Evaluation of the immunogenicity and impact on the latent HIV-1 reservoir of a conserved region vaccine, MVA.HIVconsv, in antiretroviral therapy-treated subjects.

Gemma Hancock,Emma‐Jo Hayton,Jakub Kopycinski,Annie Rose,Maria C Puertas,Lucy Dorrell,Fabian Chen,Maria Salgado,Alison Crook,Brian Angus,Sara Morón‐López,Tomas Hanke,Eleni Giannoulatou,Javier Martinez‐Picado,Hongbing Yang,Catharine Morgan

doi:10.7448/ias.20.1.21171

Abstract

Introduction: Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA).Methods: Nineteen virologically suppressed individuals were randomized to receive vaccinations with MVA.HIVconsv (5.5 × 107 plaque-forming units, pfu, n = 8; 2.2 × 108 pfu, n = 7) or placebo (n = 4) at 0, 4 and 12 weeks. Magnitude, breadth and antiviral function of vaccine-induced T cells, cell-associated HIV-1 DNA in circulating CD4+ T cells and residual viremia in plasma were measured before and after vaccination.Results: 90% of subjects completed the vaccine regimen; there were no serious vaccine-related adverse events. The magnitude of HIVconsv-specific IFN-γ-secreting T cells was not significantly boosted in vaccinees when compared with placebos in ex vivo Elispot assays, due to greater than expected variation in HIV-specific T cell responses in the latter during the observation period. Ex vivo CD8+ T cell viral inhibitory capacity was modest but significantly increased post-vaccination with MVA.HIVconsv at the higher dose (p = 0.004) and was positively correlated with the frequency of HIVconsv-specific CD8+ CD107+ IFN-α± T cells (r = 0.57, p = 0.01). Total HIV-1 DNA and residual viral load did not change significantly from baseline in any group.Conclusions: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. MVA.HIVconsv may be more effective when used in a heterologous prime-boost vaccination regimen and when combined with a latency-reversing agent.Clinical Trials Registration NCT01024842

Highlights

Vaccines may be key components of a curative strategy for HIV-1
We investigated the immunogenicity of a conserved region immunogen, HIVconsv, for the first time in HIV-1 infected individuals on antiretroviral therapy (ART)
Mapping enabled us to detect a large number of responses to viral epitopes that are infrequently recognized in natural infection, as they were restricted by HLA alleles other than that had been defined previously

Summary

Introduction

Vaccines may be key components of a curative strategy for HIV-1. We investigated whether a novel immunogen, HIVconsv, designed to re-direct T cell responses to conserved viral epitopes, could impact the HIV-1 reservoir in chronic antiretroviral therapy (ART)-treated subjects when delivered by modified vaccinia virus Ankara (MVA). Conclusions: Homologous prime-boost vaccination with MVA.HIVconsv was safe in HIV-positive ART-treated subjects but showed modest immunogenicity and did not significantly change the size of the viral reservoir. It is hypothesized that pharmacological reactivation of CD4+ T cells is needed to induce viral protein production and target the cell for immune recognition. This premise is supported by in vitro models of HIV-1 latency reversal; a poxvirus-vectored HIV-1 vaccine had only a transient effect on viral rebound whether tested alone or in combination with a candidate LRA, disulfiram in a phase I clinical trial [8,9]

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