Abstract
Sequential infection with antigenically distinct influenza viruses induces cross-protective immune responses against heterologous virus strains in animal models. Here we investigated whether sequential immunization with antigenically distinct influenza vaccines can also provide cross-protection. To this end, we compared immune responses and protective potential against challenge with A(H1N1)pdm09 in mice infected sequentially with seasonal A(H1N1) virus followed by A(H3N2) virus or immunized sequentially with whole inactivated virus (WIV) or subunit (SU) vaccine derived from these viruses. Sequential infection provided solid cross-protection against A(H1N1)pdm09 infection while sequential vaccination with WIV, though not capable of preventing weight loss upon infection completely, protected the mice from reaching the humane endpoint. In contrast, sequential SU vaccination did not prevent rapid and extensive weight loss. Protection correlated with levels of cross-reactive but non-neutralizing antibodies of the IgG2a subclass, general increase of memory T cells and induction of influenza-specific CD4+ and CD8+ T cells. Adoptive serum transfer experiments revealed that despite lacking neutralizing activity, serum antibodies induced by sequential infection protected mice from weight loss and vigorous virus growth in the lungs upon A(H1N1)pdm09 virus challenge. Antibodies induced by WIV vaccination alleviated symptoms but could not control virus growth in the lung. Depletion of T cells prior to challenge revealed that CD8+ T cells, but not CD4+ T cells, contributed to cross-protection. These results imply that sequential immunization with WIV but not SU derived from antigenically distinct viruses could alleviate the severity of infection caused by a pandemic and may improve protection to unpredictable seasonal infection.
Highlights
Influenza A virus (IAV) infections remain a worldwide public health threat
To investigate the cross-protective immune response induced by sequential infection or vaccination with antigens from different influenza virus strains, we sequentially infected mice with PR8 and X-31 influenza virus or sequentially vaccinated mice with whole inactivated virus (WIV) or SU vaccines derived from these viruses
To determine whether sequential immunization with antigenically distinct traditional vaccines could provide cross-protection, mice were sequentially immunized with WIV or SU vaccines derived from PR8 and X-31 viruses and challenged with an A(H1N1)pdm09 virus
Summary
Influenza A virus (IAV) infections remain a worldwide public health threat. Influenza vaccination is the most reliable strategy to control annual epidemics and irregular pandemics [1]. Current inactivated influenza vaccines (IIV) primarily induce strain-specific antibodies against the two major virus surface proteins, hemagglutinin (HA) and neuraminidase (NA). These strain-specific antibodies cannot provide protection against antigenically drifted and antigenically shifted strains. When a pandemic strain emerges, it takes around 6 months to develop and distribute a new vaccine [2], which is too late for a vaccine to provide effective protection during the first pandemic wave. A cross-protective vaccine that could provide immediate protection against unpredicted influenza virus strains is urgently needed
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