Immunogenicity and Cross Protection in Mice Afforded by Pandemic H1N1 Live Attenuated Influenza Vaccine Containing Wild-Type Nucleoprotein.

Andrey Rekstin,Larisa Rudenko,Irina Isakova-Sivak,Tatiana Tretiak,Igor Losev,Daniil Korenkov,Galina Petukhova,Tatiana Bousse,Svetlana Shcherbik,Tatiana Smolonogina,Svetlana Donina

doi:10.1155/2017/9359276

Abstract

Since conserved viral proteins of influenza virus, such as nucleoprotein (NP) and matrix 1 protein, are the main targets for virus-specific CD8+ cytotoxic T-lymphocytes (CTLs), we hypothesized that introduction of the NP gene of wild-type virus into the genome of vaccine reassortants could lead to better immunogenicity and afford better protection. This paper describes in vitro and in vivo preclinical studies of two new reassortants of pandemic H1N1 live attenuated influenza vaccine (LAIV) candidates. One had the hemagglutinin (HA) and neuraminidase (NA) genes from A/South Africa/3626/2013 H1N1 wild-type virus on the A/Leningrad/134/17/57 master donor virus backbone (6 : 2 formulation) while the second had the HA, NA, and NP genes of the wild-type virus on the same backbone (5 : 3 formulation). Although both LAIVs induced similar antibody immune responses, the 5 : 3 LAIV provoked greater production of virus-specific CTLs than the 6 : 2 variant. Furthermore, the 5 : 3 LAIV-induced CTLs had higher in vivo cytotoxic activity, compared to 6 : 2 LAIV. Finally, the 5 : 3 LAIV candidate afforded greater protection against infection and severe illness than the 6 : 2 LAIV. Inclusion in LAIV of the NP gene from wild-type influenza virus is a new approach to inducing cross-reactive cell-mediated immune responses and cross protection against pandemic influenza.

Highlights

Influenza A viruses are highly contagious respiratory pathogens that annually cause up to 250,000 fatal cases [1]
This paper describes preclinical studies of two new pandemic H1N1 live attenuated influenza vaccine (LAIV) candidates obtained by reverse genetics
The infectious titers of the 6 : 2 and 5 : 3 LAIV H1N1 reassortants in eggs indicated that both viruses possess the ts/ca phenotype: they grew poorly at 38∘C (viral titer compaIntar2ce6od∘nCwtria(tvshti,r3at3lh∘CetitSe>Ar 5/c.wo0mtloppgaa1rr0eenldotwawleivrt)hirau3ns3d∘gCrree

Summary

Introduction

Influenza A viruses are highly contagious respiratory pathogens that annually cause up to 250,000 fatal cases [1]. Current seasonal influenza vaccines need to be reformulated and administered every year due to continuous antigenic drift of the influenza virus; attempts are made to develop universal influenza vaccines capable of protection against broad range of influenza viruses of human or avian/animal origin, including those with pandemic potential [2]. Formulations of LAIV against pandemic influenza strains, including H1N1, H5N1, H9N2, H2N2, H7N3, and H7N9, have recently been tested in preclinical and phase I clinical studies [5,6,7]. The majority of these LAIV strains had a 6 : 2 genome formulation; that is, their hemagglutinin (HA) and neuraminidase (NA)

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