Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

García-Beltrán, Wilfredo F.; Lam, Evan C.; Denis, Kerri J St; Nitido, Adam; Garcia, Zeidy H.; Hauser, Blake M.; Feldman, Jared; Pavlovic, Maia; Gregory, David; Poznansky, Mark C.; Sigal, Alex; Schmidt, Aaron; Iafrate, A. John; Naranbhai, Vivek; Balazs, Alejandro B.

doi:10.1016/j.cell.2021.03.013

Cited by 1,270 publications

(1,156 citation statements)

References 49 publications

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“…5 In particular, the P.1 strain has been shown to escape neutralization by vaccine-induced humoral immunity in pseudoviral models. 6,7 Given the mutations acquired by P.1, questions have emerged that in addition to enhanced transmissibility and potential immune escape, it may be associated with enhanced virulence and pathogenicity. Indeed, it is reasonable to speculate that enhanced binding of the mutated virus to its host receptor (angiotensin converting enzyme 2 (ACE2)), may result in increased viral load, with resultant increased virulence.…”

Section: Introductionmentioning

confidence: 99%

Sudden rise in COVID-19 case fatality among young and middle-aged adults in the south of Brazil after identification of the novel B.1.1.28.1 (P.1) SARS-CoV-2 strain: analysis of data from the state of Parana

Oliveira

Lippi

Henry

2021

Preprint

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Brazil is currently suffering a deadly surge of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections, which has been attributed to the spread of a new strain known as P.1 (B.1.1.28.1). In this investigation, we analyzed coronavirus disease 2019 (COVID-19) public health data from Parana, the largest state in southern half of Brazil, between September 1, 2020 and March 17, 2021, to evaluate recent trends in case fatality rates in different age groups. A total of 553,518 cases of SARS-CoV-2, 8,853 currently registered as fatal, were finally included in our analysis. All age groups showed either decline or stabilization of the case fatality rates (CFRs) between September 2020 and January 2021. In February 2021, an increase in CFR for almost all age groups could be instead observed. All groups above 20 years of age showed statistically significant increases in CFR when diagnosed in February 2021 as opposed to January 2021. Patients aged 20-29 years experienced a tripling of their CFR, from 0.04% to 0.13%, while those aged 30-39, 40-49, 50-59 experienced approximate CFR doubling. Individuals between 20 and 29 years of age whose diagnosis was made in February 2021 had an over 3-fold higher risk of death compared to those diagnosed in January 2021 (Risk Ratio (RR): 3.15 [95%CI: 1.52-6.53], p<0.01), while those aged 30-39, 40-49, 50-59 years experienced 93% (1.93 [95%CI:1.31-2.85], p<0.01), 110% (RR: 2.10 [95%CI:1.62-2.72], p<0.01), and 80% (RR: 1.80 [95%CI:1.50-2.16], p<0.01) increases in risk of death, respectively. Notably, the observed CFR increase coincided with the second consecutive month of declining number of diagnosed SARS-CoV-2 cases. Taken together, these preliminary findings suggest significant increases in CFR in young and middle-aged adults after identification of a novel SARS-CoV-2 strain circulating in Brazil, and this should raise public health alarms, including the need for more aggressive local and regional public health interventions and faster vaccination.

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Section: Introductionmentioning

confidence: 99%

Sudden rise in COVID-19 case fatality among young and middle-aged adults in the south of Brazil after identification of the novel B.1.1.28.1 (P.1) SARS-CoV-2 strain: analysis of data from the state of Parana

Oliveira

Lippi

Henry

2021

Preprint

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“…With new strains of SARS-CoV-2 emerging, and the significance of TMPRSS2 in viral entry for multiple coronaviruses, it is pivotal that we uncover novel strategies to inhibit TMPRSS2 protease activity. 50,51 However, TMPRSS2 provides obstacles in multiple areas of the discovery pipeline.…”

Section: Resultsmentioning

confidence: 99%

TMPRSS2 inhibitor discovery facilitated through anin silicoand biochemical screening platform

