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

• Type of Material: Article
• Authors: Kristen W Cohen, Fred Hutchinson Cancer Center; Andrew Fiore-Gartland, Fred Hutchinson Cancer Center; Stephen R Walsh, Brigham and Women’s Hospital; Karina Yusim, Los Alamos National Laboratory; Nicole Frahm, Fred Hutchinson Cancer Center, Seattle; Marnie L Elizaga, Fred Hutchinson Cancer Center, Seattle; Janine Maenza, Fred Hutchinson Cancer Center, Seattle; Hyman Scott, San Francisco Dept Publ Hlth; Kenneth H Mayer, Harvard Medical School; Paul A Goepfert, University of Alabama Birmingham; Srilatha Edupuganti, Emory University; Giuseppe Pantaleo, Centre Hospitalier Universitaire Vaudois, Lausanne, Switzerland; Julia Hutter, National Institute of Allergy and Infectious Diseases, Bethesda; Daryl E Morris, Fred Hutchinson Cancer Center, Seattle; Stephen C De Rosa, Fred Hutchinson Cancer Center, Seattle; Daniel E Geraghty, Fred Hutchinson Cancer Center, Seattle; Merlin L Robb, Henry M. Jackson Foundation for the Advancement of Military Medicine, Bethesda; Nelson L Michael, Walter Reed Army Institute of Research, Silver Spring; Will Fischer, University of Washington; Elena E Giorgi, Los Alamos National Laboratory, and New Mexico Consortium, Los Alamos, New Mexico; Harmandeep Malhi, Fred Hutchinson Cancer Research Center; Micheal N Pensiero, National Institute of Allergy and Infectious Diseases, Bethesda, Maryland; Guido Ferrari, Duke University; Georgia D Tomaras, Duke University; David C Montefiori, Duke University; Peter B Gilbert, Fred Hutchinson Cancer Research Center; Juliana M McElrath, Fred Hutchinson Cancer Research Center; Barton F Haynes, Duke University; Bette T Korber, Los Alamos National Laboratory; Lindsey R Baden, Brigham and Women’s Hospital, Boston, Massachusetts
• Language: English
• Date: 2023-02-15
• Publisher: AMER SOC CLINICAL INVESTIGATION INC
• Publication Version: Final Published Version
• Copyright Statement: © 2023 Cohen et al.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1172/JCI163338
• Title of Journal or Parent Work: JOURNAL OF CLINICAL INVESTIGATION
• Volume: 133
• Issue: 4
• Keywords: SEQUENCES; DOUBLE-BLIND; Research & Experimental Medicine; RHESUS-MONKEYS; COVERAGE; CHALLENGE; ANTIBODIES; Science & Technology; TRIAL; CONSERVED REGIONS; HUMAN-IMMUNODEFICIENCY-VIRUS; VACCINE EFFICACY; Medicine, Research & Experimental; Life Sciences & Biomedicine
• Research Categories: Health Sciences, Medicine and Surgery; Health Sciences, Public Health

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.