Antigenic competition in CD4(+) T cell responses in a randomized, multicenter, double-blind clinical HIV vaccine trial

• Type of Material: Article
• Authors: Esper G. Kallas, University of Sao Paulo; Nicole A. Grunenberg, Fred Hutchinson Cancer Research Center; Chenchen Yu, Fred Hutchinson Cancer Research Center; Bryce Manso, Fred Hutchinson Cancer Research Center; Giuseppe Pantaleo, Lausanne University Hospital; Martin Casapia, Asociación Civil Selva Amazónica; Lindsey R. Baden, Harvard University; Javier Valencia, Asociación Civil Selva Amazónica; Magdalena Sobieszczyk, Columbia University; Van Tieu Hong, New York Blood Center; Mary Allen, National Institute for Allergy and Infectious Diseases; John Hural, Fred Hutchinson Cancer Research Center; Barney S. Graham, National Institutes of Health; James Kublin, Fred Hutchinson Cancer Research Center; Peter B. Gilbert, Fred Hutchinson Cancer Research Center; Lawrence Corey, Fred Hutchinson Cancer Research Center; Paul A. Goepfert, University of Alabama Birmingham; M. Juliana McElrath, Fred Hutchinson Cancer Research Center; Robert Johnson, Emory University; Yunda Huang, Fred Hutchinson Cancer Research Center; Nicole Frahm, Fred Hutchinson Cancer Research Center
• Language: English
• Date: 2019-11-20
• Publisher: American Association for the Advancement of Science
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 The Authors.
• Final Published Version (URL): http://dx.doi.org/10.1126/scitranslmed.aaw1673
• Title of Journal or Parent Work: Science Translational Medicine
• Volume: 11
• Issue: 519
• Grant/Funding Information: UM1 AI069481 [Seattle-Lausanne-Kampala Clinical Trials Unit: Centre Hospitalier Universitaire Vaudois Clinical Research Site], UM1 AI069412 [Harvard/Boston/Providence Clinical Trials Unit: Brigham and Women’s Hospital Clinical Research Site]; This work was supported by the National Institute of Allergy and Infectious Diseases (NIAID) U.S. Public Health Service Grants UM1 AI068614 [LOC: HIV Vaccine Trials Network], UM1 AI068635 [SDMC: HIV Vaccine Trials Network], UM1 AI068618 [LC: HIV Vaccine Trials Network]; UM1 AI069470 [Columbia Partnership for Prevention and Control of HIV/AIDS Clinical Trials Unit: College of Physicians & Surgeons and New York Blood Center Clinical Research Sites], and P51 OD011132.; UM1 AI069438 [IMPACTA Peru Clinical Trials Unit: Asociación Civil Impacta Salud y Educacion (IMPACTA) and Asociación Civil Selva Amazonica (ACSA) Clinical Research Sites], UM1 AI069420 [São Paulo Clinical Trials Unit: Centro de Referência e Treinamento DST/AIDS Clinical Research Site]
• Keywords: Complexes; Step; Highly pathogenic SIV; Life Sciences & Biomedicine; Medicine, Research & Experimental; Cell Biology; Proteins; Neutralizing antibodies; Science & Technology; Research & Experimental Medicine; Immunity; Models
• Research Categories: Health Sciences, Public Health; Health Sciences, Immunology; Biology, Cell

Abstract

T cell responses have been implicated in reduced risk of HIV acquisition in uninfected persons and control of viral replication in HIV-infected individuals. HIV Gag-specific T cells have been predominantly associated with post-infection control, whereas Env antigens are the target for protective antibodies; therefore, inclusion of both antigens is common in HIV vaccine design. However, inclusion of multiple antigens may provoke antigenic competition, reducing the potential effectiveness of the vaccine. HVTN 084 was a randomized, multicenter, double-blind phase 1 trial to investigate whether adding Env to a Gag/Pol vaccine decreases the magnitude or breadth of Gag/ Pol-specific T cell responses. Fifty volunteers each received one intramuscular injection of 1 × 1010 particle units (PU) of rAd5 Gag/Pol and EnvA/B/C (3:1:1:1 mixture) or 5 × 109 PU of rAd5 Gag/Pol. CD4+ T cell responses to Gag/ Pol measured 4 weeks after vaccination by cytokine expression were significantly higher in the group vaccinated without Env, whereas CD8+ T cell responses did not differ significantly between the two groups. Mapping of individual epitopes revealed greater breadth of the Gag/Pol-specific T cell response in the absence of Env compared to Env coimmunization. Addition of an Env component to a Gag/Pol vaccine led to reduced Gag/Pol CD4+ T cell response rate and magnitude as well as reduced epitope breadth, confirming the presence of antigenic competition. Therefore, T cell–based vaccine strategies should aim at choosing a minimalist set of antigens to reduce interference of individual vaccine components with the induction of the maximally achievable immune response.