The relative effectiveness of a high-dose quadrivalent influenza vaccine vs standard-dose quadrivalent influenza vaccines in older adults in France: a retrospective cohort study during the 2021-22 influenza season

Background High-dose quadrivalent influenza vaccine (HD-QIV) was introduced during the 2021/22 influenza season in France for adults aged ≥65 years as an alternative to standard-dose quadrivalent influenza vaccines (SD-QIV). This is the first study to estimate the relative vaccine effectiveness (rVE) of HD-QIV versus SD-QIV against influenza-related hospitalizations in France. Methods Community-dwelling individuals aged ≥65 years with reimbursed influenza vaccine claims during the 2021/22 influenza season were included from the French national health insurance database. Individuals were followed up from vaccination day to 30 June 2022, nursing home admission or death date. Baseline socio-demographic and health characteristics were identified from medical records over the 5 previous years. Hospitalizations due to influenza and other causes were recorded from 14 days after vaccination to end of follow-up. HD-QIV and SD-QIV vaccinees were matched using 1:4 propensity score matching with an exact constraint on age group, sex, week of vaccination and region. Incidence rate ratios (IRR) were estimated using zero-inflated Poisson or zero-inflated negative binomial regression models. Results We matched 405,385 (99.9%) HD-QIV to 1,621,540 SD-QIV vaccinees. HD-QIV was associated with a 23.3% (95%CI: 8.4–35.8) lower rate of influenza hospitalizations compared to SD-QIV. Post-matching, we observed higher rates in the HD-QIV group for hospitalizations non-specific to influenza and for negative control outcomes, suggesting residual confounding by indication. Conclusions HD-QIV was associated with lower influenza-related hospitalization rates versus SD-QIV, consistent with existing evidence, in the context of high SARS-CoV-2 circulation in France and likely prioritization of HD-QIV for older/more comorbid individuals. ### Competing Interest Statement HB, MCL, RH & AC are Sanofi employees and may hold shares in the company. NA, BG & FR are HEVA employees, which received funding from Sanofi to run the study. PC reports to have participated in advisory committees organized by Sanofi and being a consultant for Sanofi. JG reports to have participated in advisory committees organized by GSK, MSD, Pfizer, and Sanofi. GG reports to have participated in advisory committees organized by Astellas, AstraZeneca, BioMerieux, MSD, Pfizer, Sanofi, Sanofi Pasteur, Sanofi Pasteur-MSD and Vifor, acted as consultant and speaker for these companies, and participated in congresses on invitation by Eisai, MSD, Novartis, Pfizer, Sanofi, and Vifor. OL reports to be a principal investigator in vaccine trials sponsored by Sanofi, MSD, Pfizer, GSK, Moderna. She received financial support for travel to medical congress and personal fees for participation in advisory boards for Sanofi, MSD, Pfizer, and GSK. AM reports to have participated in an advisory committee organized by Sanofi and to be a member of the scientific board of the GEIG and of the POSTHER study (Herpes Zoster Study, GSK). LW has received consulting fees from HEVA, IQVIA and Pfizer for works outside the submitted work. ### Funding Statement The study was funded by Sanofi ### Author Declarations 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 ethics and scientific committee for health research, studies, and evaluations (CESREES, Comité Ethique et Scientifique pour les Recherches, les Etudes et les Evaluations dans le domaine de la Santé) (former CEREES) and the French data protection authority (Comité National de l Informatique et des Libertés, CNIL) gave permission to access the data for this study. The data supporting the study findings are part of the National health data system (SNDS, Systeme national des Données de Santé) and are available from the HDH (Health Data Hub https://www.health-data-hub.fr/). Restrictions apply to the availability of these data containing potentially identifying and sensitive patient information. The study protocol obtained two consecutive authorizations from the French data protection authority CNIL (initial authorization: Decision No. DR-2022-049; substantial modifications authorization: Decision DR-2023-013). 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 The data that support the findings of this study are available from the French national health insurance information system, but restrictions apply to the availability of these data, which were used under license for the current study, and so are not publicly available.