Can self-testing be enhanced to hasten safe return of healthcare workers in pandemics? Random order, open label trial using two manufacturers' SARS-CoV-2 lateral flow devices concurrently (preprint)

ObjectivesTo inform management of competing risks from Covid-19 and key-worker absence, we evaluated whether using two manufacturers lateral flow tests (LFTs) concurrently improved SARS-CoV-2 Omicron detection and was acceptable to hospital staff. In a nested study, to understand the risks of return to work after a fixed number of days of isolation or quarantine, we examined virus culture at Days 5-7 after positive test or significant exposure. Methods and Analysis1419 fully-vaccinated Liverpool (UK) University Hospitals staff participated in a random-order, open-label trial testing whether dual LFTs improved SARS-CoV2 detection, and whether dual swabbing was acceptable to users. Main outcome was self-reported LFT result. Staff enrolled via routine testing sites for symptomatic staff and close contacts. Recruitment took place between 7th February and 8th May 2022. Participants employed nose-throat swab Innova and nose-only swab Orient Gene LFTs for 10 days, with daily LFTs taken in random order. A swab for polymerase chain reaction (PCR) analysis was taken at Day-5 and, if positive, Day-10. A questionnaire on acceptability was administered on exit. Selected participants gave swabs for viral culture on Days 5-7; swabs were delivered and returned by courier. Cultures were considered positive if cytopathic effect was apparent or the SARs-COV2 N gene sub-genomic RNA was detected by sequencing. Results226 individuals reported 1466 pairs of LFT results. Tests disagreed in 127 cases (8.7%). Orient Gene was more likely (78 cf. 49, P=0.03) to be positive. Orient Gene positive Innova negative result-pairs became more frequent over time (P<0.001). If Innova was swabbed second, it was less likely to agree with a positive Orient Gene result (P=0.005); swabbing first with Innova made no significant difference (P=0.85). Of 311 individuals completing the exit questionnaire, 90.7% reported dual swabbing was easy, 57.1% said it was no barrier to their daily routine and 65.6% preferred dual testing. Respondents had more confidence in dual c.f. single test results (median 9 cf. 8 on 10-point scale, P<0.001). Viral cultures from swabs taken at Days 5-7 were positive for 6/31 (19.4%, 7.5%-37.5%) and indeterminate for 11/31 (35.5%, 19.2%-54.6%) LFT-positive participants, indicating they were likely still infectious. ConclusionsDual brand testing increased LFT detection of SARS-CoV-2 antigen by a small but meaningful margin and was acceptable to hospital workers. Viral cultures demonstrated that policies recommending safe return to work [~]5 days after Omicron infection/exposure were flawed. Key-workers should be prepared for dynamic self-testing protocols in future pandemics. Trial registrationhttps://www.isrctn.com/ISRCTN47058442 (IRAS Project ID:311842) Key messagesO_ST_ABSWhat is already known on this topicC_ST_ABSO_LIOmicron BA.1 and BA.2 waves caused large-scale healthcare worker absence in late 2021 - early 2022, risking patient safety from both Covid-19 and reduced care capacity C_LIO_LILateral flow tests (LFTs) reliably detected SARS-CoV-2 antigen, more so with Omicron than prior variants, identifying the most infectious individuals C_LIO_LISelf-testing with LFT SARS-CoV-2 rapid antigen tests reduced Covid-19 transmission, mitigating risks of return to work, including healthcare settings C_LI What this study addsO_LIDual c.f. single brand LFT testing increased SARS-CoV-2 antigen detection marginally, but more than can be explained by extending swabbing from nose-only to nose-throat C_LIO_LINHS deployment of nose-only LFTs in response to compound pressures from Omicron, winter and pandemic burnout was safe and acceptable to most participating hospital staff C_LIO_LICulturable virus was detected confidently in a fifth (and potentially in a further third) of LFT-positive hospital workers 5-7 days after their self-referral for testing, indicating substantial protracted infectiousness C_LI How this study might affect research, practice or policyO_LIThis study shows international Covid-19 policies for return to work after fixed periods (e.g. 5 days after positive test) were flawed: too little emphasis was placed on variation in infectivity between individuals C_LIO_LIFuture pandemic preparedness needs to plan testing quality assurance unified across healthcare and community self-testing contexts, including continuous study of serial daily antigen, nucleic acid and culturable virus test results C_LI

