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1.
Preprint | medRxiv | ID: ppmedrxiv-22283183

ABSTRACT

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron subvariants are expected to be resistant to Bebtelovimab (BEB) monoclonal antibody (MAb) and the real-world experience regarding its effectiveness is scarce. This retrospective cohort study reports a data analysis in Banner Healthcare System (a large not-for-profit organization) between 4/5/2022 and 8/1/2022 and included 19,778 Coronavirus disease-19 (COVID-19) positive (by PCR or direct antigen testing) patients who were selected from Cerner-Electronic Health Record after the exclusions criteria were met. The study index date for cohort was determined as the date of BEB MAb administration or the date of the first positive COVID-19 testing. The cohort consist of COVID-19 infected patients who received BEB MAb (N=1,091) compared to propensity score (PS) matched control (N=1,091). The primary outcome was the incidence of 30-day all-cause hospitalization and/or mortality. All statistical analyses were conducted on the paired (matched) dataset. For the primary outcome, the event counts and percentages were reported. Ninety-five percent Clopper-Pearson confidence intervals for percentages were computed. The study cohorts were 1:1 propensity matched without replacement across 26 covariates using an optimal matching algorithm that minimizes the sum of absolute pairwise distance across the matched sample after fitting and using logistic regression as the distance function. The pairs were matched exactly on patient vaccination status, BMI group, age group and diabetes status. Compared to the PS matched control group (2.6%; 95% confidence interval [CI]: 1.7%, 3.7%), BEB MAb use (2.2%; 95% CI: 1.4%, 3.3%) did not significantly reduce the incidence of the primary outcome (p=0.67). In the subgroup analysis, we observed similar no-difference trends regarding the primary outcomes for the propensity rematched BEB MAb treated and untreated groups, stratified by patient vaccination status, age (<65 years or [≥]65), and immunocompromised status (patients with HIV/AIDS or solid organ transplants or malignancy including lymphoproliferative disorder). The number needed to treat (1/0.026-0.022) with BEB MAb was 250 to avoid one hospitalization and/or death over 30 days. The BEB MAb use lacked efficacy in patients with SARS-CoV-2 Omicron subvariants (mainly BA.2, BA.2.12.1, and BA.5) in the Banner Healthcare System in the Southwestern United States.

2.
Preprint in English | medRxiv | ID: ppmedrxiv-22283000

ABSTRACT

The Omicron era of the COVID-19 pandemic commenced at the beginning of 2022 and whilst it started with primarily BA.1, it was latter dominated by BA.2 and related sub-lineages. Over the course of 2022, we monitored the potency and breadth of antibody neutralization responses to many emerging variants at two levels: (i) we tracked over 400,000 U.S. plasma donors over time through various vaccine booster roll outs and Omicron waves using antibody pools. (ii) we mapped the antibody response at the individual level using blood from strigently curated vaccine and convalescent cohorts. In pooled antibody samples, we observed the maturation of neutralization breadth to Omicron variants over time through continuing vaccine and infection waves. Importantly, in many cases we observed increased antibody breadth to variants that were yet to be in circulation. Resolution of viral neutralisation at the cohort level supported equivalent coverage across prior and emerging variants with emerging isolates BQ.1.1, XBB.1 and BR.2.1 the most evasive. Further, these emerging variants were resistant to Evusheld, whilst neutralization resistance to Sotrovimab was restricted to BQ.1.1 and further supported by lack of Spike glycoprotein binding to this variant. An outgrowth advantage through better utilization of TMPRSS2 was observed across BQ lineages and not those derived from BA.2.75. We conclude at this current point in time that variants derived from BQ lineages can evade antibodies at levels equivalent to their most evasive BA.2.75 counterparts but sustain an entry phenotype that would promote an additional outgrowth advantage.

3.
Preprint in English | medRxiv | ID: ppmedrxiv-22282974

ABSTRACT

Objectives: Sophisticated scores have been proposed for prognostication of mortality due to SARS-CoV-2 but perform inconsistently. We conducted these meta-analyses to uncover why and to pragmatically seek a single dependable biomarker for mortality. Design: We searched the PubMed database for the keywords SARS-CoV-2 with biomarker name and mortality. All studies published from 01st December 2019 to 30th June 2021 were surveyed. To aggregate the data, the meta library in R was used to report overall mean values and 95% confidence intervals. We fitted a random effects model to obtain pooled AUCs and associated 95% confidence intervals for the European/North American, Asian, and overall datasets. Setting and Participants: Data was collected from 131 studies on SARS-CoV-2 PCR-positive general hospital adult admissions (n=76,169 patients in total). Main Outcome Measures: We planned a comparison of pooled area under curves (AUCs) from Receiver Operator Characteristic curves plotted for admission D-dimer, CRP, urea, troponin and interleukin-6 levels. Main Results: Biomarker effectiveness varies significantly in different regions of the world. Admission CRP levels are a good prognostic marker for mortality due to SARS-CoV-2 in Asian countries, with a pooled area under curve (AUC) of 0.83 (95% CI 0.80-0.85), but only an average predictor of mortality in Europe/North America, with a pooled AUC of 0.67 (95% CI 0.63-0.71, P<0.0001). We observed the same pattern for D-dimer and IL-6. This variability explains why the proposed prognostic scores did not perform evenly. Notably, urea and troponin had pooled AUCs [≥] 0.78 regardless of location, implying that end-organ damage at presentation is a key prognostic factor. These differences might be due to age, genetic backgrounds, or different modes of death (younger patients in Asia dying of cytokine storm while older patients die of multi-organ failure). Conclusions: Biomarker effectiveness for prognosticating SARS-CoV-2 mortality varies significantly by geographical location. We propose that biomarkers and by extension prognostic scores need to be tailored for specific populations. This also implies that validation of commonly used prognostic scores for other conditions should occur before they are used in different populations.

4.
Preprint in English | medRxiv | ID: ppmedrxiv-22282077

ABSTRACT

Resolving chromatin remodeling-linked gene expression changes at cell type resolution is important for understanding disease states. We describe MAGICAL, a hierarchical Bayesian approach that leverages paired scRNA-seq and scATAC-seq data from different conditions to map disease-associated transcription factors, chromatin sites, and genes as regulatory circuits. By simultaneously modeling signal variation across cells and conditions in both omics data types, MAGICAL achieved high accuracy on circuit inference. We applied MAGICAL to study Staphylococcus aureus sepsis from peripheral blood mononuclear single-cell data that we generated from infected subjects with bloodstream infection and from uninfected controls. MAGICAL identified sepsis-associated regulatory circuits predominantly in CD14 monocytes, known to be activated by bacterial sepsis. We addressed the challenging problem of distinguishing host regulatory circuit responses to methicillin-resistant- (MRSA) and methicillin-susceptible Staphylococcus aureus (MSSA) infections. While differential expression analysis failed to show predictive value, MAGICAL identified epigenetic circuit biomarkers that distinguished MRSA from MSSA.

5.
Preprint in English | medRxiv | ID: ppmedrxiv-22283175

ABSTRACT

Background The role of thromboprophylaxis in the post-acute phase of COVID-19 is uncertain due to conflicting results from randomised controlled trials and observational studies. We aimed to determine the effectiveness of post-hospital apixaban in reducing the rate of death and hospital readmission of hospitalised adults with COVID-19. Methods HEAL COVID is an adaptive randomised open label multicentre platform trial recruiting participants from National Health Service Hospitals in the United Kingdom. Here we report the preliminary results of apixaban comparison of HEAL-COVID. Participants with a hospital admission related to confirmed COVID-19 and an expected date of discharge in the subsequent five days were randomised to either apixaban 2.5 mg twice daily or standard care (no anticoagulation) for 14 days. The primary outcome was hospital free survival at 12 months obtained through routine data sources. The trial was prospectively registered with ISRCTN (15851697) and Clincialtrials.gov (NCT04801940). Findings Between 19 May 2021 and 21 November 2022, 402 participants from 109 sites were randomised to apixaban and 399 to standard care. Seven participants withdrew from the apixaban group and one from the standard care group. Analysis was undertaken on an intention-to-treat basis. The apixaban arm was stopped on the recommendation of the oversight committees following an interim analysis due to no indication of benefit. Of the 402 participants randomised to apixaban, 117 experienced death or rehospitalisation during a median follow-up of 344.5 days (IQR 125 to 365), and 123 participants receiving standard care experienced death or rehospitalisation during a median follow-up of 349 days (IQR 124 to 365). There was no statistical difference in the rate of death and rehospitalisation (HR: 0.96 99%CI 0.69-1.34; p=0.75). Three participants in the apixaban arm experienced clinically significant bleeding during treatment. Interpretation Fourteen days of post-hospital anticoagulation with the direct oral anticoagulant apixaban did not reduce the rate of death or rehospitalisation of adults hospitalised with COVID-19. These data do not support the use of prophylactic post-hospital anticoagulation in adults with COVID-19. Funding HEAL-COVID is funded by the National Institute for Health and Care Research [NIHR133788] and the NIHR Cambridge Biomedical Research Centre [ BRC-1215-20014*].

6.
Preprint in English | medRxiv | ID: ppmedrxiv-22283203

ABSTRACT

Importance: Persistent symptoms after SARS-COV-2 infection, or long-COVID, may occur in anywhere from 10-55% of those who have had COVID-19, but the extent of impact on daily functioning and disability remains unquantified. Objective: To characterize physical and mental disability associated with long-COVID Design: Cross-sectional analysis of baseline data from a cohort study Setting: Online US nationwide survey Participants: Adults 18 years of age and older who live in the US who either report a history of COVID-19 illness (n=8,874) or report never having had COVID-19 (n=633) Main Outcome and Measures: Self-reported mobility disability (difficulty walking a quarter of a mile and/or up 10 stairs, instrumental activities of daily living [IADL] disability (difficulty doing light or heavy housework), and mental fatigue as measured by the Wood Mental Fatigue Inventory (WMFI). Results: Of 7,926 participants with long-COVID, the median age was 45 years, 84% were female, 89% self-reported white race, and 7.4% self-reported Hispanic/Latino ethnicity. Sixty-five percent of long-COVID participants were classified as having at least one disability, compared to 6% of those with resolved-COVID (n=948) and 14% of those with no-COVID (n=633). Of long-COVID participants, about 1% and 5% were classified as critically physically disabled or mentally fatigued, respectively. Age, prior comorbidity, increased BMI, female gender, hospitalization for COVID-19, non-white race, and multi-race were all associated with significantly higher disability burden. Dizziness at the time of infection (33% non-hospitalized, 39% hospitalized) was associated with all five disability components in both hospitalized and non-hospitalized groups. Heavy limbs, dyspnea, and tremors were associated with four of the five components of disability in the non-hospitalized group, and heavy limbs was associated with four of the five components in the hospitalized group. Vaccination was protective against development of disability. Conclusion and Relevance: We observed a high burden of physical and mental disability associated with long-COVID which has serious implications for individual and societal health that may be partially mitigated by vaccination. Longitudinal characterization and evaluation of COVID-19 patients is necessary to identify patterns of recovery and treatment options.

