SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies

Hoffmann, Markus; Arora, Prerna; Groß, Rüdiger; Seidel, Alina; Hörnich, Bojan F.; Hahn, Alexander S.; Krüger, Nadine; Graichen, Luise; Hofmann-Winkler, Heike; Kempf, Amy; Winkler, Martin Sebastian; Schulz, Sebastian; Jäck, Hans‐Martin; Jahrsdörfer, Bernd; Schrezenmeier, Hubert; Müller, Martin; Kleger, Alexander; Münch, Jan; Pöhlmann, Stefan

doi:10.1016/j.cell.2021.03.036

Cited by 930 publications

(1,117 citation statements)

References 57 publications

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“…18 lineages, have shown reduced susceptibility to neutralization from convalescent serum and resistance to monoclonal antibodies. [18][19][20][21][22][23][24][25] Importantly, mutations in the NTD domain, and specifically the neutralization supersite, are extensive in the B.1.351 lineage virus. 18 Using 2 orthogonal pseudovirus neutralization (PsVN) assays based on vesicular stomatitis virus (VSV) and lentivirus expressing S variants, neutralizing capacity of sera from phase 1 participants and non-human primates (NHPs) that received 2 doses of mRNA-1273 was reported.…”

Section: Introductionmentioning

confidence: 99%

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Choi

Koch

et al. 2021

Preprint

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of a global pandemic that has led to more than 2.8 million deaths worldwide. Safe and effective vaccines are now available, including Moderna's COVID-19 vaccine (mRNA-1273) that showed 94% efficacy in prevention of symptomatic COVID-19 disease in a phase 3 clinical study. mRNA-1273 encodes for a prefusion stabilized full length spike (S) protein of the Wuhan-Hu-1 isolate. However, the emergence of SARS-CoV-2 variants has led to concerns of viral escape from vaccine-induced immunity. Several emerging variants have shown decreased susceptibility to neutralization by vaccine induced immunity, most notably the B.1.351 variant, although the overall impact on vaccine efficacy remains to be determined. Here, we present the initial evaluation in mice of two updated COVID-19 mRNA vaccines designed to target emerging SARS-CoV-2 variants: (1) monovalent mRNA-1273.351 encodes for the S protein found in the B.1.351 lineage and (2) mRNA-1273.211 comprising a 1:1 mix of mRNA-1273 and mRNA-1273.351. Both vaccines were evaluated as a 2-dose primary series in mice; mRNA-1273.351 was also evaluated as a booster dose in animals previously vaccinated with 2-doses of mRNA-1273. The results demonstrated that a primary vaccination series of mRNA-1273.351 was effective at increasing neutralizing antibody titers against the B.1.351 lineage, while mRNA-1273.211 was most effective at providing broad cross-variant neutralization in mice. In addition, these results demonstrated a third dose of mRNA-1273.351 significantly increased both wild-type and B.1.351-specific neutralization titers. Both mRNA-1273.351 and mRNA-1273.211 are currently being evaluated in additional pre-clinical challenge models and in phase 1/2 clinical studies.

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Section: Introductionmentioning

confidence: 99%

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Choi

Koch

et al. 2021

Preprint

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“…E484K was responsible for near complete resistance against multiple NTD and RBD mAbs and up to >10 and >30 times lower nAb titers in vaccinees and convalescent individuals, respectively. N501Y or K417N are additional mutations, all in RBD, conferring reduced nAb activity in SARS-CoV-2 vaccine and convalescent sera [292,293,296,297,[321][322][323][324][325][326][327][328]. These results could be recapitulated in experiments with SARS-CoV-2 isolates [329][330][331], whereas another study with recombinant SARS-CoV-2 carrying the specific point mutations reported smaller effects on nAb titers against infectious SARS-CoV-2 [332].…”

Section: Sars-cov-2 Mutates On a Low But Constant Level Yielding Mutant Variants Over Timementioning

confidence: 87%

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

Duerr¹,

Jimenez²,

Dittmann³

2021

Preprint

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SARS-CoV-2 and HIV are zoonotic viruses that rapidly reached pandemic scale causing global losses and fear. The COVID-19 and AIDS pandemics ignited massive efforts worldwide to develop antiviral strategies and characterize viral architectures, biological and immunological properties, and clinical outcomes. Although both viruses have a comparable appearance as enveloped, positive-stranded RNA viruses with envelope spikes mediating cellular entry, the entry process, downstream biological and immunological pathways, clinical outcomes, and disease courses are strikingly different. This review provides a systemic comparison of both viruses’ structural and functional characteristics delineating their distinct strategies for efficient spread.

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“…Consistent with our observations, Hoffmann and colleagues have also recently shown that camostat effectively inhibits variant cell entry in the Caco-2 colorectal carcinoma cell line. They demonstrated this using pseudotyped viral particles engineered to express a series of key variants (B.1.1.7, B1.351 and P.1) implicated as variants that may alter virus-host cell interactions and confer resistance to antibodies 35 .…”

Section: Discussionmentioning

confidence: 99%

Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated primary human airway cells

et al. 2021

Preprint

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BackgroundThere are limited effective prophylactic treatments for SARS-CoV-2 infection, and limited early treatment options. Viral cell entry requires spike protein binding to the ACE2 receptor and spike cleavage by TMPRSS2, a cell surface serine protease. Targeting of TMPRSS2 by either androgen blockade or direct inhibition is already in clinical trials in early SARS-CoV-2 infection.MethodsThe likely initial cells of SARS-CoV-2 entry are the ciliated cells of the upper airway. We therefore used differentiated primary human airway epithelial cells maintained at the air-liquid interface (ALI) to test the impact of targeting TMPRSS2 on the prevention of SARS-CoV-2 infection.ResultsWe first modelled the systemic delivery of compounds. Enzalutamide, an oral androgen receptor antagonist, had no impact on SARS-Cov-2 infection. By contrast, camostat mesylate, an orally available serine protease inhibitor, blocked SARS-CoV-2 entry. However, camostat is rapidly metabolised in the circulation in vivo, and systemic bioavailability after oral dosing is low. We therefore modelled local airway administration by applying camostat to the apical surface of the differentiated ALI cultures. We demonstrated that a brief exposure to topical camostat is effective at restricting SARS-CoV-2 viral infection.ConclusionThese experiments demonstrate a potential therapeutic role for topical camostat for pre- or post-exposure prophylaxis of SARS-CoV-2, which can now be evaluated in a clinical trial.

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SARS-CoV-2 variants B.1.351 and P.1 escape from neutralizing antibodies

Abstract: Highlights d B.1.1.7, B.1.351, and P.1 do not show augmented host cell entry d Entry inhibitors under clinical evaluation block all variants d B.1.351 and P.1 can escape from therapeutic antibodies d B.1.351 and P.1 evade antibodies induced by infection and vaccination

Cited by 930 publications

References 57 publications

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

Variant SARS-CoV-2 mRNA vaccines confer broad neutralization as primary or booster series in mice

SARS-CoV-2 Portrayed Against HIV: Contrary Viral Strategies in Similar Disguise

Topical TMPRSS2 inhibition prevents SARS-CoV-2 infection in differentiated primary human airway cells

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