Effect of human H3N2 influenza virus reassortment on influenza incidence and severity during the 2017-18 influenza season in the USA: a retrospective observational genomic analysis

Hsuan Liu; Kathryn Shaw-Saliba; Jason Westerbeck; David Jacobs; Katherine Fenstermacher; Chia-Yu Chao; Yu-Nong Gong; Harrison Powell; Zexu Ma; Thomas Mehoke; Amanda W Ernlund; Amanda Dziedzic; Siddhant Vyas; Jared Evans; Lauren M Sauer; Chin-Chieh Wu; Shu-Hui Chen; Richard E Rothman; Peter Thielen; Kuan-Fu Chen; Andrew Pekosz

doi:10.1016/S2666-5247(24)00067-3

Effect of human H3N2 influenza virus reassortment on influenza incidence and severity during the 2017-18 influenza season in the USA: a retrospective observational genomic analysis

Lancet Microbe. 2024 May 7:S2666-5247(24)00067-3. doi: 10.1016/S2666-5247(24)00067-3. Online ahead of print.

Authors

Hsuan Liu¹, Kathryn Shaw-Saliba², Jason Westerbeck¹, David Jacobs¹, Katherine Fenstermacher², Chia-Yu Chao³, Yu-Nong Gong⁴, Harrison Powell¹, Zexu Ma¹, Thomas Mehoke⁵, Amanda W Ernlund⁵, Amanda Dziedzic¹, Siddhant Vyas¹, Jared Evans⁵, Lauren M Sauer², Chin-Chieh Wu⁶, Shu-Hui Chen⁷, Richard E Rothman², Peter Thielen⁵, Kuan-Fu Chen⁸, Andrew Pekosz⁹

Affiliations

¹ W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA.
² Department of Emergency Medicine, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
³ Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan.
⁴ Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Laboratory Medicine, Linkou Chang Gung Memorial Hospital, Taoyuan, Taiwan; National Institute of Infectious Diseases and Vaccinology, National Health Research Institutes, Miaoli, Taiwan.
⁵ Research and Exploratory Development Department, Johns Hopkins Applied Physics Laboratory, Laurel, MD, USA.
⁶ Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan; Department of Artificial Intelligence, College of Intelligent Computing, Chang Gung University, Taoyuan, Taiwan.
⁷ Department of Emergency Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan.
⁸ Clinical Informatics and Medical Statistics Research Center, Chang Gung University, Taoyuan, Taiwan; Research Center for Emerging Viral Infections, Chang Gung University, Taoyuan, Taiwan; College of Medicine, Chang Gung University, Taoyuan, Taiwan; Department of Artificial Intelligence, College of Intelligent Computing, Chang Gung University, Taoyuan, Taiwan; Department of Emergency Medicine, Chang Gung Memorial Hospital, Keelung, Taiwan. Electronic address: kfchen@mail.cgu.edu.tw.
⁹ W Harry Feinstone Department of Molecular Microbiology and Immunology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA. Electronic address: apekosz1@jhu.edu.

PMID: 38734029
DOI: 10.1016/S2666-5247(24)00067-3

Abstract

Background: During the 2017-18 influenza season in the USA, there was a high incidence of influenza illness and mortality. However, no apparent antigenic change was identified in the dominant H3N2 viruses, and the severity of the season could not be solely attributed to a vaccine mismatch. We aimed to investigate whether the altered virus properties resulting from gene reassortment were underlying causes of the increased case number and disease severity associated with the 2017-18 influenza season.

Methods: Samples included were collected from patients with influenza who were prospectively recruited during the 2016-17 and 2017-18 influenza seasons at the Johns Hopkins Hospital Emergency Departments in Baltimore, MD, USA, as well as from archived samples from Johns Hopkins Health System sites. Among 647 recruited patients with influenza A virus infection, 411 patients with whole-genome sequences were available in the Johns Hopkins Center of Excellence for Influenza Research and Surveillance network during the 2016-17 and 2017-18 seasons. Phylogenetic trees were constructed based on viral whole-genome sequences. Representative viral isolates of the two seasons were characterised in immortalised cell lines and human nasal epithelial cell cultures, and patients' demographic data and clinical outcomes were analysed.

Findings: Unique H3N2 reassortment events were observed, resulting in two predominant strains in the 2017-18 season: HA clade 3C.2a2 and clade 3C.3a, which had novel gene segment constellations containing gene segments from HA clade 3C.2a1 viruses. The reassortant re3C.2a2 viruses replicated with faster kinetics and to a higher peak titre compared with the parental 3C.2a2 and 3C.2a1 viruses (48 h vs 72 h). Furthermore, patients infected with reassortant 3C.2a2 viruses had higher Influenza Severity Scores than patients infected with the parental 3C.2a2 viruses (median 3·00 [IQR 1·00-4·00] vs 1·50 [1·00-2·00]; p=0·018).

Interpretation: Our findings suggest that the increased severity of the 2017-18 influenza season was due in part to two intrasubtypes, cocirculating H3N2 reassortant viruses with fitness advantages over the parental viruses. This information could help inform future vaccine development and public health policies.

Funding: The Center of Excellence for Influenza Research and Response in the US, National Science and Technology Council, and Chang Gung Memorial Hospital in Taiwan.