Efficacy of recombinant Marek’s disease virus vectored vaccines with computationally optimized broadly reactive antigen (COBRA) hemagglutinin insert against genetically diverse H5 high pathogenicity avian influenza viruses

Kateri Bertran,Aemro Kassa,Miria F Criado,Ivette A Nuñez,Dong-Hun Lee,Lindsay Killmaster,Mariana Sá E Silva,Ted M Ross,Teshome Mebatsion,Nikki Pritchard,David E Swayne

doi:10.1016/j.vaccine.2021.02.075

Abstract

The genetic and antigenic drift associated with the high pathogenicity avian influenza (HPAI) viruses of Goose/Guangdong (Gs/GD) lineage and the emergence of vaccine-resistant field viruses underscores the need for a broadly protective H5 influenza A vaccine. Here, we tested experimental vector herpesvirus of turkey (vHVT)-H5 vaccines containing either wild-type clade 2.3.4.4A-derived H5 inserts or computationally optimized broadly reactive antigen (COBRA) inserts with challenge by homologous and genetically divergent H5 HPAI Gs/GD lineage viruses in chickens. Direct assessment of protection was confirmed for all the tested constructs, which provided clinical protection against the homologous and heterologous H5 HPAI Gs/GD challenge viruses and significantly decreased oropharyngeal shedding titers compared to the sham vaccine. The cross reactivity was assessed by hemagglutinin inhibition (HI) and focus reduction assay against a panel of phylogenetically and antigenically diverse H5 strains. The COBRA-derived H5 inserts elicited antibody responses against antigenically diverse strains, while the wild-type-derived H5 vaccines elicited protection mostly against close antigenically related clades 2.3.4.4A and 2.3.4.4D viruses. In conclusion, the HVT vector, a widely used replicating vaccine platform in poultry, with H5 insert provides clinical protection and significant reduction of viral shedding against homologous and heterologous challenge. In addition, the COBRA-derived inserts have the potential to be used against antigenically distinct co-circulating viruses and future drift variants.

Highlights

computationally optimized broadly reactive antigen (COBRA) HA virus-like particle (VLP) vaccines provided clinical protection in chickens challenged with a lethal dose of homologous H5N1 high pathogenicity avian influenza (HPAI) virus [22]
Upon challenge with a drifting variant H5N1 HPAI virus, COBRA HA VLP vaccines provided no or partial clinical protection in chickens, and reduction of virus shedding was suboptimal with both challenge strains [22]
The expression of H5 recombinant protein in each herpesvirus of turkey (HVT) vaccine construct was evaluated by dual immunofluorescence antibody (IFA) assay (Figure S2)

Summary

Introduction

Several strategies have been investigated to broaden the repertoire of neutralizing antibodies in inactivated influenza vaccines or other non-replicating vaccine platforms that express influenza HA, including multivalent H5N1 vaccines [7,8], targeting conserved domains of HA [9,10,11,12], and synthetic consensus DNA antigenbased vaccines [13,14,15,16,17] In line with the latter strategy, the previously described methodology termed computationally optimized broadly reactive antigen (COBRA) was utilized to generate antigens with novel H5 HA consensus sequences [18,19]. The robust HA antibody response elicited by COBRA vaccines against the drifted strain did not translate to protective efficacy upon challenge with this virus [22] These results emphasized the need to further improve antigen consensus sequences and vaccine formulation in order to enhance both clinical protection and reduction of virus shedding upon challenge with antigenic diverse HPAI strains

Objectives

Results

Conclusion