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One possibility to control the pandemic is to induce sterilizing immunity through the induction and maintenance of neutralizing antibodies preventing SARS\u2010CoV\u20102 from entering human cells to replicate in.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We report the construction and <jats:italic>in vitro<\/jats:italic> and <jats:italic>in vivo<\/jats:italic> characterization of a SARS\u2010CoV\u20102\u00a0subunit vaccine (PreS\u2010RBD) based on a structurally folded recombinant fusion protein consisting of two SARS\u2010CoV\u20102 Spike protein receptor\u2010binding domains (RBD) fused to the N\u2010 and C\u2010terminus of hepatitis B virus (HBV) surface antigen PreS to enable the two unrelated proteins serving as immunologic carriers for each other.<\/jats:p><\/jats:sec><jats:sec><jats:title>Results<\/jats:title><jats:p>PreS\u2010RBD, but not RBD alone, induced a robust and uniform RBD\u2010specific IgG response in rabbits. Currently available genetic SARS\u2010CoV\u20102 vaccines induce mainly transient IgG<jats:sub>1<\/jats:sub> responses in vaccinated subjects whereas the PreS\u2010RBD vaccine induced RBD\u2010specific IgG antibodies consisting of an early IgG<jats:sub>1<\/jats:sub> and sustained IgG<jats:sub>4<\/jats:sub> antibody response in a SARS\u2010CoV\u20102 naive subject. PreS\u2010RBD\u2010specific IgG antibodies were detected in serum and mucosal secretions, reacted with SARS\u2010CoV\u20102 variants, including the omicron variant of concern and the HBV receptor\u2010binding sites on PreS of currently known HBV genotypes. PreS\u2010RBD\u2010specific antibodies of the immunized subject more potently inhibited the interaction of RBD with its human receptor ACE2 and their virus\u2010neutralizing titers (VNTs) were higher than median VNTs in a random sample of healthy subjects fully immunized with registered SARS\u2010CoV\u20102 vaccines or in COVID\u201019 convalescent subjects.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusion<\/jats:title><jats:p>The PreS\u2010RBD vaccine has the potential to serve as a combination vaccine for inducing sterilizing immunity against SARS\u2010CoV\u20102 and HBV by stopping viral replication through the inhibition of cellular virus entry.<\/jats:p><\/jats:sec>","DOI":"10.1111\/all.15305","type":"journal-article","created":{"date-parts":[[2022,3,31]],"date-time":"2022-03-31T13:24:33Z","timestamp":1648733073000},"page":"2431-2445","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":25,"title":["Vaccine based on folded receptor binding domain\u2010PreS fusion protein with potential to induce sterilizing immunity to SARS\u2010CoV\u20102 variants"],"prefix":"10.1111","volume":"77","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6724-8543","authenticated-orcid":false,"given":"Pia","family":"Gattinger","sequence":"first","affiliation":[{"name":"Department of Pathophysiology and Allergy Research Division of Immunopathology Center for Pathophysiology, Infectiology and Immunology Medical University of Vienna  Vienna Austria"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1091-4327","authenticated-orcid":false,"given":"Bernhard","family":"Kratzer","sequence":"additional","affiliation":[{"name":"Center for Pathophysiology, Infectiology and Immunology Institute of Immunology Medical University of Vienna  Vienna 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