Sieve study probes two genetic footprints of RV144

Scientists still do not know how the prime-boost regimen used in the R144 trial worked, but an ongoing analysis of nearly 1,000 genetic sequences from 110 HIV-infected recipients across the vaccine and placebo arms of the trial strengthen the theory that the candidate is applying selective pressure against a vulnerable region of HIV’s Envelope protein known as the V1/V2 region.

In a recently published study that was highlighted at the AIDS Vaccine 2012 conference on Monday by lead author Morgane Rolland, a virologist at the U.S. Military HIV Research Program (MHRP), a team of researchers described in detail evidence of a sieve effect—when the vaccine keeps virus strains most similar to the vaccine from establishing infection (Nature doi: 10.1038/nature11519).

Researchers uncovered two genetic footprints in the V2 region, one at amino acid position 181 and the other at amino acid 169, associated with reduced risk of HIV. For viruses carrying these two particular signatures, the vaccine efficacy was 80%. Put another way, four times as many HIV-infected controls matched both genetic footprints compared to just three of the HIV-infected vaccines.

Roland said the findings from the sieve analysis confirm previous results that showed antibodies directed to the V1/V2 region reduced the risk of infection among vaccinated volunteers, and she said this could be an “important target for immune-mediated protection.”

Still, it remains to be seen whether the findings can reasonably translate into future vaccine candidates that can improve upon the results of the modest 31.2% efficacy seen in the RV144 trial. The likelihood of a vaccine candidate connecting with viral strains that react to immune pressure at just two amino acids at the same time in a broad spectrum of at-risk individuals speaks to both the remarkable performance of the RV144 candidate but also to the vaccine candidate’s fragility.

Yet researchers involved in the post-RV144 analysis and follow-up trials said the findings only point out an association between vaccine efficacy and the V2 region, noting that the precise correlates of protection are still not known and that other factors that led to the vaccine candidate’s efficacy may still be discovered.  

Some of the preliminary data from the sieve analysis—part of the ongoing RV144 correlates analysis—were also presented earlier this year at the 19th Conference on Retroviruses and Opportunistic Infections in Seattle (see A Slew of Science in Seattle, IAVI Report, March-April 2012).

In another post-RV144 update, new data from a nonhuman primate study found that a simian immunodeficiency virus (SIV) vaccine regimen similar to the canarypox vector-based candidate ALVAC-HIV (vCP1521) prime and AIDSVAX B/E protein boost tested in combination in the RV144 trial induced similar immune responses and outcomes. The study found Env-specific binding antibodies, evidence of antibody-dependent cellular cytotoxicity and modest CD4+ and CD8+ T-cell responses. The study included 47 vaccinated animals and 27 controls. Genoveffa Franchini, chief of the animal models and retroviral vaccine section at the US National Cancer Institute, said the study conducted by her lab found that about a third of the vaccinated animals were protected but as was the case in the RV144 trial the vaccine regimen did not prevent the animals that ultimately became SIV-infected from progressing to disease.

Earlier this year, animal scientists from Franchini’s laboratory presented results of a pilot study in 31 Indian rhesus macaques that recapitulated the 31.2% efficacy observed in the RV144 trial. In that study, about a third of the animals immunized with SIV regimens mimicking the one used in the RV144 trial were protected while all of the controls became infected after five weeks of weekly challenges with a low dose of the highly pathogenic SIVmac251 (see Tapping the Sanguine Humor, IAVI Report, March-April 2012).