Single-cell analysis of lung epithelial cells reveals age and cell population-specific responses to SARS-CoV-2 infection in ciliated cells (preprint)

The ability of SARS-CoV-2 to evade antiviral immune signaling in the airway contributes to the severity of COVID-19 disease. Additionally, COVID-19 is influenced by age and has more severe presentations in older individuals. This raises questions about innate immune signaling as a function of lung development and age. Therefore, we investigated the transcriptome of different cell populations of the airway epithelium using pediatric and adult lung tissue samples from the LungMAP Human Tissue Core Biorepository. Specifically, lung lobes were digested and cultured into a biomimetic model of the airway epithelium on an air-liquid interface. Cells were then infected with SARS-CoV-2 and subjected to single-cell RNA sequencing. Transcriptional profiling and differential expression analysis were carried out using Seurat. The clustering analysis identified several cell populations: club cells, proliferating epithelial cells, multiciliated precursor cells, ionocytes, and two biologically distinct clusters of ciliated cells (FOXJ1high and FOXJ1low). Interestingly, the two ciliated cell clusters showed different infection rates and enrichment of processes involved in ciliary biogenesis and function; we observed a cell-type-specific suppression of innate immunity in infected cells from the FOXJ1low subset. We also identified a significant number of genes that were differentially expressed in lung cells derived from children as compared to adults, suggesting the differential pathogenesis of SARS-CoV-2 infection in children versus adults. We discuss how this work can be used to identify drug targets to modulate molecular signaling cascades that mediate an innate immune response and begin to understand differences in COVID-19 outcomes for pediatric vs. adult populations.

Optimisation of SARS-CoV-2 culture from clinical samples for clinical trial applications (preprint)

Clinical trials of SARS-CoV-2 therapeutics often include virological secondary endpoints to compare viral clearance and viral load reduction between treatment and placebo arms. This is typically achieved using RT-qPCR, which cannot differentiate replicant competent virus from non-viable virus or free RNA, limiting its utility as an endpoint. Culture based methods for SARS-CoV-2 exist; however, these are often insensitive and poorly standardised for use as clinical trial endpoints. We report optimisation of a culture-based approach evaluating three cell lines, three detection methods, and key culture parameters. We show that Vero-ACE2-TMPRSS2 (VAT) cells in combination with RT-qPCR of culture supernatants from the first passage provides the greatest overall detection of Delta viral replication (22/32, 68.8%), being able to identify viable virus in 83.3% (20/24) of clinical samples with initial Ct values <30. Likewise, we demonstrate that RT-qPCR using culture supernatants from the first passage of Vero hSLAM cells provides the highest overall detection of Omicron viral replication (9/31, 29%), detecting live virus in 39.1% (9/23) of clinical samples with initial Ct values < 25. This assessment demonstrates that combining RT-qPCR with virological end point analysis has utility in clinical trials of therapeutics for SARS-CoV-2; however, techniques may require optimising based on dominant circulating strain.

Broad immunogenicity to prior SARS-CoV-2 strains and JN.1 variant elicited by XBB.1.5 vaccination in nursing home residents (preprint)

