Therapeutic strategies for COVID-19: progress and lessons learned

Nature Reviews Drug Discovery, Journal Year: 2023, Volume and Issue: 22(6), P. 449 - 475

Published: April 19, 2023

Language: Английский

---

Long covid outcomes at one year after mild SARS-CoV-2 infection: nationwide cohort study

BMJ, Journal Year: 2023, Volume and Issue: unknown, P. e072529 - e072529

Published: Jan. 11, 2023

Abstract Objectives To determine the clinical sequelae of long covid for a year after infection in patients with mild disease and to evaluate its association age, sex, SARS-CoV-2 variants, vaccination status. Design Retrospective nationwide cohort study. Setting Electronic medical records from an Israeli healthcare organisation. Population 1 913 234 Maccabi Healthcare Services members all ages who did polymerase chain reaction test between March 2020 October 2021. Main outcome measures Risk evidence based list 70 reported outcomes unvaccinated infected matched uninfected people, adjusted age sex stratified by risk breakthrough compared controls. Risks were using hazard ratios differences per 10 000 measured during early (30-180 days) late (180-360 time periods infection. Results Covid-19 was significantly associated increased risks anosmia dysgeusia (hazard ratio 4.59 (95% confidence interval 3.63 5.80), difference 19.6 16.9 22.4) period; 2.96 (2.29 3.82), 11.0 (8.5 13.6) period), cognitive impairment (1.85 (1.58 2.17), 12.8, (9.6 16.1); 1.69 (1.45 1.96), 13.3 (9.4 17.3)), dyspnoea (1.79 (1.68 1.90), 85.7 (76.9 94.5); 1.30 (1.22 1.38), 35.4 (26.3 44.6)), weakness (1.78 (1.69 1.88), 108.5, 98.4 118.6; 1.37), 50.2 (39.4 61.1)), palpitations (1.49 (1.35 1.64), 22.1 (16.8 27.4); 1.16 (1.05 1.27), 8.3 (2.4 14.1)) significant but lower excess streptococcal tonsillitis dizziness. Hair loss, chest pain, cough, myalgia, respiratory disorders only phase. Male female showed minor differences, children had fewer than adults phase covid-19, which mostly resolved period. Findings remained consistent across variants. Vaccinated similar other patients. Conclusions This study suggests that covid-19 are at small number health outcomes, most within diagnosis.

Language: Английский

---

Mucosal immune responses to infection and vaccination in the respiratory tract

Immunity, Journal Year: 2022, Volume and Issue: 55(5), P. 749 - 780

Published: May 1, 2022

Language: Английский

---

A pseudovirus system enables deep mutational scanning of the full SARS-CoV-2 spike

Cell, Journal Year: 2023, Volume and Issue: 186(6), P. 1263 - 1278.e20

Published: Feb. 13, 2023

A major challenge in understanding SARS-CoV-2 evolution is interpreting the antigenic and functional effects of emerging mutations viral spike protein. Here, we describe a deep mutational scanning platform based on non-replicative pseudotyped lentiviruses that directly quantifies how large numbers impact antibody neutralization pseudovirus infection. We apply this to produce libraries Omicron BA.1 Delta spikes. These each contain ∼7,000 distinct amino acid context up ∼135,000 unique mutation combinations. use these map escape from neutralizing antibodies targeting receptor-binding domain, N-terminal S2 subunit spike. Overall, work establishes high-throughput safe approach measure ∼10

Language: Английский

---

Fitness effects of mutations to SARS-CoV-2 proteins

Virus Evolution, Journal Year: 2023, Volume and Issue: 9(2)

Published: July 1, 2023

Knowledge of the fitness effects mutations to SARS-CoV-2 can inform assessment new variants, design therapeutics resistant escape, and understanding functions viral proteins. However, experimentally measuring is challenging: we lack tractable lab assays for many proteins, comprehensive deep mutational scanning has been applied only two Here, develop an approach that leverages millions publicly available sequences estimate mutations. We first calculate how independent occurrences each mutation are expected be observed along phylogeny in absence selection. then compare these observations actual effect mutation. These estimates correlate well with measurements. For most genes, synonymous nearly neutral, stop-codon deleterious, amino acid have a range effects. some accessory proteins under little no provide interactive visualizations all (https://jbloomlab.github.io/SARS2-mut-fitness/). The framework describe applicable any virus which number sufficiently large neutral observed.

Language: Английский

---

Autophagy in health and disease: From molecular mechanisms to therapeutic target

MedComm, Journal Year: 2022, Volume and Issue: 3(3)

Published: July 10, 2022

Macroautophagy/autophagy is an evolutionally conserved catabolic process in which cytosolic contents, such as aggregated proteins, dysfunctional organelle, or invading pathogens, are sequestered by the double-membrane structure termed autophagosome and delivered to lysosome for degradation. Over past two decades, autophagy has been extensively studied, from molecular mechanisms, biological functions, implications various human diseases, development of autophagy-related therapeutics. This review will focus on latest research, covering mechanisms control biogenesis autophagosome-lysosome fusion, upstream regulatory pathways including AMPK MTORC1 pathways. We also provide a systematic discussion implication cancer, neurodegenerative disorders (Alzheimer disease, Parkinson Huntington's Amyotrophic lateral sclerosis), metabolic diseases (obesity diabetes), viral infection especially SARS-Cov-2 COVID-19, cardiovascular (cardiac ischemia/reperfusion cardiomyopathy), aging. Finally, we summarize pharmacological agents that have therapeutic potential clinical applications via targeting pathway. It believed decades hard work research eventually bring real tangible benefits improvement health diseases.

