Neutralising antibody escape of SARS‐CoV‐2 spike protein: Risk assessment for antibody‐based Covid‐19 therapeutics and vaccines

Focosi, Daniele; Maggi, Fabrizio

doi:10.1002/rmv.2231

Cited by 156 publications

(185 citation statements)

References 248 publications

(188 reference statements)

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“…The recent emergence of variants of SARS-CoV-2 with multiple mutations poses a direct threat to the viability of vaccine-based suppression strategies for the pandemic 26 This work, along with other recent findings on the stochastic nature of SARS-CoV-2 transmission 24 , suggests strategies that can be used to suppress the emergence of these fitter viral variants, thereby slowing the evolution of SARS-CoV-2. First, long-term SARS-CoV-2 infections (lasting longer than 30 days) should be treated as a serious public health concern, regardless of the presence of symptoms.…”

Section: Discussionmentioning

confidence: 76%

Controlling long-term SARS-CoV-2 infections is important for slowing viral evolution

Egeren

Novokhodko

Stoddard³

et al. 2021

Preprint

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The rapid emergence and expansion of novel SARS-CoV-2 variants is an unpleasant surprise that threatens our ability to achieve herd immunity for COVID-19. These fitter SARS- CoV-2 variants often harbor multiple point mutations, conferring one or more traits that provide an evolutionary advantage, such as increased transmissibility, immune evasion and longer infection duration. In a number of cases, variant emergence has been linked to long-term infections in individuals who were either immunocompromised or treated with convalescent plasma. In this paper, we explore the mechanism by which fitter variants of SARS-CoV-2 arise during long-term infections using a mathematical model of viral evolution and identify means by which this evolution can be slowed. While viral load and infection duration play a strong role in favoring the emergence of such variants, the overall probability of emergence and subsequent transmission from any given infection is low, suggesting that viral variant emergence and establishment is a product of random chance. To the extent that luck plays a role in favoring the emergence of novel viral variants with an evolutionary advantage, targeting these low-probability random events might allow us to tip the balance of fortune away from these advantageous variants and prevent them from being established in the population.

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Section: Discussionmentioning

confidence: 76%

Controlling long-term SARS-CoV-2 infections is important for slowing viral evolution

Egeren

Novokhodko

Stoddard³

et al. 2021

Preprint

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“…11,14,15 In contrast, many of the other monoclonal antibodies being developed for Covid-19 bind to the receptor-binding motif that engages the angiotensin-converting enzyme 2 (ACE2) receptor and is one of the most mutable and immunogenic regions of the virus; in some cases, these antibodies do not retain activity against the variants. [16][17][18][19] Sotrovimab contains a two-amino acid Fc modification (termed LS) to increase half-life and potentially improve bioavailability in the respiratory mucosa through enhanced engagement with the neonatal Fc receptor. [20][21][22] This modification potentially allows therapeutic concentrations for longer durations.…”

Section: Introductionmentioning

confidence: 99%

Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab

Gupta

Gonzalez‐Rojas²,

Juárez³

et al. 2021

Preprint

221

300

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Background: Coronavirus disease 2019 (Covid-19) disproportionately results in hospitalization and death in older patients and those with underlying comorbidities. Sotrovimab is a pan-sarbecovirus monoclonal antibody designed to treat such high-risk patients early in the course of disease, thereby preventing Covid-19 progression. Methods: In this ongoing, multicenter, double-blind, phase 3 trial, nonhospitalized patients with symptomatic Covid-19 and at least one risk factor for disease progression were randomized (1:1) to an intravenous infusion of sotrovimab 500 mg or placebo. The primary efficacy endpoint was the proportion of patients with Covid-19 progression, defined as hospitalization longer than 24 hours or death, through day 29. Results: In this preplanned interim analysis, which included an intent-to-treat population of 583 patients (sotrovimab, 291; placebo, 292), the primary efficacy endpoint was met. The risk of Covid-19 progression was significantly reduced by 85% (97.24% confidence interval, 44% to 96%; P = 0.002) with a total of three (1%) patients progressing to the primary endpoint in the sotrovimab group versus 21 (7%) patients in the placebo group. All five patients admitted to intensive care, including one who died by day 29, received placebo. Safety was assessed in 868 patients (sotrovimab, 430; placebo, 438). Adverse events were reported by 17% and 19% of patients receiving sotrovimab and placebo, respectively; serious adverse events were less common with sotrovimab (2%) versus placebo (6%). Conclusion: Sotrovimab reduced progression of Covid-19 in patients with mild/moderate disease, was well tolerated, and no safety signals were identified. Funded by Vir Biotechnology, Inc. and GlaxoSmithKline; ClinicalTrials.gov NCT04545060

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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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Neutralising antibody escape of SARS‐CoV‐2 spike protein: Risk assessment for antibody‐based Covid‐19 therapeutics and vaccines

Cited by 156 publications

References 248 publications

Controlling long-term SARS-CoV-2 infections is important for slowing viral evolution

Controlling long-term SARS-CoV-2 infections is important for slowing viral evolution

Early Covid-19 Treatment With SARS-CoV-2 Neutralizing Antibody Sotrovimab

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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