Cross-reactive immunity potentially drives global oscillation and opposed alternation patterns of seasonal influenza A viruses

Lorenzo Gatti, Mischa H. Koenen, Jitao David Zhang, Maria Anisimova, Lilly M. Verhagen, Martin Schutten, Ab Osterhaus, Erhard van der Vries*

*Corresponding author for this work

Research output: Contribution to journalArticleAcademicpeer-review

1 Citation (Scopus)
22 Downloads (Pure)


Several human pathogens exhibit distinct patterns of seasonality and circulate as pairs. For instance, influenza A virus subtypes oscillate and peak during winter seasons of the world’s temperate climate zones. Alternation of dominant strains in successive influenza seasons makes epidemic forecasting a major challenge. From the start of the 2009 influenza pandemic we enrolled influenza A virus infected patients (n = 2980) in a global prospective clinical study. Complete hemagglutinin sequences were obtained from 1078 A/H1N1 and 1033 A/H3N2 viruses. We used phylodynamics to construct high resolution spatio-temporal phylogenetic hemagglutinin trees and estimated global influenza A effective reproductive numbers (R) over time (2009–2013). We demonstrate that R oscillates around R = 1 with a clear opposed alternation pattern between phases of the A/H1N1 and A/H3N2 subtypes. Moreover, we find a similar alternation pattern for the number of global viral spread between the sampled geographical locations. Both observations suggest a between-strain competition for susceptible hosts on a global level. Extrinsic factors that affect person-to-person transmission are a major driver of influenza seasonality. The data presented here indicate that cross-reactive host immunity is also a key intrinsic driver of influenza seasonality, which determines the influenza A virus strain at the onset of each epidemic season.

Original languageEnglish
Article number8883
JournalScientific Reports
Issue number1
Early online date25 May 2022
Publication statusPublished - Dec 2022

Bibliographical note

Funding Information:
IRIS (NCT00884117) is a Roche-sponsored study. LG is funded by SNSF Projektförderung no. 157064 and he was granted with UZH-ETH MLS PhD Program Travel Grant. This research was supported by the Volkswagen Foundation.

Funding Information:
We thank Dr. Christian von Mering, Dr. Urs Greber, Dr. Alexander Roth (University of Zurich) Xiao Tong, Dr. Isabel Najera, Dr. Klaus Klumpp, Dr. James Smith and Dr. Laurent Essioux for insightful discussions and project support. Dr. Tanja Stadler, Dr. Denise Kühner, Dr. Veronika Boskova (ETH Zürich) and Dr. Alexei Drummond (University of Auckland) helped with early stage analysis with the BEAST2 software. We thank Anne Van der Linden, Martine Bakx, Danielle de Wijze, Jolanda Maaskant, Jeer Anber, Moniek Bos-van der Haven of the IRIS-team and Be Niemeijer from ErasmusMC for their assistance in the lab and Martin Ebeling from Roche for help on sequence analysis. We thank All physicians at the participating centers are thanked for their support and sample collection. We thank MICRON research for global logistics.

Publisher Copyright:
© 2022, The Author(s).


Dive into the research topics of 'Cross-reactive immunity potentially drives global oscillation and opposed alternation patterns of seasonal influenza A viruses'. Together they form a unique fingerprint.

Cite this