Next generation methodology for updating HA vaccines against emerging human seasonal influenza A(H3N2) viruses

James D. Allen,Ted M. Ross

doi:10.1038/s41598-020-79590-7

Abstract

While vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Seasonal influenza vaccines typically consist of wild-type influenza A and B viruses that are limited in their ability to elicit protective immune responses against co-circulating influenza virus variant strains. Improved influenza virus vaccines need to elicit protective immune responses against multiple influenza virus drift variants within each season. Broadly reactive vaccine candidates potentially provide a solution to this problem, but their efficacy may begin to wane as influenza viruses naturally mutate through processes that mediates drift. Thus, it is necessary to develop a method that commercial vaccine manufacturers can use to update broadly reactive vaccine antigens to better protect against future and currently circulating viral variants. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a next generation algorithm and design methodology. These next-generation broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates.

Highlights

While vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years
Annual seasonal influenza virus vaccines in the United States are typically composed of two influenza A strains representing the A(H1N1) and A(H3N2) subtypes and either one or two influenza B strains representing the Victoria and Yamagata lineages[10,11]
The next-generation computationally optimized broadly reactive antigen (COBRA) multilayered consensus building approach was applied to 22,144 human A(H3N2) HA viral amino acid sequences collected from January 1, 2002 to December 31, 2015, that resulted in the generation of 9 unique Gen HA sequences

Summary

Introduction

While vaccines remain the best tool for preventing influenza virus infections, they have demonstrated low to moderate effectiveness in recent years. Building upon the COBRA technology, nine next-generation H3N2 influenza hemagglutinin (HA) vaccines were designed using a generation algorithm and design methodology These nextgeneration broadly reactive COBRA H3 HA vaccines were superior to wild-type HA vaccines at eliciting antibodies with high HAI activity against a panel of historical and co-circulating H3N2 influenza viruses isolated over the last 15 years, as well as the ability to neutralize future emerging H3N2 isolates. Influenza A(H3N2) viruses are associated throughout recent history with widespread influenza virus induced illness[13,14,15,16] Since their introduction to the human population in 1968, A(H3N2) influenza viruses have undergone extensive genetic drift and antigenic evolution leading to numerous seasonal epidemics, exemplified by the WHO recommending 29 A(H3N2) vaccine strain changes over the last 50 years[17]. Antigenic mismatches between the chosen vaccine strain and currently circulating viruses often lead to reduced vaccine effectiveness, requiring influenza vaccines to be updated frequently[18]

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Conclusion