Analysis of allergy and hypersensitivity reactions to COVID-19 vaccines according to the EudraVigilance database (preprint)

Background: The Coronavirus Disease 2019 (COVID-19) pandemic presented a new challenge in modern medicine. The development of vaccines was followed by massive population vaccinations. A few reports on post-vaccination allergic reactions have made patients and medical personnel uneasy as to anti-COVID-19 vaccines’ allergising potential. Most of the studies in this area to date have been small, and some that were based on global databases skipped most of the allergic diseases and concentrated only on anaphylaxis. We aimed to analyse the incidence of serious allergic reactions based on the EudraVigilance (EV) database, regardless of the reported symptoms and allergy mechanism. Methods: The total number of administrated vaccine doses was extracted on the 5th October 2023 from Vaccine Tracker and included all administrations since vaccinations began in the European Economic Area (EEA). Data on serious allergic reactions to COVID-19 vaccines was extracted from the EudraVigilance database with the same time point. The code names of 147 allergic symptoms or diseases were used. Results: The frequency of serious allergic reactions per 100,000 administered vaccine doses was 1.53 for Comirnaty, 2.16 for Spikevax, 88.6 for Vaxzevria, 2.11 for Janssen, 7.9 for Novavax, 13.3 for VidPrevtyn Beta and 3.1 for Valneva. The most prevalent reported reactions were oedema (0.46) and anaphylaxis (0.40). Only 6% of these reactions were delayed hypersensitivity-oriented. Conclusions: The overall frequency of potential serious allergic reactions to COVID-19 is very rare. Therefore, COVID-19 vaccines seem to be safe for human use. The lowest frequency of allergic reaction was observed for Comirnaty and the highest for Vaxzevria.

On Bisphosphonates and COVID-19: In Silico Model Suggests Inhibition of SARS-CoV-2 RdRp as Potential Explanation (preprint)

The novel coronavirus disease (COVID-19) pandemic has resulted in over 720 million confirmed cases and 7 million deaths worldwide, with insufficient treatment options. Innumerable efforts are being made around the world for faster identification of therapeutic agents to treat the deadly disease. Postacute sequelae of SARS-CoV-2 infection or COVID-19 (PASC), also called Long COVID, is still being understood and lacks treatment options as well. A growing list of drugs are being suggested by various in silico, in vitro and ex vivo models, however currently only two treatment options are widely used: the RNA-dependent RNA polymerase (RdRp) inhibitor remdesivir, and the main protease inhibitor nirmatrelvir in combination with ritonavir. Computational drug development tools and in silicostudies involving molecular docking, molecular dynamics, entropy calculations and pharmacokinetics can be useful to identify new targets to treat COVID-19 and PASC, as shown in this work and our recent paper that identified alendronate as a promising candidate. We have now investigated all bisphosphonates which can bind competitively to nidovirus RdRp-associated nucleotidyl (NiRAN) transferase domain, and systematically down selected seven candidates (CHEMBL608526, CHEMBL196676, CHEMBL164344, CHEMBL4291724, CHEMBL4569308, CHEMBL387132, CHEMBL98211), two of whichclosely resemble the approved drugs minodronate and zoledronate. This work and our recent paper together provide an in silico mechanistic explanation for alendronate and zoledronate users having dramatically reduced odds of SARS-CoV-2 testing, COVID-19 diagnosis, and COVID-19-related hospitalizations, and indicate that similar observational studies with minodronate could be valuable.

Analysis of infection status and infection risk factors of caregivers of COVID-19 patients (preprint)

Background: Omicron infection often occurs in a family cluster, therefore, infection among caregivers of patients with COVID-19 is an important health concern. To explore the spread and risk factors of infection among caregivers of patients with COVID-19 and provide a theoretical basis for the scientific prevention and control of susceptible infections. Methods: We recruited 66 caregivers of patients with COVID-19 who were admitted to the medicine department of Jilin Provincial Hospital of Hepatobiliary Diseases supported by the First Hospital of Jilin University, between April 9, 2022 and April 30, 2022. We analyzed the impact of age, sex, vaccination history, positive conversion time, and some basic disease on the occurrence of infection among caregivers. Results: At one week after discharge of the admitted COVID-19 patients, 54 of the enrolled caregivers (including 22 males and 32 females) turned positive, while the remaining 12 did not. Among the patients with positive conversion, 79.63% had underlying diseases, 83.33% had positive conversion within 3 days after admission, and 46.30% had received the last vaccination more than 200 days. The positive conversion time, was significantly longer in women than in men. Additionally, the positive conversion time in those with underlying disease was longer than in those without. Conclusion: An understanding of the prevalence and risk factors for secondary infection among caregivers of COVID-19 patients would be useful in developing strategies for the prevention of infection in the of COVID-19-susceptible population and help improve the monitoring of various susceptible factors.

