![]() However, increased resistance to antibody neutralization is being observed for SARS-CoV-2 VOCs, especially for variants carrying mutations within the RBM region (including Beta and Omicron variants) 8, 9, 10. In addition to vaccination, the use of recombinant antibodies has proven successful for therapy and prevention of COVID-19 and several monoclonal antibodies have obtained regulatory approval, and have shown particular promise in immunocompromised individuals and the elderly 16, 17, 18. However, it is also evident that such antibodies are rare in most vaccinated individuals and convalescent patients 5, 14. Such antibodies generally bind to regions conserved among sarbecoviruses (class 3, 4 and 5 epitopes) and are expected to be more resilient to VOCs. More recently, broadly neutralizing antibodies have been identified that bind outside the RBM region 11, 12, 13, 14, 15. Such RBD- and RBM-targeted antibodies are also generated upon vaccination 7, but often lack neutralization potential against emerging variants of concern (VOCs) 8, 9, 10. Most of the neutralizing antibodies bind the spike receptor binding domain (RBD), and in particular class 1 and 2 epitopes within the receptor binding motif (RBM), directly blocking interaction with the human angiotensin converting enzyme receptor 2 (ACE2) 3, 4, 5, 6. Upon SARS-CoV-2 infection, the human adaptive immune response generates antibodies against the viral spike surface glycoprotein 2. The coronavirus SARS-CoV-2, the causative agent of the global COVID-19 pandemic, has resulted in the death of over 6 million people worldwide 1. Our results provide guidance for next generation monoclonal antibody development and vaccine design. Our results indicate that exposure to SARS-CoV-2 induces antibodies that maintain broad neutralization against emerging VOCs using two unique strategies: either by targeting the divergent class 1 epitope in a manner resistant to VOCs (ACE2 mimicry, as illustrated by GAR05 and mAbs P2C-1F11/S2K14) or alternatively, by targeting rare and highly conserved epitopes, such as the new class 6 epitope identified here (as illustrated by GAR12). They also provide prophylactic and therapeutic in vivo protection of female hACE2 mice against viral challenge. Both antibodies broadly neutralize VOCs, exceeding the potency of the clinical monoclonal sotrovimab (S309) by orders of magnitude. This is exemplified by two human antibodies, GAR05, binding to epitope class 1, and GAR12, binding to a new epitope class 6 (located between class 3 and 5). Here we demonstrate that broadly neutralizing antibodies can be isolated from peripheral blood mononuclear cells of convalescent patients using SARS-CoV-2 receptor binding domains carrying epitope-specific mutations. Nature Communications volume 14, Article number: 687 ( 2023)Įmerging variants of concern (VOCs) are threatening to limit the effectiveness of SARS-CoV-2 monoclonal antibodies and vaccines currently used in clinical practice broadly neutralizing antibodies and strategies for their identification are therefore urgently required. Include more flanking sequence > 50bp to obtain these scores.Broadly neutralizing SARS-CoV-2 antibodies through epitope-based selection from convalescent patients The efficiency scores will instead be shown as '-'. In other words, some guides may be fine, the problem may just be that the on-target is shown as an off-target.īecause there is no flanking sequence available, the guides in your sequence that are within 50bp of the ends will have no efficiency scores. In this case, the specificity scores of guide sequences are too low. When reading the list of guide sequences and off-targets below, bear in mind that in case that the input sequence is really in the genome and just has a few differences, the software will use the first found match as the on-target as it cannot distinguish 0-mismatch off-targets from 0-mismatch on-targets. Use a tool like BLAT to check if the sequence really has a 100% identical match in the target genome. If not, you might want to check if you selected the right genome for your query sequence. Warning: The query sequence was not found in the selected genome.
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