A chimeric haemagglutinin-based universal influenza virus vaccine boosts human cellular immune responses directed towards the conserved haemagglutinin stalk domain and the viral nucleoproteinResearch in context
Carly M. Bliss,
Raffael Nachbagauer,
Chiara Mariottini,
Frans Cuevas,
Jodi Feser,
Abdi Naficy,
David I. Bernstein,
Jeffrey Guptill,
Emmanuel B. Walter,
Francesco Berlanda-Scorza,
Bruce L. Innis,
Adolfo García-Sastre,
Peter Palese,
Florian Krammer,
Lynda Coughlan
Affiliations
Carly M. Bliss
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Division of Cancer & Genetics and Systems Immunity University Research Institute, School of Medicine, Cardiff University, Cardiff, UK
Raffael Nachbagauer
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Chiara Mariottini
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Frans Cuevas
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Jodi Feser
Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA
Abdi Naficy
Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA
David I. Bernstein
Department of Pediatrics, University of Cincinnati College of Medicine, Cincinnati, OH, USA; Division of Infectious Diseases, Cincinnati Children’s Hospital Medical Center, Cincinnati, OH, USA
Jeffrey Guptill
Duke Early Phase Clinical Research Unit, Duke Clinical Research Institute, Durham, NC, USA
Emmanuel B. Walter
Duke Human Vaccine Institute, Duke University School of Medicine, Durham, NC, USA
Francesco Berlanda-Scorza
Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA
Bruce L. Innis
Center for Vaccine Innovation and Access, PATH, Seattle, WA, USA
Adolfo García-Sastre
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Global Health and Emerging Pathogens Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA; The Icahn Genomics Institute, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Peter Palese
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Medicine, Division of Infectious Diseases, Icahn School of Medicine at Mount Sinai, New York, NY, USA
Florian Krammer
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Department of Pathology, Molecular and Cell-Based Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA; Center for Vaccine Research and Pandemic Preparedness (C-VaRPP), Icahn School of Medicine at Mount Sinai, New York, NY, USA
Lynda Coughlan
Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, NY, USA; University of Maryland School of Medicine, Department of Microbiology and Immunology, Baltimore, MD 21201, USA; University of Maryland School of Medicine, Center for Vaccine Development and Global Health (CVD), Baltimore, MD 21201, USA; Corresponding author. Department of Microbiology and Immunology, University of Maryland School of Medicine, Baltimore, MD 21201, USA.
Summary: Background: The development of a universal influenza virus vaccine, to protect against both seasonal and pandemic influenza A viruses, is a long-standing public health goal. The conserved stalk domain of haemagglutinin (HA) is a promising vaccine target. However, the stalk is immunosubdominant. As such, innovative approaches are required to elicit robust immunity against this domain. In a previously reported observer-blind, randomised placebo-controlled phase I trial (NCT03300050), immunisation regimens using chimeric HA (cHA)-based immunogens formulated as inactivated influenza vaccines (IIV) −/+ AS03 adjuvant, or live attenuated influenza vaccines (LAIV), elicited durable HA stalk-specific antibodies with broad reactivity. In this study, we sought to determine if these vaccines could also boost T cell responses against HA stalk, and nucleoprotein (NP). Methods: We measured interferon-γ (IFN-γ) responses by Enzyme-Linked ImmunoSpot (ELISpot) assay at baseline, seven days post-prime, pre-boost and seven days post-boost following heterologous prime:boost regimens of LAIV and/or adjuvanted/unadjuvanted IIV-cHA vaccines. Findings: Our findings demonstrate that immunisation with adjuvanted cHA-based IIVs boost HA stalk-specific and NP-specific T cell responses in humans. To date, it has been unclear if HA stalk-specific T cells can be boosted in humans by HA-stalk focused universal vaccines. Therefore, our study will provide valuable insights for the design of future studies to determine the precise role of HA stalk-specific T cells in broad protection. Interpretation: Considering that cHA-based vaccines also elicit stalk-specific antibodies, these data support the further clinical advancement of cHA-based universal influenza vaccine candidates. Funding: This study was funded in part by the Bill and Melinda Gates Foundation (BMGF).
