The rates and symptoms of natural and breakthrough infection pre- and post- Covid-19 non-mRNA vaccination at various peaks amongst Iranian healthcare workers.

BACKGROUND/AIMS: The aim of this study was to determine the rate of natural and breakthrough infection and related symptoms of Covid-19 amongst Iranian healthcare workers (HCWs) who were vaccinated by different non-mRNA-based vaccines at peak points. METHODS: In this cross-sectional study, the RT-PCR test was performed for a total of 10,581 HCWs suspicious of Covid-19 infection. For each HCW, the frequency of SARS-CoV-2 infection and the time of transmission based on vaccination administration time and schedule were examined during different waves of the pandemic. Based on these findings, the study patients were divided into three groups: natural, natural/breakthrough, and breakthrough. RESULTS: In total, 53% of the HCWs were exposed to SARS-CoV-2 infection between 1 and 5 times within two years after the current pandemic, while 20.7% and 32.3% experienced natural and breakthrough SARS-CoV-2 infection, respectively. Only 6% of the breakthrough-infected HCWs had naturally contracted SARS-CoV-2 infection during the initial waves. The highest natural peaks of infection occurred during the interval administration of the first and second dose of the first vaccination series, while the single highest peak of breakthrough infection belonged to the Omicron wave. It occurred simultaneously with the administration of the third vaccination dose. On the other hand, the highest rate of reinfection was observed amongst people who had received the Sinopharm and Bharat vaccines full-doses. CONCLUSION: This study compared the clinical differences between the two peaks of Omicron and Delta. This study indicates the rates of natural and breakthrough SARS-CoV-2 infections according to vaccination schedules and different waves of the pandemic.

COVID-19 alters human microbiomes: a meta-analysis.

Introduction: Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has infected a substantial portion of the world's population, and novel consequences of COVID-19 on the human body are continuously being uncovered. The human microbiome plays an essential role in host health and well-being, and multiple studies targeting specific populations have reported altered microbiomes in patients infected with SARS-CoV-2. Given the global scale and massive incidence of COVID on the global population, determining whether the effects of COVID-19 on the human microbiome are consistent and generalizable across populations is essential. Methods: We performed a synthesis of human microbiome responses to COVID-19. We collected 16S rRNA gene amplicon sequence data from 11 studies sampling the oral and nasopharyngeal or gut microbiome of COVID-19-infected and uninfected subjects. Our synthesis included 1,159 respiratory (oral and nasopharyngeal) microbiome samples and 267 gut microbiome samples from patients in 11 cities across four countries. Results: Our reanalyses revealed communitywide alterations in the respiratory and gut microbiomes across human populations. We found significant overall reductions in the gut microbial diversity of COVID-19-infected patients, but not in the respiratory microbiome. Furthermore, we found more consistent community shifts in the gut microbiomes of infected patients than in the respiratory microbiomes, although the microbiomes in both sites exhibited higher host-to-host variation in infected patients. In respiratory microbiomes, COVID-19 infection resulted in an increase in the relative abundance of potentially pathogenic bacteria, including Mycoplasma. Discussion: Our findings shed light on the impact of COVID-19 on the human-associated microbiome across populations, and highlight the need for further research into the relationship between long-term effects of COVID-19 and altered microbiota.

Differences in the organization of interface residues tunes the stability of the SARS-CoV-2 spike-ACE2 complex.

