key: cord-0846805-e74wlpb6 authors: Deng, Xianding; Garcia-Knight, Miguel A.; Khalid, Mir M.; Servellita, Venice; Wang, Candace; Morris, Mary Kate; Sotomayor-González, Alicia; Glasner, Dustin R.; Reyes, Kevin R.; Gliwa, Amelia S.; Reddy, Nikitha P.; San Martin, Claudia Sanchez; Federman, Scot; Cheng, Jing; Balcerek, Joanna; Taylor, Jordan; Streithorst, Jessica A.; Miller, Steve; Sreekumar, Bharath; Chen, Pei-Yi; Schulze-Gahmen, Ursula; Taha, Taha Y.; Hayashi, Jennifer; Simoneau, Camille R.; Kumar, G. Renuka; McMahon, Sarah; Lidsky, Peter V.; Xiao, Yinghong; Hemarajata, Peera; Green, Nicole M.; Espinosa, Alex; Kath, Chantha; Haw, Monica; Bell, John; Hacker, Jill K.; Hanson, Carl; Wadford, Debra A.; Anaya, Carlos; Ferguson, Donna; Frankino, Phillip A.; Shivram, Haridha; Lareau, Liana F.; Wyman, Stacia K.; Ott, Melanie; Andino, Raul; Chiu, Charles Y. title: Transmission, infectivity, and neutralization of a spike L452R SARS-CoV-2 variant date: 2021-04-20 journal: Cell DOI: 10.1016/j.cell.2021.04.025 sha: fd691e7a3d3b1419ffd549c6be358362a88ca131 doc_id: 846805 cord_uid: e74wlpb6 We identified an emerging SARS-CoV-2 variant by viral whole-genome sequencing of 2,172 nasal/nasopharyngeal swab samples from 44 counties in California, a state in the Western United States. Named B.1.427/B.1.429 to denote its 2 lineages, the variant emerged in May 2020 and increased from 0% to >50% of sequenced cases from September 2020 to January 2021, showing 18.6-24% increased transmissibility relative to wild-type circulating strains. The variant carries 3 mutations in the spike protein, including an L452R substitution. We found 2-fold increased B.1.427/B.1.429 viral shedding in vivo and increased L452R pseudovirus infection of cell cultures and lung organoids, albeit decreased relative to pseudoviruses carrying the N501Y mutation common to variants B.1.1.7, B.1.351, and P.1. Antibody neutralization assays revealed 4.0 to 6.7-fold and 2.0-fold decreases in neutralizing titers from convalescent patients and vaccine recipients, respectively. The increased prevalence of a more transmissible variant in California exhibiting decreased antibody neutralization warrants further investigation. Genetic mutation provides a mechanism for viruses to adapt to a new host and/or 61 evade host immune responses. Although SARS-CoV-2 has a slow evolutionary rate 62 relative to other RNA viruses (~0.8 x10 -3 approximately 2-fold increase in median viral loads in infected patients and increased 221 infectivity of cultured cells and lung organoids in vitro. We also observed a moderate 222 resistance to neutralization by antibodies elicited by prior infection (4.0 to 6.7-fold) or 223 vaccination (2-fold). These findings indicate that the B. influenced by other factors such as population density and/or public health 296 interventions. An alternative (but not mutually exclusive) possibility is that the additional 297 mutations in B.1.427/B.1.429, especially the W152C and S13I mutations in the spike 298 protein, may contribute to increased infectivity of the variant relative to lineages carrying 299 the L452R mutation alone. Indeed, in the current study we observed smaller but to address these hypotheses. 304 Our neutralization findings are consistent with a prior report showing decreased 305 binding of L452R-carrying pseudoviruses by antibodies from previously infected COVID-306 19 patients and escape from neutralization in 3 of 4 convalescent plasma samples (Liu 307 et al., 2020) . We speculate that mutation of the L452 residue in a hydrophobic pocket 308 may induce conformational changes in the RBD that impact neutralizing antibody 309 binding. Of note, a >4-fold decrease in neutralizing antibody titers in convalescent 310 plasma suggest that immune selection pressure from a previously exposed population may be partly driving the emergence of L452R variants. These data also raise 312 questions regarding potential higher risk of re-infection and the therapeutic 313 While in this study, we obtain robust estimates for the emergence and growth of the We gratefully acknowledge the authors from the originating laboratories and the 362 submitting laboratories who generated and shared via GISAID genetic sequence data 363 from an additional 2,737 genomes (from samples from California collected February 1 to 364 March 11, 2021) on which this research is based (Table S5) . Illumina raw paired-end reads were first screened for SARS-CoV-2 sequences using 636 BLASTn (BLAST+ package 2.9.0) alignment against viral reference genome 637 NC_045512, and then processed using the BBTools suite, v38.87 (Bushnell, 2021). 638 Adapter sequences were trimmed and low-quality reads were removed using BBDuk, 639 and then mapped to the NC_045512 reference genome using BBMap. Variants were 640 called with CallVariants and a depth cutoff of 5 was used to generate the final assembly. 641 A genome coverage breadth of ≥70% was required for inclusion in the study. Tables 804 805 Table S1 . Metadata for the 2,172 genomes analyzed in this study, related to 806 Figures 1, 2, and 3 . 807 "TableS1.xlsx" 808 809 Early transmissibility 934 assessment of the N501Y mutant strains of SARS-CoV-2 in the United Kingdom Neutralizing Activity of BNT162b2-Elicited Serum -938 Landscape analysis of escape variants 941 identifies SARS-CoV-2 spike mutations that attenuate monoclonal and serum antibody 942 neutralization. bioRxiv A genomics network established to respond rapidly Spike mutation D614G alters SARS-CoV-2 948 fitness Multiplex PCR method for MinION and Illumina sequencing of Zika and other virus genomes directly from clinical samples Estimates of serial interval for COVID-19: A 954 systematic review and meta-analysis Posterior 958 A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist 962 genomic epidemiology Preliminary genomic characterisation of an emergent 965 SARS-CoV-2 lineage in the UK defined by a novel set of spike mutations Resurgence 970 of COVID-19 in Manaus, Brazil, despite high seroprevalence neutralizing antibodies against spike mutants from global SARS-CoV-2 variants. bioRxiv Neutralization of SARS-CoV-2 spike 69/70 deletion, E484K and 1023 N501Y variants by BNT162b2 vaccine-elicited sera Emergence of a Novel SARS-CoV-2 Variant in Southern California SARS-CoV-2 spike D614G change enhances 1030 replication and transmission A Novel Coronavirus from Patients with Pneumonia in China 1.427/B.1.429 variant grew to >50% of cases in California by early 2021. 2. The variant is 20% more transmissible with 2-fold increased shedding in vivo The variant has a spike L452R mutation conferring increased infectivity in vitro In Brief A SARS-CoV-2 variant of concern bearing the L452R spike protein mutation is widely circulating in California, United States, and demonstrates increased transmissibility, infectivity, and avoidance of antibody neutralization