key: cord-0685358-2wemwbv2 authors: Rennick, Linda J.; Robinson-McCarthy, Lindsey R.; Nambulli, Sham; Duprex, W. Paul; McCarthy, Kevin R. title: Deletion disrupts a conserved antibody epitope in a SARS-CoV-2 variant of concern date: 2021-03-08 journal: bioRxiv DOI: 10.1101/2021.03.05.434168 sha: f8a6227769306b82c1db405004b6a7f3a28a7ef8 doc_id: 685358 cord_uid: 2wemwbv2 Multiple SARS-CoV-2 variants with altered antigenicity have emerged and spread internationally. In one lineage of global concern, we identify a transmitted variant with a deletion in its receptor binding domain (RBD) that disrupts an epitope which is conserved across sarbecoviruses. Overcoming antigenic variation by selectively focusing immune pressure on this conserved site may, ultimately, drive viral resistance. theory, overcome antigenic variation. These strategies rely upon sites that slowly, if ever, accrue 27 diversity. We identify a transmitted B.1.1.7 variant with a deletion in a site of pan-sarbecoviruses 28 conservation. This deletion disrupts the binding of an antibody that engages both SARS-CoV 29 and SARS-CoV-2. The acquisition of antigenic novelty in S glycoprotein has been recurrent and 30 convergent. By extension conservation at this site may not persist. Using sequences deposited in the GISAID database 5 , we have monitored variants of concern 33 for the acquisition of additional epitope-altering mutations. We identified a transmission cluster 34 of six identifiably different individuals that share a nine-nucleotide deletion within the S gene 35 encoding the RBD. These viruses belong to the B.1.1.7 lineage, which had already acquired two 36 independent deletions in recurrent deletion region 6 (RDR) 1 (Δ69-70) and RDR2 (Δ144/145). Spread via human-to-human transmission is likely given the timing of sample collection, 38 geographic proximity and the clustering of sequences within a phylogeny of contemporaneously 39 circulating B.1.1.7 isolates (Fig. 1 ). The deletion removes residues 375-377 of the RBD. All three have been conserved for the 42 duration of the pandemic. We examined their conservation among divergent sarbecoviruses, 43 including SARS-CoV, bat and pangolin sequences (Fig. 2a) . Among these isolates the three 44 codons differ only by synonymous nucleotide substitutions suggesting selective pressures to 45 preserve the identity of each amino acid. Residues 375-377 contribute to an extended surface 46 that is broadly conserved among sarbecovirus (Fig. 2b ) . This site is distal from the interface 47 between RBD and its receptor angiotensin-converting enzyme 2 (ACE2) 7 . In the "three RBD" 48 down state of the S glycoprotein trimer, residues 375-377 form a β-strand which is recessed and Focused genetic surveillance has not identified additional Δ375-377-linked cases. The virus was 71 sufficiently fit to transmit between at least five individuals and to define their viral consensus 72 sequences. This early period of S evolution has been defined by recurrent, convergent 73 evolution. Many defining mutations in current variants of concern are identical or functionally 74 equivalent. The alteration of a conserved epitope by Δ375-377 not only represents an additional 75 antigenic step in a variant of concern (B.1.1.7), but also demonstrates a capacity of this site to 76 acquire antibody resistance rapidly. The emergence of variants of concern and their continued evolution demonstrate that S is not We gratefully acknowledge the authors from the originating laboratories and the submitting 87 laboratories, who generated and shared via GISAID genetic sequence data on which this 88 research is based (Table 1) . 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