Background: SARS-CoV-2 vaccination has reduced hospitalization and mortality for nursing home residents (NHRs). However, emerging variants coupled with waning immunity, immunosenescence, and variability of vaccine efficacy undermine vaccine effectiveness. We therefore need to update our understanding of the immunogenicity of the most recent XBB.1.5 monovalent vaccine to variant strains among NHRs. Methods: The current study focuses on a subset of participants from a longitudinal study of consented NHRs and HCWs who have received serial blood draws to assess immunogenicity with each SARS-CoV-2 mRNA vaccine dose. We report data on participants who received the XBB.1.5 monovalent vaccine after FDA approval in Fall 2023. NHRs were classified based on whether they had an interval SARS-CoV-2 infection between their first bivalent vaccine dose and their XBB.1.5 monovalent vaccination. Results: The sample included 61 NHRs [median age 76 (IQR 68-86), 51% female] and 28 HCWs [median age 45 (IQR 31-58), 46% female). Following XBB.1.5 monovalent vaccination, there was a robust geometric mean fold rise (GMFR) in XBB.1.5-specific neutralizing antibody titers of 17.3 (95% confidence interval [CI] 9.3, 32.4) and 11.3 (95% CI 5, 25.4) in NHRs with and without interval infection, respectively. The GMFR in HCWs was 13.6 (95% CI 8.4,22). Similarly, we noted a robust GMFR in JN.1-specific neutralizing antibody titers of 14.9 (95% CI 7.9, 28) and 6.5 (95% CI 3.3, 13.1) among NHRs with and without interval infection, and a GMFR of 11.4 (95% CI 6.2, 20.9) in HCWs. NHRs with interval SARS-CoV-2 infection had higher neutralizing antibody titers across all analyzed strains following XBB.1.5 monovalent vaccination, compared to NHRs without interval infection. Conclusion: The XBB.1.5 monovalent vaccine significantly elevates Omicron-specific neutralizing antibody titers to XBB.1.5 and JN.1 strains in both NHRs and HCWs. This response was more pronounced in individuals known to be infected with SARS-CoV-2 since bivalent vaccination.

Persistence of S1 Spike Protein in CD16+ Monocytes up to 245 Days in SARS-CoV-2 Negative Post COVID-19 Vaccination Individuals with Post-Acute Sequalae of COVID-19 (PASC)-Like Symptoms (preprint)

There have been concerning reports about people experiencing new onset persistent complications (greater than 30 days) following approved SARS-CoV-2 vaccines (BNT162b2 (Pfizer), mRNA-1273 (Moderna), Janssen (Johnson and Johnson), and ChAdOx1 nCoV-19 (AstraZeneca)). We sought to determine the immunologic abnormalities in these patients and to investigate whether the potential etiology was similar to Post-Acute Sequalae of COVID (PASC), or long COVID. We studied 50 individuals who received one of the approved COVID-19 vaccines and who experienced new onset PASC-like symptoms along with 45 individuals post-vaccination without symptoms as controls. We performed multiplex cytokine/chemokine profiling with machine learning as well as SARS-CoV-2 S1 protein detection on CD16+ monocyte subsets using flow cytometry and mass spectrometry. We determined that post-vaccination individuals with PASC-like symptoms had similar symptoms to PASC patients. When analyzing their immune profile, Post-vaccination individuals had statistically significant elevations of sCD40L (p<0.001), CCL5 (p=0.017), IL-6 (p=0.043), and IL-8 (p=0.022). Machine learning characterized these individuals as PASC using previously developed algorithms. Of the S1 positive post-vaccination patients, we demonstrated by liquid chromatography/ mass spectrometry that these CD16+ cells from post-vaccination patients from all 4 vaccine manufacturers contained S1, S1 mutant and S2 peptide sequences. Post-COVID vaccination individuals with PASC-like symptoms exhibit markers of platelet activation and pro-inflammatory cytokine production, which may be driven by the persistence of SARS-CoV-2 S1 proteins in intermediate and non-classical monocytes. The data from this study also cannot make any inferences on epidemiology and prevalence for persistent post-COVID vaccine symptoms. Thus, further studies and research need to be done to understand the risk factors, likelihood and prevalence of these symptoms.