The Effects of SARS-CoV-2 on Angiopoietin/Tie Axis and Vascular Endothelium (preprint)

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection can cause potentially life-threatening coronavirus disease (COVID-19). COVID-19 is a multisystem disease and is associated with significant respiratory distress, systemic hyper inflammation, vasculitis and multi-organ failures. SARS-CoV-2 causes deterioration of numerous systems with increasing evidence implying that COVID-19 affects endothelium and vascular function. The endothelium is important for preserving vascular tone and homeostasis. The overactivation and dysfunction of endothelial cells are significant outcomes of severity in patients with COVID-19. The Angiopoietin 1/Tie 2 pathway plays an important role in endothelium quiescence and vessel stability. The disruption of Angiopoietins/Tie balance affects vessel contact barrier and leads to vessel leakage, and this in turn causes endothelial dysfunction. Although vascular instability through SARS-CoV-2 is associated with endothelial dysfunction, it is still not understood if the virus affects Angiopoietin/Tie axis directly or via other mechanisms such as cytokine storm and/or immune response associated with the infection. This review provides an overview of the impact SARS-CoV-2 has on endothelial function and more specifically the Angiopoietin/Tie pathway.

Distinct Immune Escape Mechanisms of Bovine Cronavirus Nucleocapsid by Suppressing beta Interferon Production via Retinoic Acid-inducible Gene I-like Receptor Pathway (preprint)

The present study aimed to explore if bovine coronavirus nucleocapsid (BCoV N) impacts beta interferon (IFN-β) production in the host cells and to reveal further molecular mechanism of BCoV pathopoiesis. Human embryonic kidney (HEK) 293T cells were transientlly transfected with pCMV-Myc-BCoV-N recombinant plasmids, then infected with the vesicular stomatitis virus (VSV). Expression levels of IFN-β mRNA were detected using qPCR. The results determinated that pCMV-Myc-BCoV-N recombinant plasmids of 1347bp was successfully constructed and transcribed into HEK 293T cells. Western-blotting assay indicated that BCoV-N recombinant plasmids had excellent antigenicity. BCoV-N recombinant proteins inhibited dose-dependently IFN-β production mediated by Vesicular stomatitis virus (VSV) (P<0.01). Furthermore, MDA5, MAVS, TBK1 and IRF3 could promote transcription levels of IFN-β mRNA. But, BCoV-N proteins demoted IFN-β levels induced by MDA5, MAVS, TBK1 and IRF3. Expression levels of MDA5, MAVS, TBK1 and IRF3 mRNAs were reduced in retinoic acid-inducible gene I-like receptor (RLR) pathway. In conclusion, BCoV-N reduced IFN-β levels in RLR pathway of HEK 293T cells. BCoV-N protein inhibited IFN-β production and activation of RLRs signal pathway. Our findings demonstrated a new mechanism evolved by BCoV to inhibit type I IFN production and provided a solid scientific basis for revealing the pathogenesis of BCoV, which is beneficial for developing novel strategy of the diagnose and therapy of BCoV disease.

Numerical Modeling of Cough Aerosol Transmission in an Upward-moving Escalator With Multi-objective Optimization Using the Genetic Algorithm for Covid-19 and Other Airborne Diseases (preprint)

Escalators have been recommended instead of elevators during the COVID-19 pandemic since it allows transportation for a large number of people without being enclosed in a small indoor space. Escalators have a tremendous capacity to move large numbers of people and are commonly used in various public facilities such as shopping centers, supermarkets, airports, and subways. This current study focused on investigating the transmission of cough droplets from an infected source person traveling on an Upward Moving Escalator (UME) using the ANSYS FLUENT. The Eulerian-Lagrangian method combined with two-way coupling was used to numerically obtain the aerosol transport, spatial distribution, and deposition information in the UME. The effect of UME operational speed and Relative Humidity (RH) was also investigated through multiphase flow. Finally, multi-objective optimization was performed using a Genetic Algorithm (GA). The investigation revealed that the hand railings were one of the most susceptible contaminated surfaces to the expelled respiratory droplets. The cough droplets expelled from the mouth entered the recirculation zones via the upper portion of the shoulder and wake zone behind the torso. The droplets contaminated the lower portion of the human body at lower operational speed if another passenger stood two steps behind the infected person. Higher operational speeds and lower RH demonstrated higher penetration lengths. The optimization indicated higher operational speed and lower RH to maintain lower concentration with higher penetration length.

