Efficacy and Safety of Ensitrelvir in Patients With Mild-to-Moderate Coronavirus Disease 2019: The Phase 2b Part of a Randomized, Placebo-Controlled, Phase 2/3 Study

Clinical Infectious Diseases, Год журнала: 2022, Номер 76(8), С. 1403 - 1411

Опубликована: Дек. 7, 2022

This phase 2b part of a randomized 2/3 study assessed the efficacy and safety ensitrelvir for mild-to-moderate coronavirus disease 2019 (COVID-19) during Omicron epidemic.Patients were (1:1:1) to orally receive fumaric acid 125 mg (375 on day 1) or 250 (750 placebo once daily 5 days. The co-primary endpoints change from baseline in severe acute respiratory syndrome 2 (SARS-CoV-2) titer 4 time-weighted average up 120 hours total score predefined 12 COVID-19 symptoms. Safety was through adverse events.A 341 patients (ensitrelvir 125-mg group: 114; 250-mg 116; 111; male: 53.5-64.9%; mean age: 35.3-37.3 years) included analyses. SARS-CoV-2 significantly greater with both doses than (differences placebo: -0.41 log10 50% tissue-culture infectious dose/mL; P < .0001 both). symptoms did not show significant difference between groups group. versus several subtotal scores, including Most events mild severity.Ensitrelvir treatment demonstrated favorable antiviral potential clinical benefit an acceptable profile.Japan Registry Clinical Trials: jRCT2031210350 (https://jrct.niph.go.jp/en-latest-detail/jRCT2031210350).

Язык: Английский

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Omicron SARS-CoV-2 mutations stabilize spike up-RBD conformation and lead to a non-RBM-binding monoclonal antibody escape

Nature Communications, Год журнала: 2022, Номер 13(1)

Опубликована: Авг. 24, 2022

Omicron SARS-CoV-2 is rapidly spreading worldwide. To delineate the impact of emerging mutations on spike's properties, we performed systematic structural analyses apo spike and its complexes with human ACE2 or S309 neutralizing antibody (NAb) by cryo-EM. The preferentially adopts one-RBD-up conformation both before after binding, which in sharp contrast to orchestrated conformational changes create more up-RBDs upon binding as observed prototype other four variants concern (VOCs). Furthermore, found that S371L, S373P S375F substitutions enhance stability prevent exposing triggered binding. increased restricts accessibility S304 NAb, targets a cryptic epitope closed conformation, thus facilitating immune evasion Omicron. These results expand our understanding receptor mechanism.

Язык: Английский

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SARS‐CoV‐2 Omicron variant: Immune escape and vaccine development

MedComm, Год журнала: 2022, Номер 3(1)

Опубликована: Март 1, 2022

Abstract New genetic variants of severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) constantly emerge through unmitigated spread the virus in ongoing Coronavirus disease 2019 pandemic. Omicron (B.1.1.529), latest variant concern (VOC), has so far shown exceptional and infectivity established itself as dominant recent months. The SARS‐CoV‐2 spike glycoprotein is a key component for recognition binding to host cell angiotensin‐converting enzyme receptors. harbors cluster substitutions/deletions/insertions, more than 30 mutations are located spike. Some noticeable mutations, including K417N, T478K, N501Y, P681H, shared with previous VOCs Alpha, Beta, Gamma, or Delta have been proven be associated higher transmissibility, viral infectivity, immune evasion potential. Studies revealed that partially resistant neutralizing activity therapeutic antibodies convalescent sera, which poses significant challenges clinical effectiveness current vaccines antibodies. We provide comprehensive analysis summary epidemiology escape mechanisms variant. also suggest some strategies against This review, therefore, aims information further research efforts prevent contain impact new during

Язык: Английский

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Effectiveness of inactivated and Ad5-nCoV COVID-19 vaccines against SARS-CoV-2 Omicron BA. 2 variant infection, severe illness, and death

BMC Medicine, Год журнала: 2022, Номер 20(1)

