Cryo-EM structures and binding of mouse and human ACE2 to SARS-CoV-2 variants of concern indicate that mutations enabling immune escape could expand host range

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(4), P. e1011206 - e1011206

Published: April 5, 2023

Investigation of potential hosts the severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) is crucial to understanding future risks spillover and spillback. SARS-CoV-2 has been reported be transmitted from humans various animals after requiring relatively few mutations. There significant interest in describing how virus interacts with mice as they are well adapted human environments, used widely infection models can infected. Structural binding data mouse ACE2 receptor Spike protein newly identified variants needed better understand impact immune system evading mutations present concern (VOC). Previous studies have developed mouse-adapted residues critical for heterologous receptors. Here we report cryo-EM structures bound trimeric ectodomains four different VOC: Beta, Omicron BA.1, BA.2.12.1 BA.4/5. These represent oldest newest known bind receptor. Our high-resolution structural complemented bio-layer interferometry (BLI) assays reveal a requirement combination that enable

Language: Английский

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A research and development (R&D) roadmap for broadly protective coronavirus vaccines: A pandemic preparedness strategy

Vaccine, Journal Year: 2023, Volume and Issue: 41(13), P. 2101 - 2112

Published: Feb. 21, 2023

Broadly protective coronavirus vaccines are an important tool for protecting against future SARS-CoV-2 variants and could play a critical role in mitigating the impact of outbreaks or pandemics caused by novel coronaviruses. The Coronavirus Vaccines Research Development (R&D) Roadmap (CVR) is aimed at promoting development such vaccines. CVR, funded Bill & Melinda Gates Foundation Rockefeller Foundation, was generated through collaborative iterative process, which led Center Infectious Disease Policy (CIDRAP) University Minnesota involved 50 international subject matter experts recognized leaders field. This report summarizes major issues areas research outlined CVR identifies high-priority milestones. covers 6-year timeframe organized into five topic areas: virology, immunology, vaccinology, animal human infection models, policy finance. Included each area key barriers, gaps, strategic goals, milestones, additional R&D priorities. roadmap includes 20 goals 86 26 ranked as high priority. By identifying issues, milestones addressing them, provides framework to guide funding campaigns that promote broadly

Language: Английский

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The interactions of SARS-CoV-2 with cocirculating pathogens: Epidemiological implications and current knowledge gaps

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(3), P. e1011167 - e1011167

Published: March 8, 2023

Despite the availability of effective vaccines, persistence severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) suggests that cocirculation with other pathogens and resulting multiepidemics (of, for example, COVID-19 influenza) may become increasingly frequent. To better forecast control risk such multiepidemics, it is essential to elucidate potential interactions SARS-CoV-2 pathogens; these interactions, however, remain poorly defined. Here, we aimed review current body evidence about interactions. Our structured in four parts. study pathogen a systematic comprehensive way, first developed general framework capture their major components: sign (either negative antagonistic or positive synergistic interactions), strength (i.e., magnitude interaction), symmetry (describing whether interaction depends on order infection interacting pathogens), duration short-lived long-lived), mechanism (e.g., modifies susceptibility infection, transmissibility severity disease). Second, reviewed experimental from animal models Of 14 studies identified, 11 focused outcomes coinfection nonattenuated influenza A viruses (IAVs), 3 pathogens. The IAV used different designs (ferrets, hamsters, mice) but generally demonstrated increased disease compared either monoinfection. By contrast, effect viral load virus was variable inconsistent across studies. Third, epidemiological human populations. Although numerous were only few specifically designed infer interaction, many prone multiple biases, including confounding. Nevertheless, results suggested pneumococcal conjugate vaccinations associated reduced infection. Finally, fourth, formulated simple transmission an epidemic endemic bacterial pathogen, showing how they can naturally incorporate proposed framework. More generally, argue models, when integrative multidisciplinary perspective, will be invaluable tools resolve substantial uncertainties

