Heterologous Two-Dose Vaccination with Simian Adenovirus and Poxvirus Vectors Elicits Long-Lasting Cellular Immunity to Influenza Virus A in Healthy Adults

L Coughlan,S Sridhar,R Payne,M Edmans,A Milicic,N Venkatraman,B Lugonja,L Clifton,C Qi,P.M Folegatti,A.M Lawrie,R Roberts,H De Graaf,P Sukhtankar,S.N Faust,D.J.M Lewis,T Lambe,Avs Hill,S.C Gilbert

doi:10.1016/j.ebiom.2018.02.011

Abstract

BackgroundT-cell responses against highly conserved influenza antigens have been previously associated with protection. However, these immune responses are poorly maintained following recovery from influenza infection and are not boosted by inactivated influenza vaccines. We have previously demonstrated the safety and immunogenicity of two viral vectored vaccines, modified vaccinia virus Ankara (MVA) and the chimpanzee adenovirus ChAdOx1 expressing conserved influenza virus antigens, nucleoprotein (NP) and matrix protein-1 (M1). We now report on the safety and long-term immunogenicity of multiple combination regimes of these vaccines in young and older adults. MethodsWe conducted a Phase I open-label, randomized, multi-center study in 49 subjects aged 18–46years and 24 subjects aged 50years or over. Following vaccination, adverse events were recorded and the kinetics of the T cell response determined at multiple time points for up to 18months. FindingsBoth vaccines were well tolerated. A two dose heterologous vaccination regimen significantly increased the magnitude of pre-existing T-cell responses to NP and M1 after both doses in young and older adults. The fold-increase and peak immune responses after a single MVA-NP+M1 vaccination was significantly higher compared to ChAdOx1 NP+M1. In a mixed regression model, T-cell responses over 18months were significantly higher following the two dose vaccination regimen of MVA/ChAdOx1 NP+M1. InterpretationA two dose heterologous vaccination regimen of MVA/ChAdOx1 NP+M1 was safe and immunogenic in young and older adults, offering a promising vaccination strategy for inducing long-term broadly cross-reactive protection against influenza A. Funding SourceMedical Research Council UK, NIHR BMRC Oxford.

Highlights

Influenza A virus (IAV) remains a significant global health problem causing seasonal epidemics and occasional pandemics
Vaccination with ChAdOx1 NP + matrix protein-1 (M1) followed by modified vaccinia virus Ankara (MVA)-NP + M1 had higher area under the curve (AUC) of immune response compared to ChAdOx1 NP + M1 alone (p = 0.04), this difference was not significant when an outlier was excluded from Group 6 (p = 0.08)
We have developed viral vectored influenza vaccines, MVA-NP + M1 and ChAdOx1 NP + M1, to provide broad spectrum protection against influenza A virus by the boosting of pre-existing T-cell responses to conserved influenza antigens

Summary

Introduction

Influenza A virus (IAV) remains a significant global health problem causing seasonal epidemics and occasional pandemics. As the induction of such cross-protective T-cells following vaccination with current influenza vaccines is limited (He et al, 2006), alternative vaccination approaches to induce T-cell responses against highly conserved internal influenza antigens capable of protecting against antigenically distinct viruses with pandemic potential, such as NP or matrix protein 1 (M1), are needed. This would benefit highrisk populations, such as the elderly, in whom there is a high risk of severe disease.

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