Influenza vaccine effectiveness (VE) varies seasonally due to host, virus and vaccine characteristics. To investigate how antigenic matching and dosage impact VE, we developed a mechanistic knowledge-based mathematical model. Immunization with a split vaccine is modeled for exposure to A/H1N1 or A/H3N2 virus strains. The model accounts for cross-reactivity of immune cells elicited during previous immunizations with new antigens. We simulated vaccine effectiveness (sVE) of high dose (HD) versus standard dose (SD) vaccines in the older population, from 2011 to 2022. We find that sVE is highly dependent on antigenic matching and that higher dosage improves immunogenicity, activation and memory formation of immune cells. Across all simulations, the HD vaccine performs better than the SD vaccine, supporting the use of the HD vaccine in the older population. This model could be adapted to predict the impact of alternative virus strain selection on clinical outcomes in future influenza seasons.

S.U., M.H., A.I.T., N.R., E.J., E.P., J-B.G., J-P.B., E.C and L. B. are employees of Novadiscovery. S.S.C., L.C. and E.T. are employees of Sanofi and may hold shares and/or stock options in the company. Novadiscovery and Sanofi founded the study.

Novadiscovery and Sanofi founded the study.

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:

All raw data used in the study was extracted from scientific publications and public CDC reports openly available before the initiation of the study, no administrative permission was required for the access. https://www.cdc.gov/flu/about/burden/index.html. Accessed: 5th of May 2023. Carrat. F. et al. Time lines of infection and disease in human influenza: A review of volunteer challenge studies. American Journal of Epidemiology 70(3), 19 (2008). Treanor J. J. et al. Effectiveness of seasonal influenza vaccines in the United States during a season with circulation of all three vaccine strains. Clinical Infectious Diseases 55(7), 951-959 (2012).

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the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 dataset generated and analyzed during the current study, the system of ODEs for the multi-strain model and each submodel in SBML are available from the corresponding author upon reasonable request.