Long COVID-19 autoantibodies and their potential effect on fertility

Laura Talamini^1,2Dennyson Leandro M Fonseca³Darja Kanduc⁴Olivier Chaloin⁵Cindy Verdot^1,2Christian Galmiche⁶Arad Dotan⁷Igor Salerno Filgueiras⁸Maria Orietta Borghi^10,9Pier Luigi Meroni¹⁰Natalia Gavrilova¹¹Varvara A Ryabkova^11,12Leonid P. Churilov^11,13Gilad Halpert^11,7Christian Lensch¹⁴Lorenz Thurner¹⁵Siew-Wai Fong¹⁶Lisa F P Ng¹⁶Laurent Rénia^16,17,18Young Barnaby^17,19,20David Chien Lye^17,19,20,21Jose Manuel Lozano²²Otávio Cabral-Marques^23,24,25Yehuda Julyus Shoenfeld^26,7Sylviane MULLER^1,2,27*

• ¹UMR7242 Biotechnologie et Signalisation Cellulaire, Illkirch, Alsace, France
• ²Université de Strasbourg, Strasbourg, Alsace, France
• ³Institute of Mathematics and Statistics, University of São Paulo, São Paulo, Sao Paulo, Brazil
• ⁴Department of Biosciences, Biotechnologies and Biopharmaceuticals, University of Bari Aldo Moro, Bari, Italy
• ⁵UPR3572 Immunopathologie et Chimie Thérapeutique (ICT), Strasbourg, Alsace, France
• ⁶UMS3415 Chronobiotron, Strasbourg, Alsace, France
• ⁷Zabludowicz Center for Autoimmune Diseases & Rheumatology Unit, Sheba Medical Center, Ramat Gan, Jerusalem, Israel
• ⁸Institute of Biomedical Sciences, University of São Paulo, São Paulo, São Paulo, Brazil
• ⁹Department of Clinical and Community Sciences, Faculty of Medicine and Surgery, University of Milan, Milan, Lombardy, Italy
• ¹⁰Immunorheumatology Research Laboratory, IRCCS Istituto Auxologico Italiano, Milan, Lombardy, Italy
• ¹¹Department of Pathology and Laboratory of the Mosaic of Autoimmunity, Saint Petersburg State University, Saint-Petersburg, Russia
• ¹²Pavlov First Saint Petersburg State Medical University, Saint Petersburg, Saint Petersburg, Russia
• ¹³Research Institute of Phthisiopulmonology, Saint-Petersburg, Russia
• ¹⁴Department of Pneumology, Allergology and Critical Care Medicine, ECLS Center Saar, Saarland University Hospital, Homburg/Saar, Germany
• ¹⁵José Carreras Institute for Immunotherapy and Gene Therapy, Saarland University Hospital, Homburg, Saarland, Germany
• ¹⁶A*STAR Infectious Disease Labs, Singapore, Singapore
• ¹⁷Lee Kong Chian School of Medicine, Nanyang Technological University, Singapore, Singapore
• ¹⁸School of Biological Sciences, College of Science, Nanyang Technological University, Singapore, Singapore
• ¹⁹National Centre for Infectious Diseases, Singapore, Singapore
• ²⁰Tan Tock Seng Hospital, Singapore, Singapore
• ²¹Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore
• ²²Departamento de Farmacia, Universidad Nacional de Colombia, Bogotá DC, Colombia
• ²³University of São Paulo, São Carlos, São Carlos, São Paulo, Brazil
• ²⁴Network of Immunity In Infection, Malignancy And Autoimmunity, Universal Scientific Education and Research Network (USERN), Tehran, Alborz, Iran
• ²⁵Instituto D'Or de Ensino e Pesquisa, São Paulo, Brazil
• ²⁶Reichman University, Herzliya, Tel Aviv District, Israel
• ²⁷Drug Discovery and Development Institute, Strasbourg, France

Impaired spermatogenesis has been reported in COVID-19 patients. However, the impact of SARS-CoV-2 on male fertility remains unclear. The purpose of this multicenter study was to investigate the possible impact of SARS-CoV-2 infection on male fertility and determine the potential reasons leading to impaired male reproductive functions. In silico approach identified ~60 amino acid sequences containing at least five continuous residues shared by SARS-CoV-2 Spike glycoprotein and spermatogenesis-linked proteins. Four synthetic peptides were tested with sera from independent cohorts of patients with acute and long COVID syndrome (LCS), and naïve vaccinated subjects. Immunogenicity and pathogenicity studies were performed by immunizing mice with two selected peptides and testing their impact on mouse pregnancy. While none of 4 peptides were recognized by antibodies from vaccinated people, infected patients exhibited high reactivity to peptide 4, and LCS patients, especially women, showed elevated antibody levels against peptide 2. Women with LCS and chronic fatigue syndrome had higher levels of peptide 2-reacting antibodies than those with idiopathic chronic fatigue syndrome. Noteworthy, peptide 2 antibodies showed, in in vitro experiment, a specific interaction with mouse testicular tissue antigens. injection of experimentally-produced into healthy male mice induced abnormal fertility in healthy females. These findings raise the possibility suggest that cross-reactive epitopes between SARS-CoV-2 Spike-protein and spermatogenesis-related antigens may affect infected patients' fertility, suggesting highlighting the a potential for autoimmune responses with significant human consequences.