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

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.

Next Generation of Computationally Optimized Broadly Reactive HA Vaccines Elicited Cross-Reactive Immune Responses and Provided Protection against H1N1 Virus Infection

“…Full length wild-type influenza A(H1N1) HA protein amino acid sequences from 6232 human H1N1 viruses collected from May 1, 2013, to April 30, 2019, were downloaded from the Global Initiative on Sharing Avian Influenza Data (GISAID) EpiFlu online database. Sequences were organized by their date of collection and used to produce consensus sequences based on the next-generation COBRA design methodology as previously described [ 7 ]. The secondary consensus sequences were then input into 2 different COBRA consensus building scenarios as previously described [ 7 ] to generate the final H1 consensus sequences.…”

“…Annual seasonal influenza virus vaccines are typically composed of two influenza A virus (IAV) strains representing the A(H1N1) and A(H3N2) subtypes, and either one or two influenza B virus (IBV) strains representing either the Victoria or Yamagata lineages [ 5 , 6 , 7 ]. Seasonal vaccines predominantly target the continually evolving globular head of the hemagglutinin (HA) protein, and their efficacy has varied between 19% and 60% from 2009 to 2020 [ 8 ] depending on the similarity between the antigens in the vaccine and those present in circulating influenza strains [ 9 , 10 ].…”

“…Previous COBRA design methodologies focus on generating antigens that are broadly reactive against historical and contemporary influenza virus vaccine strains [ 7 , 12 , 17 , 24 ]. An emphasis was placed on designing the vaccines using historical influenza isolates, viruses from specific antigenic eras, or past outbreaks.…”

“…An emphasis was placed on designing the vaccines using historical influenza isolates, viruses from specific antigenic eras, or past outbreaks. In this study, a new seasonal-based methodology that focused on current and recent circulating viruses was used to update these broadly reactive HA vaccines to better represent the antigen diversity among currently circulating viruses [ 7 ]. Using this new methodology, two promising next generation H1N1 COBRA HA vaccine candidates, Y2 and Y4, were generated to elicit antibody responses against a panel of H1N1 viruses isolated from 1983 to 2021.…”

Targeting Antigens for Universal Influenza Vaccine Development

“…COBRA H3 HA antigens have been demonstrated to induce HI antibodies to protect mice against a panel of H3N2 influenza virus cocirculating variants [60]. More recently, Ross et al developed a COBRA H3 HA vaccine by generating a consensus sequence from 22,144 human A(H3N2) viruses collected from 2002 to 2015 [62]. This vaccine candidate showed an increase in HI activity compared to wild-type HA vaccine.…”