B.1.1.7 and B.1.351 variants are highly virulent in K18-ACE2 transgenic mice and show different pathogenic patterns from early SARS-CoV-2 strains

Radvák, Peter; Kwon, Hyung Joon; Košíková, Martina; Ortega-Rodriguez, Uriel; Xiang, Ruoxuan; Phue, Je-Nie; Shen, Rong-Fong; Rozzelle, James; Kapoor, Neeraj; Rabara, Taylor; Fairman, Jeff; Xie, Hang

doi:10.1101/2021.06.05.447221

Cited by 8 publications

(10 citation statements)

References 58 publications

(62 reference statements)

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“…This result accorded with the latest report that Omicron variant which carrying N501Y mutation was capable of infecting cells expressing avian ACE2 [10]. Notably, N501Y mutation is widely exist in other VOC and VOI variants, such as Alpha, Beta, Gamma and Lambda [6,36].…”

Section: Discussionsupporting

confidence: 89%

Key mutations on spike protein altering ACE2 receptor utilization and potentially expanding host range of emerging SARS-CoV-2 variants

Wang

Zhou

et al. 2022

Preprint

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Increasing evidence supports inter-species transmission of SARS-CoV-2 variants from human to domestic or wild animals during the ongoing COVID-19 pandemic, which is posing great challenges to epidemic control. Clarifying the host range of emerging SARS-CoV-2 variants will provide instructive information for the containment of viral spillover. The spike protein (S) of SARS-CoV-2 is the key determinant of receptor utilization, and therefore amino acid mutations on S will probably alter viral host range. Here, in order to evaluate the impact of S mutations, we constructed 20 Hela cell lines stably expressing ACE2 orthologs from different animals, and prepared 27 pseudotyped SARS-CoV-2 carrying different spike mutants, among which 20 bear single mutation and the other 7 were cloned from emerging SARS-CoV-2 variants, including D614G, Alpha (B.1.1.7), Beta (B.1.351), Gamma (P.1), Delta (B.1.135), Lambda (B.1.429) and Mu (B.1.525). Using pseudoviral reporter assay, we identified that the substitutions of T478I and N501Y enabled the pseudovirus to utilize chicken ACE2, indicating potential infectivity to avian species. Furthermore, the S mutants of real SARS-CoV-2 variants comprising N501Y showed significantly acquired abilities to infect cells expressing mouse ACE2, indicating a critical role of N501Y in expanding SARS-CoV-2 host range. In addition, A262S and T478I significantly enhanced the utilization of various mammals ACE2. In summary, our results indicated that T478I and N501Y substitutions were two S mutations important for receptor adaption of SARS-CoV-2, potentially contributing to spillover of the virus to many other animal hosts. Therefore, more attention should be paid to SARS-CoV-2 variants with these two mutations.

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Section: Discussionsupporting

confidence: 89%

Key mutations on spike protein altering ACE2 receptor utilization and potentially expanding host range of emerging SARS-CoV-2 variants

Wang

Zhou

et al. 2022

Preprint

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“…The K18-hACE2 transgenic model has been extensively utilized to evaluate the vaccine efficacy and effectiveness in preventing COVID-19 in the preclinical setting (Arce and Costoya, 2021; Dong et al, 2021; Radvak et al, 2021; Winkler et al, 2020). Two key metrics to determine the severity of pathogenesis are the virus titer in the lung tissue and body weight loss following virus infection.…”

Section: Resultsmentioning

confidence: 99%

Chimeric mRNA based COVID-19 vaccine induces protective immunity against Omicron and Delta

Zhao

Shaabani

et al. 2022

Preprint

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The emerging SARS-CoV-2 variants of concern (VOCs) exhibit enhanced transmission and immune escape, reducing the efficacy and effectiveness of the two FDA-approved mRNA vaccines currently in use. Here, we explored various strategies to develop mRNA vaccines that offer potentially safer and wider coverage of VOCs. The initial mouse vaccination results showed that the individual VOC mRNAs carrying furin cleavage mutation induced the generation of neutralizing antibody in a VOC-specific manner. Moreover, we discovered that the antibodies produced from mice immunized with Beta-Furin and Washington (WA)-Furin mRNAs cross-reacted with other VOCs. The broad spectrum of generated nAb was further confirmed when vaccinated mice were challenged with the respective live viruses. However, neither WA-Furin nor Beta-Furin mRNA elicited potent neutralizing activity against the omicron variant. Interestingly, in a mix-and-match booster experiment, omicron-Furin and WA-Furin mRNA elicited comparable protection against omicron. Finally, we tested the concept of bivalent vaccine by introducing the RBD of Delta strain into the intact S antigen of Omicron. The chimeric mRNA induces potent and broadly acting nAb against Omicron and Delta, which paves the way to develop vaccine candidate to target emerging variants in the future.

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“… 36 , 40 , 42 , 48 , 51 and is higher than viral loads typically seen in human infections. Whether the amount and persistence of the B.1.351 virus in vivo in this study relates to the challenge dose or suggests that this variant has inherent properties that make it more difficult to control and clear compared to the WA-1 strain 53 , 54 is a focus of ongoing analyses.…”

Section: Discussionmentioning

confidence: 98%

“…This contrasts with the more rapid and complete reduction of viral replication following challenge with the WA-1 strain 36 , 40 , 42 , 48 , 51 and is higher than viral loads typically seen in human infections. Whether the amount and persistence of B.1.351 virus in vivo in this study relates to challenge dose or suggests that this variant has inherent properties that make it more difficult to control and clear compared to the WA-1 strain 53 , 54 is a focus of ongoing analyses. 36 , 40 , 42 , 48 , 51 and is higher than viral loads typically seen in human infections.…”

Section: Discussionmentioning

confidence: 98%

mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates

et al. 2021

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B.1.351 is the SARS-CoV-2 variant most resistant to antibody neutralization. We demonstrate how the dose and number of immunizations influence protection. Nonhuman primates (NHP) received two doses of 30 or 100 μg of Moderna’s mRNA-1273 vaccine, a single immunization of 30 μg, or no vaccine. Two doses of 100 μg of mRNA-1273 induced reciprocal ID 50 mean neutralizing antibody titers against live SARS-CoV-2 D614G and B.1.351 of 3,300 and 240, respectively. Higher neutralizing responses against B.1.617.2 were also observed after two doses compared to a single dose. Following challenge with B.1.351, there was ~4–5−log 10 reduction of viral subgenomic RNA (sgRNA) and low to undetectable replication in bronchoalveolar lavages in the two-dose vaccine groups, with a 1−log 10 reduction in nasal swabs (NS) in the 100 μg dose group. These data establish that a two-dose regimen of mRNA-1273 will be critical for providing upper and lower airway protection against major variants of concern.

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B.1.1.7 and B.1.351 variants are highly virulent in K18-ACE2 transgenic mice and show different pathogenic patterns from early SARS-CoV-2 strains

Cited by 8 publications

References 58 publications

Key mutations on spike protein altering ACE2 receptor utilization and potentially expanding host range of emerging SARS-CoV-2 variants

Key mutations on spike protein altering ACE2 receptor utilization and potentially expanding host range of emerging SARS-CoV-2 variants

Chimeric mRNA based COVID-19 vaccine induces protective immunity against Omicron and Delta

mRNA-1273 protects against SARS-CoV-2 beta infection in nonhuman primates

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