SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern induce lethal disease in K18-hACE2 transgenic mice despite convalescent plasma therapy

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) emerged at the end of 2019 and has been responsible for the still ongoing coronavirus disease 2019 (COVID-19) pandemic. Prophylactic vaccines have been authorized by the United States (US) Food and Drug Administration (FDA) for the prevention of COVID-19. Identification of SARS-CoV-2 neutralizing antibodies (NAbs) is important to assess vaccine protection efficacy, including their ability to protect against emerging SARS-CoV-2 variants of concern (VoC). Here we report the generation and use of a recombinant (r)SARS-CoV-2 USA/WA1/2020 (WA-1) strain expressing Venus and a rSARS-CoV-2 expressing mCherry and containing mutations K417N, E484K, and N501Y found in the receptor binding domain (RBD) of the spike (S) glycoprotein of the South African (SA) B.1.351 (beta, β) VoC, in bifluorescent-based assays to rapidly and accurately identify human monoclonal antibodies (hMAbs) able to neutralize both viral infections in vitro and in vivo. Importantly, our bifluorescent-based system accurately recapitulated findings observed using individual viruses. Moreover, fluorescent-expressing rSARS-CoV-2 and the parental wild-type (WT) rSARS-CoV-2 WA-1 had similar viral fitness in vitro , as well as similar virulence and pathogenicity in vivo in the K18 human angiotensin converting enzyme 2 (hACE2) transgenic mouse model of SARS-CoV-2 infection. We demonstrate that these new fluorescent-expressing rSARS-CoV-2 can be used in vitro and in vivo to easily identify hMAbs that simultaneously neutralize different SARS-CoV-2 strains, including VoC, for the rapid assessment of vaccine efficacy or the identification of prophylactic and/or therapeutic broadly NAbs for the treatment of SARS-CoV-2 infection. IMPORTANCE SARS-CoV-2 is responsible of the COVID-19 pandemic that has warped daily routines and socioeconomics. There is still an urgent need for prophylactics and therapeutics to treat SARS-CoV-2 infections. In this study, we demonstrate the feasibility of using bifluorescent-based assays for the rapid identification of human monoclonal antibodies (hMAbs) with neutralizing activity against SARS-CoV-2, including variants of concern (VoC) in vitro and in vivo. Importantly, results obtained with these bifluorescent-based assays recapitulate those observed with individual viruses demonstrating their feasibility to rapidly advance our understanding of vaccine efficacy and to identify broadly protective human NAbs for the therapeutic treatment of SARS-CoV-2.

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“…3G ). We have also observed a similar fitness advantage of a natural SARS-CoV-2 SA natural isolate over SARS-CoV-2 WA-1 ( 24 ).…”

Section: Resultssupporting

confidence: 63%

A Bifluorescent-Based Assay for the Identification of Neutralizing Antibodies against SARS-CoV-2 Variants of Concern In Vitro and In Vivo

Chiem

Vasquez

Silvas

et al. 2021

J Virol

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“…37 Multiple recent in situ and animal model studies have confirmed that emerging variants indeed cause higher viral load and prolong viral shedding, however, whether these properties are attributed to the mutations linked to RBD:ACE2 binding is still not clear. 37,44,49,50,53,54 Of interest, multiple studies have demonstrated that the WT strain of SARS-CoV-2 had gained instability for RBD:ACE2 binding when it added new muta- of the viral membrane with the host cell. 24,42,50,58 Recent evidence from in situ studies has demonstrated enhanced virus-host membrane fusion for the B.1.617 lineage variants which contain P681R.…”

Section: Increased Transmissibility and Virulencementioning

confidence: 99%

Emerging SARS‐CoV‐2 variants can potentially break set epidemiological barriers in COVID‐19

