AS03-adjuvanted H5N1 vaccine promotes antibody diversity and affinity maturation, NAI titers, cross-clade H5N1 neutralization, but not H1N1 cross-subtype neutralization

Surender Khurana,Jody Manischewitz,Elizabeth M Coyle,Jin Gao,Hana Golding,Lisa R King,John S Tsang,Pamela L Schwartzberg,Ronald N Germain

doi:10.1038/s41541-018-0076-2

Surender Khurana, Jody Manischewitz + Show 7 more

Open Access

https://doi.org/10.1038/s41541-018-0076-2

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Journal: npj Vaccines	Publication Date: Oct 1, 2018
Citations: 58	License type: open-access

Affiliation: Center for Biologics Evaluation and Research

Abstract

Immune responses to inactivated vaccines against avian influenza are poor due in part to lack of immune memory. Adjuvants significantly increased virus neutralizing titers. We performed comprehensive analyses of polyclonal antibody responses following FDA-approved adjuvanted H5N1-A/Indonesia vaccine, administered in presence or absence of AS03. Using Whole Genome Fragment Phage Display Libraries, we observed that AS03 induced antibody epitope diversity to viral hemagglutinin (HA) and neuraminidase compared with unadjuvanted vaccine. Furthermore, AS03 promoted significant antibody affinity maturation to properly folded H5-HA1 (but not to HA2) domain, which correlated with neutralization titers against both vaccine and heterologous H5N1 strains. However, no increase in heterosubtypic cross-neutralization of Group1-H1N1 seasonal strains was observed. AS03-H5N1 vaccine also induced higher neuraminidase inhibition antibody titers. This study provides insight into the differential impacts of AS03 adjuvant on H5N1 vaccine-induced antibody responses that may help optimize vaccine platforms for future vaccines with improved protection against seasonal and pandemic influenza strains.

Highlights

Humans are mostly immune-naïve to avian influenza strains as they have not been exposed to these strains in their lifetime.Transmission of avian strains from wild birds to poultry with subsequent transmission to humans resulted in high morbidity and mortality among infected individuals and represents pandemic threat
Inactivated influenza vaccines containing HA and neuraminidase genes from avian influenza reassorted with the A/Puerto Rico/8/34 (PR8) internal genes were found to be poorly immunogenic in human trials, even when the HA content was increased significantly compared with seasonal influenza vaccines.[6,7]
To explore the possibility of oil-in-water adjuvants to augment cross-subtype neutralizing antibodies, we evaluated the capacity of the AS03-adjuvanted H5N1 vaccine to elicit heterosubtypic neutralizing antibodies against H1N1 group 1 virus strains that circulated in the previous decade

Summary

Introduction

Transmission of avian strains from wild birds to poultry with subsequent transmission to humans resulted in high morbidity and mortality among infected individuals and represents pandemic threat. Pathogenic (HP) H5N1 viruses still cause significant lethality in bird populations with numerous instances of human transmission resulting in severe human disease with >60% mortality.[1,2] As of May 28, 2018, there were 860 confirmed human cases with 454 fatalities. As of July 26, 2017, there were 1582 laboratory-confirmed human cases of avian H7N9 infection, with 39% fatality rate. In February 2017, highly pathogenic H7N9 viruses possessing multibasic cleavage site in the hemagglutinin (HA) were detected in China.[3,4,5] both avian-derived A/ H5N1 and A/H7N9 influenza viruses are considered a pandemic threat due to lack of preexisting immunity in humans. Inactivated influenza vaccines containing HA and neuraminidase genes from avian influenza reassorted with the A/Puerto Rico/8/34 (PR8) internal genes were found to be poorly immunogenic in human trials, even when the HA content was increased significantly compared with seasonal influenza vaccines.[6,7]

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