SOX9-regulated matrix proteins predict poor outcomes in patients with COVID-19 and pulmonary fibrosis (preprint)

Pulmonary fibrosis is an increasing and major cause of death worldwide. Understanding the cellular and molecular mechanisms underlying the pathophysiology of lung fibrosis may lead to urgently needed diagnostic and prognostic strategies for the disease. SOX9 is a core transcription factor that has been associated with fibrotic disease, however its role and regulation in acute lung injury and/or fibrosis have not been fully defined. In this study we apply a hypothesis based approach to uncover unique SOX9-protein signatures associated with both acute lung injury and fibrotic progression. Using in vivo models of lung injury in the presence or absence of SOX9, our study shows SOX9 is essential to the damage associated response of alveolar epithelial cells from an early time-point in lung injury. In parallel, as disease progresses, SOX9 is responsible for regulating tissue damaging ECM production from pro-fibrotic fibroblasts. In determining the in vivo role of SOX9 we identified secreted ECM components downstream of SOX9 as markers of acute lung injury and fibrosis. To underscore the translational potential of our SOX9-regulated markers, we analysed serum samples from acute COVID19, post COVID19 and idiopathic pulmonary fibrosis (IPF) patient cohorts. Our hypothesis driven SOX9-panels showed significant capability in all cohorts at identifying patients who had poor disease outcomes. This study shows that SOX9 is functionally critical to disease in acute lung injury and pulmonary fibrosis and its regulated pathways have diagnostic, prognostic and therapeutic potential in both COVID19 and IPF disease.

Long COVID Disability Burden in US Adults: YLDs and NIH Funding Relative to Other Conditions (preprint)

BackgroundLong COVID (LC) is novel, debilitating and likely chronic. Yet, scant data exist about its disability burden to guide scientific research and public health planning. We estimated Long COVIDs non-fatal disease burden in US adults and its FY2024 actual: burden-commensurate research funding from the National Institutes of Health (NIH) relative to other conditions, and biological sex. MethodsWe present YLDs/100,000 for 70 NIH Research, Condition, and Disease Categories (RCDCs). Prevalence of disabling Long COVID was obtained from cross sectional surveys of representative samples of US adults, from September 2022 to August 2023. Disabling Long COVID was defined as incident symptoms persisting more than 3 months post-COVID, that significantly compromise daily activities. We calculated burden-commensurate funding for the top YLD conditions and for female vs. male dominant conditions. FindingsDisabling Long COVID was reported by 1.5% (n= 10,401) of n=757,580 respondents: Compared to the overall sample, those with disabling LC disproportionately identify as female (64.4% vs. 51.4%) and experiencing disability (80.8% vs. 52.9%) anxiety (57.5% vs. 23.8%) and depression (51.3% vs.18.5%). It ranked in the top 25% of YLDs at 320/100,000, between Alzheimers (279.4/100,000) and asthma (355.7/100,000) but received just 10% of its actual: YLD-commensurate funding. Only 5 conditions received less actual: burden: commensurate funding, including Myalgic Encephalitis/Chronic Fatigue Syndrome (<1%), another post-viral, female-dominant condition. InterpretationLC has debilitated 3.8 million (weighted frequency) US adults. Research funding for it, like other female dominant conditions, lags behind its disability burden. Research in ContextEvidence before this study - We analyzed Long-COVIDs (LC) non-fatal disease burden in the US--represented by YLD (years lived with disability= prevalence x disability weight) -- and National Institutes of Health (NIH) research 2024 funding relative to other conditions. We searched PubMed through 11/28/2023 for Long COVID prevalence (US), and Long COVID disability and disease burden (not US-specific). The keywords "years lived with disability" + "COVID" yielded n= 38 articles (11/29/23); but most referenced "disability-adjusted life years" (DALYs) in other countries. Similarly, "disease burden" + Long COVID yielded 23 papers, but no US YLD data. See Supplement 1 for meta-analyses, systematic reviews and US studies of Long COVID prevalence and impact. We instead sourced YLD data from the US Census Bureaus Household Pulse Survey (HPS) and the Institute for Health Metrics and Evaluation (IHME) /Global Burden of Disease (GBD) Long COVID Study Group. The HPS queries adults about Long COVID-related symptoms and their impact on daily activities. We applied the IHME/GBDs estimated Long COVID disability weight of 0.21 and harmonized it with our LC case definition from the HPS data in consultation with IHME/GBD researchers. To harmonize IHME/GBD disability weights for non-LC diseases/conditions with the NIHs terminology, we consulted with NIH staff. LC definition and measurement affects prevalence and burden estimates; our use of high-quality data sources and transparency in reporting how they were applied reduces the risk of biased assumptions. Added value of this study- Long COVID is a chronic debilitating condition. While there is ample research on COVIDs acute illness and loss of life, there are no population-based data on its disability burden. We provide that data. To guide scientific research and public health planning, we report YLDs associated with disabling Long COVID (i.e., symptoms significantly limit activity), and; compare it to other conditions YLDs, NIH funding, and female-vs. male-dominance. It ranked in the top 25% of YLDs at 320/100,000, between Alzheimers (279.4/100,000) and asthma (355.7/100,000) but received just 10% of its YLD-commensurate funding. Only 5 conditions received less burden-commensurate funding; 3/5 were female-dominant, including Myalgic Encephalitis/Chronic Fatigue Syndrome (ME/CFS) at <1%, another post-viral condition that shares significant overlap with Long COVID. Overall, median funding/YLD was >= 5 times greater for male-vs. female-dominant conditions. Implications of all the available evidence-Nearly 4 million US adults (weighted frequency) live with disabling Long COVID. They disproportionately identify as female and as having a disability, anxiety and depression. Yet NIH funding for diagnostic and treatment research for Long COVID hasnt kept pace with its disability burden.

