Background
Durable antiretroviral therapy (ART)-free remission from HIV will likely require a robust and targeted T cell response to limit viral reactivation.
Methods
We report a double-blind, randomized trial in people with HIV (PWH) suppressed on ART. Participants, 21-60 years (median 41 years), received modified vaccinia Ankara (MVA)-vectored vaccines, MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 (M4), alone or in combination (n=7/group) or saline placebo (n=3). M3 and M4 contain different HIVconsvX immunogens that each span the same regions in HIV Gag and Pol but differ at ~8% of amino acids. T cell immunogenicity was measured by ex vivo ELISpot and CD8 T cell virus inhibition assays. T cell phenotyping was performed using mass cytometry and HIV reservoir measured using single copy assay (SCA) and integrated proviral DNA assays (IPDA).
Results
Vaccination (all regimens) was well tolerated, significantly increased the magnitude and breadth of the HIV-specific T cell response, redirected T cells to conserved HIV regions for up to 10 weeks post vaccination and increased the ability of CD8 T cells to detect and clear participants’ autologous reservoir virus. T cell magnitude, breadth or shift in immunodominance were not statistically separable between vaccine regimens. Vaccination did not impact total memory CD4 T cell activation, low-level viremia or integrated HIV DNA. HIV-specific T cell responses to vaccination increased up to 24-fold over baseline (average >3-fold) with the contribution of new T cells to the total vaccine-specific response ranging from 0-80% (average 11%). Across timepoints, linear regression found that age was a significant negative predictor of fold T cell response to vaccination (Figure1). Slope analysis predicted a 0.05 decrease in log2 fold-change in T cell magnitude to HIVconsvX immunogens for every additional year of age suggesting the fold-change in magnitude to MVA.HIVconsvX vaccination would approximately halve over a 20-year period. Detection of new T cell responses following vaccination similarly inversely correlated with age. Conversely, years on ART correlated positively with the fold-change in T cell magnitude to vaccination.
Conclusions
MVA.HIVconsvX vaccines were safe and consistently immunogenic in PWH on ART. However, the strength of the T cell response to vaccination exhibited an inverse and linear association with age. Novel approaches are needed to improve HIV immunity in middle- to older-aged PWH.
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