Background: From 2020, influenza activities were largely affected by the coronavirus disease (COVID-19) pandemic at the global scale. The B/Yamagata lineage has become extinct since 2020, raising concerns regarding the quadrivalent influenza vaccine. Evaluating vaccine effectiveness (VE) against influenza infections is important to guide future influenza vaccine programs. Methods: A test-negative case-control study was conducted in five tertiary hospitals in Hangzhou, the capital city of Zhejiang province, China. Hospital-attended patients aged >6 months who presented with influenza-like illness (ILI) from October 1, 2023 to March 31, 2024 were enrolled in this study. The VE was estimated using multivariate logistic regression models, adjusted by sex, age, influenza detection methods and influenza testing timing. Results: In total, 157291 hospital-attended ILI participants were enrolled. 56704 (36%) were tested positive for influenza virus. The adjusted estimates of overall VE against any hospital-attended influenza infection was 48% (95% Confidence interval [CI]: 46%-51%). The overall VE of trivalent inactivated influenza vaccine (IIV3) was 59% (95% CI: 50%-66%), followed by trivalent live attenuated vaccine (LAIV3) (VE=53%, 95% CI: 42%-62%) and quadrivalent inactivated influenza vaccine (IIV4) (VE=47%, 95% CI: 45%-50%). IIV3 provided even much better protection against hospital-attended influenza B infection than IIV4 (VE=87% (95% CI: 81%-92%) for IIV3 versus VE=53%, 95% CI: 50%-57% for IIV4). Conclusions: The influenza vaccine provided moderate protection against influenza infection in the 2023/24 season in Hangzhou, China, during a massive epidemic. The results supported the World Health Organization recommendation regarding the exclusion of B/Yamagata lineage antigen in quadrivalent influenza vaccines in 2023.

The authors have declared no competing interest.

This study was supported by the innovation group on intelligent response to infectious diseases and public health emergencies of School of Public Health, Zhejiang University.

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

Yes

The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

the Institutional Review Board and Human Research Ethics Committee of the School of Medicine of Zhejiang University (No. ZGL202404-1) gave ethical approval for this work

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

Yes

I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

Yes

I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

Yes

All data produced in the present study are available upon reasonable request to the authors