Characterizing the distinct t cell profiles induced by monovalent and bivalent HIV vaccination in PWH on art - the CM study project summary: no t cell vaccines have demonstrated efficacy for either…

The National Institute of Allergy and Infectious Diseases awarded the University of North Carolina at Chapel Hill $233,250 on September 1, 2026, under the Allergy and Infectious Diseases Research program (CFDA 93.855) to characterize T cell profiles induced by monovalent and bivalent HIV vaccination in people with HIV on antiretroviral therapy.

The research examines whether increased cross-recognition following bivalent HIV vaccination improves T cell-mediated recognition and inhibition of genetically distinct viruses in the HIV reservoir. The project builds on findings from the completed CM Study, a randomized blinded vaccine trial comparing ChAdOx1- and modified vaccinia ankara-vectored vaccines expressing either one (monovalent) or two HIV immunogens (bivalent). The earlier trial demonstrated that while monovalent vaccination skewed T cell responses toward the single immunogen, bivalent immunization increased T cell frequencies against both immunogens (MOSAIC-1 and MOSAIC-2) almost equally, providing proof-of-concept that bivalent HIV immunogen designs broaden recognition of HIV-specific T cells. The current project aims to determine whether serial vaccination with bivalent immunogens enhances recognition against a greater number of epitope variants in HIV.

The award funds research performed at Chapel Hill, North Carolina, with a period of performance from September 1, 2026, through August 31, 2028. The assistance type is a Project Grant.

Characterizing the distinct t cell profiles induced by monovalent and bivalent HIV vaccination in PWH on art - the CM study project summary: no t cell vaccines have demonstrated efficacy for either prevention or therapeutic control of HIV-1. We have recently completed a randomized and blinded vaccine trial called the CM study in people with HIV (PWH) on antiretroviral therapy (art). Participants received CHIMPADENOVIRUSOX1 (CHADOX1)- and modified vaccinia ankara (MVA)- vectored vaccines expressing either one (monovalent) or two HIV immunogens (bivalent). The vaccine immunogens called mosaic-1 and mosaic-2 (collectively hivconsvx), target the same six highly conserved HIV regions but differ by 8% at the amino acid level. Vaccination with both immunogens was predicted to increase coverage of HIV variants, including those that occur in conserved regions of HIV. The CM study examined safety and immunogenicity of these vaccines and, more specifically, compared t cell responses following monovalent or bivalent vaccination. Vaccination was well tolerated and regimens significantly increased HIV-specific t cell frequencies for up to 6 months post-vaccination. We observed that while monovalent vaccination skewed t cell responses towards the single immunogen, bivalent immunization increased t cell frequencies against both immunogens (mosaic-1 and mosaic-2) almost equally. These data provide proof-of-concept that bivalent HIV immunogen designs broaden the recognition of HIV-specific t cells. This proposal examines whether increased cross-recognition following bivalent vaccination improves t cell- mediated recognition and inhibition of genetically distinct viruses in the HIV reservoir. Aim 1: hypothesis: serial vaccination with bivalent immunogens enhances recognition against a greater number of epitope variants in HIV. In 1.1., we will determine whether bivalent vaccination in CM participants expands HIV-specific t cells with broader cross-recognition of mosaic-1 and -2 epitope variants compared with (i) pre-vaccination time points and (II) monovalent vaccination. These studies will also examine the contribution of the first CHADOX1 vaccination to t cell avidity and breadth. In 1.2, we will leverage a previous study in which HIV-specific t cells were mapped against autologous reservoir viruses recovered from 25 PWH on art, with one third being women. We will directly compare in vitro expansion of t cells against bivalent or monovalent immunogens and examine if bivalent stimulation results in t cells with broader recognition of reservoir variants within each participant. Aim 2: hypothesis: vaccination with bivalent immunogens generates t cells better able to recognize variants in the HIV reservoir and, therefore, afford improved autologous virus inhibition. We will recover and sequence HIV outgrowth virus from CM participants then examine both the magnitude and breadth of CD8 t cell inhibition of individual outgrowth viruses, pre- and post-vaccination and between vaccine groups. These studies will result in data-driven recommendations to advance i) bivalent immunogen designs and II) serial CHADOX1-MVA vectored regimens in t cell vaccines against HIV.