Background:
Eliciting a robust T cell response is a central goal of many HIV therapeutic vaccines, but T cell responses are often heterogenous. We conducted systems immunology analyses to identify the immunologic signatures, at the cellular and transcriptional level, that correlate with augmented HIV-specific T cell responses post-vaccination in 30 participants with HIV who received an HIV DNA vaccine/IL-12 in the PENNVAX clinical trial (NCT03606213).
Methods:
Response to vaccination was defined as the fold change (FC) in the magnitude of HIV-specific T cell responses (averaged per HIV antigen) from pre-vaccination to 2 weeks post-boost (Week 14), as measured by IFNγ ELISpot using vaccine-matched peptide pools (median FC 2.1 [range 0.1-15.9). We characterized 473 innate and adaptive immune cell features using mass cytometry (CyTOF) and performed whole-blood RNA-sequencing. We then correlated CyTOF features and genes with ELISpot FC to identify cell subsets and immune pathways associated with enhanced vaccine responses.
Results:
Pre-vaccination, higher expression of genes involved in T cell homeostasis (e.g., IL7, IL7R; adj. p=1e-04) and innate immune sensing (e.g., TLR9, IFNAR1, IL1R1; adj. p=8e-04) pathways were associated with a greater increase in HIV-specific T cell responses after vaccination (genes in Fig. 1A). Individuals with a larger FC in their T cell response between baseline and Week 14 also demonstrated greater induction of genes in IL-2/STAT-5 signaling (adj. p=0.003) and hematopoiesis (adj. p=4e-09). By CyTOF, larger IFNγ ELISpot responses post-vaccination were significantly (p< 0.05) associated with a greater increase in the frequency in cytotoxic-skewed CD4+, CD8+, and γδ T cells expressing Granzymes A/B, Perforin, CX3CR1, and Tbet (Fig. 1B)
Conclusions:
Our data highlight that individuals who develop a larger T cell response to a DNA HIV therapeutic vaccine have a baseline immune environment that promotes T cell survival and responsiveness to innate immune signaling, and that they respond to vaccination with more robust IL-2 signaling and hematopoiesis. We also demonstrate that therapeutic vaccination with DNA/IL-12 induces not only cytotoxic CD8+ T cells, but also cytotoxic CD4+ and γδ T cells. These data provide insight into how differences in host immune responses pre- and post-vaccination can impact vaccine immunogenicity and highlight that modulation of the pre-existing immune environment (e.g., with different adjuvants) may be critical to conditioning better vaccine responses.
Immunologic features associated with a greater magnitude increase in T cell responses to therapeutic vaccination.