Mouse Models of Influenza Infection with Circulating Strains to Test Seasonal Vaccine Efficacy.

Helen T Groves,Pinky Langat,Wendy Barclay,Paul Kellam,John Mccauley,John S Tregoning,Lauren Parker,Ekaterina Kinnear,Catherine Thompson,Jacqueline U Mcdonald,Ruth Elderfield,Joanna Ellis

doi:10.3389/fimmu.2018.00126

Abstract

Influenza virus infection is a significant cause of morbidity and mortality worldwide. The surface antigens of influenza virus change over time blunting both naturally acquired and vaccine induced adaptive immune protection. Viral antigenic drift is a major contributing factor to both the spread and disease burden of influenza. The aim of this study was to develop better infection models using clinically relevant, influenza strains to test vaccine induced protection. CB6F1 mice were infected with a range of influenza viruses and disease, inflammation, cell influx, and viral load were characterized after infection. Infection with circulating H1N1 and representative influenza B viruses induced a dose-dependent disease response; however, a recent seasonal H3N2 virus did not cause any disease in mice, even at high titers. Viral infection led to recoverable virus, detectable both by plaque assay and RNA quantification after infection, and increased upper airway inflammation on day 7 after infection comprised largely of CD8 T cells. Having established seasonal infection models, mice were immunized with seasonal inactivated vaccine and responses were compared to matched and mismatched challenge strains. While the H1N1 subtype strain recommended for vaccine use has remained constant in the seven seasons between 2010 and 2016, the circulating strain of H1N1 influenza (2009 pandemic subtype) has drifted both genetically and antigenically since 2009. To investigate the effect of this observed drift on vaccine induced protection, mice were immunized with antigens from A/California/7/2009 (H1N1) and challenged with H1N1 subtype viruses recovered from 2009, 2010, or 2015. Vaccination with A/California/7/2009 antigens protected against infection with either the 2009 or 2010 strains, but was less effective against the 2015 strain. This observed reduction in protection suggests that mouse models of influenza virus vaccination and infection can be used as an additional tool to predict vaccine efficacy against drift strains.

Highlights

Influenza infection is a significant cause of morbidity and mortality worldwide; the WHO estimates that there are 3–5 million severe influenza cases every year, causing 250,000–500,000 deaths globally [1]
While animals infected with the laboratory H3N2 strain, X31, lost weight after infection, mice infected with the current seasonal H3N2 virus (A/England/691/2010) did not lose weight at the doses used
We have successfully developed mouse models of seasonal H1N1 influenza infection to test vaccine efficacy

Summary

Introduction

Influenza infection is a significant cause of morbidity and mortality worldwide; the WHO estimates that there are 3–5 million severe influenza cases every year, causing 250,000–500,000 deaths globally [1]. Seasonal influenza vaccination is considered the most effective intervention strategy for reducing the burden of influenza disease [4, 5]. Influenza vaccines have highly variable rates of efficacy, ranging from 10% in 2004–2005 [6] to 60% in 2010–2011 [7]. The main cause of vaccine failure is mismatch between the vaccine and circulating strains. The cause of these mismatches is change in the circulating strains, either through antigenic drift (small mutations in hemagglutinin sequence) or antigenic shift (major replacements of circulating virus)

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