Joanne Byrne ^1,2* Lili Gu ¹ Alejandro Garcia-Leon ¹ Colette M. Gaillard ¹ Gurvin Saini ¹ Dana Alalwan ¹ Julen T. Cortázar ¹ Grace Kenny ^1,2 Sean Donohue ² Bearach Reynolds ² Tessa O'gorman ³ Alan Landay ⁴ Peter Doran ⁵ Jannik Stemler ^6,7 Philipp Koehler ^6,7 Rebecca Cox ⁸ Ole F. Olesen ⁹ Jean-Daniel Lelievre ¹⁰ Cathal O'broin ^1,2 Stefano Savinelli ^1,2 Eoin R. Feeney ^1,2 Jane A. O'halloran ^1,2 Aoife Cotter ^1,3 Mary Horgan ^3,5 Christine Kelly ^1,3 Corrina Sadlier ¹¹ Eoghan De Barra ^12,13 Oliver A. Cornely ^14,15 Virginie Gautier ¹ Patrick Mallon ^1,2

• ¹ Centre for Experimental Pathogen Host Research, School of Medicine, College of Health and Agricultural Sciences, University College Dublin, Dublin, Ireland
• ² Department of Infectious Diseases, St. Vincent's University Hospital, Dublin, Ireland
• ³ Department of Infectious Diseases, Mater Misericordiae University Hospital, Dublin, Ireland
• ⁴ Department of Internal Medicine, University of Texas Medical Branch at Galveston, Galveston, Texas, United States
• ⁵ School of Medicine, College of Health and Agricultural Sciences, University College Dublin, Dublin, Ireland
• ⁶ Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, University of Cologne, Cologne, North Rhine-Westphalia, Germany
• ⁷ Institute of Translational Research Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), Faculty of Medicine, University of Cologne, Cologne, North Rhine-Westphalia, Germany
• ⁸ Influenza Centre, Department of Clinical Science, University of Bergen, Bergen, Hordaland, Norway
• ⁹ European Vaccine Initiative, Heidelberg University Hospital, Heidelberg, Baden-Württemberg, Germany
• ¹⁰ Institut de recherche sur les vaccins (VRI), Creteil, France
• ¹¹ Cork University Hospital - CUH, Cork, Ireland
• ¹² Department of Infectious Diseases, Beaumont Hospital, Dublin, Ireland
• ¹³ Department of International Health and Tropical Medicine,, Royal College of Surgeons in Ireland, Dublin, County Dublin, Ireland
• ¹⁴ Faculty of Medicine Institute of Translational Research, Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne, North Rhine-Westphalia, Germany
• ¹⁵ Faculty of Medicine and University Hospital Cologne, Department I of Internal Medicine, University Hospital of Cologne, Cologne, North Rhine-Westphalia, Germany

Introduction: A clear immune correlate of protection from SARS-CoV-2 infection has not been defined. We explored antibody, B cell and T cell responses to third-dose vaccine and relationship to incident SARS-CoV-2 infection. Methods: Adults in a prospective cohort provided blood samples at day 0, day 14 and 10 months post third-dose SARS-CoV-2 vaccine. Participants self-reported incident SARS-CoV-2 infection. Plasma anti-SARS-CoV-2 receptor binding domain (RBD) and spike-subunit-1 and spike-subunit-2 antibodies were measured. A sub-study assessed SARS-CoV-2-specific plasma and memory B cell and memory T cell responses in peripheral blood mononuclear cells by ELISpot. Comparative analysis between participants who developed incident infection and uninfected participants utilised non-parametric t-tests, Kaplan-Meier survival analysis and Cox proportional hazard ratios. Results: Of 132 participants, 47(36%) reported incident SARS-CoV-2 infection at a median 16.5(16.25-21) weeks post third-dose vaccination. RBD titres, B cell responses, but not T cell responses, increased post third-dose vaccine. While no significant difference in day 14 antibody titres or T cell responses was observed between participants with and without incident SARS-CoV-2 infection, RBD memory B cell frequencies were significantly higher in those who did not develop infection (10.0%(4.5-16.0%) versus 4.9%(1.6-9.3%), p=0.01). RBD titres and memory B cell frequencies remained significantly higher at 10 months than day 0 levels (p<0.01). Discussion: Robust antibody and B cell responses persisted at 10 months following third-dose vaccination. Higher memory B cell frequencies, rather than antibody titres or T cell responses, predicted protection from subsequent infection, identifying memory B cells as a correlate of protection.