Language: Английский

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Immune Responses to SARS-CoV-2 in Pregnancy: Implications for the Health of the Next Generation

The Journal of Immunology, Journal Year: 2022, Volume and Issue: 209(8), P. 1465 - 1473

Published: Oct. 15, 2022

Abstract Widespread SARS-CoV-2 infection among pregnant individuals has led to a generation of fetuses exposed in utero, but the long-term impact such exposure remains unknown. Although fetal is rare, children born mothers with may be at increased risk for adverse neurodevelopmental and cardiometabolic outcomes. Fetal programming effects are likely mediated least part by maternal immune activation. In this review, we discuss recent evidence regarding prenatal on maternal, placental, response, as well implications health offspring. Extrapolating from what known about activation other contexts (e.g., obesity, HIV, influenza), review potential morbidity Based available data suggesting risk, highlight importance establishing large cohorts monitor offspring SARS-CoV-2–positive sequelae.

Language: Английский

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Mouse-Adapted SARS-CoV-2 MA10 Strain Displays Differential Pulmonary Tropism and Accelerated Viral Replication, Neurodissemination, and Pulmonary Host Responses in K18-hACE2 Mice

mSphere, Journal Year: 2023, Volume and Issue: 8(1)

Published: Feb. 2, 2023

The COVID-19 pandemic, caused by SARS-CoV-2, is still significantly impacting health care systems around the globe. Refined animal models are needed to study SARS-CoV-2 pathogenicity as well efficacy of vaccines and therapeutics.

Language: Английский

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Preclinical characterization of the Omicron XBB.1.5-adapted BNT162b2 COVID-19 vaccine

npj Vaccines, Journal Year: 2024, Volume and Issue: 9(1)

Published: Nov. 20, 2024

Abstract As SARS-CoV-2 evolves, increasing in potential for greater transmissibility and immune escape, updated vaccines are needed to boost adaptive immunity protect against COVID-19 caused by circulating strains. Here, we report features of the monovalent Omicron XBB.1.5-adapted BNT162b2 vaccine, which contains XBB.1.5-specific sequence changes, relative original backbone, encoded prefusion-stabilized spike protein (S(P2)). Biophysical characterization XBB.1.5 S(P2) demonstrated that it maintains a prefusion conformation adopts flexible, predominantly open, state, with high affinity human ACE-2 receptor. When administered as 4th dose BNT162b2-experienced mice, vaccine elicited substantially higher serum neutralizing titers pseudotyped viruses XBB.1.5, XBB.1.16, XBB.1.16.1, XBB.2.3, EG.5.1 HV.1 sublineages phylogenetically distant BA.2.86 lineage than bivalent Wild Type + BA.4/5 vaccine. Similar trends were observed XBB sublineage pseudoviruses when was 2-dose series naive mice. Strong S-specific Th1 CD4 IFNγ CD8 T cell responses also observed. These findings, together real world performance suggest preclinical data predictive protective dominant

Language: Английский

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Differential requirement of neutralizing antibodies and T cells on protective immunity to SARS-CoV-2 variants of concern

npj Vaccines, Journal Year: 2023, Volume and Issue: 8(1)

Published: Feb. 13, 2023

The current COVID-19 vaccines protect against severe disease, but are not effective in controlling replication of the Variants Concern (VOCs). Here, we used existing pre-clinical models and moderate to evaluate efficacy a Spike-based DNA vaccine (pCTV-WS) for protection different VOCs. Immunization transgenic (K18-hACE2) mice hamsters induced significant levels neutralizing antibodies (nAbs) Wuhan Delta isolates, Gamma Omicron variants. Nevertheless, pCTV-WS offered all Consistently, lung pathology viral load or was mediated by nAbs, whereas absence T cells controlled replication, disease lethality infected with either Hence, considering conserved nature CD4 CD8 cell epitopes, corroborate hypothesis that induction effector T-cells should be main goal new emergent SARS-CoV-2

