The Journal of Clinical Investigation (Feb 2023)

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

  • 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

Journal volume & issue
Vol. 133, no. 4

Abstract

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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.

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