key: cord-0699883-j1kzjre0 authors: Schmitz, Aaron J.; Turner, Jackson S.; Liu, Zhuoming; Zhou, Julian Q.; Aziati, Ishmael D.; Chen, Rita E.; Joshi, Astha; Bricker, Traci L.; Darling, Tamarand L.; Adelsberg, Daniel C.; Altomare, Clara G.; Alsoussi, Wafaa B.; Case, James Brett; VanBlargan, Laura A.; Lei, Tingting; Thapa, Mahima; Amanat, Fatima; Jeevan, Trushar; Fabrizio, Thomas; O’Halloran, Jane A.; Shi, Pei-Yong; Presti, Rachel M.; Webby, Richard J.; Krammer, Florian; Whelan, Sean P.J.; Bajic, Goran; Diamond, Michael S.; Boon, Adrianus C.M.; Ellebedy, Ali H. title: A vaccine-induced public antibody protects against SARS-CoV-2 and emerging variants date: 2021-08-17 journal: Immunity DOI: 10.1016/j.immuni.2021.08.013 sha: 023dc3af8821c7663afe4d8e6b67aea2f256ceed doc_id: 699883 cord_uid: j1kzjre0 The emergence of SARS-CoV-2 antigenic variants with increased transmissibility is a public health threat. Some variants show substantial resistance to neutralization by SARS-CoV-2 infection- or vaccination-induced antibodies. Here, we analyzed receptor binding domain-binding monoclonal antibodies derived from SARS-CoV-2 mRNA vaccine-elicited germinal center B cells for neutralizing activity against the WA1/2020 D614G SARS-CoV-2 strain and variants of concern. Of five monoclonal antibodies that potently neutralized the WA1/2020 D614G strain, all retained neutralizing capacity against the B.1.617.2 variant, four also neutralized the B.1.1.7 variant, and only one, 2C08, also neutralized the B.1.351 and B.1.1.28 variants. 2C08 reduced lung viral load and morbidity in hamsters challenged with the WA1/2020 D614G, B.1.351, or B.1.617.2 strains. Clonal analysis identified 2C08-like public clonotypes among B cells responding to SARS-CoV-2 infection or vaccination in 41 out of 181 individuals. Thus, 2C08-like antibodies can be induced by SARS-CoV-2 vaccines and mitigate resistance by circulating variants of concern. SUMMARY 26 The emergence of SARS-CoV-2 antigenic variants with increased transmissibility is a public 27 health threat. Some variants show substantial resistance to neutralization by SARS-CoV-2 28 infection-or vaccination-induced antibodies. Here, we analyzed receptor binding domain- 29 binding monoclonal antibodies derived from SARS-CoV-2 mRNA vaccine-elicited germinal 30 center B cells for neutralizing activity against the WA1/2020 D614G SARS-CoV-2 strain and 31 variants of concern. Of five monoclonal antibodies that potently neutralized the WA1/2020 . 75 Here, we assessed the capacity of these anti-RBD mAbs to recognize and neutralize recently 76 emerged SARS-CoV-2 variants. One mAb, 2C08, potently neutralized the WA1/2020 D614G 77 SARS-CoV-2 strain also neutralized the B. and 2C08-treated animals differed by 7.1 percent 3 dpi (P < 0.001) and 10.4 percent 4 dpi (P < 119 0.001) for the D614G challenge, by 6.8 percent 3 dpi (P = 0.095) and 9.1 percent 4 dpi (P = 120 0.056) for the Wash-B.1.351 challenge, and by 8.5 percent 3 dpi (P = 0.008) and 9.7 percent 4 121 dpi (P = 0.008) for the B.1.617.2 challenge (Fig 2A) . Consistent with the weight loss data, 2C08 122 treatment reduced viral RNA by more than 10,000-fold in the lungs of the D614G-and 123 B.1.617.2-challenged hamsters (P < 0.001 and P = 0.008, respectively), and by approximately 124 1,000-fold in those challenged with Wash-B.1.351 (P = 0.008) 4 dpi compared to the isotype 125 control mAb groups (Fig. 2B) . Prophylactic treatment also significantly reduced infectious virus 126 titers for all strains detected in the lungs 4 dpi (P < 0.001 for D614G, P = 0.008 for both 127 variants) (Fig 2C) . Overall, prophylaxis with 2C08 substantially decreased morbidity and viral To define the RBD residues targeted by 2C08, we used VSV-SARS-CoV-2-S chimeric viruses 133 (S from D614G strain) to select for variants that escape 2C08 neutralization as previously in hACE2 binding (Fig. 3A) . We confirmed the specificity of 2C08 for the hACE2-binding site 139 of RBD in bio-layer interferometry (BLI)-based competition assays (Fig. 3B) (Fig. S2C) . 149 We noted that 2C08 targeted residues similar to those recognized by a previously described 150 human mAb, S2E12, which was isolated from an infected patient (Tortorici et al., 2020) . S2E12 151 shared a high sequence identity with 2C08 (95% amino acid identity) and was encoded by the 152 same immunoglobulin heavy (IGHV1-58) and light (IGKV3-20) chain variable region genes 153 (Table S2) Table S2 ). The primary heavy chain contact 178 residues described for S2E12 were largely conserved for all mAbs ( Fig. 3D and E) . Altogether 179 these results indicate that 2C08 targeted a conserved region of the RBD and 2C08-like clones 180 can be generated in response to SARS-CoV-2 infection or vaccination. Figure S1 and Table S1 . 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