Memory B Cell Proliferation Drives Differences in Neutralising Responses Between ChAdOx1 and BNT162b2 SARS-CoV-2 Vaccines

Vaccination against COVID-19 has been pivotal in reducing the global burden of the disease. However, Phase III trial results and observational studies underscore differences in efficacy across vaccine technologies and dosing regimens. Notably, mRNA vaccines have exhibited superior effectiveness compared to Adenovirus (AdV) vaccines, especially with extended dosing intervals. Using in-host mechanistic modelling, this study elucidates these variations and unravels the biological mechanisms shaping the immune responses at the cellular level. We used data on the change in memory B cells, plasmablasts, and antibody titres after the second dose of a COVID-19 vaccine for Australian healthcare workers. Alongside this dataset, we constructed a kinetic model of humoral immunity which jointly captured the dynamics of multiple immune markers, and integrated hierarchical effects into this kinetics model, including age, dosing schedule, and vaccine type. Our analysis estimated that mRNA vaccines induced 2.1 times higher memory B cell proliferation than AdV vaccines after adjusting for age, interval between doses and priming dose. Additionally, extending the duration between the second vaccine dose and priming dose beyond 28 days boosted neutralising antibody production per plasmablast concentration by 30%. We also found that antibody responses after the second dose were more persistent when mRNA vaccines were used over AdV vaccines and for longer dosing regimens. Reconstructing in-host kinetics in response to vaccination could help optimise vaccine dosing regimens, improve vaccine efficacy in different population groups, and inform the design of future vaccines for enhanced protection against emerging pathogens. SIGNIFICANCE STATEMENT There are differences in vaccine efficacy across different SARS-CoV-2 vaccine technologies and dosing regimens. Using an in-host mechanistic model that describes antibody production fitting to in-host immune markers, we found that mRNA vaccines are twice as effective at stimulating memory B cell proliferation when compared to AdVs vaccines and that a longer time between the second vaccine dose and priming dose increases the neutralising antibody production per plasmablast concentration. These findings disentangle the effect of vaccine type and time since the priming dose, aiding in the understanding of immune responses to SARS-CoV-2 vaccination. ### Competing Interest Statement SGS: Reports advisory board participation and/or consulting for Moderna, Pfizer, Novavax, CSL Seqirus and Sanofi. AF: Funding from Sanofi ### Funding Statement This work was supported by the National Institutes of Health [R01AI141534 to SGS, AF, AJK, DH]. The WHO Collaborating Centre for Reference and Research on Influenza is funded by the Australian Government Department of Health. This work was also supported by the National Institute of Allergy and Infectious Diseases, National Institutes of Health, Department of Health and Human Services Centers of Excellence for Influenza Research and Response [CEIRR] grant number HHSN272201400005C to the University of Rochester and a subcontract to KS. ### 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 and Ethics Committee (HREC/63096/MH-2020) of Royal Melbourne Hospital gave ethical approval for this work. The Royal Melbourne Hospital Human Research Ethics Committee (HREC/54245/MH-2019) and LSHTM Observational Research Ethics Committee of London School of Hygiene and Tropical Medicine gave ethical approval for the use of this data for analysis. 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 are available online at