CROSS-POSTED from Nature Medicine’s Spoonful of Medicine
By Kathleen Raven
September 10, 2012
The road to a protective HIV vaccine has not been easy thus far. The failed STEP trial, halted in 2007, was just one major trip-up among several, and two years later the massive RV144 trial from Thailand spurred controversy about efficacy rates. Part of the problem is that researchers have long struggled over the best target for the HIV vaccine.
A study published online today in Nature from researchers in the US and Thailand should help scientists inch closer to settling that debate. Through genetic analysis, the study suggests that specific amino acid sequences found in the HIV V2 protein loop—there are five total loops on the outside of the viral envelope—could lead to improve vaccine effectiveness.
The current RV144 vaccine contains three synthetic HIV genes.
One, called the ENV gene, produces the ‘envelope’ (Env) protein loops. To understand how the vaccine exerted influence on the virus, the researchers sequenced more than 1,000 HIV virus genomes from 110 ‘breakthrough’ viruses isolated from 44 vaccinated participants and regular viruses found in 66 placebo recipients.
The analysis centered on the idea that viruses that ‘break through’ vaccine protection contain a genetic signature, visible by changes in the amino acids chains they encode, compared with viruses the vaccine fends off. “Viruses that escape [the vaccine] carry the scars of the immune response,” explains Jerome Kim, a virologist at the US Military HIV Research Program (MHRP) in Silver Spring, Maryland and senior author on the paper. Based on the frequency of virus sequences in the two groups, he and his colleagues calculated that when the HIV virus and the vaccine code for the same 169 amino acid position, the vaccine is 48% effective. However, the vaccine is estimated to be 80% effective when the virus and vaccine sequences match at position 169 and—unexpectedly—do not match at position 181.* The overall efficacy rate in the original RV144 trial hovered at just 31%.
The finding raises the possibility that a future, retooled vaccine (especially one to fight the HIV virus subtype E found in Thailand) could contain an HIV envelope gene engineered to present the V2 protein loop in a way that would prompt a more effective antibody and overall immune response.
The new study also provides an independent confirmation of a correlative study published in April in the New England Journal of Medicine, which suggested that when the body produced antibodies geared toward the V2 protein loop, the result was lower rates of HIV infection. “We know that the vaccine induces antibodies, those antibodies exert some immune pressure, and so we expected to see the consequences of that pressure on the [HIV] viruses,” says Morgane Rolland, a virologist at MHRP and study co-author.
“I am cautiously optimistic [about the results],” says Andrew McMichael, an immunologist at the Weatherall Institute of Molecular Medicine in Oxford, UK, who was unaffiliated with the study. He says he is optimistic that this study confirms that V2 antibodies may play an important role in preventing HIV infection. However, McMichael points out that the mutation of the amino acid position 181 was mostly found in viruses of the placebo participants and therefore may be difficult to link to a V2 antibody response since those patients did not receive the vaccine.
But Barton Haynes, an immunologist at Duke University School of Medicine in Durham, North Carolina, and senior author of the NEJM study earlier this year, thinks research on a vaccine from the RV144 trial is moving ahead like clockwork. “It adds support to the hypothesis that these V2 antibodies may in some manner be involved in protection,” he says. The next step, which should happen soon, he says, would be to try out a retooled vaccine with this added antibody protection in macaque monkeys.
*CORRECTION: An earlier version of this post incorrectly stated the vaccine is 80% effective when the virus and vaccine sequences match at amino acid position 181. Researchers are still studying to understand how a mismatch at this site might be beneficial.