Опубликована: Окт. 20, 2022

Abstract Background Limited data are available on the effectiveness of inactivated and Ad5-nCoV COVID-19 vaccines in real-world use—especially against Omicron variants SARS-CoV-2 infection-naïve population. Methods A matched case-control study was conducted among people aged ≥ 3 years between 2 December 2021 13 May 2022. Cases were SARS-CoV-2-infected individuals, individuals with severe/critical COVID-19, or COVID-19-related deaths. Controls selected from consecutively test-negative at same time as cases diagnosed exact-matched year-of-age, gender, birthplace, illness onset date, residential district ratios 1:1 infected 4:1 death. Additionally, two subsets constructed to analyze separate vaccine (VE) (subset 1) Ad5-vectored 2) each three outcomes. Results Our included 612,597 documented infections, which 1485 progressed severe critical 568 died. Administering provided limited protection infection across all age groups (overall VE: 16.0%, 95% CI: 15.1–17.0%) but high (88.6%, 85.8–90.8%) death (91.6%, 86.8–94.6%). In subset 1, showed 16.3% (15.4–17.2%) effective infection, 88.6% (85.8–90.9%) COVIID-19, 91.7% (86.9–94.7%) Booster vaccination enhanced (92.7%, 90.1–94.6%) (95.9%, 91.4–98.1%). Inactivated VE began wane 12 weeks after last dose, doses sustained levels (> 80%) death, while 13.2% (10.9–15.5%) 77.9% (15.6–94.2%) COVIID-19. Conclusions found durable two- three-dose Omicron-associated groups, lower reinforces importance full-series timely booster dose administration for eligible individuals.

Язык: Английский

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The landscape of antibody binding affinity in SARS-CoV-2 Omicron BA.1 evolution

eLife, Год журнала: 2023, Номер 12

Опубликована: Фев. 13, 2023

The Omicron BA.1 variant of SARS-CoV-2 escapes convalescent sera and monoclonal antibodies that are effective against earlier strains the virus. This immune evasion is largely a consequence mutations in receptor binding domain (RBD), major antigenic target SARS-CoV-2. Previous studies have identified several key RBD leading to escape from most antibodies. However, little known about how these interact with each other RBD. Here, we systematically map interactions by measuring affinity all possible combinations 15 (2 =32,768 genotypes) 4 (LY-CoV016, LY-CoV555, REGN10987, S309) distinct epitopes. We find can lose diverse acquiring few large-effect reduce others through small-effect mutations. our results also reveal alternative pathways antibody does not include every mutation. Moreover, epistatic shown constrain decline S309 but only modestly shape landscapes Together previous work on ACE2 landscape, suggest mediated groups mutations, whose deleterious effects compensated another group (most notably Q498R N501Y).

Язык: Английский

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A phase 2/3 study of S-217622 in participants with SARS-CoV-2 infection (Phase 3 part)

Medicine, Год журнала: 2023, Номер 102(8), С. e33024 - e33024

Опубликована: Фев. 22, 2023

Limited treatment options exist for patients with mild-to-moderate coronavirus disease 2019 (COVID-19), irrespective of vaccination history or risk status. Ensitrelvir is a novel oral severe acute respiratory syndrome 2 (SARS-CoV-2) 3C-like (3CL) protease inhibitor. While phase studies ensitrelvir have demonstrated promising results in treating COVID-19, evaluation its clinical efficacy due to shifting status and emergence the Omicron variant represents significant challenges. Here, we describe protocol 3 study designed evaluate safety regardless history.This multicenter, randomized, double-blind, placebo-controlled, study. Patients COVID-19 within 120 hours from onset will be randomized 1:1:1 ratio into arms-ensitrelvir 125 mg (375 loading dose on Day 1), 250 (750 placebo. The interventions administered orally, once-daily, 5 days. primary endpoint time resolution symptoms (stuffy runny nose, sore throat, cough, feeling hot feverish, low energy tiredness), key secondary endpoints include change baseline 4 amount SARS-CoV-2 viral ribonucleic acid (RNA) first negative titer. population <72 randomization and, subsequently, entire patient (<120 hours) group. Closed testing procedure used both populations. All assessments adverse events (AE) reported.In post hoc analysis 2b study, compared placebo, reduced COVID-19. Through this intend validate establish