Social determinants of recovery from ongoing symptoms following COVID-19 in two UK longitudinal studies: a prospective cohort study (preprint)

BackgroundSocial gradients in COVID-19 exposure, illness severity, and mortality have been observed in multiple international contexts. Whether pre-existing social factors affect recovery from ongoing symptoms following COVID-19 and long COVID is less well understood. MethodsWe analysed data on self-perceived recovery following self-reported COVID-19 illness in two United Kingdom community-based cohorts, COVID Symptom Study Biobank (CSSB) (N = 2548) and TwinsUK (N = 1334). Composite variables quantifying socio-demographic advantage and disadvantage prior to the COVID-19 pandemic were generated from sex, ethnic group, education, local area deprivation and employment status. Associations between self-perceived recovery and composite variables were tested with multivariable logistic regression models weighted for inverse probability of study participation, adjusting for potential confounding by age, region and pre- pandemic health factors, and potential mediation by COVID-19 illness characteristics and adverse experiences during the pandemic. Further analyses tested associations between recovery and individual socio-demographic variables reflecting status prior to and during the COVID-19 pandemic. FindingsSocio-demographic gradients in recovery were observed, with unadjusted recovery rate varying between 50% and 80% in CSSB and 70% and 90% in TwinsUK based on composite socio-demographic variables. Likelihood of recovery was lower for individuals with more indicators of pre-pandemic social disadvantage in both cohorts (CSSB: odds ratio, OR = 0.74, 95% confidence interval, CI: 0.62-0.88, TwinsUK: OR = 0.79, 95% CI: 0.64-0.98 per disadvantage) and higher with more social advantages (CSSB: OR = 1.26, 95% CI: 1.08-1.47, TwinsUK: OR = 1.36, 95% CI: 1.09-1.70 per advantage). Associations were neither explained by differences in COVID-19 illness severity or timing, nor adverse social experiences during the pandemic, which were themselves inversely associated with recovery. InterpretationStrong social inequalities in the likelihood of recovery from COVID-19 were observed, with ongoing symptoms several months after coronavirus infection more likely for individuals with multiple indicators of social disadvantage. Work is needed to identify modifiable biopsychosocial factors to enable interventions that address inequalities. FundingChronic Disease Research Foundation, National Institute for Health and Care Research, Medical Research Council, Wellcome LEAP, Wellcome Trust, Engineering & Physical Sciences Research Council, Biotechnology and Biological Sciences Research Council, Versus Arthritis, European Commission, Zoe Ltd. Plain language summaryAcross the world acute COVID-19 illness has affected the most disadvantaged in society the most. However, we have not looked in detail whether peoples social circumstances affect their recovery from COVID-19. In our study, we asked people from two UK-based health studies if they still had symptoms after having COVID-19. We looked at how advantaged or disadvantaged they were at the start of the pandemic, based on information about their sex, ethnic group, education level, local area, and employment. In both studies, people who were more disadvantaged were more likely to still have symptoms long after having COVID-19. In contrast, more advantaged people were more likely to have fully recovered. We also saw that people who had negative experiences during the pandemic such as losing their job, being unable to afford their bills or not being able to access health & social care services were less likely to recover. More work is needed to understand how and why recovery was so different for people with different circumstances. Research in contextO_ST_ABSEvidence before this studyC_ST_ABSTo search for previous reports on associations between recovery from COVID-19 and socio-demographic factors, we screened abstracts identified from the PubMed search query on December 21, 2023: "((COVID-19) AND ((recovery) OR (convalescence) OR (" ongoing symptoms")) AND ((socioeconomic) OR (sociodemographic) OR (social) OR (gradient))) AND LitCLONGCOVID[filter]", where LitCLONGCOVID is a filter for articles relating to long COVID (https://pubmed.ncbi.nlm.nih.gov/help/#covid19-article-filters), which returned 210 results published between July, 2020 and December, 2023. A small number (N = 11) of studies contained direct measures of recovery from COVID-19 in terms of presence/absence of ongoing symptoms relating to COVID-19 illness, either as perceived by the individual or inferred from current symptom reports. Of these, most focused on associations with COVID-19 illness factors such as severity and symptomatology, and prior health indicators. Socio-demographics were mostly used for sample description and adjustments in models rather than as exposures of interest. Of the few studies (N = 8) that tested associations with socio-demographic variables, the range of socio-demographics tested was limited and/or follow-up time typically restricted to 6-12 months since symptom onset. In these studies, associations with recovery were reported for age (N = 4), sex (N = 7), race/ethnicity (N = 2), local area deprivation (N = 1), and education level (N = 1). Associations between long-term symptoms and education or income have been reported in single separate studies. Monthly bulletins up to March 2023 from the UK Coronavirus Infection Survey highlighted prevalence of individuals reporting current effects on daily activities due to long COVID was associated with age, sex, race/ethnicity, local area deprivation and economic activity. No studies were identified that tested for associations of multiple socio-demographics in combination with the likelihood of recovery following COVID-19. Added value of this studyThis is the first study to testing the effects of multiple socio-demographics on self-perceived recovery in combination. Measures that attempt to quantify social advantage and disadvantage were generated from multiple known social determinants of health. We tested a wider range of socio-demographic factors than previous studies, including UK geographic region, educational qualification level, employment status and income. Our study has a longer follow-up time than previous comparable reports, with most participants assessed more than one year after infection onset. Detailed data on health before the coronavirus pandemic and COVID-19 illness allowed models to be adjusted extensively and mediation effects to be tested. Implications of all the available evidenceThe likelihood of full recovery following COVID-19 appears to follow a social gradient, higher for individuals with multiple indicators of social advantages and fewer disadvantages, and lower for those with multiple social disadvantages and fewer advantages prior to the coronavirus pandemic. This reflects and reaffirms the established cycle of social inequalities in health, between individuals status within social hierarchies and ill-health. More work is needed to understand the pathways through which this inequality operates so that interventions can be made.