Racial/Ethnic Differences in Long-COVID-Associated Symptoms among Pediatrics Population: Findings from Difference-in-differences Analyses in RECOVER Program (preprint)

Racial/ethnic differences are associated with the potential symptoms and conditions of post-acute sequelae SARS-CoV-2 infection (PASC) in adults. These differences may exist among children and warrant further exploration. We conducted a retrospective cohort study for children and adolescents under the age of 21 from the thirteen institutions in the RECOVER Initiative. The cohort is 225,723 patients with SARS-CoV-2 infection or COVID-19 diagnosis and 677,448 patients without SARS-CoV-2 infection or COVID-19 diagnosis between March 2020 and October 2022. The study compared minor racial/ethnic groups to Non-Hispanic White (NHW) individuals, stratified by severity during the acute phase of COVID-19. Within the severe group, Asian American/Pacific Islanders (AAPI) had a higher prevalence of fever/chills and respiratory symptoms, Hispanic patients showed greater hair loss prevalence in severe COVID-19 cases, while Non-Hispanic Black (NHB) patients had fewer skin symptoms in comparison to NHW patients. Within the non-severe group, AAPI patients had increased POTS/dysautonomia and respiratory symptoms, and NHB patients showed more cognitive symptoms than NHW patients. In conclusion, racial/ethnic differences related to COVID-19 exist among specific PASC symptoms and conditions in pediatrics, and these differences are associated with the severity of illness during acute COVID-19.

Humoral immunity across the SARS-CoV-2 Spike after Sputnik V (Gam‑COVID‑Vac) vaccination (preprint)

Keywords: COVID-19, SARS-CoV-2, Antibody, ELISA, Spike, S1, S2, RBD, epitopes, Neutralization

Comparative safety and effectiveness of Pfizer BA.4-5 versus Sanofi during the spring 2023 COVID-19 booster vaccination programme in England: a matched cohort study in OpenSAFELY-TPP (preprint)

Introduction: The spring 2023 COVID-19 booster vaccination programme in England used both Pfizer BA.4-5 and Sanofi vaccines. All people aged 75 years or over and the clinically vulnerable were eligible to receive a booster dose. Direct comparisons of the effectiveness of these two vaccines in boosting protection against severe COVID-19 events have not been made in trials or observational data. Methods With the approval of NHS England, we used the OpenSAFELY-TPP database to compare effectiveness of the Pfizer BA.4-5 and Sanofi vaccines during the spring 2023 booster programme, between 1 April and 30 June 2023. We investigated two cohorts separately: those aged 75 or over (75+); and those aged 50 or over and clinically vulnerable (CV). In each cohort, vaccine recipients were matched on date of vaccination, COVID-19 vaccine history, age, and other characteristics. Effectiveness outcomes were COVID-19 hospital admission, COVID-19 critical care admission, and COVID-19 death up to 16 weeks after vaccination. Safety outcomes were pericarditis and myocarditis up to 4 weeks after vaccination. We report the cumulative incidence of each outcome, and compare safety and effectiveness using risk differences (RD), relative risks (RR), and incidence rate ratios (IRRs). Results 492,642 people were 1-1 matched in the CV cohort, and 673,926 in the 75+ cohort, contributing a total of 7,423,251 and 10,173,230 person-weeks of follow-up, respectively. The incidence of COVID-19 hospital admission was higher for Sanofi than for Pfizer BA.4-5. In the CV cohort, 16-week risks per 10,000 people were 22.3 (95%CI 20.4 to 24.3) for Pfizer BA.4-5 and 26.4 (24.4 to 28.7) for Sanofi, with an IRR of 1.19 (95%CI 1.06 to 1.34). In the 75+ cohort, these were 17.5 (16.1 to 19.1) for Pfizer BA.4-5 and 20.4 (18.9 to 22.1) for Sanofi, with an IRR of 1.18 (1.05-1.32). These findings were similar across all pre-specified subgroups. More severe COVID-19 related outcomes (critical care admission and death), and safety outcomes at 4 weeks, were rare in both vaccines so we could not reliably compare effectiveness of the two vaccines. Conclusion This observational study comparing effectiveness of Pfizer BA.4-5 and Sanofi vaccine during the spring 2023 programme in England in the two main eligible cohorts - people aged 75 and over and in clinically vulnerable people - found some evidence of superior effectiveness against COVID-19 hospital admission for Pfizer BA.4-5 compared with Sanofi within 16 weeks after vaccination.

