Adjuvanted H5N1 influenza vaccine enhances both cross-reactive memory B cell and strain-specific naive B cell responses in humans

• Type of Material: Article
• Authors: Ali H. Ellebedy, Emory University; Raffael Nachbagauer, Icahn School of Medicine at Mount Sinai; Katherine J.L. Jackson, Stanford University; Ya-Nan Dai, Washington University; Julianna Han, Scripps Research Institute; Wafaa B. Alsoussi, Washington University; Carl Davis, Emory University; Daniel Stadlbauer, Icahn School of Medicine at Mount Sinai; Nadine Rouphael, Emory University; Veronika Chromikova, Icahn School of Medicine at Mount Sinai; Megan McCausland, Emory University; Cathy Y. Chang, Emory University; Mario Cortese, Emory University; Mary Bower, Emory University; Chakravarthy Chennareddy, Emory University; Aaron J. Schmitz, Washington University; Veronika Zarnitsyna, Emory University; Lilin Lai, Emory University; Arvind Rajabhathor, Icahn School of Medicine at Mount Sinai; Cheyann Kazemian, Emory University; Rustom Antia, Emory University; Mark Mulligan, Emory University; Andrew B. Ward, Scripps Research Institute; Daved H. Fremont, Washington University; Scott D. Boyd, Stanford University; Bali Pulendran, Emory University; Florian Krammer, Icahn School of Medicine at Mount Sinai; Rafi Ahmed, Emory University
• Language: English
• Date: 2020-07-28
• Publisher: NATL ACAD SCIENCES
• Publication Version: Final Published Version
• Copyright Statement: 2020
• Final Published Version (URL): http://dx.doi.org/10.1073/pnas.1906613117
• Title of Journal or Parent Work: PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
• Volume: 117
• Issue: 30
• Start Page: 17957
• End Page: 17964
• Grant/Funding Information: This work was supported by National Institute of Allergy and Infectious Diseases (NIAID) Grants U19 AI109946 (to F.K.), and HHSN2722019 (to R. Ahmed), Grants R21 AI139813 and U01 AI141990 (to A.H.E.), and grants from the NIAID-funded Centers of Excellence in Influenza Research and Surveillance (CEIRS; HHSN272201400004C [to R. Ahmed] and HHSN272201400008C [to F.K. and A.H.E.]). R. Antia and V.I.Z. are also supported by U19 AI117891. The vaccination study was supported by The Human Immunology Project Consortium (HIPC) U19AI090023 (B.P.). S.D.B. is supported by NIAID Grants R01AI130398, R01AI127877, and U19AI057229.
• Keywords: Multidisciplinary Sciences; VIRUS; Science & Technology; adjuvant; Science & Technology - Other Topics; influenza; B cells; H5N1; HUMAN MONOCLONAL-ANTIBODIES; memory; AS03 ADJUVANT
• Research Categories: Biology, Virology; Health Sciences, Medicine and Surgery; Biology, Cell

Abstract

There is a need for improved influenza vaccines. In this study we compared the antibody responses in humans after vaccination with an AS03-adjuvanted versus nonadjuvanted H5N1 avian influenza virus inactivated vaccine. Healthy young adults received two doses of either formulation 3 wk apart. We found that AS03 significantly enhanced H5 hemagglutinin (HA)-specific plasmablast and antibody responses compared to the nonadjuvanted vaccine. Plasmablast response after the first immunization was exclusively directed to the conserved HA stem region and came from memory B cells. Monoclonal antibodies (mAbs) derived from these plasmablasts had high levels of somatic hypermutation (SHM) and recognized the HA stem region of multiple influenza virus subtypes. Second immunization induced a plasmablast response to the highly variable HA head region. mAbs derived from these plasmablasts exhibited minimal SHM (naive B cell origin) and largely recognized the HA head region of the immunizing H5N1 strain. Interestingly, the antibody response to H5 HA stem region was much lower after the second immunization, and this suppression was most likely due to blocking of these epitopes by stem-specific antibodies induced by the first immunization. Taken together, these findings show that an adjuvanted influenza vaccine can substantially increase antibody responses in humans by effectively recruiting preexisting memory B cells as well as naive B cells into the response. In addition, we show that high levels of preexisting antibody can have a negative effect on boosting. These findings have implications toward the development of a universal influenza vaccine.