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Transcriptomic profiling of human peripheral blood samples collected three days or two weeks after the primary RV144 ALVAC/gp120 vaccine series

ABSTRACT: We previously showed in NHP studies that a protective gene signature that was enriched in uninfected monkeys after Ad26/gp140 vaccination also associated with higher magnitude of ADCP (Ehrenberg et al., 2019). In the RV144 human trial a number of immunological parameters were previously measured as part of the immune-correlates analysis, but not ADCP. The RV306 immunogenicity trial that employed a similar prime boost RV144 vaccine regimen with additional late boosts provided us with a unique opportunity to test if the gene signature was associated with ADCP (Pitisuttithum et al., 2020). We generated transcriptome-wide gene expression data from peripheral blood two weeks after the RV144 vaccine regimen (prior to the additional boosts) and assessed for enrichment of the gene signature with the magnitude of ADCP measured at the same timepoint in 24 participants. The gene signature with 118 enriched genes was significantly associated with higher magnitude of ADCP (NES=3.0, P<0.001). Using the same geneset, 93 genes were found to be enriched in a subset of overlapping participants (N=21), where samples were collected 3 days after the RV144 immunizations (NES=2.5, P<0.001).

ORGANISM(S): Homo sapiens

PROVIDER: GSE181932 | GEO | 2021/09/23

REPOSITORIES: GEO

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Project description:Despite the critical role antigen-specific T cells play in containing viral infections, their aggregate frequencies in peripheral blood have not correlated with clinical protection during HIV infection. However, a subset of HIV-specific T cells, which are capable of simultaneously producing multiple effector cytokines, termed polyfunctional T cells, have correlated with delayed disease progression. HIV-specific polyfunctional T cells have been enumerated and characterized using the intracellular cytokine staining (ICS) assay, which allows for simultaneous multiplexed analysis of cytokine expression at the single-cell level. In addition, using an unbiased computational analysis of ICS data generated through the RV144 HIV vaccine case-control study, we identified vaccine-induced HIV envelope (Env)-specific polyfunctional CD4 T cells as a novel correlate of reduced risk of HIV infection. However, very little is known about these cells and what differentiates them from other vaccine-elicited T cells. In addition, the use of sample fixation in the ICS assay prevents those cells from being further interrogated for transcriptional differences. Thus, we developed a novel live-cell multiplexed cytokine capture assay which allows for identification, sorting and transcriptional profiling of individual antigen-specific polyfunctional T cells by single-cell RNA-sequencing (scRNA-seq). We applied these methods to peripheral blood samples from participants who had received the RV144 vaccine regimen as part of the HVTN 097 clinical trial. Using this approach, we discovered transcriptional signatures that specifically identify the single-cell Env-specific CD4 T-cell functional profiles which had correlated with reduced risk of HIV infection in RV144. Interestingly, this signature is particularly characterized by upregulation of Th2 cytokines, supporting the hypothesis that the vaccine-induced Env-specific CD4 T cells likely contributed to the reduced risk of infection by providing T cell help to the Env-specific antibody responses. By interrogating the gene signatures that correlated with polyfunctionality, we have identified potential mechanisms of how vaccine-elicited polyfunctional T cells may contribute to reduced risk of HIV infection.

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Transcriptomic profiling of human peripheral blood samples collected three days or two weeks after the primary RV144 ALVAC/gp120 vaccine series

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