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

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-naive 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. Naive 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 Fc gamma R2a and Fc gamma R3a 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-gamma-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-naive individuals and also in the event of a pandemic outbreak. Author summary Influenza viral infections cause significant morbidity and mortality. Although current split virus (SV) vaccines are the most effective way to combat seasonal influenza, their efficacy can be modest. We investigated immune responses directed towards inactivated whole influenza virus particle vaccine (WPV) formulations in a non-human primate model as an important step towards clinical testing in humans. Our analysis of 46 immune parameters found that compared to SV vaccination, WPV-induced antibody responses were significantly increased in scope and magnitude, together with higher frequencies of influenza-specific B-cell and CD4(+) T-cell responses. Our study provides key insights into the immune responses induced by WPV vaccination in immunologically-naive animals.

Automated summary

Compared to split virus vaccines, inactivated whole influenza virus particle vaccines induce stronger humoral responses, higher frequencies of influenza-specific B-cell and CD4(+) T-cell responses, and enhanced hemagglutination inhibition titers. These findings provide key insights into the immune responses induced by inactivated whole influenza virus particle vaccines in immunologically-naive individuals.