Mosaic HIV-1 vaccination induces anti-viral CD8 + T cell functionality in the phase 1/2a clinical trial APPROACH

Abstract

ABSTRACT The ability of vaccine-induced T cells to inhibit viral replication may contribute to protect against human immunodeficiency virus (HIV) acquisition. Here, we tested ex vivo viral inhibitory activity of T cell responses induced by a multivalent HIV vaccine based on the replication-incompetent recombinant adenovirus serotype 26 vector with a mosaic immunogen strategy (Ad26.Mos.HIV), designed for broad immune coverage of diverse HIV-1 strains. Using clinical trial samples with a diverse range of T cell responses measured by IFN-γ ELISpot, anti-viral function of vaccine-induced CD8+ T cells was assessed by inhibition of HIV-1 replication in autologous CD4+ T cells to a panel of HIV-1 isolates. Ex vivo expanded CD8+ T cells were able to inhibit replication of HIV in autologous CD4+ T cells, with 94% of vaccinees inhibiting at least one out of eight HIV isolates, and a median of 5 isolates inhibited at peak immunogenicity. Correlations between viral inhibition and ICS as well as ELISpot responses were explored, demonstrating positive correlations. Broad ELISpot responsiveness to different regions of the Env, Gag, and Pol proteins was associated with breadth of viral inhibitory responses. Moreover, polyfunctionality of CD8+ T cells correlated well with viral inhibition. These findings indicate that functional immunological breadth as well as antigenic breadth is important to induce antiviral activity. This study advances the understanding of vaccine-induced T cell functionality and demonstrates for the first time that Ad26.Mos.HIV vaccination in combination with adjuvanted gp140 can induce broad viral inhibitory activity toward a panel of diverse HIV-1 clades. IMPORTANCE The functionality of CD8+ T cells against human immunodeficiency virus-1 (HIV-1) antigens is indicative of HIV-progression in both animal models and people living with HIV. It is, therefore, of interest to assess CD8+ T cell responses in a prophylactic vaccination setting, as this may be an important component of the immune system that inhibits HIV-1 replication. T cell responses induced by the adenovirus serotype 26 (Ad26) mosaic vaccine regimen were assessed previously by IFN-γ ELISpot and flow cytometric assays, yet these assays only measure cytokine production but not the capacity of CD8+ T cells to inhibit replication of HIV-1. In this study, we demonstrate direct anti-viral function of the clinical Ad26 mosaic vaccine regimen through ex vivo inhibition of replication of diverse clades of HIV-1 isolates in the participant’s own CD4+ T cells.