Healthcare utilisation in people with long COVID: an OpenSAFELY cohort study (preprint)

BackgroundLong COVID, characterised by various symptoms and complications, potentially increases healthcare utilisation and costs. However, its impact on the NHS remains to be determined. ObjectiveThis study aims to assess the healthcare utilisation of individuals with long COVID. MethodsWith the approval of NHS England, we conducted a matched cohort study using primary and secondary care data via OpenSAFELY, a platform for analysing anonymous electronic health records. The long COVID exposure group, defined by diagnostic codes, was matched with five comparators without long COVID between Nov 2020 and Jan 2023. We compared their total healthcare utilisation from GP consultations, prescriptions, hospital admissions, A&E visits, and outpatient appointments. Healthcare utilisation and costs were evaluated using a two-part model adjusting for covariates. Using a difference-in-difference model, we also compared healthcare utilisation after long COVID with pre-pandemic records. ResultsWe identified 52,988 individuals with a long COVID diagnosis, matched to 264,867 comparators without a diagnosis. In the 12 months post-diagnosis, there was strong evidence that those with long COVID were more likely to use healthcare resources (OR: 8.07, 95% CI: 7.54 - 8.64), and have 49% more healthcare utilisation (RR: 1.49, 95% CI: 1.47 - 1.50). Our model estimated that the long COVID group had 30 healthcare visits per year (predicted mean: 29.23, 95% CI: 28.58 - 29.92), compared to 16 in the comparator group (predicted mean visits: 16.04, 95% CI: 15.73 - 16.36). Individuals with long COVID were more likely to have non-zero healthcare expenditures (OR = 7.47, 95% CI = 7.02 - 7.95), with costs being 43% higher than the comparator group (cost ratio = 1.43, 95% CI: 1.38 - 1.49). The long COVID group costs approximately {pound}2,500 per person per year (predicted mean cost: {pound}2,562.50, 95% CI: {pound}2,335.60 - {pound}2,819.22), and the comparator group costs {pound}1,500 (predicted mean cost: {pound}1,527.43, 95% CI: {pound}1,404.33 - 1,664.45.) Historically, individuals with long COVID utilised healthcare resources more frequently, but their average healthcare utilisation increased more after being diagnosed with long COVID, compared to the comparator group. ConclusionLong COVID increases healthcare utilisation and costs. Public health policies should allocate more resources towards preventing, treating, and supporting individuals with long COVID.

Ursodeoxycholic acid and severe COVID-19 outcomes in people with liver disease: a cohort study using the OpenSAFELY platform (preprint)

Biological evidence suggests ursodeoxycholic acid (UDCA) - a common treatment of cholestatic liver disease - may prevent severe COVID-19 outcomes. With the approval of NHS England, we conducted a population-based cohort study using primary care records, linked to death registration data and hospital records through the OpenSAFELY-TPP platform. We estimated the hazard of COVID-19 hospitalisation or death between 1 March 2020 and 31 December 2022, comparing UDCA treatment to no UDCA treatment in a population with indication. Of 11,320 eligible individuals, 642 were hospitalised or died with COVID-19 during follow-up, 402 (63%) events among UDCA users. After confounder adjustment, UDCA was associated with a 21% (95% CI 7%-33%) relative reduction in the hazard of COVID-19 hospitalisation or death, consistent with an absolute risk reduction of 1.3% (95% CI 1.0%-1.6%). Our findings support calls for clinical trials investigating UDCA as a preventative measure for severe COVID-19 outcomes.

The impact of Long COVID on Health-Related Quality-of-life using OpenPROMPT (preprint)

Background: Long COVID is a major problem affecting patient health, the health service, and the workforce. To optimise the design of future interventions against COVID-19, and to better plan and allocate health resources, it is critical to quantify the health and economic burden of this novel condition. Methods With the approval of NHS England, we developed OpenPROMPT, a UK cohort study measuring the impact of long COVID on health-related quality-of-life (HRQoL). OpenPROMPT invited responses to Patient Reported Outcome Measures (PROMs) using a smartphone application and recruited between November 2022 and October 2023. We used the validated EuroQol EQ-5D questionnaire with the UK Value Set to develop disutility scores (1-utility) for respondents with and without Long COVID using linear mixed models, and we calculated subsequent Quality-Adjusted Life-Months (QALMs) for long COVID. Results We used data from 6,070 participants where 24.7% self-reported long COVID. In multivariable regressions, long COVID had a consistent impact on HRQoL, showing a high probability of reporting loss in quality-of-life (OR: 22, 95% CI:12.35-39.29) compared with people who did not report long COVID. Reporting a disability was the largest predictor of losses of HRQoL (OR: 60.2, 95% CI: 27.79-130.57) across survey responses. Self-reported long COVID was associated with an 0.37 QALM loss. Conclusions We found substantial impacts on quality-of-life due to long COVID, representing a major burden on patients and the health service. We highlight the need for continued support and research for long COVID, as HRQoL scores compared unfavourably to patients with conditions such as multiple sclerosis, heart failure, and renal disease.

