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In Study of HIV Vaccine Trial Subjects, Genotype Defines Subsets with Strong and Weak Response

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NEW YORK (GenomeWeb) — A retrospective study of variations in genes associated with immune response has shown that patients from an HIV vaccine trial responded differently to vaccination — some developing much more immunity than others — based on their genotype.

According to the authors, the results help confirm earlier evidence that only subjects with specific patterns of antibody binding benefited from vaccination in the trial. The study also demonstrates the role genetics may play in vaccine efficacy, something that may benefit future HIV vaccine development and human trials.

Led by researchers from the Statistical Center for HIV/AIDS Research and Prevention at the Fred Hutchinson Cancer Research Center, the study, published this month in the Journal of Clinical Investigation examined samples from patients in RV144 ALVAC/AIDSVAX, a clinical trial in Thailand that combined two vaccines that had previously failed individually. Overall, RV144 resulted in a vaccine efficacy of about 30 percent.

Shuying Li, the study's first author told PGx Reporter this week that because the trial had only a partial positive result, it offered a chance to investigate the genetics behind why this vaccine combination may have been effective for some, but not all subjects.

Previous research on RV144 found that patients who developed antibodies to a specific HIV envelope protein signature had a better immune response, and lower risk of HIV infection. In their new study, Li and her colleagues set out to identify an alteration in genes that plays a role in antibody production and might account for that difference.

The researchers sequenced the external protein domains and transmembrane regions of five genes associated with the creation of antibodies in 125 HIV-infected subjects from the trial, 51 of whom received vaccination, and 74 of whom received placebo.

The group identified several single nucleotide variations, but initially none of these appeared to be associated with vaccine efficacy. They then narrowed down to look at a single HIV-1 subtype, which previous research indicated the vaccines in the trial had been particularly effective against.

Based on this analysis, the researchers found one SNP in the FCGR2C gene that was strongly associated with better immune response and better HIV protection both specific to this virus subtype, and in the trial in general.

For patients carrying two normal alleles, vaccine efficacy for all HIV strains was only about 11 percent versus 64 percent for patients with one or two variant copies. Efficacy against the HIV-1 CRF01_AE 169K strain specifically was 15 percent for those with a homozygous normal genotype and 91 percent for those with heterozygous or homozygous variant types.

According to Li, significant work remains to be done to understand the biology and mechanisms behind how FCGR2C genotype influences HIV vaccine efficacy. The hope though, she said, is that the team's study may be a first step toward developing better, more broadly effective vaccines.

Unlike therapeutics, which can find utility even if they only target a small genetic subset of patients, vaccines require wide effectiveness to impact public health.

In vaccine research, Li said, "people want to find something that works for most people."

"This study could be a lead for future vaccine designs," she added, if follow-up research can help illuminate why those carrying a favorable genotype did so much better, and somehow replicate that for people regardless of genotype.

Moving forward, Li said, efforts are underway by the study's first author Daniel Geraghty and colleagues to measure whether study subjects' mRNA expression matches the genetic polymorphisms the group identified, in order to better understand the functional mechanisms behind the influence of these immunogenetic changes on clinical vaccine efficacy.

Li also said that it might be interesting to look at the stratification of patients in previous failed vaccine trials to see if the same SNP may have played a role in reduced vaccine effectiveness for other regimens. However, because vaccines differ in their mechanisms and design, it's unclear whether the same genetic grouping may translate across different vaccines.

According to Li and her coauthors, future upcoming phase I/II HIV vaccine trials may benefit from looking at FCGR2C genotype in their secondary analyses. The study researchers are already engaged in efforts along these lines, looking to see if the same genotype pattern they discovered in their analysis of RV144 is associated with efficacy in another failed HIV vaccine trial, HVTN 505.

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