SARS-CoV-2 antibody prevalence by industry, workplace characteristics, and workplace infection prevention and control measures, North Carolina, 2021 to 2022 (preprint)

Background: The COVID-19 pandemic has disproportionately affected workers in certain industries and occupations, and the workplace can be a high risk setting for SARS-CoV-2 transmission. In this study, we measured SARS-CoV-2 antibody prevalence and identified work-related risk factors in a population primarily working at industrial livestock operations. Methods: We used a multiplex salivary SARS-CoV-2 IgG antibody assay to determine infection-induced antibody prevalence among 236 adult (>=18 years) North Carolina residents between February 2021 and August 2022. We used the National Institute for Occupational Safety and Health Industry and Occupation Computerized Coding System (NIOCCS) to classify employed participants' industry and compared infection-induced IgG prevalence by participant industry and with the North Carolina general population. We also combined antibody results with reported SARS-CoV-2 molecular test positivity and vaccination history to identify evidence of prior infection. We used logistic regression to estimate odds ratios of prior infection by potential work-related risk factors, adjusting for industry and date. Results: Most participants (55%) were infection-induced IgG positive, including 71% of animal slaughtering and processing industry workers, which is 1.5 to 4.3 times higher compared to the North Carolina general population, as well as higher than molecularly-confirmed cases and the only other serology study we identified of animal slaughtering and processing workers. Considering questionnaire results in addition to antibodies, the proportion of participants with evidence of prior infection increased slightly, to 61%, including 75% of animal slaughtering and processing workers. Participants with more than 1000 compared to 10 or fewer coworkers at their jobsite had higher odds of prior infection (adjusted odds ratio [aOR] 4.5, 95% confidence interval [CI] 1.0 to 21.0). Conclusions: This study contributes evidence of the severe and disproportionate impacts of COVID-19 on animal processing and essential workers and workers in large congregate settings. We also demonstrate the utility of combining non-invasive biomarker and questionnaire data for the study of workplace exposures.

The seroprevalence of SARS-CoV-2-specific antibodies in Australian children: a cross sectional study (preprint)

Background: Following reduction of public health and social measures concurrent with SARS-CoV-2 Omicron emergence in late 2021 in Australia, COVID-19 case notification rates rose rapidly. As rates of direct viral testing and reporting dropped, true infection rates were most likely to be underestimated. Objective: To better understand infection rates and immunity in this population, we aimed to estimate SARS-CoV-2 seroprevalence in Australians aged 0-19 years. Methods: We conducted a national cross sectional serosurvey from June 1, 2022, to August 31, 2022, in children aged 0-19 years undergoing an anesthetic procedure at eight tertiary pediatric hospitals. Participant questionnaires were administered, and blood samples tested using the Roche Elecsys Anti-SARS-CoV-2 total spike and nucleocapsid antibody assays. S and N seroprevalence adjusted for geographic and socioeconomic imbalances in the participant sample compared to the Australian population was estimated using multilevel regression and poststratification within a Bayesian framework. Results: Blood was collected from 2,046 participants (median age: 6.6 years). Adjusted seroprevalence of spike-antibody was 92.1 % (95% credible interval (CrI) 91.0-93.3%) and nucleocapsid-antibody was 67.0% (95% CrI 64.6-69.3). In unvaccinated children spike and nucleocapsid antibody seroprevalences were 84.2% (95% CrI 81.9-86.5) and 67.1% (95%CrI 64.0-69.8), respectively. Seroprevalence increased with age but was similar across geographic distribution and socioeconomic quintiles. Conclusion: Most Australian children and adolescents aged 0-19 years, across all jurisdictions were infected with SARS-CoV-2 by August 2022, suggesting rapid and uniform spread across the population in a very short time period. High seropositivity in unvaccinated children informed COVID-19 vaccine recommendations in Australia. Funding: Australian Government Department of Health and Aged Care.