The continuous emergence of novel variants represents one of the major problems in dealing with the SARS-CoV-2 virus. Indeed, also due to its prolonged circulation, more than ten variants of concern emerged, each time rapidly overgrowing the current viral version due to improved spreading features. As, up to now, all variants carry at least one mutation on the spike Receptor Binding Domain, the stability of the binding between the SARS-CoV-2 spike protein and the human ACE2 receptor seems one of the molecular determinants behind the viral spreading potential. In this framework, a better understanding of the interplay between spike mutations and complex stability can help to assess the impact of novel variants. Here, we characterize the peculiarities of the most representative variants of concern in terms of the molecular interactions taking place between the residues of the spike RBD and those of the ACE2 receptor. To do so, we performed molecular dynamics simulations of the RBD-ACE2 complexes of the seven variants of concern in comparison with a large set of complexes with different single mutations taking place on the RBD solvent-exposed residues and for which the experimental binding affinity was available. Analyzing the strength and spatial organization of the intermolecular interactions of the binding region residues, we found that (i) mutations producing an increase of the complex stability mainly rely on instaurating more favorable van der Waals optimization at the cost of Coulombic ones. In particular, (ii) an anti-correlation is observed between the shape and electrostatic complementarities of the binding regions. Finally, (iii) we showed that combining a set of dynamical descriptors is possible to estimate the outcome of point mutations on the complex binding region with a performance of 0.7. Overall, our results introduce a set of dynamical observables that can be rapidly evaluated to probe the effects of novel isolated variants or different molecular systems.

Virus infection pattern imprinted and diversified the differentiation of T-cell memory in transcription and function.

Introduction: Memory T (Tm) cells are a subpopulation of immune cells with great heterogeneity. Part of this diversity came from T cells that were primed with different viruses. Understanding the differences among different viral-specific Tms will help develop new therapeutic strategies for viral infections. Methods: In this study, we compared the transcriptome of Tm cells that primed with CMV, EBV and SARS-CoV-2 with single-cell sequencing and studied the similarities and differences in terms of subpopulation composition, activation, metabolism and transcriptional regulation. Results: We found that CMV is marked by plentiful cytotoxic Temra cells, while EBV is more abundant in functional Tem cells. More importantly, we found that CD28 and CTLA4 can be used as continuous indicators to interrogate the antiviral ability of T cells. Furthermore, we proposed that REL is a main regulatory factor for CMV-specific T cells producing cytokines and plays an antiviral role. Discussion: Our data gives deep insight into molecular characteristics of Tm subsets from different viral infection, which is important to understand T cell immunization. Furthermore, our results provide basic background knowledges for T cell based vaccine development in future.

A Path-Based Analysis of Infected Cell Line and COVID-19 Patient Transcriptome Reveals Novel Potential Targets and Drugs Against SARS-CoV-2.

Most transcriptomic studies of SARS-CoV-2 infection have focused on differentially expressed genes, which do not necessarily reveal the genes mediating the transcriptomic changes. In contrast, exploiting curated biological network, our PathExt tool identifies central genes from the differentially active paths mediating global transcriptomic response. Here we apply PathExt to multiple cell line infection models of SARS-CoV-2 and other viruses, as well as to COVID-19 patient-derived PBMCs. The central genes mediating SARS-CoV-2 response in cell lines were uniquely enriched for ATP metabolic process, G1/S transition, leukocyte activation and migration. In contrast, PBMC response reveals dysregulated cell-cycle processes. In PBMC, the most frequently central genes are associated with COVID-19 severity. Importantly, relative to differential genes, PathExt-identified genes show greater concordance with several benchmark anti-COVID-19 target gene sets. We propose six novel anti-SARS-CoV-2 targets ADCY2, ADSL, OCRL, TIAM1, PBK, and BUB1, and potential drugs targeting these genes, such as Bemcentinib, Phthalocyanine, and Conivaptan.

Drugsniffer: An Open Source Workflow for Virtually Screening Billions of Molecules for Binding Affinity to Protein Targets.

The SARS-CoV2 pandemic has highlighted the importance of efficient and effective methods for identification of therapeutic drugs, and in particular has laid bare the need for methods that allow exploration of the full diversity of synthesizable small molecules. While classical high-throughput screening methods may consider up to millions of molecules, virtual screening methods hold the promise of enabling appraisal of billions of candidate molecules, thus expanding the search space while concurrently reducing costs and speeding discovery. Here, we describe a new screening pipeline, called drugsniffer, that is capable of rapidly exploring drug candidates from a library of billions of molecules, and is designed to support distributed computation on cluster and cloud resources. As an example of performance, our pipeline required ∼40,000 total compute hours to screen for potential drugs targeting three SARS-CoV2 proteins among a library of ∼3.7 billion candidate molecules.