7.
Preprint in English | medRxiv | ID: ppmedrxiv-22283193

ABSTRACT

Objectives: We assessed the causal association of three COVID-19 phenotypes with insulin-like growth factor 1 (IGF-1), estrogen, testosterone, dehydroepiandrosterone (DHEA), thyroid-stimulating hormone (TSH), thyrotropin-releasing hormone (TRH), luteinizing hormone (LH), and follicle-stimulating hormone (FSH). Methods: We used a bidirectional two-sample univariate and multivariable Mendelian randomization (MR) analysis to evaluate the direction, specificity, and causality of the association between CNS-regulated hormones and COVID-19 phenotypes. Genetic instruments for CNS-regulated hormones were selected from the largest publicly available genome-wide association studies in the European population. Summary-level data on COVID-19 severity, hospitalization, and susceptibility were obtained from the COVID-19 host genetic initiative. Results: DHEA was associated with increased risks of very severe respiratory syndrome (OR=4.21, 95% CI: 1.41-12.59), consistent with the results in multivariate MR (OR=3.72, 95% CI: 1.20-11.51), and hospitalization (OR = 2.31, 95% CI: 1.13-4.72) in univariate MR. LH was associated with very severe respiratory syndrome (OR=0.83; 95% CI: 0.71-0.96) in univariate MR. Estrogen was negatively associated with very severe respiratory syndrome (OR=0.09, 95% CI: 0.02-0.51), hospitalization (OR=0.25, 95% CI: 0.08-0.78), and susceptibility (OR=0.50, 95% CI: 0.28-0.89) in multivariate MR. Conclusions: We found strong evidence for the causal relationship of DHEA, LH, and estrogen with COVID-19 phenotypes.

8.
Preprint in English | medRxiv | ID: ppmedrxiv-22283145

ABSTRACT

Introduction: Serious harms of the COVID-19 vaccines have been underreported in published trial reports. Methods: Systematic review of papers with data on serious adverse events (SAEs) associated with a COVID-19 vaccine. Results: We included 18 systematic reviews, 14 randomised trials, and 34 other studies with a control group. Most studies were of poor quality. The most reliable one was a systematic review of regulatory data on the two pivotal randomised trials of the mRNA vaccines. It found significantly more SAEs of special interest with the vaccines than with placebo, and the excess risk was considerably larger than the benefit, measured as the risk of hospitalisation. The adenovirus vector vaccines increased the risk of venous thrombosis and thrombocytopenia, and the mRNA-based vaccines increased the risk of myocarditis, with a mortality of about 1-2 per 200 cases. We also found evidence of serious neurological harms, including Bel's palsy, Guillain-Barre syndrome, myasthenic disorder and stroke, which are likely due to an autoimmune reaction, as has been suggested also for the HPV vaccines. Severe harms, i.e. those that prevent daily activities, were hugely underreported in the randomised trials. These harms were very common in studies of booster doses after a full vaccination and in a study of vaccination of previously infected people. Discussion: Serious and severe harms of the COVID-19 vaccines have been ignored or downplayed, and sometimes been deliberately excluded by the study sponsors in high impact medical journals. This area needs further study. Authorities have recommended virtually everyone get vaccinated and receive booster doses. They fail to consider that the balance between benefits and harms becomes negative in low-risk groups such as children and people who have already acquired natural immunity.

9.
Preprint | bioRxiv | ID: ppbiorxiv-519007

ABSTRACT

The role of autoimmunity in post-acute sequelae of COVID-19 (PASC) is not well explored, although clinicians observe a growing population of convalescent COVID-19 patients with manifestation of post-acute sequelae of COVID-19. We analyzed the immune response in 40 post-acute sequelae of COVID-19 patients with non-specific PASC manifestation and 15 COVID-19 convalescent healthy donors. The phenotyping of lymphocytes showed a significantly higher number of CD8+ T cells expressing the Epstein-Barr virus induced G protein coupled receptor 2, chemokine receptor CXCR3 and C-C chemokine receptor type 5 playing an important role in inflammation and migration in PASC patients compared to controls. Additionally, a stronger, SARS-CoV-2 reactive CD8+ T cell response, characterized by IFN{gamma} production and predominant TEMRA phenotype but low SARS-CoV-2 avidity was detected in PASC patients compared to controls. Furthermore, higher titers of several autoantibodies were detected among PASC patients. Our data suggest that a persistent inflammatory response triggered by SARS-CoV-2 might be responsible for the observed sequelae in PASC patients. These results may have implications on future therapeutic strategies.

10.
Preprint in English | bioRxiv | ID: ppbiorxiv-519322

ABSTRACT

Conventional mRNA-based vaccines were instrumental in lowering the burden of the pandemic on healthcare systems and in reducing mortality. However, such first-generation vaccines have significant weaknesses. Here, we describe a high-performance binary recombinant vectoral platform offering the flexibility to be used as a self-amplifying mRNA or a self-amplifying DNA. Both formats drive long-lasting expression and actuate robust antibody responses against SAR-CoV-2 spike, and neither format require encapsulation with lipid nanoparticles (LNP) in the generation immune responses. The platform combines the power of conventional mRNA with the low-dosage of self-amplifying vectors together with the simplicity, rapid creation, ease of storage, and convenience of distribution of plasmid DNA vectors. This platform promises to pave the way for more effective, less expensive, and truly democratized vaccines and therapeutics.

11.
Preprint in English | bioRxiv | ID: ppbiorxiv-519460

ABSTRACT

Obesity and Type 2 Diabetes Mellitus (T2DM) are associated with an increased risk of severe outcomes from infectious diseases, including COVID-19. These conditions are also associated with distinct responses to immunization, including an impaired response to widely used SARS-CoV-2 mRNA vaccines. Establishing a connection between reduced immunization efficacy via modeling the effects of metabolic diseases on vaccine immunogenicity is essential for the development of more effective vaccines for this distinct vulnerable population. Here, we utilized a murine model of diet-induced obesity and insulin resistance to model the effects of comorbid T2DM and obesity on vaccine immunogenicity and protection. Mice fed a high-fat diet (HFD) developed obesity, hyperinsulinemia, and glucose intolerance. Relative to mice fed a normal diet (ND), HFD mice vaccinated with a SARS-CoV-2 mRNA vaccine exhibited significantly lower anti-spike IgG titers, predominantly in the IgG2c subclass, associated with a lower type 1 response, along with a 3.83-fold decrease in neutralizing titers. Furthermore, enhanced vaccine-induced spike-specific CD8+ T cell activation and protection from lung infection against SARS-CoV-2 challenge were seen only in ND mice but not in HFD mice. Overall, we demonstrate impaired immunity following SARS-CoV-2 mRNA immunization in a murine model of comorbid T2DM and obesity, supporting the need for further research into the basis for impaired anti-SARS-CoV-2 immunity in T2DM and investigation of novel approaches to enhance vaccine immunogenicity among those with metabolic diseases.

12.
Preprint in English | medRxiv | ID: ppmedrxiv-22283013

ABSTRACT

Objectives: The aim of this paper is to perform a Statewise Analysis of the Second Covid Wave experienced by India using the Gompertz Curves and to assess the role played by vaccinations in reshaping the trajectory of Covid Infections for India. A total of 21 prominent states are chosen for the analysis encompassing 97\% of the Indian population. Since the vaccination program in India was rolled out after the First wave of infections had almost subsided, the current analysis is only relevant for the Second Wave. Methods: We will try to explore how the different properties of the Gompertz Curves can be used as a convenient tool to study the COVID-19 outbreak in India. The impact of vaccinations has also been studied at the state level to assess the extent to which the roll out of vaccination program has augmented the covid scenario of India. Vaccinations have been incorporated in the analysis by taking the daily cumulative number of individuals having the first and second shots of vaccine in each state as the explanatory variables. Results: The preliminary question that the paper tries to investigate is whether the vaccines capable of checking infection growth. Out of the chosen 21 states, 16 states show positive outcomes with some observable ambiguity for the states of Telangana, West Bengal, Tamil Nadu, Rajasthan and Kerala. Conclusions: Our analysis found that most of the states (16 out of 21 states) has positive impact of vaccination in reducing the Covid-19 cases.