Perceived Risk of Developing Severe Illness or Complications Due to Covid-19 in the Brazilian Population (preprint)

Background The perception of the risk of developing serious illness as a result of COVID-19 was one of the first reports used to reflect the health condition of infected people after hospital admission. The effects of COVID-19 are more severe in individuals with chronic noncommunicable diseases (NCDs), indicating that the characteristics and implications of these diseases in people with COVID-19 need to be investigated.Methods This cross-sectional study was was carried out with 1961 people aged 18 or older living in Brazil. An open research approach (survey) was used for the sample design, which involved the use of an online questionnaire. Descriptive statistical analysis and logistic regression were applied to identify factors associated with the perceived risk of complications due to COVID-19.Results The sample was mostly composed of women (n = 1383; 70.5%), 18 to 39 years old (n = 1144; 58.3%), and white (n = 1140; 56.4%). It was possible to observe that people who perceived a risk of developing diseases or complications if they became infected with COVID-19 were more likely to have a chronic noncommunicable disease (NCD) (OR: 4.51; 95% CI: 3.61–5.65), self-perception of potential risk of becoming infected with COVID-19 (OR: 2.34; 95% CI: 1.87–2.93), self-perceived potential risk of the population becoming infected with COVID-19 (OR: 5.80; 95% CI: 3.30–10.74), wearing a protective mask (OR: 12.98; 95% CI: 5.8–31.35) during the pandemic period and having a religion (OR: 1.29; 95% CI: 1.02–1.63).Conclusions The study showed that the perception of the risk of developing a severe form of the disease was significant in certain groups, such as religious people or those with chronic noncommunicable diseases.