Distinct Characteristics of COVID-19 Infection in Children.

SARS-CoV-2, a member of the family coronaviridae, has triggered a lethal pandemic termed coronavirus disease 2019 (COVID-19). Pediatric patients, mainly from families with a cluster of infection or a history of exposure to epidemic areas, get infected via direct contacts or air-borne droplets. Children (aged below 18 years) are susceptible to COVID-19, with an average incubation period of about 6.5 days. Most cases present asymptomatic or common cold symptoms such as fever, cough, and myalgia or fatigue, which is milder than adult patients. Besides, most abnormal laboratory and radiologic findings in children with COVID-19 are non-specific. Since no specific chemotherapeutic agents have been approved for children, timely preventive methods could effectively forestall the transmission of SARS-CoV-2. To date, mostly studied cases have been adults with COVID-19, whereas data on pediatrics patients remain poorly defined. We herein conducted a literature review for papers published in PubMed and medRxiv (preprints) between December 2019 and December 2020 that reported on pediatrics patients (aged below 18 years) with a confirmed COVID-19 diagnosis. In this review, we summarized and discussed the pathogenesis, epidemiology, and clinical management of COVID-19 in pediatrics patients to improve our understanding of this new disease in children.

High intelligence may exacerbate paediatric inflammatory response to SARS-CoV-2 infection.

The body's innate and acquiredimmunesystems are critical in responses to a wide spectrum of assaults, including SARS-CoV-2 infection. We identify studies of autoimmunity to support our hypothesis that a high intelligence quotient (IQ) may put children at increased risk for severe COVID-19 sequelae; especially those whose viral load is high and/or who develop multisystem inflammatory syndrome in children (MIS-C). MIS-C is associated with a higher risk of COVID-19 morbidity and death, even in otherwise healthy children. As information and evidence about SARS-CoV-2 infection continue to expand, our hypothesis suggests adding a potentially intriguing piece to the pandemic puzzle for further investigation. Drawing on a select review of published research and case reports, we discuss immune dysregulation in paediatric patients with a high IQ, including post-infection cytokine expression in the myocardium. Further, we provide a review of 27 paediatric (≤19 years; median age 16) cases of severe COVID-19 outcomes, drawn from media sources published between March and September 2020, in which we identify possible evidence of a 'hyper brain, hyper body' response to infection. We aver these cases are noteworthy given that paediatric death with COVID-19 disease is remarkably rare, and the estimated prevalence of a high IQ (or giftedness) is only 2% in the general population. These observations warrant prospective and retrospective studies of autoinflammatory markers and mechanisms to elucidate any special psychoneuroimmunological vulnerability in children with a high IQ, as such studies may raise implications for how and when prophylactic medical care is provided to children.

The demand for a COVID-19 vaccine in Kenya.

The goal of achieving herd immunity to the coronavirus requires high vaccination acceptance levels on the part of the population. The objectives of this study were to: 1) Measure individuals' willingness to pay (WTP) for a COVID-19 vaccine in Kenya; 2) evaluate the effect of vaccine characteristics (duration of protection and efficacy) and individuals' socioeconomic variables on WTP, and 3) estimate the aggregate demand and economic value of a COVID-19 vaccine. The contingent valuation (CV) method was used as the basis for the analyses. Data for this study were obtained from a survey of 1,050 individuals in Kenya conducted from April 7 to April 15, 2020. The survey included CV questions using a double-bounded dichotomous choice format. Results reveal that most of the individuals in Kenya (at least 96%) were willing to accept a COVID-19 vaccine. Approximately 80% of individuals were willing to pay a positive amount. Conservative estimates of individuals' mean WTP for the vaccine range from USD 49.81 to USD 68.25 (depending on vaccine characteristics). Both vaccine duration of protection and efficacy were found to influence WTP (p < .10). The perceived probability of being hospitalized, age, gender, education, location and region of residence, and household income were also found to be associated with WTP for the vaccine (p < .10). In conclusion, the COVID-19 vaccine is highly valued and accepted by the Kenyan population; however, a high percent of the population is unwilling to pay for it or is only willing to pay a low price.

