Adjuvants and Immunization Strategies to Induce Influenza Virus Hemagglutinin Stalk Antibodies

Peter H. Goff,Rong Hai,Florian Krammer,Luis Martínez-Gil,Christopher W. Seibert,Peter Palese,Dirk Eggink,Shibo Jiang

doi:10.1371/journal.pone.0079194

Abstract

The global population remains vulnerable in the face of the next pandemic influenza virus outbreak, and reformulated vaccinations are administered annually to manage seasonal epidemics. Therefore, development of a new generation of vaccines is needed to generate broad and persistent immunity to influenza viruses. Here, we describe three adjuvants that enhance the induction of stalk-directed antibodies against heterologous and heterosubtypic influenza viruses when administered with chimeric HA proteins. Addavax, an MF59-like nanoemulsion, poly(I:C), and an RNA hairpin derived from Sendai virus (SeV) Cantell were efficacious intramuscularly. The SeV RNA and poly(I:C) also proved to be effective respiratory mucosal adjuvants. Although the quantity and quality of antibodies induced by the adjuvants varied, immunized mice demonstrated comparable levels of protection against challenge with influenza A viruses on the basis of HA stalk reactivity. Finally, we present that intranasally, but not intramuscularly, administered chimeric HA proteins induce mucosal IgA antibodies directed at the HA stalk.

Highlights

Influenza viruses cause substantial annual morbidity and mortality with seasonal epidemic outbreaks of influenza A subtypes H1 and H3 and influenza B viruses as the etiologic agents in the vast majority of human cases
We have previously described the use of an in vitro transcribed (IVT) RNA hairpin derived from the defective interfering (DI) RNA of the Sendai virus (SeV) Cantell strain as an effective influenza virus vaccine adjuvant [12]
We have previously reported that IVT SeV DI RNA (RIG-I agonist) is an effective influenza virus vaccine adjuvant in the context of a homologous vaccine and challenge virus

Summary

Introduction

Influenza viruses cause substantial annual morbidity and mortality with seasonal epidemic outbreaks of influenza A subtypes H1 and H3 and influenza B viruses as the etiologic agents in the vast majority of human cases. Seasonal influenza epidemics may be managed by vaccination, and trivalent vaccines containing H1N1 and H3N2 influenza A components plus an influenza B component have been most widely distributed [2]. This immunization strategy relies upon accurate prediction of the seasonal viruses to circulate in order to reformulate and manufacture the vaccine each year. The correlate of protective immunity for traditional influenza vaccines is a hemagglutination inhibiting (HAI) humoral response to the immunodominant globular head of influenza hemagglutinin [5]. While the majority of neutralizing antibodies target epitopes in the globular head domain, its antigenic regions are highly variable and continually escape the human immune system’s humoral response [2]

Methods

Results

Conclusion