora of information yielded from RV144. In a high profile study published in The New England Journal of Medicine in April of this year, scientists looked for immune responses that correlated with vaccine protection (i.e., ‘immune correlates’). Using immunological assays on blood from 41 infected and 205 uninfected vaccinees, they investigated the potential role T cells and IgG and IgA antibodies play in the risk of HIV infection. Of the six primary variables tested, the authors, including eight VIDD faculty members, identified two that were significantly associated with HIV acquisition: an inverse correlation with levels of IgG antibodies targeting the V1-V2 region of the HIV envelope protein (Env), and a direct correlation to the HIV Env-binding IgA antibody response. This study spurs the hypotheses that an HIV vaccine designed to increase the V1-V2 Env-targeted IgG response and/or reduce Env-binding IgA antibody levels will offer improved protection against HIV acquisition.
Quick on the heels of the RV144 immune correlates study came an exciting finding from VIDD scientists and collaborators that was recently published in the high impact journal Nature. The authors, including seven VIDD faculty members, compared the sequences of HIV strains from vaccinated and unvaccinated participants, all of whom acquired HIV, to determine if vaccine-induced immune responses could protect against, or ‘weed out,’ some HIV variants. After sequencing over 900 HIV genome sequences from 44 vaccine and 66 placebo recipients, the authors identified evidence of a sieve effect: statistically significant differences between the HIV sequences from vaccine recipients and those from placebo recipients. The authors found that HIV variants with certain ‘signatures’ were less common among the vaccinated participants. These two signature sites were located in the V2 region of HIV Env, a crucial site for successful HIV infection of host immune cells. HIV strains containing these signatures, those matching the vaccine sequence at lysine-169 (K169) and mismatching at isoleucine-181 (I181), were proportionately less likely to infect vaccinated persons than those who received the placebo.
Interestingly, these amino acids are in the same HIV Env region that is targeted by the IgG V2-directed antibodies identified in the preceding NEJM publication. One possible conclusion from this study is that vaccine-induced IgG antibodies targeting V2 may have a protective effect against viral strains containing K169 (and conversely for I181) and could help explain the partial efficacy found in the RV144 trial.
Next steps will build upon these findings to finer pinpoint the immunological mechanisms and sieve effects responsible for the vaccine efficacy of RV144 and subsequently accelerate the pace of vaccine clinical trial design and development, led by VIDD scientists through the HIV Vaccine Trials Network.
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Haynes BF, et al. Immune-correlates analysis of an HIV-1 vaccine efficacy trial. N Engl J Med. 2012 Apr 5;366(14):1275-86.
Rolland M, et al. Increased HIV-1 vaccine efficacy against viruses with genetic signatures in Env V2. Nature. 2012 Oct 18;490(7420):417-20.