Язык: Английский

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Challenges in the Vaccination of the Elderly and Strategies for Improvement

Pathophysiology, Год журнала: 2023, Номер 30(2), С. 155 - 173

Опубликована: Апрель 22, 2023

In recent years, the elderly has become a rapidly growing proportion of world's population as life expectancy is extending. Immunosenescence and inflammaging contribute to increased risk chronic non-communicable acute infectious diseases. Frailty highly prevalent in associated with an impaired immune response, higher propensity infection, lower response vaccines. Additionally, presence uncontrolled comorbid diseases also contributes sarcopenia frailty. Vaccine-preventable that threaten include influenza, pneumococcal herpes zoster, COVID-19, which significant disability-adjusted years lost. Previous studies had shown conventional vaccines only yielded suboptimal protection wanes shorter time. This article reviews published papers on several vaccination strategies were developed for solve these problems: more immunogenic vaccine formulations using larger doses antigen, stronger adjuvants, recombinant subunit or protein conjugated vaccines, newly mRNA giving booster shots, exploring alternative routes administration. Included are publications senolytic medications under investigation boost system elderly. With all those regard, currently recommended presented.

Язык: Английский

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Mathematical Modeling of COVID-19 Dynamics under Two Vaccination Doses and Delay Effects

Mathematics, Год журнала: 2023, Номер 11(2), С. 369 - 369

Опубликована: Янв. 10, 2023

The aim of this paper is to investigate the qualitative behavior COVID-19 pandemic under an initial vaccination program. We constructed a mathematical model based on nonlinear system delayed differential equations. time delay represents that vaccine takes provide immune protection against SARS-CoV-2. impact transmission rates, vaccination, and dynamics system. was developed for beginning implementation programs control pandemic. perform stability analysis at equilibrium points show, using methods systems, undergoes Hopf bifurcation. theoretical results reveal some conditions related values parameters basic reproduction number, approaches disease-free point, but if number larger than one, endemic SARS-CoV-2 cannot be eradicated. Numerical examples corroborate methodology. Finally, conclusions discussions about are presented.

Язык: Английский

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Mutational dynamics of SARS-CoV-2: Impact on future COVID-19 vaccine strategies

Heliyon, Год журнала: 2024, Номер 10(9), С. e30208 - e30208

Опубликована: Апрель 25, 2024

The rapid emergence of multiple strains Severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2) has sparked profound concerns regarding the ongoing evolution virus and its potential impact on global health. Classified by World Health Organization (WHO) as variants concern (VOC), these exhibit heightened transmissibility pathogenicity, posing significant challenges to existing vaccine strategies. Despite widespread vaccination efforts, continual SARS-CoV-2 presents a formidable obstacle achieving herd immunity. Of particular is coronavirus spike (S) protein, pivotal viral surface protein crucial for host cell entry infectivity. Mutations within S have been shown enhance confer resistance antibody-mediated neutralization, undermining efficacy traditional platforms. Moreover, undergoes molecular under selective immune pressure, leading diverse with distinct mutation profiles. This review underscores urgent need vigilance adaptation in development efforts combat evolving landscape mutations ensure long-term effectiveness immunization campaigns.

Язык: Английский

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Significance of Conserved Regions in Coronavirus Spike Protein for Developing a Novel Vaccine against SARS-CoV-2 Infection

Vaccines, Год журнала: 2023, Номер 11(3), С. 545 - 545

Опубликована: Фев. 24, 2023

Over the years, several distinct pathogenic coronaviruses have emerged, including pandemic SARS-CoV-2, which is difficult to curtail despite availability of licensed vaccines. The difficulty in managing SARS-CoV-2 linked changes variants’ proteins, especially spike protein (SP) used for viral entry. These mutations, SP, enable virus evade immune responses induced by natural infection or vaccination. However, some parts SP S1 subunit and S2 are considered conserved among coronaviruses. In this review, we will discuss epitopes proteins that been demonstrated various studies be may immunogenic development a vaccine. Considering higher conservancy S2, further likely challenges could limit from inducing robust promising approaches increase its immunogenicity.

Язык: Английский

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