A Single Dose of Inactivated Influenza Virus Vaccine Expressing COBRA Hemagglutinin Elicits Broadly-Reactive and Long-Lasting Protection

Abstract

Influenza virus infections present a pervasive global health concern resulting in millions of hospitalizations and thousands of fatalities annually. To address the influenza antigenic variation, the computationally optimized broadly reactive antigen (COBRA) methodology was used to design influenza hemagglutinin (HA) or neuraminidase (NA) for universal influenza vaccine candidates. In this study, whole inactivated virus (WIV) or split inactivated virus (SIV) vaccine formulations expressing either the H1 COBRA HA or H3 COBRA HA were formulated with or without an adjuvant and tested in ferrets with pre-existing anti-influenza immunity. A single dose of the COBRA-WIV vaccine elicited a robust and broadly reactive antibody response against H1N1 and H3N2 influenza viruses. In contrast, the COBRA-SIV elicited antibodies that recognized fewer viruses, but with R-DOATP, its specificity was expanded. Vaccinated ferrets were protected against morbidity and mortality following challenge with A/California/07/2009 at 14 weeks post-vaccination with reduced viral shedding post-infection compared to the naive mock-vaccinated ferrets. However, the COBRA-IIVs did not block the viral transmission to naive ferrets. The contact infection induced less severe disease and delayed viral shedding than direct infection. Overall, the COBRA HA WIV or the COBRA HA SIV plus R-DOTAP elicited broadly reactive antibodies with long-term protection against viral challenge and reduced viral transmission following a single dose of vaccine in ferrets pre-immune to historical H1N1 and H3N2 influenza viruses. IMPORTANCEA next-generation influenza virus vaccine aims to provide broadly reactive protection against various drifted influenza strains. COBRA HA-based vaccines elicit broadly-reactive antibodies following two or three vaccinations. However, people are administered a single vaccination of current commercial influenza virus vaccines. In this study, ferrets with pre-existing anti-influenza immunity were administered a single shot COBRA-WIV that elicited long-lasting, broadly-reactive antibodies that protected ferrets against pdmH1N1 viral challenge. This is the first study describing the immune responses elicited by COBRA-IIV vaccines in ferrets that protected ferrets 14 weeks post-vaccination.