Redeployment Experiences of Healthcare Workers in the UK during COVID-19: data from the nationwide UK-REACH study (preprint)

Background Increasing demands of COVID-19 on the healthcare system necessitated redeployment of HCWs outside their routine specialties. Previous studies, highlighting ethnic and occupational inequalities in redeployment, are limited by small cohorts with limited ethnic diversity. Aims To assess how ethnicity, migration status, and occupation are associated with HCWs redeployment experiences during COVID-19 in a nationwide ethnically diverse sample. Methods We conducted a cross-sectional analysis using data from the nationwide United Kingdom Research Study into Ethnicity And COVID-19 outcomes in Healthcare workers (UK-REACH) cohort study. We used logistic regression to examine associations of ethnicity, migration status, and occupation with redeployment experiences of HCWs, including provision of training and supervision, patient contact during redeployment and interaction with COVID-19 patients. Results Of the 10,889 HCWs included, 20.4% reported being redeployed during the first UK national lockdown in March 2020. Those in nursing roles (Odds Ratio (OR) 1.22, 95% Confidence Interval (CI) 1.04 to 1.42, p=0.009) (compared to medical roles) had higher likelihood of being redeployed as did migrants compared to those born in the UK (OR 1.26, 95% CI 1.06 to 1.49, p=0.01) (in a subcohort of HCWs on the agenda for change (AfC) pay scales). Asian HCWs were less likely to report receiving training (OR 0.66, 95% CI 0.50 to 0.88, p=0.005) and Black HCWs (OR 2.02, 95% CI 1.14 to 3.57, p=0.02) were more likely to report receiving supervision, compared to White colleagues. Finally, redeployed Black (OR 1.33, 95% CI 1.07 to 1.66, p=0.009) and Asian HCWs (OR 1.30, 95% CI 1.14 to 1.48, p<0.001) were more likely to report face-to-face interaction with COVID-19 patients than White HCWs. Conclusions Our findings highlight disparities in HCWs redeployment experiences by ethnicity, migration, and job role which are potentially related to structural inequities in healthcare. For future emergencies, redeployment should be contingent upon risk assessments, accompanied by training and supervision tailored to individual HCWs experience and skillset.

Machine Learning for COVID-19 Patient Management: Predictive Analytics and Decision Support (preprint)

Background: The global impact of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has profoundly affected economies and healthcare systems around the world, including Lebanon. While numerous meta-analyses have explored the systemic manifestations of COVID-19, few have linked them to patient history. Our study aims to fill this gap by using cluster analysis to identify distinct clinical patterns among patients, which could aid prognosis and guide tailored treatments. Methods. We conducted a retrospective cohort study at Beirut's largest teaching hospital on 556 patients with SARS-CoV-2. We performed cluster analyses using K-prototypes, KAMILA and LCM algorithms based on 26 variables, including laboratory results, demographics and imaging findings. Silhouette scores, concordance index and signature variables helped determine the optimal number of clusters. Subsequent comparisons and regression analyses assessed survival rates and treatment efficacy according to clusters. Results. Our analysis revealed three distinct clusters: "resilient recoverees" with varying disease severity and low mortality rates, "vulnerable veterans" with severe to critical disease and high mortality rates, and "paradoxical patients" with a late presentation but eventual recovery. Conclusions. These clusters offer insights for prognosis and treatment selection. Future studies should include vaccination data and various COVID-19 strains for a comprehensive understanding of the disease's dynamics.

