Vaccination against Human Influenza A/H3N2 Virus Prevents the Induction of Heterosubtypic Immunity against Lethal Infection with Avian Influenza A/H5N1 Virus

Rogier Bodewes,Judith M A Van Den Brand,Martina M Geelhoed-Mieras,Geert Van Amerongen,Ron A M Fouchier,Chantal Baas,Guus F Rimmelzwaan,Joost H C M Kreijtz,Gerrie De Mutsert,Albert D M E Osterhaus

doi:10.1371/journal.pone.0005538

Abstract

Annual vaccination against seasonal influenza viruses is recommended for certain individuals that have a high risk for complications resulting from infection with these viruses. Recently it was recommended in a number of countries including the USA to vaccinate all healthy children between 6 and 59 months of age as well. However, vaccination of immunologically naïve subjects against seasonal influenza may prevent the induction of heterosubtypic immunity against potentially pandemic strains of an alternative subtype, otherwise induced by infection with the seasonal strains.Here we show in a mouse model that the induction of protective heterosubtypic immunity by infection with a human A/H3N2 influenza virus is prevented by effective vaccination against the A/H3N2 strain. Consequently, vaccinated mice were no longer protected against a lethal infection with an avian A/H5N1 influenza virus. As a result H3N2-vaccinated mice continued to loose body weight after A/H5N1 infection, had 100-fold higher lung virus titers on day 7 post infection and more severe histopathological changes than mice that were not protected by vaccination against A/H3N2 influenza.The lack of protection correlated with reduced virus-specific CD8+ T cell responses after A/H5N1 virus challenge infection. These findings may have implications for the general recommendation to vaccinate all healthy children against seasonal influenza in the light of the current pandemic threat caused by highly pathogenic avian A/H5N1 influenza viruses.

Highlights

Since 2003, more than 380 human cases of infection with highly pathogenic avian influenza A virus (IAV) of the H5N1 subtype have been reported to the World Health Organization (WHO) of which more than 60% were fatal [1]
We demonstrate that successful vaccination of mice against human IAV HK/68 (H3N2) prevented the induction of heterosubtypic immunity against a lethal challenge with IAV IND/05 (H5N1)
It has been well established that infection with IAV can induce a certain degree of protective immunity against infection with an heterosubtypic strain of IAV, which was already recognized more than 40 years ago [17]

Summary

Introduction

Since 2003, more than 380 human cases of infection with highly pathogenic avian influenza A virus (IAV) of the H5N1 subtype have been reported to the World Health Organization (WHO) of which more than 60% were fatal [1]. Because of the continuous spread of these viruses among domestic birds, the frequent introduction into wild birds and the increasing number of human cases, a pandemic outbreak caused by influenza A/H5N1 viruses is feared [2,3,4] It has been demonstrated in animal models that prior exposure to an IAV can induce heterosubtypic immunity to infection with an IAV of an unrelated subtype (for review see [5]). Cell-mediated immunity induced by natural infection with seasonal IAVs may confer protection against heterosubtypic pandemic influenza viruses In this respect, the disproportional age distribution of severe human H5N1 cases is of interest [11]. Younger individuals are at risk and other confounding factors cannot be excluded, it is tempting to speculate that young subjects have been infected with seasonal influenza viruses less frequently and have not developed protective heterosubtypic immune responses against infection with the highly pathogenic avian A/H5N1 viruses

Methods

Results

Conclusion