13.
Preprint in English | medRxiv | ID: ppmedrxiv-22283130

ABSTRACT

ABSTRACT Coronavirus 2019 (COVID-19) was caused by the novel severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) and not just affected the Philippines but also globally. Data on real-time PCR cycle threshold (Ct) values were accessible in the healthcare facility and previous studies did not support its direct clinical significance on patients' management. The aim of this study was to investigate the RT-PCR Ct values of admitted COVID-19 confirmed patients in the epidemiologic context from April 2021 to November 2021. A total of 1,245 were tested and out of the 1,038 confirmed COVID-19 admitted patients, 579 (55.78%) were females and 459 were males (44.22%). There were 4 genes detected, namely: N, E, ORF1ab and RdRP genes, and the majority was N gene 925 (88.94%) while the least detected was 203 E gene of SARS-CoV-2. This study described the utilization of five (5) different COVID-19 test kits. Comparing the Ct values between the male and female groups, this study showed no significant differences. To compare between the different age groups and the three classifications of CT values was shown in Table 6. For the N gene, the current study showed a significant difference of CT value <25 among 0-17 years old vs 46-60 years old (p=0.00054), and among 0-17 years old vs >61 (senior citizens) years old group (p=0.00945). Moreover, a significant difference was observed for CT value >30 among 0-17 years vs 18-45 years old (p=0.00411) and among 0-17 years old vs >61 years old group (p=0.00025). CT values for the ORF gene showed significant differences. CT value <25 showed significant differences among 0-17 years versus 45-60 years old (p=0.00907) and 0-17 years versus >60 years old (p=0.04298). Moreover, CT value >30 showed significant differences among 0-17 years versus 46-60 years old (p=0.02344) and 0-17 years versus >60 years old (p=0.3411). Comparing the mean CT values of two consecutive months from April to November, this study showed a significant difference between April and May (p value= 0.0004), August and September (p value= 0.0212), and September and October (p value= 0.002). There was no significant difference with the following months: May and June, June and July, July and August, and October and November (Table 9). Keywords: utilization, cycle threshold values, RT-PCR SARS-Cov-2, COVID-19, cross-sectional study, admitted COVID-19 confirmed patients

14.
Preprint in English | medRxiv | ID: ppmedrxiv-22283023

ABSTRACT

Background: This study aimed to examine whether there have been sustained impacts of the Covid-19 pandemic on smoking patterns in England. Methods: Data were from 101,960 adults ([≥]18y) participating in a monthly representative household survey between June-2017 and August-2022. Interview were conducted face-to-face until March 2020 and via telephone thereafter. Generalised additive models estimated associations of the pandemic onset (March-2020) with current smoking, uptake, cessation, quit attempts, medium-term abstinence, and use of support. Models adjusted for seasonality, sociodemographic characteristics, and (where relevant) dependence and tobacco control mass-media expenditure. Findings: Before the Covid-19 pandemic, smoking prevalence fell by 5.2% per year; this rate of decline slowed to 0.3% per year during the pandemic (RR{Delta}trend=1.06, 95%CI=1.02-1.09). This slowing was evident in more but not less advantaged social grades (RR{Delta}trend=1.15, 1.08-1.21; RR{Delta}trend=1.00, 0.96-1.05). There were sustained step-level changes in different age groups: a 34.9% (95%CI=17.7-54.7%) increase in smoking prevalence among 18-24-year-olds, indicating a potential rise in uptake, in contrast to a 13.6% (95%CI=4.4-21.9%) decrease among 45-65-year-olds. There were sustained increases in quitting among past-year smokers, with a 120.4% (95%CI=79.4-170.9%) step-level increase in cessation and a 41.7% (95%CI=29.7-54.7%) increase in quit attempts. Interpretation: In England, the rate of decline in adult smoking prevalence stagnated during the Covid-19 pandemic. Potential reductions in smoking prevalence among middle-aged adults and sustained increases in quitting among smokers may have been offset by a sustained rise in uptake among young adults. The slowing in the rate of decline was pronounced in more advantaged social grades.

15.
Preprint in English | medRxiv | ID: ppmedrxiv-22283050

ABSTRACT

Since authorization of the Moderna mRNA COVID-19 Vaccine, real-world evidence has indicated its effectiveness in preventing COVID-19 cases. However, increased cases of mRNA vaccine-associated myocarditis/pericarditis have been reported, predominantly in young adults and adolescents. The Food and Drug Administration conducted benefit-risk assessment to inform review of the Biologics License Application for use of the Moderna vaccine among individuals ages 18 years and older. We modeled benefit-risk per million individuals who receive two complete doses of the vaccine. Benefit endpoints were vaccine-preventable COVID-19 cases, hospitalizations, intensive care unit (ICU) admissions, and deaths. The risk endpoints were vaccine-related myocarditis/pericarditis cases, hospitalizations, ICU admissions and deaths. The analysis was conducted on the age-stratified male population, due to data signals and previous work showing males to be the main risk group. We constructed six scenarios to evaluate the impact of uncertainty associated with pandemic dynamics, vaccine effectiveness (VE) against novel variants, and rates of vaccine-associated myocarditis/pericarditis cases on the model results. For our most likely scenario, we assumed the US COVID-19 incidence was for the week of December 25, 2021, and a VE of 30% against cases and 72% against hospitalization with the Omicron-dominant strain. Our source for estimating vaccine-attributable myocarditis/pericarditis rates was FDA's CBER Biologics Effectiveness and Safety (BEST) System databases. Overall, our results supported the conclusion that the benefits of the vaccine outweigh its risks. Remarkably, we predicted vaccinating one million 18-25 year-old males would prevent 82,484 cases, 4,766 hospitalizations, 1,144 ICU admissions, and 51 deaths due to COVID-19, comparing to 128 vaccine-attributable myocarditis/pericarditis cases, 110 hospitalizations, zero ICU admissions, and zero deaths. Uncertainties in the pandemic trajectory, effectiveness of vaccine against novel variants, and vaccine-attributable myocarditis/pericarditis rate are important limitations of our analysis. Also, the model does not evaluate potential long-term adverse effects due to either COVID-19 or vaccine-attributable myocarditis/pericarditis.

16.
Preprint in English | medRxiv | ID: ppmedrxiv-22282992

ABSTRACT

Background: Previous studies have shown that coronavirus disease 2019 (COVID-19) mitigation measures lead to reductions in health status and health-related fitness in children, whereas no data are currently available on the development of children after the removal of these mitigation measures. Therefore, we aimed to investigate the influence of different stringent measures, during and after COVID-19, on the longitudinal development of fitness and health status of primary school children. METHODS: A longitudinal cohort study of 331 primary school children in Austria aged 7.7 (SD-0.4) years at the start of the observation period was conducted. Before (Sept 2019), and during (June 2020, Sept 2020) and after (March 2021, June 2021, Sept 2021, and June 2022) the COVID-19 mitigation measures, fitness tests were carried out and anthropometric data of the children were collected. Age- and sex-specific standard deviation scores (SDSs) were calculated for seven individual fitness tests of the AUT FIT [1] test battery, body mass index, and waist-to-height ratio. In addition, children were classified into different fitness categories based on the AUT FIT summary score. Results: After the implementation of COVID-19 mitigation measures, cardiorespiratory fitness and action speed decreased dramatically, and the number of children with overweight or obesity increased. At the last measurement after the COVID-19 mitigation measures (June 2022), significant improvements in cardiorespiratory fitness and weight status were observed . However, pre-COVID fitness levels were not achieved and BMI was still higher compared to Sept 2019. Interpretation: Our study showed a trend reversal, in that the negative indirect effects of the COVID-19 measures on fitness and health parameters of children were followed by significant improvements in these parameters after the removal of those mitigation measures. At the end of the observation period, a positive trend in the development of fitness and health status was observed, although pre-COVID levels were not reached. Collaborative efforts are needed to reinforce the observed positive trend, and to continue to improve the level of fitness and health status of primary school children, and to mitigate the long-term negative health consequences of the COVID-19 pandemic. Funding: Austrian Federal Ministry of Arts, Culture, Public Service and Sports (GZ2021-0.361.671).

17.
Preprint in English | medRxiv | ID: ppmedrxiv-22282987

ABSTRACT

Importance: Prolonged symptoms following SARS-CoV-2 infection, or Long COVID, is common, but few prospective studies of Long COVID risk factors have been conducted. Objective: To determine whether sociodemographic factors, lifestyle, or medical history preceding COVID-19 or characteristics of acute SARS-CoV-2 infection are associated with Long COVID. Design: Cohort study with longitudinal assessment of symptoms before, during, and after SARS-CoV-2 infection, and cross-sectional assessment of Long COVID symptoms using data from the COVID-19 Citizen Science (CCS) study. Setting: CCS is an online cohort study that began enrolling March 26, 2020. We included data collected between March 26, 2020, and May 18, 2022. Participants: Adult CCS participants who reported a positive SARS-CoV-2 test result (PCR, Antigen, or Antibody) more than 30 days prior to May 4, 2022, were surveyed. Exposures: Age, sex, race/ethnicity, education, employment, socioeconomic status/financial insecurity, self-reported medical history, vaccination status, time of infection (variant wave), number of acute symptoms, pre-COVID depression, anxiety, alcohol and drug use, sleep, exercise. Main Outcome: Presence of at least 1 Long COVID symptom greater than 1 month after acute infection. Sensitivity analyses were performed considering only symptoms beyond 3 months and only severe symptoms. Results: 13,305 participants reported a SARS-CoV-2 positive test more than 30 days prior, 1480 (11.1% of eligible) responded to a survey about Long COVID symptoms, and 476 (32.2% of respondents) reported Long COVID symptoms (median 360 days after infection). Respondents' mean age was 53 and 1017 (69%) were female. Common Long COVID symptoms included fatigue, reported by 230/476 (48.3%), shortness of breath (109, 22.9%), confusion/brain fog (108, 22.7%), headache (103, 21.6%), and altered taste or smell (98, 20.6%). In multivariable models, number of acute COVID-19 symptoms (OR 1.30 per symptom, 95%CI 1.20-1.40), lower socioeconomic status/financial insecurity (OR 1.62, 95%CI 1.02-2.63), pre-infection depression (OR 1.08, 95%CI 1.01-1.16), and earlier variants (OR 0.37 for Omicron compared to ancestral strain, 95%CI 0.15-0.90) were associated with Long COVID symptoms. Conclusions and Relevance: Variant wave, severity of acute infection, lower socioeconomic status and pre-existing depression are associated with Long COVID symptoms.

18.
Preprint in English | medRxiv | ID: ppmedrxiv-22281853

ABSTRACT

The spread of SARS-CoV-2, like that of many other pathogens, is governed by heterogeneity. "Superspreading," or "over-dispersion," is an important factor in transmission, yet it is hard to quantify. Estimates from contact tracing data are prone to potential biases due to the increased likelihood of detecting large clusters of cases, and may reflect variation in contact behavior more than biological heterogeneity. In contrast, the average number of secondary infections per contact is routinely estimated from household surveys, and these studies can minimize biases by testing all members of a household. However, the models used to analyze household transmission data typically assume that infectiousness and susceptibility are the same for all individuals or vary only with predetermined traits such as age. Here we develop and apply a combined forward simulation and inference method to quantify the degree of inter-individual variation in both infectiousness and susceptibility from observations of the distribution of infections in household surveys. First, analyzing simulated data, we show our method can reliably ascertain the presence, type, and amount of these heterogeneities with data from a sufficiently large sample of households. We then analyze a collection of household studies of COVID-19 from diverse settings around the world, and find strong evidence for large heterogeneity in both the infectiousness and susceptibility of individuals. Our results also provide a framework to improve the design of studies to evaluate household interventions in the presence of realistic heterogeneity between individuals.

