Post-vaccine HAI antibody kinetics are driven by pre-vaccination HAI titre and vaccine history

Epidemiological studies suggest that heterogeneity in influenza vaccine antibody response is associated with host factors, including pre-vaccination immune status, age, gender, and vaccination history. However, the pattern of reported associations varies between studies. To better understand the underlying influences on antibody responses, we combined host factors and vaccine-induced in-host antibody kinetics from a cohort study conducted across multiple seasons with a unified analysis framework. We developed a flexible Bayesian model to estimate associations and interactions between host factors, including pre-vaccine HAI titre, age, sex, vaccine history and study setting, and vaccine-induced HAI titre antibody boosting and waning. We applied the model to derive population-level and individual effects of post-vaccine antibody kinetics for vaccinating and circulating strains for A(H1N1) and A(H3N2) influenza subtypes. We found that post-vaccine HAI titre dynamics were significantly influenced by pre-vaccination HAI titre and vaccination history. In addition, we find the common heuristic of a four-fold rise in titre is valid for detecting seroconversion in an infrequently vaccinated cohort (<2 vaccines in last 5 years) within six months of vaccination if their pre-vaccination HAI titres are equal to or below 1:20. The same heuristic only works for a frequently vaccinated population (2 or more vaccines in last 5 years) for up to 3 months post-vaccination providing their pre-vaccination HAI titres are equal to or below 1:20. In future, seroepidemiological studies should ensure the impact of pre-vaccine HAI and prior vaccination status on vaccine-induced fold-rises is properly quantified, as these significantly influence an individual's post-vaccination antibody kinetics. ### Competing Interest Statement Annette Fox: reports receiving study funding from Sanofi and payments to her research group from Evidera Inc for consulting work. Sheena Sullivan: reports consulting for CSL Seqirus, Moderna, Pfizer, and Evo Health. ### Funding Statement This work was supported by the US National Institutes of Health (grant # R01AI41534, SGS, SF, AJK) and by the US Centers for Disease Control and Prevention (contract #HHSD2002013M53890B and #NMR-9619/CDC13FED1310208/NMR9864/CDC16FED1612328, AJK). AJK was also supported by a Sir Henry Dale Fellowship jointly funded by the Wellcome Trust and the Royal Society (grant Number 206250/Z/17/Z). ### 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 Royal Melbourne Hospital Human Research Ethics Committee of Royal Melbourne Hospital gave ethical approval for study protocol and protocol addendums for follow-up of COVID-19 vaccinations and SARS-CoV-2 infections (HREC/54245/MH-2019). LSHTM Observational Research Ethics Committee of London School of Hygiene and Tropical Medicine gave ethical approval for the use of this data for analysis (ref 22631). 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 https://github.com/dchodge/ab\_boosting\_published. However, some data needs to be requested from the corresponding author.