Language: Английский

---

Mucosal vaccines for SARS-CoV-2: scientific gaps and opportunities—workshop report

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

Published: April 12, 2023

On November 7th and 8th, 2022, The National Institute of Allergy Infectious Diseases (NIAID), part the Institutes Health (NIH), Coalition for Epidemic Preparedness Innovation (CEPI), Bill & Melinda Gates Foundation (BMGF), Biomedical Advanced Research Development Authority (BARDA), Wellcome Trust hosted a virtual workshop entitled "Mucosal Vaccines SARS-CoV-2: Scientific Gaps Opportunities." During workshop, researchers vaccine developers from around world discussed potential mucosal vaccines to block SARS-CoV-2 transmission reviewed status research. Here, we summarize key challenges opportunities in basic, translational, clinical research that were highlighted during meeting. We also provide recommendations advance field accelerate development SARS-CoV-2.

Language: Английский

---

Sequential intrahost evolution and onward transmission of SARS-CoV-2 variants

Nature Communications, Journal Year: 2023, Volume and Issue: 14(1)

Published: June 3, 2023

Abstract Persistent severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections have been reported in immune-compromised individuals and people undergoing immune-modulatory treatments. Although intrahost evolution has documented, direct evidence of subsequent transmission continued stepwise adaptation is lacking. Here we describe sequential persistent SARS-CoV-2 three that led to the emergence, forward transmission, a new Omicron sublineage, BA.1.23, over an eight-month period. The initially transmitted BA.1.23 variant encoded seven additional amino acid substitutions within spike protein (E96D, R346T, L455W, K458M, A484V, H681R, A688V), displayed substantial resistance neutralization by sera from boosted and/or BA.1-infected study participants. Subsequent replication resulted (S254F, N448S, F456L, M458K, F981L, S982L) as well five other virus proteins. Our findings demonstrate not only BA.1 lineage can diverge further its already exceptionally mutated genome but also patients with transmit these viral variants. Thus, there is, urgent need implement strategies prevent prolonged limit spread newly emerging, neutralization-resistant variants vulnerable patients.

Language: Английский

---

Global landscape of SARS-CoV-2 mutations and conserved regions

Journal of Translational Medicine, Journal Year: 2023, Volume and Issue: 21(1)

Published: Feb. 25, 2023

Abstract Background At the end of December 2019, a novel strain Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) disease (COVID-19) has been identified in Wuhan, central city China, and then spread to every corner globe. As October 8, 2022, total number COVID-19 cases had reached over 621 million worldwide, with more than 6.56 confirmed deaths. Since SARS-CoV-2 genome sequences change due mutation recombination, it is pivotal surveil emerging variants monitor changes for improving pandemic management. Methods 10,287,271 sequence samples were downloaded FASTA format from GISAID databases February 24, 2020, April 2022. Python programming language (version 3.8.0) software was utilized process files identify conservation. The NCBI RefSeq (accession no. NC_045512.2) considered as reference sequence. Results Six mutations 50% frequency global SARS-CoV-2. These include P323L (99.3%) NSP12, D614G (97.6) S, T492I (70.4) NSP4, R203M (62.8%) N, T60A (61.4%) Orf9b, P1228L (50.0%) NSP3. In genome, no observed 90% nsp11, nsp7, nsp10, nsp9, nsp8, nsp16 regions. On other hand, nsp3, nsp4, nsp12, M maximum rate mutations. S protein, highest aa 508–635(0.77%) 381–508 (0.43%). 66–88 (2.19%), 7–14, 164–246 (2.92%) M, E, N proteins, respectively. Conclusion Therefore, monitoring proteomic detecting hot spots conserved regions could be applied improve SARS‐CoV‐2 diagnostic efficiency design safe effective vaccines against variants.

Language: Английский

---

SARS-CoV-2-infection- and vaccine-induced antibody responses are long lasting with an initial waning phase followed by a stabilization phase

Immunity, Journal Year: 2024, Volume and Issue: 57(3), P. 587 - 599.e4

Published: Feb. 22, 2024

It is thought that mRNA-based vaccine-induced immunity to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) wanes quickly, based mostly on short-term studies. Here, we analyzed the kinetics and durability of humoral responses SARS-CoV-2 infection vaccination using >8,000 longitudinal samples collected over a 3-year period in New York City. Upon primary immunization, participants with pre-existing mounted higher antibody faster achieved steady-state titers than naive individuals. Antibody were characterized by two phases: an initial rapid decay, followed stabilization phase very slow decay. Booster equalized differences concentration between without hybrid immunity, but peak decreased each successive antigen exposure. Breakthrough infections increased antibodies similar as additional vaccine dose Our study provides strong evidence are long lasting, waning stabilization.

Language: Английский

---