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 4

T cell response epitope breadth.

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T cell response epitope breadth. The minimum number of T cell epitopes t...
The minimum number of T cell epitopes that could explain each participant’s peptide responses (i.e., epitope breadth) was determined from the participant’s ELISpot responses to HIV-1 envelope 15-mers and on the basis of the assumption that responses to 2 or more 15-mers sharing a region of ≥8 positions can be explained as a response to a single epitope (see Methods for description of the prespecified, deterministic algorithm for identifying targeted epitopes). (A) Breadth was estimated based on all of the peptides/responses (Overall) or on a subset of the peptides matching the DNA (Prime-matched), circulating strains (Heterologous), or the MVA immunogen (Boost-matched). Each participant is plotted (colored circle) with a treatment group mean and 95% confidence interval (non-parametric bootstrap) overlaid. Groups were compared using a permutation test on the mean (2-sided); significant differences (unadjusted P < 0.05) are annotated with a P value. (B) Overall epitope breadth was also analyzed separately for CD4+ and CD8+ T cell responses (determined by ICS). A small, arbitrary amount of “jitter” along the x axis has been added to each data point to increase visibility.