Clinical coding of long COVID in primary care 2020-2023 in a cohort of 19 million adults: an OpenSAFELY analysis (preprint)

Background Long COVID is the patient-coined term for the persistent symptoms of COVID-19 illness for weeks, months or years following the acute infection. There is a large burden of long COVID globally from self-reported data, but the epidemiology, causes and treatments remain poorly understood. Primary care is used to help identify and treat patients with long COVID and therefore Electronic Health Records (EHRs) of past COVID-19 patients could be used to help fill these knowledge gaps. We aimed to describe those with long COVID in primary care records in England. Methods With the approval of NHS England we used routine clinical data from over 19 million adults in England linked to SARS-COV-2 test result, hospitalisation and vaccination data to describe trends in the recording of 16 clinical codes related to long COVID between November 2020 and January 2023. We calculated rates per 100,000 person-years and plotted how these changed over time. We compared crude and minimally adjusted rates of recorded long COVID in patient records between different key demographic and vaccination characteristics using negative binomial models. Findings We identified a total of 55,465 people recorded to have long COVID over the study period, with incidence of new long COVID records increasing steadily over 2021, and declining over 2022. The overall rate per 100,000 person-years was 177.5 cases in women (95% CI: 175.5-179) and 100.5 men (99.5-102). In terms of vaccination against COVID-19, the lowest rates were observed in those with 3+ vaccine doses (103.5 [95% CI: 101.5-105]). Finally, the majority of those with a long COVID record did not have a recorded positive SARS-COV-2 test 12 weeks before the long COVID record. Interpretation EHR recorded long COVID remains very low compared and incident records of long COVID declined over 2022. We found the lowest rates of recorded long COVID in people with 3 or more vaccine doses. We summarised several sources of possible bias for researchers using EHRs to study long COVID. Funding This research was supported by the National Institute for Health and Care Research (NIHR) (OpenPROMPT: COV-LT2-0073))

Identification of key mutations responsible for the enhancement of receptor-binding affinity and immune escape of SARS-CoV-2 Omicron variant.

The Omicron variant of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has raised concerns worldwide due to its enhanced transmissibility and immune escapability. The first dominant Omicron BA.1 subvariant harbors more than 30 mutations in the spike protein from the prototype virus, of which 15 mutations are located at the receptor binding domain (RBD). These mutations in the RBD region attracted significant attention, which potentially enhance the binding of the receptor human angiotensin-converting enzyme 2 (hACE2) and decrease the potency of neutralizing antibodies/nanobodies. This study applied the molecular dynamics simulations combined with the molecular mechanics-generalized Born surface area (MMGBSA) method, to investigate the molecular mechanism behind the impact of the mutations acquired by Omicron on the binding affinity between RBD and hACE2. Our results indicate that five key mutations, i.e., N440K, T478K, E484A, Q493R, and G496S, contributed significantly to the enhancement of the binding affinity by increasing the electrostatic interactions of the RBD-hACE2 complex. Moreover, fourteen neutralizing antibodies/nanobodies complexed with RBD were used to explore the effects of the mutations in Omicron RBD on their binding affinities. The calculation results indicate that the key mutations E484A and Y505H reduce the binding affinities to RBD for most of the studied neutralizing antibodies/nanobodies, mainly attributed to the elimination of the original favorable gas-phase electrostatic and hydrophobic interactions between them, respectively. Our results provide valuable information for developing effective vaccines and antibody/nanobody drugs.

Forward-backward and period doubling bifurcations in a discrete epidemic model with vaccination and limited medical resources.

A discrete epidemic model with vaccination and limited medical resources is proposed to understand its underlying dynamics. The model induces a nonsmooth two dimensional map that exhibits a surprising array of dynamical behavior including the phenomena of the forward-backward bifurcation and period doubling route to chaos with feasible parameters in an invariant region. We demonstrate, among other things, that the model generates the above described phenomena as the transmission rate or the basic reproduction number of the disease gradually increases provided that the immunization rate is low, the vaccine failure rate is high and the medical resources are limited. Finally, the numerical simulations are provided to illustrate our main results.

Modeling COVID-19 transmission dynamics incorporating media coverage and vaccination.