19.
Preprint in English | medRxiv | ID: ppmedrxiv-22282996

ABSTRACT

Since the emergence of SARS-CoV-2 in 2019 through to mid-2021, much of the Australian population lived in a COVID-19 free environment. This followed the broadly successful implementation of a strong suppression strategy, including international border closures. With the availability of COVID-19 vaccines in early 2021, the national government sought to transition from a state of minimal incidence and strong suppression activities to one of high vaccine coverage and reduced restrictions but with still-manageable transmission. This transition is articulated in the national ``re-opening" plan released in July 2021. Here we report on the dynamic modelling study that directly informed policies within the national re-opening plan including the identification of priority age groups for vaccination, target vaccine coverage thresholds and the anticipated requirements for continued public health measures --- assuming circulation of the Delta SARS-CoV-2 variant. Our findings demonstrated that adult vaccine coverage needed to be at least 70% to minimise public health and clinical impacts following the establishment of community transmission. They also supported the need for continued application of test-trace-isolate-quarantine and social measures during the vaccine roll-out phase and beyond.

20.
Preprint in English | medRxiv | ID: ppmedrxiv-22283077

ABSTRACT

Background COVID and Influenza with non-communicable chronic diseases (NCDs) complicate the diagnosis, treatment, prognosis, and increase mortality rate. The aim: to evaluate the effects of the fast weight loss on clinic and laboratory inflammation profile, metabolic profile, reactive oxygen species (ROS) and body composition in patients with COVID and Influenza in comorbidity with NCDs. Methods A 6-week open, pilot prospective clinical trial including 62 adult patients with COVID (n=27) and influenza (n=35) in comorbidity with T2D, hypertension, and NASH. Overweight in 33 patients (53.2%) with BMI 28.14{+/-}0.39 kg/m2, and 29 patients without overweight with BMI 23.37 {+/-} 0.38 kg/m2. T2D in 26 (41.9%); Hypertension in 38 (61.3%) (incl. 12 patients with T2D); NASH in 51 patients (82.2%) (incl. 8 patients with NASH, T2D and Hypertension; 6 patients with NASH and T2D; 18 patients with NASH and Hypertension; 19 patients with only NASH). Primary endpoints Clinic/infectious/inflammation tests for COVID and Influenza; weight loss during 14 days. Secondary endpoints: fasting blood glucose, HbA1c, blood insulin; systolic/diastolic BP; blood lipids; ALT, AST, chest CT-scan. Results The patients with overweight lost -12,4% from baseline or BMI= -4.2 kg/m2, and patients without overweight lost -9,14% from baseline or BMI= -2.2 kg/m2 (-9.7{+/-}0.7 kg vs. -6.4{+/-}0.6 kg, respectively; P<0.001) at 14-day of the treatment. Weight loss in both groups was due to reduction of fat mass (P<0.0001). Sputum production increased in 1.0-1.5 liter/day on 2-3 days, decreased in 7-9 days. Body temperature normalized in 6-9 days. On 3-5 days, in most patients their urine became turbid/muddy/intensively colored. Urine microscopy showed organic and non-organic salts, and leukocyturia (20-35/sight). White blood cells, lymphocytes, NLR normalized at 14 days (P<0.0001). Total-fibrinogen, C-reactive-protein, and Erythrocyte-sedimentation-rate, ROS normalized at 14-day of treatment (P<0.0001). COVID and Influenza were a negative in >96.3% patients at 14-day. Systolic/diastolic BP decreased (161.3{+/-}1.31/101.6{+/-}0.85 vs. 118.3{+/-}0.46/80.89{+/-}0.66, P<0.0001), glucose and lipids metabolism in patients with T2D (n=26) (P<0.0001); ALT and AST in patients with NASH (n=51) were significantly normalized (from baseline 134.3{+/-}5.4 and 166.5{+/-}5.5 U/L, respectively, and at 14-day to 78.4{+/-}4.2 and 92.4{+/-}4.9 U/L, respectively (P<0.0001)), platelets increased from baseline (186.5{+/-}4.6, x109/L) at 14-day of treatment (238.5{+/-}5.8, x109/L) (P<0.0001), and at 6-week follow-up (278.3{+/-}6.9, x109/L) (P<0.0001). The mean score of chest-CT for the patients (n=44) was 13.12{+/-}0.38 from baseline, and at 14-day the score was 1.72{+/-}0.12 (P<0.0001). ROS level normalized at 14-day treatment and 6-week follow-up from baseline (P<0.0001). The previous antidiabetic, antihypertensive, antiinflammatory and hepatoprotective, and other symptomatic medications were adequately decreased in 2-5 days to completely stopping by 5-8 days treatment. Conclusions The fast weight loss is clinical/laboratory benefit in treatment of patients with COVID-19 and Influenza in comorbidity with T2D, hypertension, and NASH.

21.
Preprint in English | medRxiv | ID: ppmedrxiv-22283103

ABSTRACT

Background: The global COVID-19 pandemic has peaked but some countries such as China are reporting serious infectious outbreaks due to SARS-CoV-2 variants. Waning vaccine-derived immunogenicity and mutations in variants allowing vaccine evasion require new booster immunization approaches. We compared homologous and heterologous boosting in adults previously fully primed with a whole-virus inactivated COVID-19 vaccine. Methods: At multiple sites in the Philippines we enrolled 430 adults (18-72 years) immunized with two doses of CoronaVac at least 3 months previously and randomly assigned them to receive homologous (CoronaVac, n = 216) or heterologous (recombinant protein vaccine, SCB-2019, n = 214) booster doses. Non-inferiority/superiority of the neutralizing antibody (NAb) response 15 days after boosting was measured by microneutralization against prototype SARS-CoV-2, and Delta and Omicron variants in subsets (50 per arm). Participants recorded solicited local and systemic adverse events for 7 days, unsolicited AEs until Day 29, and serious adverse events until Day 60. Results: NAb geometric mean titers (GMT) against prototype on Day 15 were 744 (95% CI: 669-828) and 164 (143-189) in heterologous and homologous groups, respectively, with a heterologous/homologous GMT ratio of 4.63 (3.95-5.41), meeting both pre-defined non-inferiority and superiority criteria. Similarly, geometric mean-fold rises for NAb against Delta and Omicron BA.1, BA.2, BA.4 and BA.5 variants were superior after heterologous SCB-2019 (range 3.01-4.66) than homologous CoronaVac (range 0.85-1.6) in an exploratory analysis. Reactogenicity and safety measures were evenly balanced between groups; the most frequent local reaction was mild or moderate injection site pain; mild or moderate headache and fatigue were the most frequent systemic adverse events. No vaccine-related serious adverse events were reported. Conclusion: Heterologous boosting of CoronaVac-immunized adults with SCB-2019 was well tolerated with superior immunogenicity than homologous boosting, particularly for newly emerged variants, supporting use of SCB-2019 for booster vaccination.

22.
Preprint in English | medRxiv | ID: ppmedrxiv-22283185

ABSTRACT

Healthcare workers (HCW) who come into contact with tuberculosis (TB) patients are at elevated risk of TB infection and disease. The collection and handling of sputum samples for TB diagnosis poses exposure risks to HCW, particularly in settings where aerosol containment is limited. An alternative sample collection method, tongue swabbing, was designed to help mitigate this risk, and is under evaluation in multiple settings. This study assessed risk perceptions among South African HCW who used tongue swabbing in TB diagnostic research during the COVID-19 pandemic. We characterized their context-specific preferences as well as the facilitators and barriers of tongue swab use in clinical and community settings. Participants (n=18) were HCW with experience using experimental tongue swabbing methods at the South African Tuberculosis Vaccine Initiative (SATVI). We used key informant semi-structured interviews to assess attitudes toward two tongue swab strategies: Provider-collected swabbing (PS) and supervised self-swabbing (SSS). Responses from these interviews were analyzed by rapid qualitative analysis and thematic analysis methods. Facilitators included aversion to sputum (PS and SSS), perceived safety of the method (SSS), and educational resources to train patients (SSS). Barriers included cultural stigmas, as well as personal security and control of their work environment when collecting swabs in community settings. COVID-19 risk perception was a significant barrier to the PS method. Motivators for HCW use of tongue swabbing differed substantially by use case, and whether the HCW has the authority and agency to implement safety precautions in specific settings. These findings point to a need for contextually specific educational resources to enhance safety of and adherence to the SSS collection method.

23.
Preprint in English | medRxiv | ID: ppmedrxiv-22283134

ABSTRACT

Background: Information about the effectiveness of oral antivirals in preventing short- and long-term COVID-19-related outcomes during the Omicron surge is limited. We sought to determine the effectiveness of nirmatrelvir-ritonavir and molnupiravir for the outpatient treatment of COVID-19. Methods: We conducted three retrospective target trial emulation studies comparing matched patient cohorts who received nirmatrelvir-ritonavir versus no treatment, molnupiravir versus no treatment, and nirmatrelvir-ritonavir versus molnupiravir in the Veterans Health Administration (VHA). Participants were Veterans in VHA care at risk for severe COVID-19 who tested positive for SARS-CoV-2 in the outpatient setting during January and February 2022. Primary outcomes included all-cause 30-day hospitalization or death and 31-180-day incidence of acute or long-term care admission, death, or post-COVID-19 conditions. For 30-day outcomes, we calculated unadjusted risk rates, risk differences, and risk ratios. For 31-180-day outcomes, we used unadjusted time-to-event analyses. Results: Participants were 90% male with median age 67 years and 26% unvaccinated. Compared to matched untreated controls, nirmatrelvir-ritonavir-treated participants (N=1,587) had a lower 30-day risk of hospitalization (27.10/1000 versus 41.06/1000, risk difference [RD] -13.97, 95% CI -23.85 to -4.09) and death (3.15/1000 versus 14.86/1000, RD -11.71, 95% CI -16.07 to -7.35). Among persons who were alive at day 31, further significant reductions in 31-180-day incidence of hospitalization (sub-hazard ratio 1.07, 95% CI 0.83 to 1.37) or death (hazard ratio 0.61, 95% CI 0.35 to 1.08) were not observed. Molnupiravir-treated participants aged [≥]65 years (n=543) had a lower combined 30-day risk of hospitalization or death (55.25/1000 versus 82.35/1000, RD -27.10, 95% CI -50.63 to -3.58). A statistically significant difference in 30-day or 31-180-day risk of hospitalization or death was not observed between matched nirmatrelvir- or molnupiravir-treated participants. Incidence of most post-COVID conditions was similar across comparison groups. Conclusions: Nirmatrelvir-ritonavir was highly effective in preventing 30-day hospitalization and death. Short-term benefit from molnupiravir was observed in older groups. Significant reductions in adverse outcomes from 31-180 days were not observed with either antiviral.

