Convergent Evolution in SARS-CoV-2 Spike Creates a Variant Soup from Which New COVID-19 Waves Emerge

International Journal of Molecular Sciences, Journal Year: 2023, Volume and Issue: 24(3), P. 2264 - 2264

Published: Jan. 23, 2023

The first 2 years of the COVID-19 pandemic were mainly characterized by recurrent mutations SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 emerging independently across different variants concern (Alpha, Beta, Gamma, Delta). Such homoplasy is a marker convergent evolution. Since Spring 2022 third year pandemic, with advent Omicron its sublineages, evolution has led to observation lineages acquiring an additional group amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, S494. Mutations these have become increasingly prevalent during Summer Autumn 2022, combinations showing increased fitness. most likely reason for this convergence selective pressure exerted previous infection- or vaccine-elicited immunity. accelerated caused failure all anti-Spike monoclonal antibodies, including bebtelovimab cilgavimab. While we are learning how fast coronaviruses can mutate recombine, should reconsider opportunities economically sustainable escape-proof combination therapies, refocus antibody-mediated therapeutic efforts on polyclonal preparations that less allow viral immune escape.

Language: Английский

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Recombination in Coronaviruses, with a Focus on SARS-CoV-2

Viruses, Journal Year: 2022, Volume and Issue: 14(6), P. 1239 - 1239

Published: June 7, 2022

Recombination is a common evolutionary tool for RNA viruses, and coronaviruses are no exception. We review here the evidence recombination in SARS-CoV-2 reconcile nomenclature recombinants, discuss their origin fitness, speculate how recombinants could make difference future of COVID-19 pandemics.

Language: Английский

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COVID-19 Convalescent Plasma and Clinical Trials: Understanding Conflicting Outcomes

Clinical Microbiology Reviews, Journal Year: 2022, Volume and Issue: 35(3)

Published: March 9, 2022

Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available soon there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light on mechanisms of action, safety, and efficacy CP using modern evidence-based medicine approaches. Studies ranging from observational case series randomized controlled trials (RCTs) have reported highly variable results for (CCP), resulting uncertainty. We analyzed variables associated with efficacy, such clinical settings, disease severity, CCP SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) antibody levels function, dose, timing administration (variously defined time onset symptoms, molecular diagnosis, diagnosis pneumonia, or hospitalization, by serostatus), outcomes (defined requirement ventilation, improvement, mortality), provenance collection, criteria efficacy. conflicting trial results, along both recent WHO guidelines discouraging usage expansion FDA emergency use authorization (EUA) include outpatient CCP, create confusion clinicians patients about appropriate CCP. A review 30 RCTs demonstrated that signals (including reductions mortality) were more likely if neutralizing titer was >160 randomization less than 9 days. emergence Omicron variant also reminds us benefits polyclonal therapies, especially bridge development availability specific therapies.

Language: Английский

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Mucosal Vaccines, Sterilizing Immunity, and the Future of SARS-CoV-2 Virulence

Viruses, Journal Year: 2022, Volume and Issue: 14(2), P. 187 - 187

Published: Jan. 19, 2022

Sterilizing immunity after vaccination is desirable to prevent the spread of infection from vaccinees, which can be especially dangerous in hospital settings while managing frail patients. requires neutralizing antibodies at site infection, for respiratory viruses such as SARS-CoV-2 implies occurrence IgA mucosal secretions. Systemic by intramuscular delivery induces no or low-titer against vaccine antigens. Mucosal priming boosting, needed provide sterilizing immunity. On other side coin, immunity, zeroing interhuman transmission, could confine animal reservoirs, preventing spontaneous attenuation virulence humans presumably happened with endemic coronaviruses. We review here pros and cons each strategy, current vaccines under development, their implications public health.

Language: Английский

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Prescription of Anti-Spike Monoclonal Antibodies in COVID-19 Patients with Resistant SARS-CoV-2 Variants in Italy

Pathogens, Journal Year: 2022, Volume and Issue: 11(8), P. 823 - 823

Published: July 22, 2022

Anti-Spike monoclonal antibodies have been considered a promising approach to COVID-19 therapy. Unfortunately, the advent of resistant lineages jeopardized their effectiveness and prompted limitations in clinical use. Change dominant variant can be fast such an extent that, absence timely medical education, prescribers keep using these drugs for relatively long periods even patients with variants. Therefore, many could exposed unlikely benefits probable risks. We show here that about 20% bamlanivimab+etesevimab, 30% casirivimab+imdevimab, sotrovimab courses were administered Italy during which fully was dominant. Additionally, antibody cocktails, vast majority usage occurred against variants one mAbs within cocktail ineffective. Given high costs potential side effects, it would important consider frequent review appropriateness communication when benefit/risk balance is no longer favorable.

