Title
Antigenic competition in CD4+ T cell responses in a randomized, multicenter, double-blind clinical HIV vaccine trial
Date Issued
20 November 2019
Access level
open access
Resource Type
journal article
Author(s)
Kallas E.G.
Grunenberg N.A.
Yu C.
Manso B.
Pantaleo G.
Baden L.R.
Valencia J.
Sobieszczyk M.
van Tieu H.
Allen M.
Hural J.
Graham B.S.
Kublin J.
Gilbert P.B.
Corey L.
Goepfert P.A.
Juliana McElrath M.
Paul Johnson R.
Huang Y.
Frahm N.
Publisher(s)
American Association for the Advancement of Science
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.
Volume
11
Issue
519
Language
English
OCDE Knowledge area
Enfermedades infecciosas
Scopus EID
2-s2.0-85075446016
PubMed ID
Source
Science Translational Medicine
ISSN of the container
19466234
Sponsor(s)
We thank the HVTN 084 study volunteers, the staff and community members at each of the study sites, and the staff at the HVTN Administrative Core and SCHARP Statistical Center. We thank S. Self for statistical leadership in the design of this study and H. Ahmed for statistical analysis support. We thank S. De Rosa and K. Cohen for technical expertise and oversight; T. Stewart, K. Hawkins, A. Seese, and P. Newling for technical assistance; C. Marty for data management; and M. Stirewalt for quality assurance oversight. 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 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), 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), UM1 AI069470 (Columbia Partnership for Prevention and Control of HIV/AIDS Clinical Trials Unit: College of Physicians and Surgeons and New York Blood Center Clinical Research Sites), and P51 OD011132 (Yerkes NPRC Base Grant). The opinions expressed in this article are those of the authors and do not necessarily represent the official views of the NIAID or the NIH.
Sources of information: Directorio de Producción Científica Scopus