24.
Preprint in English | medRxiv | ID: ppmedrxiv-22282933

ABSTRACT

Background COVID-19 vaccines with alternative strain compositions are needed to provide broad protection against newly emergent SARS-CoV-2 variants of concern. Methods We conducted a global Phase 3, multi-stage efficacy study (NCT04904549) among adults aged [≥]18 years. Participants were randomized 1:1 to receive two intramuscular injections 21 days apart of a bivalent SARS-CoV-2 recombinant protein vaccine with AS03-adjuvant (5 g of ancestral (D614) and 5 g of B.1.351 [beta] variant spike protein) or placebo. Symptomatic COVID-19 was defined as laboratory-confirmed COVID-19 with COVID-19-like illness (CLI) symptoms. The primary efficacy endpoint was the prevention of symptomatic COVID-19 [≥]14 days after the second injection. Results Between 19 Oct 2021 and 15 Feb 2022, 12,924 participants received [≥]1 study injection. 75% of participants were SARS-CoV-2 non-naive. 11,416 participants received both study injections (efficacy-evaluable population [vaccine, n=5,736; placebo, n=5,680]). Up to 15 March 2022, 121 symptomatic COVID-19 cases were reported (32 in the vaccine group and 89 in the placebo group) [≥]14 days after the second injection with a vaccine efficacy (VE) of 64.7% (95% confidence interval [CI] 46.6; 77.2%). VE was 75.1% (95% CI 56.3; 86.6%) in non-naive and 30.9% (95% CI -39.3; 66.7%) in naive participants. Viral genome sequencing identified the infecting strain in 68 cases (Omicron [BA.1 and BA.2 subvariants]: 63; Delta: 4; Omicron and Delta: 1). The vaccine was well-tolerated and had an acceptable safety profile. Conclusions A bivalent vaccine conferred heterologous protection against symptomatic infection with newly emergent Omicron (BA.1 and BA.2) in non-naive adults 18-59 years of age. ClinicalTrials.gov: NCT04904549

25.
Preprint in English | bioRxiv | ID: ppbiorxiv-519191

ABSTRACT

Biomolecular condensates formed by liquid-liquid phase separation have been implicated in multiple diseases. Modulation of condensate dynamics by small molecules has therapeutic potential, but so far, few condensate modulators have been disclosed. The SARS-CoV-2 nucleocapsid (N) protein forms phase separated condensates that are hypothesized to play critical roles in viral replication, transcription and packaging, suggesting that N condensation modulators might have anti-coronavirus activity across multiple strains and species. Here, we show that N proteins from all seven human coronaviruses (HCoVs) vary in their tendency to undergo phase separation when expressed in human lung epithelial cells. We developed a cell-based high-content screening platform and identified small molecules that both promote and inhibit condensation of SARS-CoV-2 N. Interestingly, these host-targeted small molecules exhibited condensate-modulatory effects across all HCoV Ns. Some have also been reported to exhibit antiviral activity against SARS-CoV-2, HCoV-OC43 and HCoV-229E viral infections in cell culture. Our work reveals that the assembly dynamics of N condensates can be regulated by small molecules with therapeutic potential. Our approach allows for screening based on viral genome sequences alone and might enable rapid paths to drug discovery with value for confronting future pandemics.

26.
Preprint in English | bioRxiv | ID: ppbiorxiv-519032

ABSTRACT

The present study was designed to investigate the effects of a soluble ACE2 protein termed ACE2 618-DDC-ABD, bioengineered to have long duration of action and high binding affinity to SARS-CoV-2, when administered either intranasally (IN) or intraperitoneally (IP) and before or after SARS-CoV-2 inoculation. K18hACE2 mice permissive for SARS-CoV-2 infection were inoculated with 2x104 PFU wildtype SARS-CoV-2. In one protocol, ACE2 618-DDC-ABD was given either IN or IP, pre- and post-viral inoculation. In a second protocol, ACE2 618-DDC-ABD was given either IN, IP or IN+IP but only post-viral inoculation. In addition, A549 and Vero E6 cells were used to test neutralization of SARS-CoV-2 variants by ACE2 618-DDC-ABD at different concentrations. Survival by day 5 was 0% in infected untreated mice, and 40% in mice from the ACE2 618-DDC-ABD IP-pre treated group. By contrast, in the IN-pre group survival was 90%, histopathology of brain and kidney was essentially normal and markedly improved in the lungs. When ACE2 618-DDC-ABD was administered only post viral inoculation, survival was 30% in the IN+IP group, 20% in the IN and 0% in the IP group. Brain SARS-CoV-2 titers were high in all groups except for the IN-pre group where titers were undetectable in all mice. In cells permissive for SARS-CoV-2 infection, ACE2 618-DDC-ABD neutralized wildtype SARS-CoV-2 at high concentrations, whereas much lower concentrations neutralized omicron BA.1. We conclude that ACE2 618-DDC-ABD provides much better survival and organ protection when administered IN and prior to viral inoculation than when given IP or after inoculation and that lowering brain titers is a critical determinant of survival and organ protection.

27.
Preprint in English | bioRxiv | ID: ppbiorxiv-519037

ABSTRACT

The global COVID-19 pandemic has lasted for three years since its outbreak, however its origin is still unknown. Here, we analyzed the genotypes of 3.14 million SARS-CoV-2 genomes based on the amino acid 614 of the Spke (S) and the amino acid 48 of NS8 (nonstructural protein 8), and identified 16 linkage haplotypes. The GL haplotype (S_614G and NS8_48L) was the major haplotype driving the global pandemic and accounted for 99.2% of the sequenced genomes, while the DL haplotype (S_614D and NS8_48L) caused the pandemic in China in the spring of 2020 and accounted for approximately 60% of the genomes in China and 0.45% of the global genomes. The GS (S_614G and NS8_48S), DS (S_614D and NS8_48S) and NS (S_614N and NS8_48S) haplotypes accounted for 0.26%, 0.06%, and 0.0067% of the genomes, respectively. The main evolutionary trajectory of SARS-CoV-2 is DS[->]DL[->]GL, whereas the other haplotypes are minor byproducts in the evolution. Surprisingly, the newest haplotype GL had the oldest time of most recent common ancestor (tMRCA), which was May 1 2019 by mean, while the oldest haplotype had the newest tMRCA with a mean of October 17, indicating that the ancestral strains that gave birth to GL had been extinct and replaced by the more adapted newcomer at the place of its origin, just like the sequential rise and fall of the delta and omicron variants. However, they arrived and evolved into toxic strains and ignited a pandemic in China where the GL strains did not exist at the end of 2019. The GL strains had spread all over the world before they were discovered, and ignited the global pandemic, which had not been noticed until the pandemic was declared in China. However, the GL haplotype had little influence in China during the early phase of the pandemic due to its late arrival as well as the strict transmission controls in China. Therefore, we propose two major onsets of the COVID-19 pandemic, one was mainly driven by the haplotype DL in China, the other was driven by the haplotype GL globally.

28.
Preprint in English | bioRxiv | ID: ppbiorxiv-518611

ABSTRACT

Despite the worldwide success of mRNA-LNP Covid-19 vaccines, the nanoscale structure of these formulations is still poorly understood. To fill this gap, we used a combination of atomic force microscopy (AFM), dynamic light scattering (DLS), transmission electron microscopy (TEM), cryogenic transmission electron microscopy (cryo-TEM) and the determination of LNP pH gradient to analyze the nanoparticles (NPs) in BNT162b2 (Comirnaty), comparing it with the well characterized pegylated liposomal doxorubicin (Doxil). Comirnaty NPs had similar size to Doxil, however, unlike Doxil liposomes, wherein the stable ammonium and pH gradient enables accumulation of 14C-methylamine in the intraliposomal aqueous phase, Comirnaty LNPs lack such pH gradient in spite of the fact that the pH 4, at which LNPs are prepared, is raised to pH 7.2 after loading of the mRNA. Mechanical manipulation of Comirnaty NPs with AFM revealed soft, compliant structures. The sawtooth-like force transitions seen during cantilever retraction implies that molecular strands, corresponding to mRNA, can be pulled out of NPs, and the process is accompanied by stepwise rupture of mRNA-lipid bonds. Unlike Doxil, cryo-TEM of Comirnaty NPs revealed a granular, solid core enclosed by mono- and bilayers. Negative staining TEM shows 2-5 nm electron-dense spots in the liposoms interior that are aligned into strings, semicircles, or labyrinth-like networks, which may imply crosslink-stabilized supercoils. The neutral intra-LNP core questions the dominance of ionic interactions holding together this scaffold, raising the alternative possibility of hydrogen bonding between the mRNA and the lipids. Such interaction, described previously for another mRNA/lipid complex, is consistent with the steric structure of ionizable lipid in Comirnaty, ALC-0315, displaying free =O and -OH groups. It is hypothesized that the latter groups can get into steric positions that enable hydrogen bonding with the nitrogenous bases in the mRNA. These newly recognized structural features of mRNA-LNP may be important for the vaccines efficacy.

29.
Preprint in English | bioRxiv | ID: ppbiorxiv-518843

ABSTRACT

The first 2 years of the COVID-19 pandemic were mainly characterized by convergent evolution of mutations of SARS-CoV-2 Spike protein at residues K417, L452, E484, N501 and P681 across different variants of concern (Alpha, Beta, Gamma, and Delta). Since Spring 2022 and the third year of the pandemic, with the advent of Omicron and its sublineages, convergent evolution has led to the observation of different lineages acquiring an additional group of mutations at different amino acid residues, namely R346, K444, N450, N460, F486, F490, Q493, and S494. Mutations at these residues have become increasingly prevalent during Summer and Autumn 2022, with combinations showing increased fitness. The most likely reason for this convergence is the selective pressure exerted by previous infection- or vaccine-elicited immunity. Such accelerated evolution has caused failure of all anti-Spike monoclonal antibodies, including bebtelovimab and cilgavimab. While we are learning how fast coronaviruses can mutate and recombine, we should reconsider opportunities for economically sustainable escape-proof combination therapies, and refocus antibody-mediated therapeutic efforts on polyclonal preparations that are less likely to allow for viral immune escape.

