Immunization with inactivated whole virus particle influenza virus vaccines improves the humoral response landscape in cynomolgus macaques

PLoS Pathog. 2022 Oct 7;18(10):e1010891. doi: 10.1371/journal.ppat.1010891. eCollection 2022 Oct.

Abstract

Although antibody-inducing split virus vaccines (SV) are currently the most effective way to combat seasonal influenza, their efficacy can be modest, especially in immunologically-naïve individuals. We investigated immune responses towards inactivated whole influenza virus particle vaccine (WPV) formulations, predicated to be more immunogenic, in a non-human primate model, as an important step towards clinical testing in humans. Comprehensive analyses were used to capture 46 immune parameters to profile how WPV-induced responses differed to those elicited by antigenically-similar SV formulations. Naïve cynomolgus macaques vaccinated with either monovalent or quadrivalent WPV consistently induced stronger antibody responses and hemagglutination inhibition (HI) antibody titres against vaccine-matched viruses compared to SV formulations, while acute reactogenic effects were similar. Responses in WPV-primed animals were further increased by boosting with the same formulation, conversely to modest responses after priming and boosting with SV. 28-parameter multiplex bead array defined key antibody features and showed that while both WPV and SV induced elevated IgG responses against A/H1N1 nucleoprotein, only WPV increased IgG responses against A/H1N1 hemagglutinin (HA) and HA-Stem, and higher IgA responses to A/H1N1-HA after each vaccine dose. Antibodies to A/H1N1-HA and HA-Stem that could engage FcγR2a and FcγR3a were also present at higher levels after one dose of WPV compared to SV and remained elevated after the second dose. Furthermore, WPV-enhanced antibody responses were associated with higher frequencies of HA-specific B-cells and IFN-γ-producing CD4+ T-cell responses. Our data additionally demonstrate stronger boosting of HI titres by WPV following prior infection and support WPV administered as a priming dose irrespective of the follow up vaccine for the second dose. Our findings thus show that compared to SV vaccination, WPV-induced humoral responses are significantly increased in scope and magnitude, advocating WPV vaccination regimens for priming immunologically-naïve individuals and also in the event of a pandemic outbreak.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Antibodies, Viral
  • Hemagglutination Inhibition Tests
  • Hemagglutinins
  • Humans
  • Immunoglobulin A
  • Immunoglobulin G
  • Influenza A Virus, H1N1 Subtype*
  • Influenza Vaccines*
  • Influenza, Human*
  • Macaca fascicularis
  • Nucleoproteins
  • Vaccination
  • Vaccines, Inactivated
  • Virion

Substances

  • Influenza Vaccines
  • Hemagglutinins
  • Antibodies, Viral
  • Vaccines, Inactivated
  • Immunoglobulin A
  • Immunoglobulin G
  • Nucleoproteins

Grants and funding

The project was supported by the Japan Initiative for Global Research Network on Infectious Diseases (J-GRID; JP19fm0108008 to HK and MS), the Japan Program for Infectious Diseases Research and Infrastructure (JIDRI; JP20wm0125008 to HK and MS), a Research Program on Emerging and Re-emerging Infectious Diseases (21fk0108142 to HK and MS) from the Japan Agency for Medical Research and Development (AMED), the GI-CoRE Program of Hokkaido University, the Doctoral Program for World-leading Innovative & Smart Education Program (WISE; 1801 to MS) from the Ministry of Education, Culture, Sports, Science and Technology (MEXT). MO, MS and YI were supported by grants from JSPS KAKENHI (grant numbers 21H02376, 17K15367, 18K07135 and 15H04720, respectively). The work was partly funded by an Australian National Health and Medical Research Council (NHMRC) Program Grant (1071916) awarded to KK, DCJ, LEB. KK was supported by an NHMRC Senior Research Fellowship Level B (#1102792), NHMRC Investigator Grant (#1173871) and a Dame Kate Campbell Fellowship from The University of Melbourne. BYC was supported by a CR Roper Fellowship from the University of Melbourne. THON and MK was supported by NHMRC Emerging Leadership Level 1 Investigator Grants (#1194036 and #1195698, respectively). JRH was supported by a Melbourne Research Scholarship from The University of Melbourne. The work of PMH and BDW were supported by an NHMRC Project grant (#GNT1145303). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.