Surveillance on Healthcare Workers During the First Wave of SARS-CoV-2 Pandemic in Italy: The Experience of a Tertiary Care Pediatric Hospital.

Healthcare workers (HCWs) play a central role in handling the ongoing coronavirus disease 2019 (COVID-19) pandemic. Monitoring HCWs, both symptomatic and asymptomatic, through screening programs, are critical to avoid the spread of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in the hospital environment to rapidly identify and isolate infected individuals and to allow their prompt return to work as soon as necessary. We aim to describe our healthcare surveillance experience (April 2-May 6, 2020) based on a combined screening consisting of real-time PCR (RT-PCR) on nasopharyngeal (NP) swabs and rapid serologic tests (RST) for SARS-CoV-2 in all HCWs of Meyer Children's University Hospital in Florence. Among the analyzed workers, 13/1690 (0.8%), all of them without clinical manifestations, was found positive for SARS-CoV-2 by using RT-PCR on NP swab: 8/1472 (0.5%) were found positive during the screening, 1/188 (0.5%) during contact with a positive individual (p > 0.05 vs. screening group), while 4/30 (13.3%) were found positive on the day of re-admission at work after an influenza-like-illness (p < 0.05). Concerning working areas, the majority of RT-PCR positivity (12/13) and serologic positivity (34/42) was found in non-COVID-19 dedicated areas (p > 0.05 vs. COVID-19 dedicated areas). No cases were registered among non-patients-facing workers (p = 0.04 vs. patient-facing group). Nurses and residents represented, respectively, the working role with the highest and lowest percentage of RT-PCR positivity. In conclusion, accurate surveillance is essential to reduce virus spread among HCWs, patients, and the community and to limit the shortage of skilled professionals. The implementation of the surveillance system through an efficient screening program was offered to all professionals, regardless of the presence of clinical manifestations and the level of working exposure risk, maybe wise and relevant.

AutoPlate: Rapid Dose-Response Curve Analysis for Biological Assays.

The emergence of COVID-19 has emphasised that biological assay data must be analysed quickly to develop safe, effective and timely vaccines/therapeutics. For viruses such as SARS-CoV-2, the primary way of measuring immune correlates of protection is through assays such as the pseudotype microneutralisation (pMN) assay, thanks to its safety and versatility. However, despite the presence of existing tools for data analysis such as PRISM and R the analysis of these assays remains cumbersome and time-consuming. We introduce an open-source R Shiny web application and R library (AutoPlate) to accelerate data analysis of dose-response curve immunoassays. Using example data from influenza studies, we show that AutoPlate improves on available analysis software in terms of ease of use, flexibility and speed. AutoPlate (https://philpalmer.shinyapps.io/AutoPlate/) is a tool for the use of laboratories and wider scientific community to accelerate the analysis of biological assays in the development of viral vaccines and therapeutics.

COVID-19 Sets off Mass Migration in India.

The communication discusses COVID-19 triggered reverse migration in India. India has witnessed the second largest mass migration in its history after the Partition of India in 1947, where more than 14 million people were displaced and migrated to India and Pakistan respectively, depending on their religious faiths. The opinion describes the trend of migration and related effects on the migrants as well as the nation at large.

Addition of Tocilizumab to the Standard of Care Reduces Mortality in Severe COVID-19: A Systematic Review and Meta-Analysis.