Changes in opioid prescribing during the COVID-19 pandemic in England: cohort study of 20 million patients in OpenSAFELY-TPP (preprint)

Background: The COVID-19 pandemic led to disruptions in healthcare delivery, including postponement of elective procedures and difficulty accessing in-person care, which may have increased the need for strong pharmacological pain relief in some patients. Methods: With NHS England approval, we used routine clinical data from >20 million general practice adult patients in OpenSAFELY-TPP. We used interrupted time series analysis to quantify trends in prevalent and incident opioid prescribing prior to the pandemic (January 2018-February 2020) and changes during the COVID-19 lockdown period (March 2020-March 2021) and recovery period (April 2021-June 2022). We identified how these changes varied in people living in care homes, and by age, sex, deprivation, ethnicity, and geographic region. Results: The median number of people prescribed an opioid per month was 50.9 per 1000 patients prior to the pandemic. We observed little change in overall prescribing after the start of the pandemic, except for a temporary increase in March 2020. There was a 9.8% (95%CI -14.5%, -6.5%) reduction in new opioid prescribing from March 2020, sustained to the end of the study period. Reductions in new prescribing were observed for all demographics except people 80+ years. Among care home residents, in April 2020 new opioid prescribing increased by 112.5% (95%CI 92.2%, 134.9%) and parenteral opioid prescribing increased by 186.3% (95%CI 153.1%, 223.9%). Conclusion: Changes in opioid prescribing during the COVID-19 pandemic were mostly consistent across subgroups with the exception of differences by age and care home residence. Among people in care homes, increases in parenteral opioid prescribing likely reflect use to treat end-of-life COVID-19 symptoms. Further research is needed to understand what is driving the reduction in new opioid prescribing and its relation to changes to health care provision during the pandemic.

Early, robust mucosal secretory IgA but not IgG response to SARS-CoV-2 spike in oral fluid is associated with faster viral clearance and COVID-19 symptom resolution (preprint)

High priority efforts are under way to support the development of novel mucosal COVID-19 vaccines, such as the US Governments Project NextGen and the Center for Epidemic Preparedness Innovations (CEPI) goal to respond to the next pandemic with a new vaccine in 100 days. However, there is limited consensus about the complementary role of mucosal immunity in disease progression and how the immunogenicity of mucosal vaccines will be evaluated. This study investigated the role of oral mucosal antibody responses in viral clearance and in COVID-19 symptom duration. Participants with PCR-confirmed SARS-CoV-2 infection provided oral fluid for testing with SARS-CoV-2 antibody multiplex assays, nasal swabs for RT-PCR and symptom information at up to eight follow-ups from April 2020 to February 2022. High and moderate oral fluid anti-spike (S) SIgA post infection was associated with significantly higher likelihood of viral clearance and of COVID-19 symptom resolution across age groups. Those with high and moderate anti-S SIgA cleared the virus and recovered 14 days (95% CI: 10-18 days) and 9-10 days (95% CI: 6-14 days) earlier, respectively. Delayed but higher oral fluid anti-S IgG was associated with significantly longer time to viral clearance and recovery. The effect size of moderate or high SIgA was equivalent to prior COVID-19 vaccine immunity, which was also associated with faster clearance and recovery. Unvaccinated adults with prolonged COVID-19 symptoms had significantly lower anti-RBD SIgA 15-30 days after infection onset (p<0.001). Robust mucosal SIgA early post infection appears to support faster clearance of SARS-CoV-2 and recovery from COVID-19 symptoms. This research underscores the importance of harmonizing mucosal immune response assays to evaluate new vaccines that can boost local mucosal immunity. DisclaimerThe findings and conclusions in this report are those of the authors and do not necessarily represent the official position of the Centers for Disease Control and Prevention.

