Vaccination potential of B and T epitope-enriched NP and M2 against Influenza A viruses from different clades and hosts.

Irina Tutykhina,Andrey Lysenko,Maxim Shmarov,Alexey Pichugin,Ravshan Ataullakhanov,Ilias Esmagambetov,Alexander Gintsburg,Dmitry Shcherbinin,Alexander Bagaev,Denis Logunov,Elena Sedova,Boris Naroditsky,Stephen J Turner

doi:10.1371/journal.pone.0191574

Irina Tutykhina, Andrey Lysenko + Show 11 more

Open Access

https://doi.org/10.1371/journal.pone.0191574

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Abstract

To avoid outbreaks of influenza virus epidemics and pandemics among human populations, modern medicine requires the development of new universal vaccines that are able to provide protection from a wide range of influenza A virus strains. In the course of development of a universal vaccine, it is necessary to consider that immunity must be generated even against viruses from different hosts because new human epidemic virus strains have their origins in viruses of birds and other animals. We have enriched conserved viral proteins–nucleoprotein (NP) and matrix protein 2 (M2)—by B and T-cell epitopes not only human origin but also swine and avian origin. For this purpose, we analyzed M2 and NP sequences with respect to changes in the sequences of known T and B-cell epitopes and chose conserved and evolutionarily significant epitopes. Eventually, we found consensus sequences of M2 and NP that have the maximum quantity of epitopes that are 100% coincident with them. Consensus epitope-enriched amino acid sequences of M2 and NP proteins were included in a recombinant adenoviral vector. Immunization with Ad5-tet-M2NP induced strong CD8 and CD4 T cells responses, specific to each of the encoded antigens, i.e. M2 and NP. Eight months after immunization with Ad5-tet-M2NP, high numbers of M2- and NP-responding “effector memory” CD44posCD62neg T cells were found in the mouse spleens, which revealed a long-term T cell immune memory conferred by the immunization. In all, the challenge experiments showed an extraordinarily wide-ranging efficacy of protection by the Ad5-tet-M2NP vaccine, covering 5 different heterosubtypes of influenza A virus (2 human, 2 avian and 1 swine).

Highlights

Influenza viral disease remains one of the most significant global challenges
We have suggested that the enrichment of conserved viral proteins by B and T-cell epitopes may become one of the strategies to develop a universal vaccine against influenza virus
We show that a single intranasal administration of Adtet-M2NP induces strong systemic antibody and T-cell responses, and confers an extraordinary heterosubtypic protection from lethal challenge with 5 influenza virus strains belonging to 3 different clades (clade H1—H1N1 (A/USSR/90/77), H2N3 (A/BlackDuck/NewJersey/ 1580/78), and H5N2 (A/Duck(Mallard)/Pennsylvania/10218/84); clade H3—H3N2 (A/Aichi/ 2/68); H9—H9N2 (A/Swine/Hong Kong/9A-1/98)) and 3 different original hosts (Homo sapiens, Gallus gallus and Sus domesticus)

Summary

Introduction

Potentially pandemic strains, such as so-called “bird flu” H5N1 and “swine flu” H1N1, are a constant threat because of their significant mortality rates (greater than 50% for H5N1) [1,2,3,4]. A universal influenza vaccine that would effectively protect from any seasonally appearing as well as potential pandemic strains is considered to be an ultimate research goal [5]. The mechanism of action of a “universal” vaccine depends on the induction of broad-spectrum immune responses, e.g., the occurrence of heterosubtypic immunity in an organism. Under these circumstances, virus replication and transmission should be restricted, lowering morbidity and mortality caused by influenza

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