Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455–456 synergistically enhances antibody evasion and ACE2 binding

PLoS Pathogens, Год журнала: 2023, Номер 19(12), С. e1011868 - e1011868

Опубликована: Дек. 20, 2023

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of the receptor-binding domain (RBD) L455F F456L is observed, resulting in variants with substantial growth advantages, such as EG.5, FL.1.5.1, XBB.1.5.70, HK.3. Here, we show that neutralizing antibody (NAb) evasion drives convergent F456L, while epistatic shift caused by enables subsequent convergence through ACE2 binding enhancement further immune evasion. evade RBD-targeting Class 1 public NAbs, reducing neutralization efficacy breakthrough infection (BTI) reinfection convalescent plasma. Importantly, single substitution significantly dampens receptor binding; however, combination forms an adjacent residue flipping, which leads to enhanced NAbs resistance affinity. The perturbed mode exceptional NAb evasion, revealed structural analyses. Our results indicate flexibility contributed epistasis cannot be underestimated, potential SARS-CoV-2 RBD remains high.

Язык: Английский

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Strategies for the development and approval of COVID-19 vaccines and therapeutics in the post-pandemic period

Signal Transduction and Targeted Therapy, Год журнала: 2023, Номер 8(1)

Опубликована: Дек. 21, 2023

The spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has resulted in significant casualties and put immense strain on public health systems worldwide, leading to economic recession social unrest. In response, various prevention control strategies have been implemented globally, including vaccine drug development the promotion preventive measures. Implementing these effectively curbed transmission virus, reduced infection rates, gradually restored normal activities. However, mutations SARS-CoV-2 led inevitable infections reinfections, number deaths continues rise. Therefore, there is still a need improve existing strategies, mainly focusing developing novel vaccines drugs, expediting medical authorization processes, keeping epidemic surveillance. These measures are crucial combat Coronavirus disease (COVID-19) pandemic achieve sustained, long-term prevention, management, control. Here, we summarized characteristics COVID-19 drugs suggested potential future directions for their development. Furthermore, discussed COVID-19-related policies over past years presented some future.

Язык: Английский

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Convergent evolution of SARS-CoV-2 XBB lineages on receptor-binding domain 455-456 synergistically enhances antibody evasion and ACE2 binding

bioRxiv (Cold Spring Harbor Laboratory), Год журнала: 2023, Номер unknown

Опубликована: Авг. 31, 2023

Summary Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) XBB lineages have achieved dominance worldwide and keep on evolving. Convergent evolution of the receptor-binding domain (RBD) L455F F456L is observed, resulting in variants like EG.5, FL.1.5.1, XBB.1.5.70, HK.3. Here, we show that neutralizing antibody (NAb) evasion drives convergent F456L, while epistatic shift caused by enables subsequent convergence through ACE2 binding enhancement further immune evasion. evade Class 1 NAbs, reducing neutralization efficacy breakthrough infection (BTI) reinfection convalescent plasma. Importantly, single substitution significantly dampens receptor binding; however, combination forms an adjacent residue flipping, which leads to enhanced NAbs resistance affinity. The perturbed mode exceptional NAb evasion, as revealed structural analyses. Our results indicate flexibility contributed epistasis cannot be underestimated, potential SARS-CoV-2 RBD remains high.

Язык: Английский

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A monoclonal antibody targeting a large surface of the receptor binding motif shows pan-neutralizing SARS-CoV-2 activity

Nature Communications, Год журнала: 2024, Номер 15(1)

Опубликована: Фев. 5, 2024

Abstract Here we report the characterization of 17T2, a SARS-CoV-2 pan-neutralizing human monoclonal antibody isolated from COVID-19 convalescent individual infected during first pandemic wave. 17T2 is class 1 VH1-58/κ3-20 antibody, derived receptor binding domain (RBD)-specific IgA + memory B cell, with broad neutralizing activity against former and new variants, including XBB.1.16 BA.2.86 Omicron subvariants. Consistently, demonstrates in vivo prophylactic therapeutic BA.1.1 infection K18-hACE2 mice. Cryo-electron microscopy reconstruction shows that binds BA.1 spike RBD “up” position blocks motif, as other structurally similar antibodies do, S2E12. Yet, unlike S2E12, retains its all variants tested, probably due to larger contact area. These results highlight impact small structural changes on performance identify potential candidate for future clinical interventions.

