Conserved-region MVA vaccines can shift HIV T cell immunodominance in PWH on ART - the M&M Study

Abstract CD8+ T cell immunity is essential to the control of HIV viremia. We examined the safety and immunogenicity of MVA-vectored vaccines expressing highly conserved HIV regions in a first-in-man Phase I study in people living with HIV on ART. Participants received a single intramuscular dose of MVA.tHIVconsv3 (M3), MVA.tHIVconsv4 (M4), combined M3+M4 or saline in a 7:7:7:3 ratio. M3 and M4 span the same 6 HIV regions but differ by approximately 10% of amino acids; a design to increase vaccine coverage of circulating HIV variants. We employed ex vivo IFN-g ELISpot assays to measure changes in HIV-specific T cell magnitude and breadth to M3 and/or M4 immunogens following vaccination. We also examined whether M3, M4 or M3+M4 vaccination increased the ability of CD8+ T cells inhibit HIV in vitro replication. The M&M study is fully enrolled but presently is blinded. Analysis of blinded data show that vaccination was safe and well tolerated. Vaccination induced strong increases in the T cell response to M3, M4 vaccine immunogens producing a 2- to 18-fold increase in magnitude in 16/20 participants tested to date. M3/M4-specific T cell breadth also increased across participants. Vaccine-associated T cell responses mostly remained elevated (>2-fold increase) for at least 70 days post-vaccination visit. Vaccination was also associated with clear and sustained increases in in vitro virus inhibition. The percentage of the total HIV T cell response targeting conserved HIV regions in participants increased on average from 40 to 60% post-vaccination, suggesting M3/M4/M3+4 vaccination successfully produced a sustained shift in T cell immunodominance. Unblinded data will be presented at this meeting. Supported by U01AI131310