Real-world Effectiveness and Causal Mediation Study of BNT162b2 on Long COVID Risks in Children and Adolescents (preprint)

BackgroundThe impact of pre-infection vaccination on the risk of long COVID remains unclear in the pediatric population. Further, it is unknown if such pre-infection vaccination can mitigate the risk of long COVID beyond its established protective benefits against SARS-CoV-2 infection. ObjectiveTo assess the effectiveness of BNT162b2 on long COVID risks with various strains of the SARS-CoV-2 virus in children and adolescents, using comparative effectiveness methods. To disentangle the overall effectiveness of the vaccine on long COVID outcomes into its independent impact and indirect impact via prevention of SARS-CoV-2 infections, using causal mediation analysis. DesignReal-world vaccine effectiveness study and mediation analysis in three independent cohorts: adolescents (12 to 20 years) during the Delta phase, children (5 to 11 years) and adolescents (12 to 20 years) during the Omicron phase. SettingTwenty health systems in the RECOVER PCORnet electronic health record (EHR) Program. Participants112,590 adolescents (88,811 vaccinated) in the Delta period, 188,894 children (101,277 vaccinated), and 84,735 adolescents (37,724 vaccinated) in the Omicron period. ExposuresFirst dose of the BNT162b2 vaccine vs. no receipt of COVID-19 vaccine. MeasurementsOutcomes of interest include conclusive or probable diagnosis of long COVID following a documented SARS-CoV-2 infection, and body-system-specific condition clusters of post-acute sequelae of SARS-CoV-2 infection (PASC), such as cardiac, gastrointestinal, musculoskeletal, respiratory, and syndromic categories. The effectiveness was reported as (1-relative risk)*100 and mediating effects were reported as relative risks. ResultsDuring the Delta period, the estimated effectiveness of the BNT162b2 vaccine against long COVID among adolescents was 95.4% (95% CI: 90.9% to 97.7%). During the Omicron phase, the estimated effectiveness against long COVID among children was 60.2% (95% CI: 40.3% to 73.5%) and 75.1% (95% CI: 50.4% to 87.5%) among adolescents. The direct effect of vaccination, defined as the effect beyond their impact on SARS-CoV-2 infections, was found to be statistically non-significant in all three study cohorts, with estimates of 1.08 (95% CI: 0.75 to 1.55) in the Delta study among adolescents, 1.24 (95% CI: 0.92 to 1.66) among children and 0.91 (95% CI: 0.69 to 1.19) among adolescents in the Omicron studies. Meanwhile, the estimated indirect effects, which are effects through protecting SARS-CoV-2 infections, were estimated as 0.04 (95% CI: 0.03 to 0.05) among adolescents during Delta phase, 0.31 (95% CI: 0.23 to 0.42) among children and 0.21 (95% CI: 0.16 to 0.27) among adolescents during the Omicron period. LimitationsObservational study design and potentially undocumented infection. ConclusionsOur study suggests that BNT162b2 was effective in reducing risk of long COVID outcomes in children and adolescents during the Delta and Omicron periods. The mediation analysis indicates the vaccines effectiveness is primarily derived from its role in reducing the risk of SARS-CoV-2 infection. Primary Funding SourceNational Institutes of Health.

Cardioprotective effects of vaccination in hospitalized patients with COVID-19 (preprint)

Background COVID-19 vaccination has been shown to prevent and reduce the severity of COVID-19 disease. Aim The aim of this study was to explore the cardioprotective effect of COVID-19 vaccination in hospitalized COVID-19 patients. Methods In this retrospective, single-center cohort study, we included hospitalized COVID-19 patients with confirmed vaccination status from July 2021 to February 2022. We assessed outcomes such as acute cardiac events and cardiac biomarker levels through clinical and laboratory data. Results Our analysis covered 167 patients (69% male, mean age 58 years, 42% being fully vaccinated). After adjustment for confounders, vaccinated hospitalized COVID-19 patients displayed a reduced relative risk for acute cardiac events (RR: 0.33, 95% CI [0.07; 0.75]) and showed diminished troponin T levels (Cohen’s d: -0.52, 95% CI [-1.01; -0.14]), compared to their non-vaccinated peers. Type 2 diabetes (OR: 2.99, 95% CI [1.22; 7.35]) and existing cardiac diseases (OR: 4.31, 95% CI [1.83; 10.74]) were identified as significant risk factors for the emergence of acute cardiac events. Conclusion Our findings suggest that COVID-19 vaccination may confer both direct and indirect cardioprotective effects in hospitalized COVID-19 patients.