“If it all goes digital we’ll have to learn”: Facilitators and barriers to uptake of digital health in British South Asians with cardiometabolic disease (preprint)

Background: Although availability and utilisation of digital health interventions (DHIs) for management of diabetes and cardiovascular disease (“cardiometabolic disease”) have increased, they may exacerbate health inequalities. South Asians have increased cardiometabolic risk, but their experiences of DHIs are poorly investigated and characterised. Objective: To explore facilitators and barriers to DHI uptake and use in South Asian individuals in the UK with cardiometabolic disease. Methods: Mixed-methods approach encompassing online/face-to-face/individual interviews (n=45) and survey (n=100). After informed consent, transcription and coding, we conducted a thematic analysis informed by a framework for inequalities in DHIs to examine perceptions at the individual, healthcare professional, societal and intervention level. Results: Participants described an intersection of factors resulting in varied digital skills and confidence within the community, including individual characteristics, awareness, and support. COVID-19 restrictions acted as both a positive (use of online shopping and social media increasing digital confidence) and negative (lack of access to health services) drivers to DHI uptake. Participants made recommendations for improving DHI uptake in the health service and policy area, such as promotion and upskilling through culturally and language-appropriate avenues such as community organisations and outlets. Participants suggested DHI design improvements should focus on literacy, numeracy, accessibility, and cultural appropriateness. Conclusions: DHIs have the potential to support South Asian populations in the UK to prevent and manage cardiometabolic disease. In order to improve their uptake, approaches to their implementation should consider community diversity to provide appropriate promotion, education, and support.

Unagi: Deep Generative Model for Deciphering Cellular Dynamics and In-Silico Drug Discovery in Complex Diseases (preprint)

Human diseases are characterized by intricate cellular dynamics. Single-cell sequencing provides critical insights, yet a persistent gap remains in computational tools for detailed disease progression analysis and targeted in-silico drug interventions. We introduce UNAGI, a deep generative neural network tailored to analyze time-series single-cell transcriptomic data. This innovative tool captures the complex cellular dynamics underlying disease progression, enhancing drug perturbation modeling and discovery. When applied to a dataset from patients with Idiopathic Pulmonary Fibrosis (IPF), UNAGI adeptly learns disease-informed cell embeddings that sharpen our understanding of disease progression, leading to the identification of potential therapeutic drug candidates. Validation via proteomics reveals the accuracy of UNAGI’s cellular dynamics analyses, and the use of the Fibrotic Cocktail treated human Precision-cut Lung Slices confirms UNAGI’s predictions that Nifedipine, an antihypertensive drug, may have antifibrotic effects on human tissues. UNAGI's versatility extends to other diseases, including a COVID dataset, demonstrating adaptability and confirming its broader applicability in decoding complex cellular dynamics beyond IPF, amplifying its utility in the quest for therapeutic solutions across diverse pathological landscapes.

The prevalence and influencing factors of COVID-19 in pregnant women in Hunan Province, China, immediately following the relaxation of epidemic control measures (preprint)

Objective: To investigate the prevalence and influencing factors of COVID-19 in pregnant women in Hunan Province immediately following the relaxation of epidemic control measures. Methods: This was a cross-sectional study with a multistage stratified sampling method. The questionnaire collected basic maternal information, data on COVID-19 infection status, and pregnancy-related information. The survey was conducted by trained investigators, and data quality checks were carried out twice per week. Results: Among the 7761 included pregnant women, 5191 (66.9%) had a positive SARS-CoV-2 test result or related symptoms. The majority of maternal infections were mild (90.0%), and very few were severe and critical (0.4% and 0.1%), and headache and body aches (65.3%) were the most common symptoms. A total of 2711 (52.2%) women gave birth, and 449 (16.6%) newborns had infections. Logistic multivariable regression analysis showedthatpregnant women with an education level of junior college and above (OR=1.392, 95% CI: 1.182, 1.639), those with a monthly household income ≥3000 yuan and above (OR=1.175, 95% CI: 1.027, 1.344), those who lived with their family during family member infection (OR=1.476, 95% CI: 1.316, 1.655), and those with pulmonary (OR=1.408, 95% CI: 1.070, 1.854) or other (OR=1.398, 95% CI: 1.188, 1.645) underlying diseases were more likely to have COVID-19. A farmer/worker occupation type (OR=0.617, 95% CI: 0.484, 0.786) was a protective factor. Conclusions: Many pregnantwomen had COVID-19 immediately following the relaxation of epidemic control measures, but most had mild cases, and few effects on newborns were observed. Mobility is the most critical factor influencing infection. The continued utilization of masks and adherence to social distancing measures remain crucial in mitigating COVID-19 transmission.