30.
Preprint in English | bioRxiv | ID: ppbiorxiv-518956

ABSTRACT

Protein is the building block for all organisms. Protein structure prediction is always a complicated task in the field of proteomics. DNA and protein databases can find the primary sequence of the peptide chain and even similar sequences in different proteins. Mainly, there are two methodologies based on the presence or absence of a template for Protein structure prediction. Template-based structure prediction (threading and homology modeling) and Template-free structure prediction (ab initio). Numerous web-based servers that either use templates or do not can help us forecast the structure of proteins. In this current study, ORF7a, a transmembrane protein of the SARS-coronavirus, is predicted using Phyre2, IntFOLD, and Robetta. The protein sequence is straightforwardly entered into the sequence bar on all three web servers. Their findings provided information on the domain, the region with the disorder, the global and local quality score, the predicted structure, and the estimated error plot. Our study presents the structural details of the SARS-CoV protein ORF7a. This immunomodulatory component binds to immune cells and induces severe inflammatory reactions.

31.
Preprint in English | bioRxiv | ID: ppbiorxiv-518937

ABSTRACT

The major concern of COVID-19 therapeutic monoclonal antibodies is the loss of efficacy to continuously emerging SARS-CoV-2 variants. To predict the antibodies efficacy to the future Omicron subvariants, we conducted deep mutational scanning (DMS) encompassing all single mutations in the receptor binding domain of BA.2 strain. In case of bebtelovimab that preserves neutralization activity against BA.2 and BA.5, broad range of amino acid substitutions at K444, V445 and G446 and some substitutions at P499 and T500 were indicated to achieve the antibody escape. Among currently increasing subvariants, BA2.75 carrying G446S partly and XBB with V445P and BQ.1 with K444T completely evade the neutralization of bebtelovimab, consistent with the DMS results. DMS can comprehensively characterize the antibody escape for efficient and effective management of future variants.

32.
Preprint in English | bioRxiv | ID: ppbiorxiv-518963

ABSTRACT

The continuous evolution of SARS-CoV-2 strains is contributing to the prolongation of the global pandemic. We previously reported the prevention or more rapid clearance of SARS-CoV-2 from the nasal turbinates and lungs of susceptible K18-hACE2 mice that had been vaccinated intranasally (IN) rather than intramuscularly (IM) with a recombinant MVA (rMVA) expressing a modified S protein of the ancestor SARS-CoV-2 strain. Here, we constructed additional rMVAs and pseudoviruses expressing modified S protein of SARS-CoV-2 variants and compared the ability of vaccines with S proteins that were matched or mismatched to neutralize variants, bind to S proteins and protect K18-hACE2 mice against SARS-CoV-2 challenge. Although vaccines with matched S proteins induced higher neutralizing antibodies, vaccines with mismatched S proteins still protected against severe disease and reduced virus and mRNAs in the lungs and nasal turbinates, though not as well as vaccines with matched S proteins. In mice earlier primed and boosted with rMVA expressing ancestral S, antibodies to the latter increased after one immunization with rMVA expressing Omicron S, but neutralizing antibody to Omicron required a second immunization. Passive transfer of Wuhan immune serum with Omicron S binding but undetectable neutralizing activities reduced infection of the lungs by the variant. Notably, the reduction in infection of the nasal turbinates and lungs was significantly greater when the rMVAs were administered IN rather than IM and this held true for vaccines that were matched or mismatched to the challenge SARS-CoV-2.

33.
Preprint in English | bioRxiv | ID: ppbiorxiv-519085

ABSTRACT

In late 2022, although the SARS-CoV-2 Omicron subvariants have highly diversified, some lineages have convergently acquired amino acid substitutions at five critical residues in the spike protein. Here, we illuminated the evolutionary rules underlying the convergent evolution of Omicron subvariants and the properties of one of the latest lineages of concern, BQ.1.1. Our phylogenetic and epidemic dynamics analyses suggest that Omicron subvariants independently increased their viral fitness by acquiring the convergent substitutions. Particularly, BQ.1.1, which harbors all five convergent substitutions, shows the highest fitness among the viruses investigated. Neutralization assays show that BQ.1.1 is more resistant to breakthrough BA.2/5 infection sera than BA.5. The BQ.1.1 spike exhibits enhanced binding affinity to human ACE2 receptor and greater fusogenicity than the BA.5 spike. However, the pathogenicity of BQ.1.1 in hamsters is comparable to or even lower than that of BA.5. Our multiscale investigations provide insights into the evolutionary trajectory of Omicron subvariants.

34.
Preprint in English | bioRxiv | ID: ppbiorxiv-519151

ABSTRACT

Entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) into host cells depends on refolding of the virus-encoded spike protein from a prefusion conformation, metastable after cleavage, to a lower energy, stable postfusion conformation. This transition overcomes kinetic barriers for fusion of viral and target cell membranes. We report here a cryo-EM structure of the intact postfusion spike in a lipid bilayer that represents single-membrane product of the fusion reaction. The structure provides structural definition of the functionally critical membraneinteracting segments, including the fusion peptide and transmembrane anchor. The internal fusion peptide forms a hairpin-like wedge that spans almost the entire lipid bilayer and the transmembrane segment wraps around the fusion peptide at the last stage of membrane fusion. These results advance our understanding of the spike protein in a membrane environment and may guide development of intervention strategies.

35.
Preprint in English | bioRxiv | ID: ppbiorxiv-518997

ABSTRACT

Recent advancements in the use of single-cell technologies in large cohort studies enable the investigation of cellular response and mechanisms associated with disease outcome, including COVID-19. Several efforts have been made using single-cell RNA-sequencing to better understand the immune response to COVID-19 virus infection. Nonetheless, it is often difficult to compare or integrate data from multiple data sets due to challenges in data normalisation, metadata harmonisation, and having a common interface to quickly query and access this vast amount of data. Here we present Covidscope (http://covidsc.d24h.hk/), a well-curated open web resource that currently contains single-cell gene expression data and associated metadata of almost 5 million blood and immune cells extracted from almost 1,000 COVID-19 patients across 20 studies around the world. Our collection contains the integrated data with harmonised metadata and multi-level cell type annotations. By combining NoSQL and optimised index, our Covidscope achieves rapid subsetting of high-dimensional gene expression data based on both data set level, donor-level (e.g., age and sex of patients) and cell-level (e.g., expression of specific gene markers) metadata, enabling multiple efficient downstream single-cell meta-analysis.

36.
Preprint in English | bioRxiv | ID: ppbiorxiv-519135

ABSTRACT

Topologically associating domains (TADs) are critical structural units in three-dimensional genome organization of mammalian genome. Dynamic reorganizations of TADs between health and disease states are associated with transcription and other essential genome functions. However, computational methods that can identify reorganized TADs are still in the early stages of development. Here, we present DiffDomain, an algorithm leveraging high-dimensional random matrix theory to identify structurally reorganized TADs using chromatin contact maps. Method comparison using multiple real Hi-C datasets reveals that DiffDomain outperforms alternative methods for FPRs, TPRs, and identifying a new subtype of reorganized TADs. The robustness of DiffDomain and its biological applications are demonstrated by applying on Hi-C data from different cell types and disease states. Identified reorganized TADs are associated with structural variations and changes in CTCF binding sites and other epigenomic changes. By applying to a single-cell Hi-C data from mouse neuronal development, DiffDomain can identify reorganized TADs between cell types with reasonable reproducibility using pseudo-bulk Hi-C data from as few as 100 cells per condition. Moreover, DiffDomain reveals that TADs have clear differential cell-to-population variability and heterogeneous cell-to-cell variability. Therefore, DiffDomain is a statistically sound method for better comparative analysis of TADs using both Hi-C and single-cell Hi-C data.

37.
Preprint in English | bioRxiv | ID: ppbiorxiv-518949

ABSTRACT

While vaccines have by large been found to effective against the evolving SARS-CoV-2 variants, the profound and rapid effectivity of monoclonal antibodies (mAbs) in significantly reducing hospitalization to severe disease outcomes have also been demonstrated. In the present study, by high resolution cryo-electron microscopy (cryo-EM), we examined the structural insights of two trimeric spike (S) protein bound mAbs isolated from an Indian convalescent individual infected with ancestral SARS-CoV-2 which we recently reported to potently neutralize SARS-CoV-2 from its ancestral form through highly virulent Delta form however different in their ability to neutralize Omicron variants. Our findings showed binding and conformational heterogeneities of both the mAbs (THSC20.HVTR04 and THSC20.HVTR26) bound to S trimer in its apo and hACE-2 bound forms. Additionally, cryo-EM resolved structure assisted modeling highlighted key residues associated with the ability of these two mAbs to neutralize Omicron variants. Our findings highlighted key interacting features modulating antigen-antibody interacting that can further aid in structure guided antibody engineering to enhance their breadth and potency. HighlightsO_LITwo potent human mAbs obtained from a single donor differ binding to Omicron spikes C_LIO_LIPattern of binding and conformation of these mAbs bound to full length spike differs C_LIO_LIAntibody binding alters the conformational states of S trimer in its apo and hACE-2 bound forms. C_LIO_LICryo-EM structure guided modeling highlighted correlates of interacting residues associated with resistance and sensitivity of BA.1, BA.2, BA.4/BA.5 resistance and sensitivity against these mAbs. C_LI

38.
Preprint in English | bioRxiv | ID: ppbiorxiv-519140

ABSTRACT

With the resurgence of the coronavirus pandemic, the repositioning of FDA-approved drugs against coronovirus and finding alternative strategies for antiviral therapy are both important. We previously identified the viral lipid envelope as a potential target for the prevention and treatment of SARS-CoV-2 infection with plant alkaloids [1]. Here, we investigated the effects of eleven cyclic lipopeptides (CLPs), including well-known antifungal and antibacterial compounds, on the liposome fusion triggered by calcium, polyethylene glycol 8000, and a fragment of SARS-CoV-2 fusion peptide (816-827) by calcein release assays. Differential scanning microcalorimetry of the gel-to-liquid-crystalline and lamellar-to-inverted hexagonal phase transitions and confocal fluorescence microscopy demonstrated the relation of the fusion inhibitory effects of CLPs to alterations in lipid packing, membrane curvature stress and domain organization. The effects of the compounds were evaluated in an in vitro Vero-based cell model, and aculeacin A, anidulafugin, iturin A, and mycosubtilin attenuated the cytopathogenicity of SARS-CoV-2 without specific toxicity.

