Laura Donadeu Casassas ^1,2 Susana Gomez-Olles ^2,3,4 Franc Casanova ^1,2 Alba Torija ^1,2 Manuel Lopez- Meseguer ^2,3,4,5 Meritxell Boada ^2,3 Delphine Kervella ^1,2,6 Elena Crespo ^1,2 Claudia Carrera- Muñoz ^1,2,6 Isabel Campos-Varela ^2,7,8 Lluís Castells ^2,7 Maria F. Cortese ⁹ Juliana Esperalba ^2,9 Candela Fernández-Naval ⁹ Jesús Quintero ^10,2 Marina Muñoz ^11,2 Fernando Agüero ¹² José Gonzalez-Costello ¹³ Laura Lladó ¹⁴ Àlex Favà ¹⁵ Laura Cañas ¹⁶ María Del Mar De La Hoz- Caballero ¹⁷ Maria Meneghini ^1,2,6 Irina B. Torres ^2,6 Mariona Juvé ^1,2 Florianne M. Hafkamp ^1,2 Marta Vila ⁹ Alba G. Robles ¹⁸ Maria J Buzon ¹⁸ Nestor Toapanta ^2,6 José M. Zúñiga ^2,6 Victor Monforte ^19,2,3 Berta Saez-Gimenez ^19,2,3 Oscar Len ^2,20 Ibai Los ^2,20 Enric Miret ^2,21 Gema Ariceta ^11,2 Emma Pardo ^2,6 Xavier Martínez ²² Francesc J. Moreso ^2,6 Oriol Bestard ^1,2,6*

• ¹ Laboratory of Nephrology and Transplantation, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Barcelona, Spain
• ² Vall d'Hebron for Solid Organ Transplantation Research Group, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Barcelona, Spain
• ³ Laboratory of Pneumology, Vall d'Hebron Research Institute, Vall d'Hebron University Hospital, Barcelona, Spain
• ⁴ Ciber Enfermedades Respiratorias (Ciberes), Madrid, Spain
• ⁵ Lung Transplant Univt, Pneumology Department, Vall d'Hebron University Hospital, Barcelona, Spain
• ⁶ Kidney Transplant.Unit, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain
• ⁷ Liver Unit, Vall d'Hebron University Hospital, Barcelona, Spain
• ⁸ Centro de Investigación Biomédica en Red de Enfermedades Hepáticas y Digestivas (CIBERehd), Madrid, Spain
• ⁹ Microbiology Department, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain
• ¹⁰ Pediatric Hepatology and Liver Transplant Department, Vall d'Hebron University Hospital, Barcelona, Spain
• ¹¹ Department of Pediatric Nephrology, Vall d'Hebron University Hospital, Barcelona, Catalonia, Spain
• ¹² Department of Preventive Medicine and Epidemiology, Bellvitge University Hospital, Barcelona, Spain
• ¹³ Advanced Heart Failure and Heart Transplant Unit, Department of Cardiology, Bellvitge University Hospital, Barcelona, Spain
• ¹⁴ Liver Transplant Unit, Bellvitge University Hospital, Barcelona, Spain
• ¹⁵ Kidney Transplant Unit, Bellvitge University Hospital, Barcelona, Spain
• ¹⁶ Kidney Transplant Unit, Nephrology Department, Germans Trias i Pujol Hospital, Badalona, Spain
• ¹⁷ Equipo de Atención Primaria Sant Rafael, SAP Muntanya, Gerència Territorial de Barcelona Ciutat, Institut Català de la Salut, Barcelona, Spain
• ¹⁸ Infectious Diseases Department, Vall d'Hebron Research Institute, Barcelona, Spain
• ¹⁹ Lung Transplant Unit, Pneumology Department, Vall d'Hebron University Hospital, Barcelona, Spain
• ²⁰ Department of Infectious Diseases, Vall d'Hebron University Hospital, Barcelona, Spain
• ²¹ Urology Department, Vall d'Hebron University Hospital, Barcelona, Spain
• ²² Department of Preventive Medicine and Epidemiology, Vall d'Hebron University Hospital, Barcelona, Spain

Solid organ transplant (SOT) recipients display weak seroconversion and neutralizing antibodies (NAb) responses after SARS-CoV-2 vaccination and remain at risk of severe COVID-19. B-cell memory is the hallmark of serological immunity, but their role driving successful vaccine responses and immune protection in SOT is unclear.We investigated the function and interplay of SARS-CoV-2-specific memory B cells (mBc), different cytokine-producing T-cells and cross-reactive NAb, driving seroconversion and protection against COVID-19 in two cohorts. First, in a large cohort of 148 SOT and 32 immunocompetent individuals undergoing several vaccinations and afterwards, in 25 SOT participating in a randomized controlled trial in which we assessed two different immunosuppressive strategies to allow successful seroconversion and memory-cell responses after booster vaccination.We corroborate previous findings that B and T-cell memory responses are weaker and more delayed in SOT patients than immunocompetent (IC) individuals; however, within the SOT cohort, we find that these responses are relatively stronger and more robust in patients not receiving mycophenolate mofetil (MMF)-based therapies. Anti-Spike IgG titers strongly correlated with RBD-specific IgG-producing mBc, both displaying broad viral cross-reactivity. Pre-booster SARS-CoV-2-specific mBc and IL2producing T cells accurately predicted NAb seroconversion (AUC 0.828) and protection against severe COVID-19. While switching unresponsive SOT from CNI/MMF to low-exposure CNI/mTOR-i favored wider SARS-CoV-2-specific immune responses after a 4 th booster vaccination, preformed RBD-specific mBc predicted NAb seroconversion.Our study adds new insight on the pathobiology of immune memory and highlights the pivotal role of SARS-CoV-2-specific mBc promoting immune protection in SOT patients.