Trends in Nationally Notifiable Infectious Diseases in Humans and Animals During the COVID-19 Pandemic in South Korea (preprint)

Non-pharmaceutical interventions (NPIs) were implemented to cope with the coronavirus disease 2019 (COVID-19) pandemic in South Korea. These interventions could also have affected other infectious diseases, but there have been no comprehensive studies regarding their impacts. This study examined trends in notifiable infectious diseases in both humans and animals during the COVID-19 pandemic. Autoregressive integrated moving average (ARIMA) models were developed for each disease using data from 2016 to 2019, and the incidences for 2020 to 2021 were predicted. Subsequently, the predicted numbers of cases were compared with actual observations. Our findings indicated a substantial reduction in human respiratory infectious diseases during implementation of NPIs. However, human gastrointestinal infectious diseases and livestock diseases did not show a significant decrease. The results revealed that the preventive effect sizes of NPIs varied among diseases and indicated the potential for side effects, suggesting that complementary interventions are needed to minimize these negative effects.

A nationwide study of 331 rare diseases among 58 million individuals: prevalence, demographics, and COVID-19 outcomes (preprint)

Background: The Global Burden of Disease study has provided key evidence to inform clinicians, researchers, and policy makers across common diseases, but no similar effort with single study design exists for hundreds of rare diseases. Consequently, many rare conditions lack population-level evidence including prevalence and clinical vulnerability. This has led to the absence of evidence-based care for rare diseases, prominently in the COVID-19 pandemic. Method: This study used electronic health records (EHRs) of more than 58 million people in England, linking nine National Health Service datasets spanning healthcare settings for people alive on Jan 23, 2020. Starting with all rare diseases listed in Orphanet, we quality assured and filtered down to analyse 331 conditions with ICD-10 or SNOMED-CT mappings clinically validated in our dataset. We report 1) population prevalence, clinical and demographic details of rare diseases, and 2) investigate differences in mortality with SARs-CoV-2. Findings: Among 58,162,316 individuals, we identified 894,396 with at least one rare disease. Prevalence data in Orphanet originates from various sources with varying degrees of precision. Here we present reproducible age and gender-adjusted estimates for all 331 rare diseases, including first estimates for 186 (56.2%) without any reported prevalence estimate in Orphanet. We identified 49 rare diseases significantly more frequent in females and 62 in males. Similarly we identified 47 rare diseases more frequent in Asian as compared to White ethnicity and 22 with higher Black to white ratios as compared to similar ratios in population controls. 37 rare diseases were overrepresented in the white population as compared to both Black and Asian ethnicities. In total, 7,965 of 894,396 (0.9%) of rare-disease patients died from COVID-19, as compared to 141,287 of 58,162,316 (0.2%) in the full study population. Eight rare diseases had significantly increased risks for COVID-19-related mortality in fully vaccinated individuals, with bullous pemphigoid (8.07[3.01-21.62]) being worst affected. Interpretation: Our study highlights that National-scale EHRs provide a unique resource to estimate detailed prevalence, clinical and demographic data for rare diseases. Using COVID-19-related mortality analysis, we showed the power of large-scale EHRs in providing insights to inform public health decision-making for these often neglected patient populations.

Exploring COVID-19 vaccine uptake among healthcare workers in Zimbabwe: A mixed methods study (preprint)

With COVID-19 no longer categorized as a public health emergency of international concern, vaccination strategies and priority groups for vaccination have evolved. Africa Centers for Diseases Prevention and Control proposed the 100-100-70% strategy which aims to vaccinate all healthcare workers, all vulnerable groups, and 70% of the general population. Understanding whether healthcare workers were reached during previous vaccination campaigns and what can be done to address concerns, anxieties, and other influences on vaccine uptake, will be important to optimally plan how to achieve these ambitious targets. In this mixed-methods study, between June 2021 and July 2022 a quantitative survey was conducted with healthcare workers accessing a comprehensive health check in Zimbabwe to determine whether and, if so, when they had received a COVID-19 vaccine. Healthcare workers were categorized as those who had received the vaccine early (before 30.06.2021) and those who had received it late (after 30.06.2021). In addition, 17 in-depth interviews were conducted to understand perceptions and beliefs about COVID-19 vaccines. Of the 2905 healthcare workers employed at 37 facilities who participated in the study, 2818 (97%, 95% CI [92%-102%]) reported that they had received at least one vaccine dose. Geographical location, older age, higher educational attainment and having a chronic condition was associated with receiving the vaccine early. Qualitatively, (mis)information, infection risk perception, quasi-mandatory vaccination requirements, and legitimate concerns such as safety and efficacy influenced vaccine uptake. Meeting the proposed 100-100-70 target entails continued emphasis on strong communication while engaging meaningfully with healthcare workers concerns. Mandatory vaccination may undermine trust and should not be a substitute for sustained engagement.

