Cold-Adapted Influenza and Recombinant Adenovirus Vaccines Induce Cross-Protective Immunity against pH1N1 Challenge in Mice

Mark R Soboleski,S Mark Tompkins,Daniel R Perez,Suzanne L Epstein,Graeme E Price,Jon D Gabbard,Julia A Misplon,Jianqiang Ye,Chia-Yun Lo,Troy D Randall

doi:10.1371/journal.pone.0021937

Abstract

BackgroundThe rapid spread of the 2009 H1N1 pandemic influenza virus (pH1N1) highlighted problems associated with relying on strain-matched vaccines. A lengthy process of strain identification, manufacture, and testing is required for current strain-matched vaccines and delays vaccine availability. Vaccines inducing immunity to conserved viral proteins could be manufactured and tested in advance and provide cross-protection against novel influenza viruses until strain-matched vaccines became available. Here we test two prototype vaccines for cross-protection against the recent pandemic virus.Methodology/Principal FindingsBALB/c and C57BL/6 mice were intranasally immunized with a single dose of cold-adapted (ca) influenza viruses from 1977 or recombinant adenoviruses (rAd) expressing 1934 nucleoprotein (NP) and consensus matrix 2 (M2) (NP+M2-rAd). Antibodies against the M2 ectodomain (M2e) were seen in NP+M2-rAd immunized BALB/c but not C57BL/6 mice, and cross-reacted with pH1N1 M2e. The ca-immunized mice did not develop antibodies against M2e. Despite sequence differences between vaccine and challenge virus NP and M2e epitopes, extensive cross-reactivity of lung T cells with pH1N1 peptides was detected following immunization. Both ca and NP+M2-rAd immunization protected BALB/c and C57BL/6 mice against challenge with a mouse-adapted pH1N1 virus.Conclusion/SignificanceCross-protective vaccines such as NP+M2-rAd and ca virus are effective against pH1N1 challenge within 3 weeks of immunization. Protection was not dependent on recognition of the highly variable external viral proteins and could be achieved with a single vaccine dose. The rAd vaccine was superior to the ca vaccine by certain measures, justifying continued investigation of this experimental vaccine even though ca vaccine is already available. This study highlights the potential for cross-protective vaccines as a public health option early in an influenza pandemic.

Highlights

Influenza virus is a significant public health concern, with the average influenza season in the U.S resulting in millions of cases and tens of thousands of deaths [1]
We have previously demonstrated that prime-boost immunization involving boosting with recombinant adenoviruses (rAd) expressing NP and matrix 2 (M2) resulted in protection against challenge with divergent influenza strains, including virulent H1N1 and H3N2, and a highly pathogenic H5N1 avian virus [14,15]
This study examined cross-protection against pH1N1 by vaccines based on recombinant adenovirus and cold-adapted influenza viruses given intranasally

Summary

Introduction

Influenza virus is a significant public health concern, with the average influenza season in the U.S resulting in millions of cases and tens of thousands of deaths [1]. These deaths occur despite large-scale vaccination efforts, use of multiple antiviral influenza drugs, and in-patient care. Due to the time required for manufacture of new strain-matched vaccines, this can result in large proportions of the population being unprotected during the initial pandemic wave. A lengthy process of strain identification, manufacture, and testing is required for current strain-matched vaccines and delays vaccine availability. We test two prototype vaccines for cross-protection against the recent pandemic virus

Methods

Results

Conclusion