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Review 1: "Emergence of a novel SARS-CoV-2 strain in Southern California, USA"

This preprint, for which additional peer reviews are pending, identifies a CAL20C variant, which has spread throughout southern California. Additional epidemiological research is needed to determine if this variant could be responsible for increased transmissibility state-wide.

Published onFeb 11, 2021
Review 1: "Emergence of a novel SARS-CoV-2 strain in Southern California, USA"
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key-enterThis Pub is a Review of
Emergence of a novel SARS-CoV-2 strain in Southern California, USA

AbstractSince October 2020, novel strains of SARS-CoV-2 including B.1.1.7, have been identified to be of global significance from an infection and surveillance perspective. While this strain (B.1.1.7) may play an important role in increased COVID rates in the UK, there are still no reported strains to account for the spike of cases in Los Angeles (LA) and California as a whole, which currently has some of the highest absolute and per-capita COVID transmission rates in the country. From the early days of the pandemic when LA only had a single viral genome uploaded onto GISAID we have been at the forefront of generating and analyzing the SARS-CoV-2 sequencing data from the LA region. We report a novel strain emerging in Southern California. Most current cases in the catchment population in LA fall into two distinct subclades: 1) 20G (24% of total) is the predominant subclade currently in the United States 2) a relatively novel strain in clade 20C, CAL.20C strain (∼36% of total) is defined by five concurrent mutations. After an analysis of all of the publicly available data and a comparison to our recent sequences, we see a dramatic growth in the relative percentage of the CAL.20C strain beginning in November of 2020. The predominance of this strain coincides with the increased positivity rate seen in this region. Unlike 20G, this novel strain CAL.20C is defined by multiple mutations in the S protein, a characteristic it shares with both the UK and South African strains, both of which are of significant clinical and scientific interest

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



Lately, N501Y and other strains which might have distinct characteristics of clinical importance have been discovered globally. Identifying and characterizing these variants for infectivity and potential vaccine escapes are crucial to containing the virus from further expansion.  In this study, Zhang et al. have focused on CAL.C20 (452R.V1 and PANGO B.1.429), which gained momentum since last October in Southern California.

The defining haplotype for CAL.C20 consists of ORF1a: I4205V (NSP9 I65V), ORF1b: D1183Y (NSP13 D260Y), S: S13I; W152C; L452R. Among these variants, the most notable one is L452R, which is located within the receptor-binding domain (RBD) and it is reported to lead to higher RBD protein expression by Starr et al1 despite almost no significant enhanced binding affinity with ACE2. Furthermore, W152C might alter cysteine disulfide bonding partners and might induce major structural change in spike protein. Spike S13I and NSP9 I65V seem to be more recently joined compared with the other three variants. Although this is not a mandatory request, to accommodate more strains, the defining haplotype might better be relaxed by dropping Spike S13I and NSP I65V. Among genomes sequenced globally, a strain discovered in Mexico in early July (GISAID2: EPI_ISL_942929) is the oldest discovered in this strain; therefore, the strain has been existing for quite some time a few months earlier than the outbreak observed in Southern California.

Although the manuscript is succinct and well written, it is advised that the prevalence of the strain across the US and the rest of the world need to be updated. For instance, besides Oceania, the strain has been identified in Japanese Airport Quarantines among travelers from US and Mexico. Furthermore, authors better unify nomenclatures to either PANGO3 or NextStrain4 throughout the document, for instance, B.1.1.7 to be noted as 20I/501Y.V1 or vice versa.

The authors played an important role in identifying the emerging strain, which potentially aggravates the COVID-19 situations in other regions as well as Southern California. Only minor issues were identified in the manuscript. Therefore, I recommend just minor revisions for the acceptance.

1      Starr, T. N. et al. Deep mutational scanning of SARS-CoV-2 receptor binding domain reveals constraints on folding and ACE2 binding. bioRxiv : the preprint server for biology, 2020.2006.2017.157982, doi:10.1101/2020.06.17.157982 (2020).

2      Shu, Y. & McCauley, J. GISAID: Global initiative on sharing all influenza data - from vision to reality. Euro Surveill 22, doi:10.2807/1560-7917.ES.2017.22.13.30494 (2017).

3      Rambaut, A. et al. A dynamic nomenclature proposal for SARS-CoV-2 lineages to assist genomic epidemiology. Nature Microbiology 5, 1403-1407, doi:10.1038/s41564-020-0770-5 (2020).

4      Emma B Hodcroft, J. H., Richard A Neher, Trevor Bedford. Year-letter Genetic Clade Naming for SARS-CoV-2 on  (2020).


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