Language: Английский

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A Web Tool to Estimate Baseline Anti-Spike Monoclonal Antibody Efficacy Based on Regional Genomic Surveillance

Viruses, Journal Year: 2023, Volume and Issue: 15(5), P. 1048 - 1048

Published: April 25, 2023

Drug appropriateness is a pillar of modern evidence-based medicine, but the turnaround times genomic sequencing are not compatible with urgent need to deliver treatments against microorganisms. Massive worldwide surveillance has created an unprecedented landscape for exploiting viral therapeutic purposes. When it comes antiviral antibodies, using IC

Language: Английский

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Potent universal-coronavirus therapeutic activity mediated by direct respiratory administration of a Spike S2 domain-specific human neutralizing monoclonal antibody

bioRxiv (Cold Spring Harbor Laboratory), Journal Year: 2022, Volume and Issue: unknown

Published: March 7, 2022

Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) marks the third novel β-coronavirus to cause significant human mortality in last two decades. Although vaccines are available, too few have been administered worldwide keep virus check and prevent mutations leading immune escape. To determine if antibodies could be identified with universal coronavirus activity, plasma from convalescent subjects was screened for IgG against a stabilized pre-fusion SARS-CoV-2 spike S2 domain, which is highly conserved between β-coronavirus. From these subjects, several S2-specific monoclonal (hmAbs) were developed that neutralized recognition of all variants concern (VoC) tested (Beta, Gamma, Delta, Epsilon, Omicron). The hmAb 1249A8 emerged as most potent broad hmAb, able recognize neutralize SARS-CoV MERS-CoV. demonstrated prophylactic activity K18 hACE2 mice infected lineage A B Beta, Omicron VoC. delivered single 4 mg/kg intranasal (i.n.) dose hamsters 12 hours following infection Delta protected them weight loss, therapeutic further enhanced when combined 1213H7, an S1-specific neutralizing hmAb. As little 2 i.n. Urbani strain, loss significantly reduced upper lower respiratory viral burden. These results indicate vivo cooperativity S1 specific hmAbs mAbs potential can induced humans guide vaccine development.

Language: Английский

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Monoclonal Antibodies as Potential COVID-19 Therapeutic Agents

COVID, Journal Year: 2022, Volume and Issue: 2(5), P. 599 - 620

Published: May 12, 2022

The COVID-19 pandemic continues to cause tremendous loss of life and put massive strain on the functioning societies worldwide. Despite cataclysmic proportions this viral outbreak, as yet, no effective curative treatment is available. vaccines, while a scientific achievement historical proportions, can only be utilized in prophylaxis require vaccination majority given population. Convalescent plasma therapies blood group testing patient hospitalization are difficult into place scale Monoclonal antibodies mass produced with hybridoma cell culture highly specific antigens. What more, monoclonal produce far more reproducible effects than other approaches active immunization further enhanced through engineering. Currently, there exist two use antibodies, each several currently under development or clinical testing. first utilizes which target spike proteins block entry host mark particles for destruction by immune cells. second approach that neutralize cytokines, take part cytokine release syndrome, responsible many most damaging symptoms associated COVID-19, thus reducing systemic inflammation ultimately—patient morbidity mortality. There yet remain challenges overcome if become mainstream therapeutic agents COVID-19. this, field research experiencing forward leap exceptional amount data gathered so serve groundwork widely available antiviral antibody treatments.

Language: Английский

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Analysis of the Neutralizing Activity of Antibodies Targeting Open or Closed SARS-CoV-2 Spike Protein Conformations

International Journal of Molecular Sciences, Journal Year: 2022, Volume and Issue: 23(4), P. 2078 - 2078

Published: Feb. 14, 2022

SARS-CoV-2 infection elicits a polyclonal neutralizing antibody (nAb) response that primarily targets the spike protein, but it is still unclear which nAbs are immunodominant and what distinguishes them from subdominant nAbs. This information would however be crucial to predict evolutionary trajectory of virus design future vaccines. To shed light on this issue, we gathered 83 structures in complex with protein domains. We analyzed silico ability these bind full trimer open closed conformations, predicted change binding affinity most frequently observed variants circulating strains. led us define four nAb classes distinct variant escape fractions. By comparing fractions those measured plasma infected patients, showed class contributes immune able its conformation. Although only partially inhibits host’s angiotensin converting enzyme 2 (ACE2), has been suggested lock pre-fusion conformation therefore prevent transition an state. Furthermore, comparison our predictions mRNA-1273 vaccinated patient measurements suggests proteins contained vaccines elicit different than one elicited by natural highly stable closed-form as next-generation vaccine immunogens.

Language: Английский

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COVID-19 convalescent plasma and randomized clinical trials: explaining conflicting outcomes and finding signals of efficacy

medRxiv (Cold Spring Harbor Laboratory), Journal Year: 2021, Volume and Issue: unknown

Published: Sept. 15, 2021

Abstract Convalescent plasma (CP) recurs as a frontline treatment in epidemics because it is available soon there are survivors. The COVID-19 pandemic represented the first large-scale opportunity to shed light into mechanisms of action, safety and efficacy CP using modern evidence-based medicine approaches. Studies ranging from observational case series randomized controlled trials (RCT) have reported highly variable results for (CCP), resulting uncertainty. Reasons CCP success failure may be hidden study details, which usually difficult explain physicians public but provide fertile ground designing next-generation studies. We analyzed variables associated with such clinical settings, disease severity, SARS-CoV-2 antibody levels function, dose, timing administration (variously defined time onset symptoms, molecular diagnosis, diagnosis pneumonia, or hospitalization, by serostatus), outcomes (defined requirement ventilation, improvement mortality), provenance collection, criteria efficacy. Focusing only on 30 RCTs we noted that these were more likely show signals efficacy, including reductions mortality, if neutralizing titer was ≥ 160 randomization ≤ 9 days, consistent passive therapy requiring dosing sufficient antibody. fact most studies revealed despite variability its use suggest therapeutic effects become apparent data noise. Despite recent WHO guidelines discouraging usage, Omicron variant concern reminding us superiority polyclonal therapies over monoclonal antibodies, vaccinated convalescents evaluated

Language: Английский

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