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Author Notes:

Correspondence: Nicole Frahm, PhD, Bill & Melinda Gates Medical Research Institute, 245 Main Street, Cambridge, MA 02142, nicole.frahm@gatesmri.org

Author contributions: E.G.K, L.R.B., M.A., J.H., B.S.G., J.K., P.A.G., R.P.J. designed research; N.G. contributed to study design, protocol development, implementation management and safety data monitoring; B.M. conducted the epitope mapping assays;

C.Y. and Y.H performed the statistical analyses and generated tables and figures. G.P., M.C., J.V., M.S. and H.V.T. enrolled participants. All authors contributed to discussions about the results and critically revised the manuscript. N.F. wrote the manuscript. P.B.G, L.C. and M.J.M. supervised the research.

We thank the HVTN 084 study volunteers; the staff and community members at each of the study sites; the staff at the HVTN Administrative Core and SCHARP Statistical Center. We thank Steve Self for his statistical leadership in the design of this study and Hasan Ahmed for his statistical analysis support.

We thank Stephen De Rosa and Kristen Cohen for technical expertise and oversight; Terri Stewart, Kevin Hawkins, Aaron Seese and Paul Newling for technical assistance, Carol Marty for data management and Michael Stirewalt for quality assurance oversight.

Disclosures: The authors declare that they have no competing interests.

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Research Funding:

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 & Surgeons and New York Blood Center Clinical Research Sites], and P51 OD011132.

Keywords:

  • Science & Technology
  • Life Sciences & Biomedicine
  • Cell Biology
  • Medicine, Research & Experimental
  • Research & Experimental Medicine
  • Highly pathogenic SIV
  • Neutralizing antibodies
  • Proteins
  • Immunity
  • Models
  • Complexes
  • Step

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

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Journal Title:

Science Translational Medicine

Volume:

Volume 11, Number 519

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Type of Work:

Article | Post-print: After Peer Review

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.

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© 2019 The Authors.

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