39.
Preprint in English | medRxiv | ID: ppmedrxiv-22283069

ABSTRACT

Epidemiological application of chaos theory methods have uncovered the existence of chaotic markers in SARS-CoV-2s epidemiological data, including low dimensional attractors with positive Lyapunov exponents, and evidence markers of a dynamics that is close to the onset of chaos for different regions. We expand on these previous works, performing a comparative study of United States of America (USA) and Canadas COVID-19 daily hospital occupancy cases, applying a combination of chaos theory, machine learning and topological data analysis methods. Both countries show markers of low dimensional chaos for the COVID-19 hospitalization data, with a high predictability for adaptive artificial intelligence systems exploiting the recurrence structure of these attractors, with more than 95% R2 scores for up to 42 days ahead prediction. The evidence is favorable to the USAs hospitalizations being closer to the onset of chaos and more predictable than Canada, the reasons for this higher predictability are accounted for by using topological data analysis methods.

40.
Preprint in English | medRxiv | ID: ppmedrxiv-22283067

ABSTRACT

RT-qPCR is considered the gold standard for diagnosis of COVID-19; however, it is laborious, time-consuming, and expensive. RADTs have evolved recently as relatively inexpensive methods to address these shortcomings, but their performance for detecting different SARS-COV-2 variants remains limited. RADT test performance could be enhanced using different antibody labeling and signal detection techniques. Here, we aimed to evaluate the performance of two Wondfo antigen RADTs for detecting different SARS-CoV-2 variants: (i) the conventional colorimetric RADT (Ab-conjugated with gold beads); and (ii) the new Finecare RADT (Ab-coated fluorescent beads). Finecare is a meter used for the detection of a fluorescent signal. 187 frozen nasopharyngeal swabs collected in Universal transport (UTM) that are RT-qPCR positive for different SARS-CoV-2 variants were selected, including 60 Alpha, 59 multiple Delta, and 108 multiple Omicron variants. 60 flu and 60 RSV-positive samples were included as negative controls (total sample number=349). The conventional RADT showed sensitivity, specificity, positive predictive value (PPV), and negative predictive value (NPV) of 62.4% (95%CI: 54-70), 100% (95%CI: 97-100), 100% (95%CI: 100-100), and 58% (95%CI: 49-67) respectively. These measurements were enhanced using the Finecare RADT: sensitivity, specificity, PPV, and NPV were 92.6% (95%CI: 89.08-92.3), 96% (95%CI: 96-99.61), 98% (95%CI: 89-92.3), and 85% (95%CI: 96-99.6) respectively. The sensitivity of both RADTs could be greatly underestimated because nasopharyngeal swab samples collected UTM and stored at -80 {degrees}C were used. Despite that, our results indicate that the Finecare RADT is appropriate for clinical laboratory and community-based surveillance due to its high sensitivity and specificity.

41.
Preprint in English | medRxiv | ID: ppmedrxiv-22283006

ABSTRACT

BackgroundSevere acute respiratory syndrome-coronavirus-2 (SARS-CoV-2) infection can be asymptomatic in young children. Therefore, the true rate of infection is likely underestimated. Few data are available on the rate of infections in young children, and studies on the SARS-CoV-2 seroprevalence among children during omicron wave are limited. Our study aims to assess the SARS-CoV-2 infection-induced seroprevalence among children and estimated the associated risk factors for seropositivity. MethodsA longitudinal serological survey was conducted from January 2021 through November 2022. Samples were tested for anti-nucleocapsid (N) IgG, anti-receptor binding domain (RBD) IgG using a chemiluminescent microparticle immunoassay (CMIA) and detected anti-RBD Immunoglobulin (Ig) using an electrochemiluminescence immunoassay (ECLIA). The vaccination and SARS-CoV-2 infection history were collected. ResultsA total of 452 serum samples were obtained from 249 children aged 5-7 years old who were annually followed-up in the longitudinal serological survey. Of these, 191 participants provided samples at two serial time points, including during the pre-and omicron dominant wave. Overall, seroprevalence induced by SARS-CoV-2 infection was increased from 9.1% (95%CI: 0.6-12.6%) during the pre-omicron wave to 49.7% (95%CI: 35.9-66.8%) during the omicron wave. Amongst seropositive individuals, the infection-induced seroprevalence was lower in vaccinated participants than those with no vaccination (40.4% vs. 57.4%; risk ratio, 0.71; 95%CI: 0.52-0.95). Nevertheless, the ratio of seropositive cases per recalled infection was 1.56 during the omicron dominant wave. In addition, overall seroprevalence induced by infection, vaccination and hybrid immunity was 76.6% (151/197; 95%CI: 54.6-97.9%) between January and November 2022. Conclusionsour study reports an increase in infection-induced seroprevalence among children during the omicron wave. These findings highlight that estimating seroprevalence is crucial to monitor SARS-CoV-2 exposure, particularly in asymptomatic infection, and help to optimize public health policies and determine the effect of immunization in the pediatric population.

42.
Preprint in English | medRxiv | ID: ppmedrxiv-22282927

ABSTRACT

BackgroundIn low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can characterise the scale and determinants of the pandemic, as well as elucidate protection conferred by prior exposure. MethodsWe conducted repeated cross-sectional serosurveys (July 2020 - November 2021) using residual plasma from routine convenient blood samples from patients with non-COVID-19 conditions from Cape Town, South Africa. SARS-CoV-2 anti-nucleocapsid antibodies and linked clinical information were used to investigate: (1) seroprevalence over time and risk factors associated with seropositivity, (2) ecological comparison of seroprevalence between subdistricts, (3) case ascertainment rates, and (4) the relative protection against COVID-19 associated with seropositivity and vaccination statuses, to estimate variant disease severity. FindingsAmong the subset sampled, seroprevalence of SARS-CoV-2 in Cape Town increased from 39.2% in July 2020 to 67.8% in November 2021. Poorer communities had both higher seroprevalence and COVID-19 mortality. Only 10% of seropositive individuals had a recorded positive SARS-CoV-2 test. Antibody positivity before the start of the Omicron BA.1 wave (28 November 2021) was strongly protective for severe disease (adjusted odds ratio [aOR] 0.15; 95%CI 0.05-0.46), with additional benefit in those who were also vaccinated (aOR 0.07, 95%CI 0.01-0.35). InterpretationThe high population seroprevalence in Cape Town was attained at the cost of substantial COVID-19 mortality. At the individual level, seropositivity was highly protective against subsequent infections and severe COVID-19. FundingWellcome Trust, National Health Laboratory Service, the Division of Intramural Research, NIAID, NIH (ADR) and Western Cape Government Health. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSIn low- and middle-income countries where SARS-CoV-2 testing is limited, seroprevalence studies can help describe the true extent of the pandemic. Infection from Omicron was associated with less severe disease in South Africa, but it is unclear whether this was due to a decrease in virulence of the variant or if prior infection provided protection. Added value of this studyThe seroprevalence data nested within a population cohort enabled us to assess differential case ascertainment rates, as well as to examine the contribution of both natural and vaccine-induced immunity in protecting communities against infections and severe disease with different SARS-CoV-2 variants. Implications of the available evidenceInequality and differential access to resources resulted in poorer communities having higher seroprevalence and COVID-19 death rates, with lower case ascertainment rates. Antibody positivity provided strong protection against an immune escape variant like Omicron but came at a high mortality cost.

43.
Preprint in English | medRxiv | ID: ppmedrxiv-22282902

ABSTRACT

Age is a significant risk factor for the coronavirus disease 2019 (COVID-19) outcomes due to immunosenescence and certain age-dependent medical conditions (e.g., obesity, cardiovascular disorder, diabetes, chronic respiratory disease). However, despite the well-known influence of age on autoantibody biology in health & disease, its impact on the risk of developing severe COVID-19 remains poorly explored. Here, we performed a cross-sectional study of autoantibodies directed against 58 targets associated with autoimmune diseases in 159 individuals with different COVID-19 outcomes (with 71 mild, 61 moderate, and 27 severe patients) and 73 healthy controls. We found that the natural production of autoantibodies increases with age and is exacerbated by SARS-CoV-2 infection, mostly in severe COVID-19 patients. Multivariate regression analysis showed that severe COVID-19 patients have a significant age-associated increase of autoantibody levels against 16 targets (e.g., amyloid {beta} peptide, {beta} catenin, cardiolipin, claudin, enteric nerve, fibulin, insulin receptor a, and platelet glycoprotein). Principal component analysis with spectrum decomposition based on these autoantibodies indicated an age-dependent stratification of severe COVID-19 patients. Random forest analysis ranked autoantibodies targeting cardiolipin, claudin, and platelet glycoprotein as the three most crucial autoantibodies for the stratification of severe elderly COVID-19 patients. Follow-up analysis using binomial regression found that anti-cardiolipin and anti-platelet glycoprotein autoantibodies indicated a significantly increased likelihood of developing a severe COVID-19 phenotype, presenting a synergistic effect on worsening COVID-19 outcomes. These findings provide new key insights to explain why elderly patients less favorable outcomes have than young individuals, suggesting new associations of distinct autoantibody levels with disease severity.