Introduction: Tocilizumab (TCZ) is an anti-interleukin-6 antibody that has been used for the treatment of severe coronavirus disease 2019 (COVID-19). However, concrete evidence of its benefit in reducing mortality in severe COVID-19 is lacking. Therefore, we performed a systematic review and meta-analysis of relevant studies that compared the efficacy of TCZ in severe COVID-19 vs. standard of care (SOC) alone. Methods: A literature search for studies that compared "tocilizumab" and "standard of care" in the treatment of COVID-19 was done using major online databases from December 2019 to June 14, 2020. Search words "Tocilizumab," "anti-interleukin-6 antibody," and "COVID-19" or "coronavirus 2019" in various combinations were used. Articles in the form of abstracts, letters without original data, case reports, and reviews were excluded. Data were gathered on an Excel sheet, and statistical analysis was performed using Review Manager 5.3. Results: Sixteen studies were eligible from 693 initial studies, including 3,641 patients (64% males). There were 13 retrospective studies and three prospective studies. There were 2,488 patients in the SOC group (61.7%) and 1,153 patients (68.7%) in the TCZ group. The death rate in the TCZ group, 22.4% (258/1,153), was lower than in the SOC group, 26.21% (652/2,488) [pooled odds ratio 0.57 (95% CI 0.36-0.92), p = 0.02]. There was a significant heterogeneity (inconsistency index = 80%) among the included studies. Conclusion: The addition of TCZ to the SOC might reduce mortality in severe COVID-19. More extensive randomized clinical trials are needed to validate these findings.

The demand for a COVID-19 vaccine in Ecuador.

In Latin America, the country of Ecuador was one of the first and most severely affected by the COVID-19 pandemic. This study aimed to evaluate the demand for a COVID-19 vaccine in Ecuador by estimating individuals' willingness to pay (WTP) for the vaccine, and by assessing the effect of vaccine attributes (duration of protection and efficacy) and individuals' characteristics on this valuation. The sample used (N = 1,050) was obtained through an online survey conducted from April 2 to April 7, 2020. Two levels of vaccine efficacy (70% and 98%) and two levels of vaccine duration of protection (1 and 20 years) were considered. The willingness to pay estimates were obtained using a double-bounded dichotomous-choice contingent valuation format. Survey results show that a very large proportion of individuals (at least 97%) were willing to accept a COVID-19 vaccine, and at least 85% of individuals were willing to pay a positive amount for that vaccine. Conservative estimates of the average WTP values ranged from USD 147.61 to 196.65 and the median WTP from USD 76.9 to 102.5. Only the duration of protection was found to influence individuals' WTP for the vaccine (p < 0.01). On average, respondents were willing to pay 30% more for a COVID-19 vaccine with 20 years of protection relative to the vaccine with 1 year of protection. Regression results show that WTP for the vaccine was associated with income, employment status, the perceived probability of needing hospitalization if contracting the virus causing COVID-19, and region of residence.

SARS-CoV-2 pathophysiology and its clinical implications: An integrative overview of the pharmacotherapeutic management of COVID-19.

Common manifestations of COVID-19 are respiratory and can extend from mild symptoms to severe acute respiratory distress. The severity of the illness can also extend from mild disease to life-threatening acute respiratory distress syndrome (ARDS). SARS-CoV-2 infection can also affect the gastrointestinal tract, liver and pancreatic functions, leading to gastrointestinal symptoms. Moreover, SARS-CoV-2 can cause central and peripheral neurological manifestations, affect the cardiovascular system and promote renal dysfunction. Epidemiological data have indicated that cancer patients are at a higher risk of contracting the SARS-CoV-2 virus. Considering the multitude of clinical symptoms of COVID-19, the objective of the present review was to summarize their pathophysiology in previously healthy patients, as well as in those with comorbidities. The present review summarizes the current, though admittedly fluid knowledge on the pathophysiology and symptoms of COVID-19 infection. Although unclear issues still remain, the present study contributes to a more complete understanding of the disease, and may drive the direction of new research. The recognition of the severity of the clinical symptoms of COVID-19 is crucial for the specific therapeutic management of affected patients.