NEW YORK – A gene expression signature found in B cells in response to multiple HIV-1 vaccine candidates appears to coincide with protection against the virus, according to a team from the Walter Reed Army Institute of Research US Military HIV Research Program (MHRP), Janssen Vaccines and Prevention, and elsewhere.
"We think this B cell signature is a broad indicator of effective responses after vaccination and could potentially be used to help design effective vaccines against HIV and other pathogens," senior author Rasmi Thomas, chief for MHRP's host genomics section, said in a statement.
Using RNA sequencing, Thomas and her colleagues tracked transcriptional profiles in various lymphocyte cell types isolated from peripheral blood samples from non-human primates. The animals did or did not have protection from simian immunodeficiency virus (SIV) or simian-human immunodeficiency virus (SHIV) after vaccination with a mosaic adenovirus 26-based vaccine candidate. The search highlighted a B cell transcriptional profile that was linked to protection from the viruses.
When the team studied B cell RNA-seq profiles for more than 170 human participants in a trial for the proposed HIV vaccine RV144, it saw a rise in expression of genes from the same signature. The results appeared online today in Science Translational Medicine.
"We're excited because the identified gene signature associates with protective efficacy for the two vaccine regimens that are currently being tested in human efficacy trials in Africa, the Imbokodo study and HVTN702," Thomas said, noting that the signature "provides a clue as to why the vaccines were partially protective previously and may help to understand the mechanisms of efficacy in these new studies."
To explore potential contributors to vaccine response or resistance, the researchers performed RNA-seq on sorted cells from peripheral blood mononuclear cells collected over time from 21 rhesus macaque monkeys that received the mosaic adenovirus 26 vaccine Ad26/gp140 for two prior studies. The proposed vaccine protected half of the rhesus macaques from SIV after half a dozen infection challenges but showed just 33 percent efficacy after the same number of challenges with SHIV.
"Current HIV vaccines are only partially efficacious, presenting an opportunity to identify correlates of protection and, thereby, potential insights into mechanisms that prevent HIV acquisition," the authors wrote.
Although they did not see any individual genes with strong expression differences related to vaccine response, the investigators' analyses uncovered a gene set that was significantly more common in B cells from the uninfected rhesus macaques — a signature reported in human B cells profiled for past influenza vaccine immunogenicity trials.
"Of the 200 genes enriched in humans, only 140 genes were detected in the RNA-seq data generated in the [non-human primate] studies," the authors wrote, noting that the gene set was not enhanced in other lymphocyte cell types.
When the team turned its attention to peripheral blood mononuclear cell samples collected from 172 individuals during a vaccine efficacy trial focused on the human HIV-1 vaccine RV144, it again saw enrichment for the gene set signature in B cells from individuals who remained infection-free after vaccination.
Genes within that signature also appeared at higher-than-usual levels in B cells from two more vaccine-protected cohorts challenged with SIV, the researchers reported. Even so, the number of genes from the signature that showed increased activity varied from one study and cohort to the next, prompting them to focus on a smaller set of 53 predictive genes.
The team used RNA-seq and qPCR to test that more focused 53-gene set in rhesus macaques that got a mosaic adenovirus 26-based vaccine jab, where it showed promise for predicting non-human primate protection from SIV and SHIV. A subsequent network analysis that took into account both co-expression and genetic interactions suggested that the B cell signature may coincide with shifts in metabolic, cell signaling, cell migration, immune, and other pathways.
"That this gene set was first identified in the context of influenza immunogenicity, and has now been shown to associate with protective efficacy of HIV vaccination, suggests these genes may be broadly involved in responses to vaccination, although the particular changes that are protective likely differ between viruses," the authors wrote, adding that it will be "important to evaluate baseline expression of this gene signature before vaccination, as such variation has demonstrated detectable effects on influenza vaccine responses when using systems biology approaches."