44.
Preprint in English | medRxiv | ID: ppmedrxiv-22282932

ABSTRACT

In summer of 2022, a cohort of 28 staff members were recruited from a UK primary school setting. The prevalent variants at the time were Omicron BA.1.159, BA.4/5 and BA.2: 61% of the cohort reported a lateral flow confirmed positive test for SARS-CoV-2 infection in late 2021 or 2022. A fully quantitative antibody screen for concentration and affinity was performed for spike protein variants Wuhan, Alpha, Beta, Gamma, Delta and Omicron BA.1, BA.2.75, BA.2.12.1, BA.4 and BA.5 and a pH dependent affinity was derived from disruption of the epitope-paratope complex at pH 3.2. The cohort showed a Universal positive immunity endotype, U(+), incidence of 78% (95% CI 60% - 88%) with good antibody concentrations to all ten variants; the incidence drops to 25% (95% CI 13% - 43%) when the affinity spectrum is measured. The antibody affinity profiles for each Omicron variant were all significantly better than Alpha, Beta, Gamma and Delta reflecting exposure to the antigens; we surmise either from the booster vaccines or continual contact with the virus, presenting in the school children either asymptomatically or symptomatically. Significant antibody affinity maturation was seen to the spike protein in all prevalent variants of SARS-CoV-2. Antibody concentrations were waning compared to the post-booster vaccine response. Using our hypothesised 3.4 mg/L nasal mucosal protection threshold, we postulate 46% of the cohort required boosting within 60 days and 66% within 120 days. We propose a smart boosting programme around the constant-exposure teacher cohort and parents of children could reduce community transmission.

45.
Preprint in English | medRxiv | ID: ppmedrxiv-22283089

ABSTRACT

Structured AbstractO_ST_ABSObjectiveC_ST_ABSIt has been hypothesized that SARS-CoV-2 infection in children can increase risk of developing type 1 diabetes. Research Design and MethodsWe undertook a prospective analysis based on all children in Denmark where we investigated the association between SARS-CoV-2 infection and subsequent risk of type 1 diabetes, using information from several different national Danish registers. Denmark had one of the highest test-rates per capita in the world during the pandemic. ResultsWe did not observe a higher risk of a first time diagnosis of type 1 diabetes in children 30 days or more after a positive SARS-CoV-2 test, compared to children with a history of only negative SARS-CoV-2 tests (Hazard ratio 0.85, 95% CI 0.70, 1.04). ConclusionsOur data do not support that SARS-CoV-2 infection is associated with type 1 diabetes, or that type 1 diabetes should be a special focus after a SARS-CoV-2 infection in children. Article HighlightsO_ST_ABSWhy did we undertake this study?C_ST_ABSO_LIStudies have shown an association between SARS-CoV-2 infection and subsequent risk of type 1 diabetes, supporting the possibility of a viral etiology in type 1 diabetes and adding to concerns regarding adverse health consequences of COVID-19. C_LI What is the specific question(s) we wanted to answer?O_LIIs the risk of new onset type 1 diabetes increased among children in the period after SARS-CoV-2 infection? C_LI What did we find?O_LIWe estimated the relative risk of being diagnosed with type 1 diabetes after a positive compared to a negative SARS-CoV-2 test, to 0.85 (95% CI 0.70, 1.04). C_LI What are the implications of our findings?O_LIOur data do not support an association between SARS-CoV-2 infection and subsequent risk of type 1 diabetes among children. C_LI Twitter SummaryA study based on all children in Denmark does not show any association between #SarsCoV2 infection and subsequent risk of #Type1Diabetes among persons < 18 years. #Type1Diabetes should not be a special focus after a #SarsCoV2 infection in children.

46.
Preprint in English | medRxiv | ID: ppmedrxiv-22283074

ABSTRACT

Colleges and universities in the US struggled to provide safe in-person education throughout the COVID-19 pandemic. Testing coupled with isolation is a nimble intervention strategy that can be tailored to mitigate health and economic costs, as the virus and our arsenal of medical countermeasures continue to evolve. We developed a decision-support tool to aid in the design of university-based testing strategies using a mathematical model of SARS-CoV-2 transmission. Applying this framework to a large public university reopening in the fall of 2021 with a 60% student vaccination rate, we find that the optimal strategy, in terms of health and economic costs, is twice weekly antigen testing of all students. This strategy provides a 95% guarantee that, throughout the fall semester, case counts would not exceed the CDCs original high transmission threshold of 100 cases per 100k persons over 7 days. As the virus and our medical armament continue to evolve, testing will remain a flexible tool for managing risks and keeping campuses open. We have implemented this model as an online tool to facilitate the design of testing strategies that adjust for COVID-19 conditions, university-specific parameters, and institutional goals. Author SummaryAs a part of the COVID-19 response team at a large public university in the US, we performed an analysis that considered together, the potential health and economic costs of different testing policies for the student body. University administrators had to weigh the up-front effort needed to implement wide scale testing against the potential costs of responding to high levels of disease on campus in the Fall of 2021, after vaccines were widely available but vaccination rates among college students were uncertain. The results presented here are applied to this specific instance, but the online tool provided can be tailored to university specific parameters, the epidemiological conditions, and the goals of the university. As we confront newly emerging variants of COVID-19 or novel pathogens, consideration of both the health and economic costs of proactive testing may serve as a politically tractable and cost-effective disease mitigation strategy.

47.
Preprint in English | medRxiv | ID: ppmedrxiv-22282938

ABSTRACT

The spatio-temporal course of an epidemic (such as Covid-19) can be significantly affected by non-pharmaceutical interventions (NPIs), such as full or partial lockdowns. Bayesian Susceptible-Infected-Removed (SIR) models can be applied to the spatio-temporal spread of infectious disease (STIF) (such as Covid-19). In causal inference it is classically of interest to investigate counterfactuals. In the context of STIF it is possible to use nowcasting to assess the possible counterfactual realization of disease in incidence that would have been evidenced with no NPI. Classic lagged dependency spatio-temporal IF models will be discussed and the importance of the ST component in nowcasting will be assessed. The real example of lockdowns for Covid-19 in two US states during 2020 and 2021 is provided. The degeneracy in prediction in longer time periods is highlighted and the wide confidence intervals characterize the forecasts.

48.
Preprint in English | medRxiv | ID: ppmedrxiv-22282697

ABSTRACT

SARS-CoV-2 Omicron has become the predominant variant globally. Current infection models are limited by the need for large datasets or calibration to specific contexts, making them difficult to cater for different settings. To ensure public health decision-makers can easily consider different public health interventions (PHIs) over a wide range of scenarios, we propose a generalized multinomial probabilistic model of airborne infection to systematically capture group characteristics, epidemiology, viral loads, social activities, environmental conditions, and PHIs, with assumptions made on social distancing and contact duration, and estimate infectivity over short time-span group gatherings. This study is related to our 2021 work published in Nature Scientific Reports that modelled airborne SARS-CoV-2 infection (Han, Lam, Li, et al., 2021).1 It is differentiated from former works on probabilistic infection modelling in terms of the following: (1) predicting new cases arising from more than one infectious in a gathering, (2) incorporating additional key infection factors, and (3) evaluating the effectiveness of multiple PHIs on SARS-CoV-2 infection simultaneously. Although our results reveal that limiting group size has an impact on infection, improving ventilation has a much greater positive health impact. Our model is versatile and can flexibly accommodate other scenarios by allowing new factors to be added, to support public health decision-making.

49.
Preprint in English | medRxiv | ID: ppmedrxiv-22283026

ABSTRACT

BackgroundHealthcare across all sectors, in the UK and globally, was negatively affected by the COVID-19 pandemic. We investigated the effect of the COVID-19 pandemic on the quantity of healthcare services delivered to people with pancreatic cancer. MethodsWith the approval of NHS England, and drawing from a nationally representative OpenSAFELY-TPP dataset of 24 million patients (over 40% of the English population), we undertook a cohort study of people diagnosed with pancreatic cancer. We queried electronic healthcare records for information on the provision of healthcare services across the pancreatic cancer pathway. To estimate the effect of the COVID-19 pandemic, we predicted the rates of healthcare services if the pandemic had not happened. We used generalised linear models (GLM) and the pre-pandemic data from January 2015 to February 2020 to predict rates in March 2020 to September 2022. The 95% confidence intervals of the predicted values were used to estimate the significance of the difference between the predicted and observed rates. ResultsThe rate of pancreatic cancer and diabetes diagnoses in the cohort was not affected by the pandemic. There were 24,500 people diagnosed with pancreatic cancer from January 2015 to September 2022. The mean age at diagnosis was 72 ({+/-}11 SD), 48% of people were female, 95% were of White ethnicity and 39% were diagnosed with diabetes. We found a reduction in surgical resections by nearly 25% during the pandemic. In addition, 20%, 10% and 5% fewer people received BMI, HbA1c and liver function tests respectively before they were diagnosed with pancreatic cancer. There was no impact of the pandemic on the number of people making contact with primary care, but the number of contacts increased on average by 1 to 2 per person amongst those who made contact. Abdominal scans decreased by 7% and reporting of jaundice decreased by 20%, but recovered within six months into the pandemic. Emergency department visits, hospital admissions and deaths were not affected. ConclusionsThe pandemic affected healthcare in England across the pancreatic cancer pathway. Positive lessons could be learnt from services that recovered quickly. The reductions in healthcare experienced by people with cancer have the potential to lead to worse outcomes. Current efforts should focus on addressing the unmet needs of people with cancer.

50.
Preprint in English | medRxiv | ID: ppmedrxiv-22282946

ABSTRACT

Background: Social determinants of health are non-medical factors that influence health outcomes (SDOH). There is a wealth of SDOH information available via electronic health records, clinical reports, and social media, usually in free texts format, which poses a significant challenge and necessitates the use of natural language processing (NLP) techniques to extract key information. Objective: The objective of this research is to advance the automatic extraction of SDOH from clinical texts. Setting and Data: The case reports of COVID-19 patients from the published literature are curated to create a corpus. A portion of the data is annotated by experts to create gold labels, and active learning is used for corpus re-annotation. Methods: A named entity recognition (NER) framework is developed and tested to extract SDOH along with a few prominent clinical entities (diseases, treatments, diagnosis) from the free texts. The proposed model consists of three deep neural networks-A Transformer-based model, a BiLSTM model and a CRF module. Results: The proposed NER implementation achieves an accuracy (F1-score) of 92.98% on our test set and generalizes well on benchmark data. A careful analysis of case examples demonstrates the superiority of the proposed approach in correctly classifying the named entities. Conclusions: NLP can be used to extract key information, such as SDOH from free texts. A more accurate understanding of SDOH is needed to further improve healthcare outcomes.

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