Language: Английский

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Pharmacometrics of high-dose ivermectin in early COVID-19 from an open label, randomized, controlled adaptive platform trial (PLATCOV)

eLife, Journal Year: 2023, Volume and Issue: 12

Published: Feb. 21, 2023

Background: There is no generally accepted methodology for in vivo assessment of antiviral activity SARS-CoV-2 infections. Ivermectin has been recommended widely as a treatment COVID-19, but whether it clinically significant uncertain. Methods: In multicentre open label, randomized, controlled adaptive platform trial, adult patients with early symptomatic COVID-19 were randomized to one six arms including high-dose oral ivermectin (600 µg/kg daily 7 days), the monoclonal antibodies casirivimab and imdevimab mg/600 mg), study drug. The primary outcome was comparison viral clearance rates modified intention-to-treat population. This derived from log 10 densities standardized duplicate oropharyngeal swab eluates. ongoing trial registered at https://clinicaltrials.gov/ (NCT05041907). Results: Randomization arm stopped after enrolling 205 into all arms, prespecified futility threshold reached. Following ivermectin, mean estimated rate 9.1% slower (95% confidence interval [CI] –27.2% +11.8%; n=45) than drug (n=41), whereas preliminary analysis casirivimab/imdevimab 52.3% faster CI +7.0% +115.1%; n=10 (Delta variant) vs. n=41). Conclusions: High-dose did not have measurable COVID-19. Pharmacometric evaluation frequent serial qPCR density estimates highly efficient well-tolerated method assessing therapeutics vivo. Funding: ‘Finding treatments COVID-19: A phase 2 multi-centre assess pharmacodynamics (PLAT-COV)’ supported by Wellcome Trust Grant ref: 223195/Z/21/Z through Therapeutics Accelerator. Clinical number: NCT05041907 .

Language: Английский

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Pathogenicity, tissue tropism and potential vertical transmission of SARSr-CoV-2 in Malayan pangolins

PLoS Pathogens, Journal Year: 2023, Volume and Issue: 19(5), P. e1011384 - e1011384

Published: May 17, 2023

Malayan pangolin SARS-CoV-2-related coronavirus (SARSr-CoV-2) is closely related to SARS-CoV-2. However, little known about its pathogenicity in pangolins. Using CT scans we show that SARSr-CoV-2 positive pangolins are characterized by bilateral ground-glass opacities lungs a similar manner COVID-19 patients. Histological examination and blood gas tests indicative of dyspnea. infected multiple organs pangolins, with the major target, histological expression data revealed ACE2 TMPRSS2 were co-expressed viral RNA. Transcriptome analysis indicated virus-positive likely have inadequate interferon responses, relative greater cytokine chemokine activity lung spleen. Notably, both RNA proteins detected three fetuses, providing initial evidence for vertical virus transmission. In sum, our study outlines biological framework revealing striking similarities humans.

Language: Английский

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Host Genetic Variation Impacts SARS-CoV-2 Vaccination Response in the Diversity Outbred Mouse Population

Vaccines, Journal Year: 2024, Volume and Issue: 12(1), P. 103 - 103

Published: Jan. 20, 2024

The COVID-19 pandemic led to the rapid and worldwide development of highly effective vaccines against SARS-CoV-2. However, there is significant individual-to-individual variation in vaccine efficacy due factors including viral variants, host age, immune status, environmental genetic factors. Understanding those determinants driving this may inform more broadly protective strategies. While are known impact for respiratory pathogens such as influenza tuberculosis, on not well understood. To model SARS-CoV-2 efficacy, while controlling non-genetic factors, we used Diversity Outbred (DO) mouse model. We found that DO mice immunized exhibited high levels vaccine-induced neutralizing antibody responses. majority vaccinated were protected from virus-induced disease, similar human populations, observed breakthrough a subset mice. Importantly, antibody, titer heritable, indicating serves useful system studying contribution both disease outcomes.

Language: Английский

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