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.
Original language | English |
---|---|
Article number | 2312 |
Journal | Frontiers in Immunology |
Volume | 9 |
Issue number | OCT |
DOIs | |
Publication status | Published - Oct 9 2018 |
Bibliographical note
Funding Information:The authors would like to thank Meiling Dai, Utrecht University, Utrecht, The Netherlands, for technical assistance and David A. Price, Institute of Infection and Immunity, Cardiff University School of Medicine, Cardiff, United Kingdom, for a gift of tetramers. This research was funded by the European Union Seventh Framework Program 19 (FP7/2007-2013) Universal Influenza Vaccines Secured (UNISEC) consortium under grant agreement no. 602012 and by the EU Horizon 2020 Program under the Marie Skłodowska-Curie grant agreement 713660. DW received a PhD scholarship from the University Medical Center Groningen, Groningen, The Netherlands, and Shantou University Medical College, Shantou, China. This manuscript has been released as a preprint at https://www.biorxiv.org/content/ early/2018/05/31/335281.
Publisher Copyright:
© 2007 - 2018 Frontiers Media S.A. All Rights Reserved.
ASJC Scopus Subject Areas
- Immunology and Allergy
- Immunology