biostudies-literatureUnknownZayou LNIAID NIH HHSSince early 2020, several SARS-CoV-2 variants of concern (VOCs) continue to emerge, evading waning antibody mediated immunity produced by the current Spike-alone based COVID-19 vaccines. This caused a prolonged and persistent COVID-19 pandemic that is going to enter its fifth year. Thus, the need remains for innovative next generation vaccines that would incorporate protective Spike-derived B-cell epitopes that resist immune evasion. Towards that goal, in this study we (<i>i</i>) Screened the sequences of Spike among many VOCs and identified conserved and non-conserved linear B-cell epitopes; (<i>ii</i>) Compared titers and neutralization antibodies specific to these conserved and non-conserved B-cell epitopes from serum of symptomatic and asymptomatic COVID-19 patients that were exposed to multiple VOCs across the 5^-year COVID-19 pandemic, and (<i>iii</i>) Compared protective efficacy of conserved versus non-conserved B-cell epitopes against the most pathogenic Delta variant in a "humanized" ACE-2/HLA transgenic mouse model. We found robust conserved B-cell epitope-specific antibody titers and neutralization in sera from asymptomatic COVID-19 patients. In contrast, sera from symptomatic patients contained weaker antibody responses specific to conserved B-cell epitopes. A multi-epitope COVID-19 vaccine that incorporated the conserved B-cell epitopes, but not the non-conserved B-cell epitopes, significantly protected the ACE2/HLA transgenic mice against infection and COVID-19 like symptoms caused by the Delta variant. These findings underscore the importance of conserved B-cell epitopes in generating robust protective immunity against severe COVID-19 symptoms caused by various VOCs, providing valuable insights for the development of broad-spectrum next generation Coronavirus vaccines capable of conferring cross-variant protective immunity.bioRxiv : the preprint server for biology2024.09.22.614369https://www.ebi.ac.uk/biostudies/studies/S-EPMC11463540biostudies-literatureDynamics of Spike-Specific Neutralizing Antibodies Across Five-Year Emerging SARS-CoV-2 Variants of Concern Reveal Conserved Epitopes that Protect Against Severe COVID-19.PMC11463540R01 AI158060R21 AI147499R01 AI143348R01 AI150091R41 AI138764R43 AI124911R21 AI110902R21 AI143326R43 AI174383Zayou LLemkhente ZVahed HQuadiri APrakash SDhanushkodi NRGil DBenMohamed LUlmer JBBelmouden AChentoufi AfalseDynamics of Spike-Specific Neutralizing Antibodies Across Five-Year Emerging SARS-CoV-2 Variants of Concern Reveal Conserved Epitopes that Protect Against Severe COVID-19.Since early 2020, several SARS-CoV-2 variants of concern (VOCs) continue to emerge, evading waning antibody mediated immunity produced by the current Spike-alone based COVID-19 vaccines. This caused a prolonged and persistent COVID-19 pandemic that is going to enter its fifth year. Thus, the need remains for innovative next generation vaccines that would incorporate protective Spike-derived B-cell epitopes that resist immune evasion. Towards that goal, in this study we (<i>i</i>) Screened the sequences of Spike among many VOCs and identified conserved and non-conserved linear B-cell epitopes; (<i>ii</i>) Compared titers and neutralization antibodies specific to these conserved and non-conserved B-cell epitopes from serum of symptomatic and asymptomatic COVID-19 patients that were exposed to multiple VOCs across the 5^-year COVID-19 pandemic, and (<i>iii</i>) Compared protective efficacy of conserved versus non-conserved B-cell epitopes against the most pathogenic Delta variant in a "humanized" ACE-2/HLA transgenic mouse model. We found robust conserved B-cell epitope-specific antibody titers and neutralization in sera from asymptomatic COVID-19 patients. In contrast, sera from symptomatic patients contained weaker antibody responses specific to conserved B-cell epitopes. A multi-epitope COVID-19 vaccine that incorporated the conserved B-cell epitopes, but not the non-conserved B-cell epitopes, significantly protected the ACE2/HLA transgenic mice against infection and COVID-19 like symptoms caused by the Delta variant. These findings underscore the importance of conserved B-cell epitopes in generating robust protective immunity against severe COVID-19 symptoms caused by various VOCs, providing valuable insights for the development of broad-spectrum next generation Coronavirus vaccines capable of conferring cross-variant protective immunity.2024-01-01T00:00:00Z2024 Sep2026-04-08T18:41:30.146Z2025-04-06T01:58:06.597ZS-EPMC114635403938656710.1101/2024.09.22.614369