11/13/2023 0 Comments S9.6 antibody cross reactivityExpectedly, this evolutionary pressure on the wt SARS-CoV-2 triggered mutations in immunodominant epitopes to escape the immune system in recovered and vaccinated people ( 7), as shown for Ab therapies ( 8, 9). The rapid spread of the virus and especially the high vaccination rates obtained in many countries lead to a broad immunity in the population. Antibodies (Abs) binding to this domain most likely have a pronounced neutralizing effect ( 3, 5), although epitopes of the S1-protein outside the RBD have also been reported to be neutralizing ( 5, 6). The receptor-binding domain (RBD) comprises 222 residues, around one-third of the S1 region ( 2, 3), which binds to the ACE-2 receptor on the surface of the host cell in the first step of viral entry, initiating the infection cycle. Considering the SARS-CoV-2 infection cycle in humans, the S-protein located at the outer surface of the virus binds via the S1 region to the angiotensin-converting enzyme-2 (ACE-2) receptor of a host cell, initiating the fusion of viral and host membranes via the S2 region, allowing the virus to enter the cell and finally to replicate ( 3, 4). The S-protein, which is the largest of the four major structural proteins found in coronaviruses, assembles into a homotrimer with each monomer consisting of a ~670-residue-long N-terminal S1 region located on the outer surface of the virus particle and a ~590-residue-long C-terminal S2 region. These vaccines were clinically approved at an extraordinary speed ( 2), allowing the first vaccination programs to start in late 2020, i.e., less than a year after identifying the disease. Genome sequences of this original SARS-CoV-2 variant, reported shortly after identification of the virus, were immediately used for the design and consecutive development of vaccines, which relied on the wild-type (wt) sequence of the SARS-CoV-2 spike (S) protein. Identification of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan in late 2019 and the rapid global spreading due to delayed and ineffective measures triggered an unprecedented pandemic situation within weeks that has persisted for more than 2 years so far ( 1). Importantly, neutralization linearly increased with the IgG titers. The third vaccination after 6 months strongly increased both the IgG titers and the neutralizing effect against all variants, especially for omicron, leading to 63% ± 13% neutralization potential. The IgG titers and inhibition of ACE-2 binding were lower for beta and gamma RBDs and much lower for omicron RBD. Both vaccines initiated similarly high IgG titers after two vaccinations against the wild-type and even two VOC-RBDs (alpha and delta) and strongly inhibited the corresponding RBD-ACE-2 binding. We have expressed the RBDs of wild-type SARS-CoV-2 and five variants of concern (VOCs) to test the immune response in people before vaccination with mRNA vaccines BNT162b2 and mRNA-1273 and after up to three vaccinations using in-house ELISA and inhibition assays. Antibodies (Abs) recognizing the S-protein can inhibit binding of the virus via the S-protein to the angiotensin-converting enzyme-2 (ACE-2) receptor expressed on different human cells, especially when these Abs bind to the interaction site, the so-called receptor-binding domain (RBD). These vaccines induce an immune response against the SARS-CoV-2 spike (S) protein located on the surface of the virus particle. The rapid development, approval, and production of vaccines against the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in less than 1 year after the first reports of a new infectious disease was a real game changer, providing 80%–90% efficacy in preventing severe etiopathologies of the coronavirus disease 2019 (COVID-19). 2Center for Biotechnology and Biomedicine, Universität Leipzig, Leipzig, Germany.1Institute of Bioanalytical Chemistry, Faculty of Chemistry and Mineralogy, Universität Leipzig, Leipzig, Germany.Mandy Schwarze 1,2† Andor Krizsan 1,2† Alexandra Brakel 1,2 Fabian Pohl 1,2 Daniela Volke 1,2 Ralf Hoffmann 1,2*
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