The B.1.427/1.429 (epsilon) SARS-CoV-2 variants are more virulent than ancestral B.1 (614G) in Syrian hamsters
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Abstract
As novel SARS-CoV-2 variants continue to emerge, it is critical that their potential to cause severe disease and evade vaccine-induced immunity is rapidly assessed in humans and studied in animal models. In early January 2021, a novel SARS-CoV-2 variant designated B.1.429 comprising 2 lineages, B.1.427 and B.1.429, was originally detected in California (CA) and it was shown to have enhanced infectivity in vitro and decreased antibody neutralization by plasma from convalescent patients and vaccine recipients. Here we examine the virulence, transmissibility, and susceptibility to pre-existing immunity for B 1.427 and B 1.429 in the Syrian hamster model. We find that both variants exhibit enhanced virulence as measured by increased body weight loss compared to hamsters infected with ancestral B.1 (614G), with B.1.429 causing the most marked body weight loss among the 3 variants. Faster dissemination from airways to parenchyma and more severe lung pathology at both early and late stages were also observed with B.1.429 infections relative to B.1. (614G) and B.1.427 infections. In addition, subgenomic viral RNA (sgRNA) levels were highest in oral swabs of hamsters infected with B.1.429, however sgRNA levels in lungs were similar in all three variants. This demonstrates that B.1.429 replicates to higher levels than ancestral B.1 (614G) or B.1.427 in the oropharynx but not in the lungs. In multi-virus in-vivo competition experiments, we found that B.1. (614G), epsilon (B.1.427/B.1.429) and gamma (P.1) dramatically outcompete alpha (B.1.1.7), beta (B.1.351) and zeta (P.2) in the lungs. In the nasal cavity, B.1. (614G), gamma, and epsilon dominate, but the highly infectious alpha variant also maintains a moderate size niche. We did not observe significant differences in airborne transmission efficiency among the B.1.427, B.1.429 and ancestral B.1 (614G) and WA-1 variants in hamsters. These results demonstrate enhanced virulence and high relative oropharyngeal replication of the epsilon (B.1.427/B.1.429) variant in Syrian hamsters compared to an ancestral B.1 (614G) variant.
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SciScore for 10.1101/2021.08.25.457626: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Ethics statement: Approval of all animal experiments was obtained from the Institutional Animal Care and Use Committee of UC Davis, UC Berkeley, or the Rocky Mountain Laboratories. Sex as a biological variable The male and female Syrian Hamsters used at UCD and UCB were 7-9 weeks old, and they were purchased from Charles River Inc. Randomization not detected. Blinding Image files were uploaded on a Leica hosted web-based site and a board certified veterinary anatomic pathologist blindly evaluated sections for SARS-CoV-2 induced histologic lesions. Power Analysis not detected. Cell Line Authentication Contamination: No contaminants were detected in any of the virus stocks except in the P.1 stock … SciScore for 10.1101/2021.08.25.457626: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Ethics IACUC: Ethics statement: Approval of all animal experiments was obtained from the Institutional Animal Care and Use Committee of UC Davis, UC Berkeley, or the Rocky Mountain Laboratories. Sex as a biological variable The male and female Syrian Hamsters used at UCD and UCB were 7-9 weeks old, and they were purchased from Charles River Inc. Randomization not detected. Blinding Image files were uploaded on a Leica hosted web-based site and a board certified veterinary anatomic pathologist blindly evaluated sections for SARS-CoV-2 induced histologic lesions. Power Analysis not detected. Cell Line Authentication Contamination: No contaminants were detected in any of the virus stocks except in the P.1 stock in which mycoplasma was detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources Virus propagation was performed in Vero-86 cells in Dulbecco’s Modified Eagle Medium (DMEM) supplemented with 5% fetal bovine serum (FBS), 2 mM L-glutamine, 100 U/mL penicillin and 100 g/mL streptomycin. Vero-86suggested: NoneAll virus stocks except P1a were the second passage of the patient isolate on Vero cells, the original isolation being the first passage on Vero cells. Verosuggested: CLS Cat# 605372/p622_VERO, RRID:CVCL_0059)Homogenates were serial 10-fold diluted in Vero E6 growth medium and added to Vero E6 cells. Vero E6suggested: RRID:CVCL_XD71)Software and Algorithms Sentences Resources Raw FASTQ sequences were preprocessed using an in-house computational pipeline that is part of the SURPI software package [27,28]. SURPIsuggested: (SURPI, RRID:SCR_003071)The preprocessing step consisted of trimming low-quality and adapter sequences using cutadapt [29], retaining reads of trimmed length >75 bp, and then removing low-complexity sequences using the DUST algorithm in PrinSeq [30]. PrinSeqsuggested: (PRINSEQ, RRID:SCR_005454)After filtering the preprocessed dataset for SARS-CoV-2-specific viral reads using the nucleotide BLAST algorithm with an e-value threshold cutoff of 10-8, lineage-specific mutation single nucleotide polymorphisms (SNPs) were identified and counted using a custom in-house computational script. BLASTsuggested: (BLASTX, RRID:SCR_001653)Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:The QUILLS strategy to identify relative frequencies of viral variants within a mixed population by sequencing of key single nucleotide mutations has limitations in that only variants with known mutations can be identified. All the variants used in the mixed inoculum experiments in this study, have lineage-defining mutations in spike and orf1ab on the backbone of ancestral B.1 (614G) and these 6 variants are unambiguously identified in the infected animals by QUILLS. However, the variant identified as B.1 (614G) using QUILLS is an aggregate of all variants carrying 614G that cannot be otherwise be assigned to one of the other 6 variants in the inoculum. This would include novel variants arising from the inoculum B.1 (614G) and revertants that may arise in each VOC quasispecies. Because of this, the relative frequency assigned to the ancestral B.1 (614G) is less reliable than the frequencies of the other 6 variants that are based on positively identified sequences in the samples. Similarly, a single point mutation in orf1ab, that can arise or revert spontaneously, distinguishes B.1.427 and B.1.429. This makes it difficult to unambiguously identify B.1.429 and B.1.427 in mixtures and thus we reported the results as the frequency of the “epsilon”, the arrogate of the B.1.429 and B.1.427 frequencies. As previously reported with ancestral B.1 and other VOC [11,25,26], in this study intranasal inoculation of hamsters with the SARS-CoV-2 B.1 (614G) or epsilon variants (B.1.247/B.1.2...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
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- No protocol registration statement was detected.
Results from scite Reference Check: We found no unreliable references.
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