Jm²,

Wu³

et al. 2021

Preprint

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The COVID-19 pandemic has highlighted the need for new antiviral targets, as many of the currently approved drugs have proven ineffective against mitigating SARS-CoV-2 infections. The host transmembrane serine protease TMPRSS2 is a highly promising antiviral target, as it plays a direct role in priming the spike protein before viral entry occurs. Further, unlike other targets such as ACE2, TMPRSS2 has no known biological role. Here we utilize virtual screening to curate large libraries into a focused collection of potential inhibitors. Optimization of a recombinant expression and purification protocol for the TMPRSS2 peptidase domain facilitates subsequent biochemical screening and characterization of selected compounds from the curated collection in a kinetic assay. In doing so, we demonstrate that serine protease inhibitors camostat, nafamostat, and gabexate inhibit through a covalent mechanism. We further identify new non-covalent compounds as TMPRSS2 protease inhibitors, demonstrating the utility of a combined virtual and experimental screening campaign in rapid drug discovery efforts.

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“…On the other hand, a plethora of studies has demonstrated antibody evasion for some of the novel VOCs. [19][20][21][22][23][24][25][26][27][28] However, data correlating immune evasion of SARS-CoV-2 VOCs with binding free energies are currently not available. In order to evaluate the thermodynamics contribution of such low cross-reactivity, we calculated the variation in binding free energy values for a selected set of SARS-CoV-2 VOCs RBDs complexed to 21 known nAbs for which atomic coordinates were made publicly available (Table S2).…”

Section: Resultsmentioning

confidence: 99%

SARS-CoV-2 VOCs Immune Evasion from Previously Elicited Neutralizing Antibodies Is Mainly Driven by Lower Cross-Reactivity Due to Spike RBD Electrostatic Surface Changes

Ferraz¹,

MOREIRA²,

Coêlho³

et al. 2021

Preprint

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<div> <div> <div> <p>Leveraging structural data and computer modelling techniques, we investigated the variation in the binding free-energy (𝛥𝛥𝐺) profile of VOCs and VOIs SARS-CoV-2 lineages with hACE2 and with a dataset of known human nAbs. In agreement with the available experimental data, our results show only a marginal impact of VOC RBD amino acid changes to hACE2 affinity. On the other hand, we found that VOCs RBDs have a significant unfavorable 𝛥𝛥𝐺 to nAbs that can be related to changes in the electrostatic potential surface profiles, hence identifying the molecular and thermodynamical components behind SARS-CoV-2 antibody evasion. In addition, our data suggests that a close attention should be given to lineage P.3, as it likely holds a high spreading potential in a human population with rising immunity. In summary, the current observed higher transmission of SARS-CoV-2 VOCs is likely associated with a partial or complete failure of the antibody recognition and neutralization in individuals previously exposed to SARS-CoV-2 non-VOC variants. These results have key implications on i. the basic understanding of VOCs emergence and maintenance; ii. on the rational design of antibody-based therapeutics; iii. vaccine efficacy and updates; and iv. may be exploited to rapidly screen immune scape worrisome lineages. </p> </div> </div> </div>

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Multiple SARS-CoV-2 variants escape neutralization by vaccine-induced humoral immunity

Cited by 1,270 publications

References 49 publications

Sudden rise in COVID-19 case fatality among young and middle-aged adults in the south of Brazil after identification of the novel B.1.1.28.1 (P.1) SARS-CoV-2 strain: analysis of data from the state of Parana

Sudden rise in COVID-19 case fatality among young and middle-aged adults in the south of Brazil after identification of the novel B.1.1.28.1 (P.1) SARS-CoV-2 strain: analysis of data from the state of Parana

TMPRSS2 inhibitor discovery facilitated through anin silicoand biochemical screening platform

SARS-CoV-2 VOCs Immune Evasion from Previously Elicited Neutralizing Antibodies Is Mainly Driven by Lower Cross-Reactivity Due to Spike RBD Electrostatic Surface Changes

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