Pandemic influenza virus vaccines boost hemagglutinin stalk-specific antibody responses in primed adult and pediatric cohorts

Damien Friel,Ronan N. Rouxel,Randy A. Albrecht,Bruce L. Innis,Corey P. Mallett,Florian Krammer,Bruno Salaun,Mohammad A. Behzadi,Adolfo García-Sastre,Raffael Nachbagauer,Carine Claeys,Daniel Stadlbauer,Arvind Rajabhathor,Muriel Debois,Angela Choi,Peter Palese,Weina Sun

doi:10.1038/s41541-019-0147-z

Abstract

Licensed influenza virus vaccines target the head domain of the hemagglutinin (HA) glycoprotein which undergoes constant antigenic drift. The highly conserved HA stalk domain is an attractive target to increase immunologic breadth required for universal influenza virus vaccines. We tested the hypothesis that immunization with a pandemic influenza virus vaccine boosts pre-existing anti-stalk antibodies. We used chimeric cH6/1, full length H2 and H18 HA antigens in an ELISA to measure anti-stalk antibodies in recipients participating in clinical trials of A/H1N1, A/H5N1 and A/H9N2 vaccines. The vaccines induced high titers of anti-H1 stalk antibodies in adults and children, with higher titers elicited by AS03-adjuvanted vaccines. We also observed cross-reactivity to H2 and H18 HAs. The A/H9N2 vaccine elicited plasmablast and memory B-cell responses. Post-vaccination serum from vaccinees protected mice against lethal challenge with cH6/1N5 and cH5/3N4 viruses. These findings support the concept of a chimeric HA stalk-based universal influenza virus vaccine. clinicaltrials.gov: NCT02415842.

Highlights

Influenza is a major public health burden with substantial clinical and economic impact.[1]
In the homologous prime-boost adult studies, vaccination with pandemic A/H1N1, A/H5N1 and A/H9N2 vaccines elicited an immune response against the H1 stalk (Fig. 1a)
mean geometric increase (MGI) were higher with the A/H1N1 vaccine than with the A/H5N1 or A/H9N2 vaccines (Fig. 1b; Supplementary Table 3)

Summary

Introduction

Influenza is a major public health burden with substantial clinical and economic impact.[1] Vaccination is the cornerstone of influenza prevention, and is recommended by the World Health Organization (WHO) for young children, the elderly, pregnant women, people with certain chronic medical conditions, and health care workers.[2]. Hemagglutinin (HA) and neuraminidase (NA) are the two major glycoproteins on the influenza virus surface. HA consists of a membrane-distal globular head domain and a membraneproximal stalk domain. It has high plasticity and undergoes constant antigenic drift,[6,7,8] meaning that seasonal influenza virus vaccines must be reformulated almost every year to allow them to induce antibodies that recognize the new variants produced.[9]

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Conclusion