Kumar

Parashar

Kumar

et al. 2021

Journal of Medical Virology

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Young age, female sex, absence of comorbidities, and prior infection or vaccination are known epidemiological barriers for contracting the new infection and/or increased disease severity. Demographic trends from the recent coronavirus disease 2019 waves, which are believed to be driven by newer severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants, indicate that the aforementioned epidemiological barriers are being breached and a larger number of younger and healthy individuals are developing severe disease. The new SARS-CoV-2 variants have key mutations that can induce significant changes in the virus-host interactions. Recent studies report that, some of these mutations, singly or in a group, enhance key mechanisms, such as binding of the receptor-binding domain (RBD) of the viral spike protein with the angiotensin-converting enzyme 2 (ACE2) receptor in the hostcells, increase the glycosylation of spike protein at the antigenic sites, and enhance the proteolytic cleavage of the spike protein, thus leading to improved host-cell entry and the replication of the virus. The putative changes in the virus-host interactions imparted by the mutations in the RBD sequence can potentially be the reason behind the breach of the observed epidemiological barriers. Susceptibility for contracting SARS-CoV-2 infection and the disease outcomes are known to be influenced by host-cell expressions of ACE2 and other proteases. The new variants can act more efficiently, and even with the lesser availability of the viral entryreceptor and the associated proteases, can have more efficient host-cell entry and greater replication resulting in high viral loads and prolonged viral shedding, widespread tissue-injury, and severe inflammation leading to increased transmissibility and lethality. Furthermore, the accumulating evidence shows that multiple new variants have reduced neutralization by both, natural and vaccine-acquired antibodies, indicating that repeated and vaccine breakthrough infections may arise as serious health concerns in the ongoing pandemic.

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“…It has been suggested that selected nonsynonymous mutations may be associated with more severe disease and inferior outcomes [ 6 ]. In vivo data indicated that infection with VOCs such as B.1.1.7 and B.1.351 reveal significant differences in pathogenicity with increased clinical progression and lower survival [ 7 ]. However, this has not been confirmed in the observational studies of hospitalized patients [ 8 ].…”

Section: Introductionmentioning

confidence: 99%

Demographic and Clinical Overview of Hospitalized COVID-19 Patients during the First 17 Months of the Pandemic in Poland

Flisiak

Rzymski

Zarębska-Michaluk

et al. 2021

JCM

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Long-term analyses of demographical and clinical characteristics of COVID-19 patients can provide a better overview of the clinical course of the disease. They can also help understand whether changes in infection symptomatology, disease severity, and outcome occur over time. We aimed to analyze the demographics, early symptoms of infection, laboratory parameters, and clinical manifestation of COVID-19 patients hospitalized during the first 17 months of the pandemic in Poland (March 2020–June 2021). The patients’ demographical and clinical data (n = 5199) were extracted from the national SARSTer database encompassing 30 medical centers in Poland and statistically assessed. Patients aged 50–64 were most commonly hospitalized due to COVID-19 regardless of the pandemic period. There was no shift in the age of admitted patients and patients who died throughout the studied period. Men had higher C-reactive protein and interleukin-6 levels and required oxygenation and mechanical ventilation more often. No gender difference in fatality rate was seen, although the age of males who died was significantly lower. A share of patients with baseline SpO2 < 91%, presenting respiratory, systemic and gastrointestinal symptoms was higher in the later phase of a pandemic than in the first three months. Cough, dyspnea and fever were more often presented in men, while women had a higher frequency of anosmia, diarrhea, nausea and vomiting. This study shows some shifts in SARS-CoV-2 pathogenicity between March 2020 and July 2021 in the Polish cohort of hospitalized patients and documents various gender-differences in this regard. The results represent a reference point for further analyses conducted under the dominance of different SARS-CoV-2 variants.

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SARS-CoV-2 B.1.1.7 and B.1.351 variants of concern induce lethal disease in K18-hACE2 transgenic mice despite convalescent plasma therapy

Cited by 18 publications

References 70 publications

A Bifluorescent-Based Assay for the Identification of Neutralizing Antibodies against SARS-CoV-2 Variants of Concern In Vitro and In Vivo

A Bifluorescent-Based Assay for the Identification of Neutralizing Antibodies against SARS-CoV-2 Variants of Concern In Vitro and In Vivo

Emerging SARS‐CoV‐2 variants can potentially break set epidemiological barriers in COVID‐19

Demographic and Clinical Overview of Hospitalized COVID-19 Patients during the First 17 Months of the Pandemic in Poland

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