Trivalent mosaic or consensus HIV immunogens prime humoral and broader cellular immune responses in adults
Kristen W. Cohen, … , Lindsey R. Baden, the NIAID HVTN 106 Study Group
Kristen W. Cohen, … , Lindsey R. Baden, the NIAID HVTN 106 Study Group
Published February 15, 2023
Citation Information: J Clin Invest. 2023;133(4):e163338. https://doi.org/10.1172/JCI163338.
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Clinical Research and Public Health AIDS/HIV

Trivalent mosaic or consensus HIV immunogens prime humoral and broader cellular immune responses in adults

Abstract

BACKGROUND Mosaic and consensus HIV-1 immunogens provide two distinct approaches to elicit greater breadth of coverage against globally circulating HIV-1 and have shown improved immunologic breadth in nonhuman primate models.METHODS This double-blind randomized trial enrolled 105 healthy HIV-uninfected adults who received 3 doses of either a trivalent global mosaic, a group M consensus (CON-S), or a natural clade B (Nat-B) gp160 env DNA vaccine followed by 2 doses of a heterologous modified vaccinia Ankara–vectored HIV-1 vaccine or placebo. We performed prespecified blinded immunogenicity analyses at day 70 and day 238 after the first immunization. T cell responses to vaccine antigens and 5 heterologous Env variants were fully mapped.RESULTS Env-specific CD4+ T cell responses were induced in 71% of the mosaic vaccine recipients versus 48% of the CON-S recipients and 48% of the natural Env recipients. The mean number of T cell epitopes recognized was 2.5 (95% CI, 1.2–4.2) for mosaic recipients, 1.6 (95% CI, 0.82–2.6) for CON-S recipients, and 1.1 (95% CI, 0.62–1.71) for Nat-B recipients. Mean breadth was significantly greater in the mosaic group than in the Nat-B group using overall (P = 0.014), prime-matched (P = 0.002), heterologous (P = 0.046), and boost-matched (P = 0.009) measures. Overall T cell breadth was largely due to Env-specific CD4+ T cell responses.CONCLUSION Priming with a mosaic antigen significantly increased the number of epitopes recognized by Env-specific T cells and enabled more, albeit still limited, cross-recognition of heterologous variants. Mosaic and consensus immunogens are promising approaches to address global diversity of HIV-1.TRIAL REGISTRATION ClinicalTrials.gov NCT02296541.FUNDING US NIH grants UM1 AI068614, UM1 AI068635, UM1 AI068618, UM1 AI069412, UL1 RR025758, P30 AI064518, UM1 AI100645, and UM1 AI144371, and Bill & Melinda Gates Foundation grant OPP52282.

Authors

Kristen W. Cohen, Andrew Fiore-Gartland, Stephen R. Walsh, Karina Yusim, Nicole Frahm, Marnie L. Elizaga, Janine Maenza, Hyman Scott, Kenneth H. Mayer, Paul A. Goepfert, Srilatha Edupuganti, Giuseppe Pantaleo, Julia Hutter, Daryl E. Morris, Stephen C. De Rosa, Daniel E. Geraghty, Merlin L. Robb, Nelson L. Michael, Will Fischer, Elena E. Giorgi, Harman Malhi, Michael N. Pensiero, Guido Ferrari, Georgia D. Tomaras, David C. Montefiori, Peter B. Gilbert, M. Juliana McElrath, Barton F. Haynes, Bette T. Korber, Lindsey R. Baden, the NIAID HVTN 106 Study Group

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Figure 3

T cell ELISpot responses to vaccine-matched and heterologous HIV-1 envelope 15-mer peptides.

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T cell ELISpot responses to vaccine-matched and heterologous HIV-1 envel...
T cell epitope mapping was conducted with PBMC samples collected 2 weeks after second MVA (day 238) using IFN-γ ELISpot. Using a response-conditional, hierarchical pooling approach, 15-mer peptides spanning envelope (11 aa overlap) were used from the 6 vaccine immunogens (NAT-B [B.1059], CON-S [M.ConS], mosaic [Mmos3.1, Mmos3.2, Mmos3.3], MVA [01.CM235]) and 5 heterologous circulating strains (B.US.2011, B.ZA.2009, B.ES.2010, A1.KE.2009, C.ZA.2009). The vaccine-matched peptides for each group are indicated by gray shading at the top of each column. Only participants with a significant T cell response by ICS were included in the epitope mapping, with each row of the tables representing an individual in the Nat-B (A, n = 25 mapped), CON-S (B, n = 21 mapped), or mosaic (C, n = 21 mapped) treatment group, and positive responses annotated with their single-peptide response magnitude (spot-forming cells per million). Determinations of the responding T cell subset were made using single-peptide ICS experiments (indicated by the color of the rectangle: blue, CD4+; red, CD8+; gray, unknown). Each row of the tables indicates a response to a single epitope across variants. Often these epitopes are variable between strains, and a complete mapping of targeted epitope variation is available in Supplemental Excel Files 1–3. Empty rows indicate that no responses were detected in a given individual. The number and percentage of individuals with at least one CD4+ or CD8+ response are indicated below each table. The restricting HLA allele for each response was determined using peptide binding prediction (NetMHCpan 4.0), a database of previously observed HIV-1 responses (Los Alamos National Laboratory), and the participant’s HLA genotype.