Matrix M Adjuvanted H5N1 Vaccine Elicits Broadly Neutralizing Antibodies and Neuraminidase Inhibiting Antibodies in Humans That Correlate With In Vivo Protection.

Fan Zhou,Rebecca Cox,Lena Hansen,Gunnveig Grødeland,Gabriel Pedersen

doi:10.3389/fimmu.2021.747774

Abstract

The highly pathogenic avian influenza H5N1 viruses constantly evolve and give rise to novel variants that have caused widespread zoonotic outbreaks and sporadic human infections. Therefore, vaccines capable of eliciting broadly protective antibody responses are desired and under development. We here investigated the magnitude, kinetics and protective efficacy of the multi-faceted humoral immunity induced by vaccination in healthy adult volunteers with a Matrix M adjuvanted virosomal H5N1 vaccine. Vaccinees were given escalating doses of adjuvanted vaccine (1.5μg, 7.5μg, or 30μg), or a non-adjuvanted vaccine (30μg). An evaluation of sera from vaccinees against pseudotyped viruses covering all (sub)clades isolated from human H5N1 infections demonstrated that the adjuvanted vaccines (7.5μg and 30μg) could elicit rapid and robust increases of broadly cross-neutralizing antibodies against all clades. In addition, the adjuvanted vaccines also induced multifaceted antibody responses including hemagglutinin stalk domain specific, neuraminidase inhibiting, and antibody-dependent cellular cytotoxicity inducing antibodies. The lower adjuvanted dose (1.5µg) showed delayed kinetics, whilst the non-adjuvanted vaccine induced overall lower levels of antibody responses. Importantly, we demonstrate that human sera post vaccination with the adjuvanted (30μg) vaccine provided full protection against a lethal homologous virus challenge in mice. Of note, when combining our data from mice and humans we identified the neutralizing and neuraminidase inhibiting antibody titers as correlates of in vivo protection.

Highlights

Enveloped RNA viruses, such as influenza viruses and coronaviruses, constantly evolve, causing zoonotic outbreaks and occasional pandemics in humans
We have previously demonstrated that the adjuvanted H5N1 vaccines elicited potent vaccine specific neutralizing antibodies, and to a lesser extent cross-reactive hemagglutination inhibition (HI) antibodies and Th1 and Th2 CD4+ T cell responses against closely related strains [16,17,18]
All 3 adjuvanted groups had antibodies above the protective level (HI titer ≥32), while the non-adjuvanted 30mg - group remained below the protective level (Figure 1B)

Summary

INTRODUCTION

Enveloped RNA viruses, such as influenza viruses and coronaviruses, constantly evolve, causing zoonotic outbreaks and occasional pandemics in humans. Different vaccines formats, including subunit, live attenuated, and adenoviral vectores have been tested in clinical trials alone, or in combination with adjuvants such as AS03 and MF59 [5,6,7,8,9] These vaccines elicited protective homologous antibody responses and low to moderate levels of neutralizing antibodies to closely related strains. Non-neutralizing antibodies can trigger cytotoxicity and phagocytosis to clear infected cells [14, 15] Whether these nonneutralizing antibodies correlate with in vivo protection against the highly pathogenic H5N1 virus remains unclear. We established an expanded panel of H5N1 pseudotypes covering all (sub)clades isolated from human infections; and characterized the kinetics and breadth of antibody responses after vaccination, including dissection of the multifaceted non-neutralizing antibody responses. We assessed the in vivo protection from vaccine induced antibodies in a passive transfer murine model and investigated immunological candidates for correlates of protection

Study Design

RESULTS

DISCUSSION

ETHICS STATEMENT