Influenza Hemagglutinin Nanoparticle Vaccine Elicits Broadly Neutralizing Antibodies against Structurally Distinct Domains of H3N2 HA.

Alyse D. Portnoff,Gale Smith,Jing-Hui Tian,Nita Patel,Haixia Zhou,Bin Zhou,Vivek Shinde,Gregory M. Glenn,Michael J. Massare

doi:10.3390/vaccines8010099

Abstract

Influenza vaccine effectiveness varies annually due to the fast evolving seasonal influenza A(H3N2) strain and egg-derived mutations—both of which can cause a mismatch between the vaccine and circulating strains. To address these limitations, we have developed a hemagglutinin (HA)-based protein-detergent nanoparticle influenza vaccine (NIV) with a saponin-based Matrix-M™ adjuvant. In a phase 1 clinical trial of older adults, the vaccine demonstrated broadly cross-reactive A(H3N2) HA antibody responses. Two broadly neutralizing monoclonal antibodies derived from NIV-immunized mice were characterized by transmission electron microscopy (TEM), antibody competition assays, fluorescence-activated cell sorting (FACS) analysis, and protein–protein docking. These antibodies recognize two conserved regions of the head domain, namely the receptor binding site and the vestigial esterase subdomain, thus demonstrating the potential for an HA subunit vaccine to elicit antibodies targeting structurally and antigenically distinct but conserved sites. Antibody competition studies with sera from the phase 1 trial in older adults confirmed that humans also make antibodies to these two head domains and against the highly conserved stem domain. This data supports the potential of an adjuvanted recombinant HA nanoparticle vaccine to induce broadly protective immunity and improved vaccine efficacy.

Highlights

Influenza disease burden in the United States is estimated to cause 140,000–960,000 hospitalizations each year and 12,000–79,000 deaths according to the Centers for Disease Control and Prevention (CDC)reporting over the last eight seasons [1]
Despite an increase in vaccination of older adults (≥ 65 years) in the US from 15% to 65% between 1980 and 2001, influenza-related mortality continued to increase [2]. This older adult population accounts for 71–85% of all influenza-related deaths, emphasizing the need for a better vaccine that can overcome the challenges of immune senescence and reduced adaptability of B cell responses to influenza after years of repeated exposure [3,4,5]
To identify the domains of HA targeted by the two isolated mAbs, negative-stain transmission electron microscopy (TEM) of AHK14 HA NP alone was compared to TEM of AHK14 HA NP incubated with either A2.91.3 or A2.4.1 Fab domains (Figure 1)

Summary

Introduction

Influenza disease burden in the United States is estimated to cause 140,000–960,000 hospitalizations each year and 12,000–79,000 deaths according to the Centers for Disease Control and Prevention (CDC)reporting over the last eight seasons [1]. Despite an increase in vaccination of older adults (≥ 65 years) in the US from 15% to 65% between 1980 and 2001, influenza-related mortality continued to increase [2]. This older adult population accounts for 71–85% of all influenza-related deaths, emphasizing the need for a better vaccine that can overcome the challenges of immune senescence and reduced adaptability of B cell responses to influenza after years of repeated exposure [3,4,5]. Seasonal influenza is caused by co-circulation of influenza A(H1N1), A(H3N2), and influenza B strains. Seasons dominated by influenza A(H3N2) viruses are more severe, with average pneumonia and influenza mortality rates up to 2.8 times greater than seasons in which A(H1N1) or influenza B strains dominate circulation [2,6].

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Conclusion