Язык: Английский

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A potent pan-sarbecovirus neutralizing antibody resilient to epitope diversification

Cell, Год журнала: 2024, Номер unknown

Опубликована: Окт. 1, 2024

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) evolution has resulted in viral escape from clinically authorized monoclonal antibodies (mAbs), creating a need for mAbs that are resilient to epitope diversification. Broadly neutralizing sufficiently potent clinical development and retain activity despite remain elusive. We identified human mAb, designated VIR-7229, which targets the receptor-binding motif (RBM) with unprecedented cross-reactivity all sarbecovirus clades, including non-ACE2-utilizing bat sarbecoviruses, while potently SARS-CoV-2 variants since 2019, recent EG.5, BA.2.86, JN.1. VIR-7229 tolerates extraordinary variability, partly attributed its high binding affinity, receptor molecular mimicry, interactions RBM backbone atoms. Consequently, features barrier selection of mutants, rare associated reduced fitness, underscoring potential be future evolution. is strong candidate become next-generation medicine.

Язык: Английский

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Breakthrough infection elicits hypermutated IGHV3-53/3-66 public antibodies with broad and potent neutralizing activity against SARS-CoV-2 variants including the emerging EG.5 lineages

PLoS Pathogens, Год журнала: 2023, Номер 19(12), С. e1011856 - e1011856

Опубликована: Дек. 4, 2023

The rapid emergence of SARS-CoV-2 variants concern (VOCs) calls for efforts to study broadly neutralizing antibodies elicited by infection or vaccination so as inform the development vaccines and antibody therapeutics with broad protection. Here, we identified two convalescents breakthrough relatively high titers against all tested viruses. Among 50 spike-specific monoclonal (mAbs) cloned from their B cells, top 6 mAbs (KXD01-06) belong previously defined IGHV3-53/3-66 public antibodies. Although most in this class are dramatically escaped VOCs, KXD01-06 exhibit capacity, particularly KXD01-03, which neutralize prototype emerging EG.5.1 FL.1.5.1. Deep mutational scanning reveals that can be current prospective mutations on D420, Y421, L455, F456, N460, A475 N487. Genetic functional analysis further indicates extent somatic hypermutation is critical breadth other Overall, prevalence these provides rationale novel based Meanwhile, developed candidates through affinity maturation.

Язык: Английский

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A Pseudovirus-Based Neutralization Assay for SARS-CoV-2 Variants: A Rapid, Cost-Effective, BSL-2–Based High-Throughput Assay Useful for Vaccine Immunogenicity Evaluation

Microorganisms, Год журнала: 2024, Номер 12(3), С. 501 - 501

Опубликована: Фев. 29, 2024

Neutralizing antibody responses from COVID-19 vaccines are pivotal in conferring protection against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Effective and assays measuring neutralizing antibodies emerging variants (i.e., XBB.1.5, XBB.1.16, XBB.2.3) needed. The use of biosafety level (BSL)-3 laboratories for live virus results higher costs a longer turnaround time; therefore, BSL-2–based pseudovirus neutralization assay (PNT) was developed. pseudoviruses were produced by cotransfecting cells with plasmids encoding lentiviral backbone-expressing luciferase reporter; non-surface proteins production; ancestral or Omicron (BA.1 BA.5) SARS-CoV-2 spike (S) proteins. PNT developed optimized dose kinetics experiments. representative serum samples (COVID-19–convalescent NVX-CoV2373–vaccinated participants enrolled the 2019nCoV-101 trial) demonstrated wide dynamic range. data showed robust correlation validated anti-recombinant IgG levels angiotensin-converting enzyme inhibition titers (ancestral). This is suitable measurement ability clinical individuals infected immunized vaccine. suggest that this provides lower cost, high-throughput, rapid alternative to BSL-3–based microneutralization enables discovery development effective variants.

Язык: Английский

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A novel strategy for an anti-idiotype vaccine: nanobody mimicking neutralization epitope of porcine circovirus type 2

Journal of Virology, Год журнала: 2024, Номер 98(2)

Опубликована: Янв. 25, 2024

Anti-idiotype vaccines utilize idiotype-anti-idiotype network theory, eliminating the need for external antigens as vaccine candidates. Especially dangerous pathogens, they were safer because did not contact live pathogenic microorganisms. However, developing anti-idiotype with traditional monoclonal and polyclonal antibodies is complex has a high failure rate. We present novel, universal, simple, low-cost strategy producing nanobody technology. Using neutralization antibody against PCV2-Cap, (Ab2) was successfully produced could mimic neutralizing epitope of PCV2-Cap. The can induce protective immune responses PCV2 infection in mice pigs. It highlighted that using very good application future, especially pathogens.

Язык: Английский

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Safety and tolerability of intramuscular sotrovimab administered at different injection sites: results from the Phase 1 COSMIC study

mAbs, Год журнала: 2025, Номер 17(1)

Опубликована: Янв. 29, 2025

ClinicalTrials.gov identifier, NCT05280717.

Язык: Английский

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Replication Features of SARS-CoV-2 and Advantages of Targeting S Protein with Aptamers to Block Viral Entry

ACS Omega, Год журнала: 2025, Номер unknown

Опубликована: Апрель 21, 2025

Язык: Английский

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