Oral immunization with rVSV bivalent vaccine elicits protective immune responses, including ADCC, against both SARS-CoV-2 and Influenza A viruses (preprint)

COVID-19 and influenza both cause enormous disease burdens, and vaccines are the primary measures for their control. Since these viral diseases are transmitted through the mucosal surface of the respiratory tract, developing an effective and convenient mucosal vaccine should be a high priority. We previously reported a recombinant vesicular stomatitis virus (rVSV)-based bivalent vaccine (v-EM2/SP{Delta}C1Delta) that protects animals from both SARS-CoV-2 and influenza viruses via intramuscular and intranasal immunization. Here, we further investigated the immune response induced by oral immunization with this vaccine and its protective efficacy in mice. The results demonstrated that the oral cavity delivery, like the intranasal route, elicited strong and protective systemic immune responses against SARS-CoV-2 and influenza A virus. This included high levels of neutralizing antibodies (NAbs) against SARS-CoV-2, as well as strong anti-SARS-CoV-2 spike protein (SP) antibody-dependent cellular cytotoxicity (ADCC) and anti-influenza M2 ADCC responses in mice sera. Furthermore, it provided efficient protection against challenge with influenza H1N1 virus in a mouse model, with a 100% survival rate and a significant low lung viral load of influenza virus. All these findings provide substantial evidence for the effectiveness of oral immunization with the rVSV bivalent vaccine.

Production and performance assessment of a SARS-CoV-2 biomimetic in a verification program for pandemic readiness (preprint)

During the early stages of the Covid-19 pandemic in South Africa, one of many challenges included availability of control material proficiency testing programs. Control material utilising live SARS-CoV-2 or RNA extracted from cell culture was either biohazardous and costly, particularly in resource limited settings. Here, we report the development and application of a non-infectious SARS-CoV-2 biomimetic Mycobacterium smegmatis strain that mimics a positive result in the GeneXpert SARS-CoV-2 Xpert Xpress cartridge. Nucleotide sequences located in genes encoding the RNA-dependent RNA polymerase, the nucleocapsid and the envelope proteins were used. The resulting biomimetic was prepared as a Quality Control specimen and distributed to laboratories in South Africa for validation prior to testing of clinical specimens. Between April 2020 and December 2020, a total of 151 instruments were validated to bring Covid-19 mass testing online. These instruments capacitated the country to perform tests in 2532 modules. False negative or false positive findings reflected issues such as workflow/technician error or other related technical issues. This non-infectious, easily scalable control material became available within two months after the start of the pandemic in South Africa and represents a useful approach to consider for other diseases and future pandemics.

Safety, Immunogenicity, and Antibody Persistence of COVID-19 Boosters in BBIP-CorV Immunized Individuals with Comorbidities (preprint)

Data on immunogenicity, immune response persistency, and safety of COVID-19 boosters in patients with comorbidities are limited. Therefore, we aimed to evaluate and compare three different boosters in individuals who received two doses of the BBIBP-CorV vaccine including underlying diseases and healthy cases as control. One hundred forty subjects including 63 ones with at least one of three underlying diseases (UD) (including obesity, hypertension, and diabetes mellitus) and 77 healthy ones (HC) who had received a booster dose (either PastoCovac Plus or PastoCovac or BBIBP-CorV) were enrolled. The presence of SARS-CoV-2 antibodies was assessed before the booster injection and 28, 60, 90, and 180 days after it. Moreover, the adverse events (AEs) were recorded on days 7 and 21 post-booster shot for evaluating safety outcomes. Significantly increased titers of anti-spike, anti-RBD, and neutralizing antibodies were observed in both UD and HC groups 28 days after the booster dose, although the titer rise of anti-spike IgG and anti-RBD IgG was insignificantly inferior in the UD group compared to the HC group. All antibodies’ titers declined, with no significant differences between the two groups over time. Notably, all specific antibodies persisted up to 180 days; particularly the neutralizing antibody in both groups. Furthermore, no significant difference in antibody levels was observed between each UD subgroup and the HC group, except for neutralizing antibodies in the hypertension sub-group. PastoCovac Plus and PastoCovac boosters induced higher antibodies’ fold rise in UD individuals than BBIBP-CorV booster recipients. Safety outcomes did not show any serious AEs after the booster injection. The overall incidence of AEs post the booster injection was higher in the UD group than the HC group. Furthermore, the highest systemic AEs rate was reported in the UD group receiving the BBIBP-CorV booster. In conclusion, administration of COVID-19 boosters can equally induce robust and persistent humoral immune responses in individuals with or without UD primarily vaccinated with 2-doses of the BBIBP-CorV. Protein-based boosters with higher antibodies' fold rise and lower AEs in individuals with comorbidities might be considered a better choice for these individuals.