The COVID-19 pandemic has caused widespread concern around the world. In order to study the impact of media coverage and vaccination on the spread of COVID-19, we establish an SVEAIQR infectious disease model, and fit the important parameters such as transmission rate, isolation rate and vaccine efficiency based on the data from Shanghai Municipal Health Commission and the National Health Commission of the People's Republic of China. Meanwhile, the control reproduction number and the final size are derived. Moreover, through sensitivity analysis by PRCC (partial rank correlation coefficient), we discuss the effects of both the behavior change constant $ k $ according to media coverage and the vaccine efficiency $ \varepsilon $ on the transmission of COVID-19. Numerical explorations of the model suggest that during the outbreak of the epidemic, media coverage can reduce the final size by about 0.26 times. Besides that, comparing with $ 50\% $ vaccine efficiency, when the vaccine efficiency reaches $ 90\% $, the peak value of infected people decreases by about 0.07 times. In addition, we simulate the impact of media coverage on the number of infected people in the case of vaccination or non-vaccination. Accordingly, the management departments should pay attention to the impact of vaccination and media coverage.

Using a Layered Ensemble of Physics-Guided Graph Attention Networks to Predict COVID-19 Trends

The COVID-19 pandemic has spread rapidly and significantly impacted most countries in the world. Providing an accurate forecast of COVID-19 at multiple scales would help inform public health decisions, but recent forecasting models are typically used at the state or country level. Furthermore, traditional mathematical models are limited by simplifying assumptions, while machine learning algorithms struggle to generalize to unseen trends. This motivates the need for hybrid machine learning models that integrate domain knowledge for accurate long-term prediction. We propose a three-layer, geographically informed ensemble, an extensive peer-learning framework, for predicting COVID-19 trends at the country, continent, and global levels. As the base layer, we develop a country-level predictor using a hybrid Graph Attention Network that incorporates a modified SIR model, adaptive loss function, and edge weights informed by mobility data. We aggregated 163 country GATs to train the continent and world MLP layers of the ensemble. Our results indicate that incorporating quantitatively accurate equations and real-world data to model inter-community interactions improves the performance of spatio-temporal machine learning algorithms. Additionally, we demonstrate that integrating geographic information (continent composition) improves the performance of the world predictor in our layered architecture. (PsycInfo Database Record (c) 2022 APA, all rights reserved)

Thoughts on the effects of moxa smoke in the epidemic prevention.

Through summarizing and analyzing the modern mechanism researches and controversial questions of moxibustion fumigation in the epidemic prevention, the thoughts on tackling the critical points are proposed in the paper, such as the recognition of moxa smoke in traditional Chinese medicine (TCM), the mechanism of moxa smoke in air disinfection and the characteristics of clinical application of moxa smoke so as to provide the references to the prevention and control of COVID-19 in TCM.

Pharmacological disruption of mSWI/SNF complex activity restricts SARS-CoV-2 infection.

Identification of host determinants of coronavirus infection informs mechanisms of viral pathogenesis and can provide new drug targets. Here we demonstrate that mammalian SWItch/Sucrose Non-Fermentable (mSWI/SNF) chromatin remodeling complexes, specifically canonical BRG1/BRM-associated factor (cBAF) complexes, promote severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and represent host-directed therapeutic targets. The catalytic activity of SMARCA4 is required for mSWI/SNF-driven chromatin accessibility at the ACE2 locus, ACE2 expression and virus susceptibility. The transcription factors HNF1A/B interact with and recruit mSWI/SNF complexes to ACE2 enhancers, which contain high HNF1A motif density. Notably, small-molecule mSWI/SNF ATPase inhibitors or degraders abrogate angiotensin-converting enzyme 2 (ACE2) expression and confer resistance to SARS-CoV-2 variants and a remdesivir-resistant virus in three cell lines and three primary human cell types, including airway epithelial cells, by up to 5 logs. These data highlight the role of mSWI/SNF complex activities in conferring SARS-CoV-2 susceptibility and identify a potential class of broad-acting antivirals to combat emerging coronaviruses and drug-resistant variants.

Protocol for an OpenSAFELY cohort study collecting patient-reported outcome measures using the TPP Airmid smartphone application and linked big data to quantify the health and economic costs of long COVID (OpenPROMPT).

INTRODUCTION: The impact of long COVID on health-related quality of-life (HRQoL) and productivity is not currently known. It is important to understand who is worst affected by long COVID and the cost to the National Health Service (NHS) and society, so that strategies like booster vaccines can be prioritised to the right people. OpenPROMPT aims to understand the impact of long COVID on HRQoL in adults attending English primary care. METHODS AND ANALYSIS: We will ask people to participate in this cohort study through a smartphone app (Airmid), and completing a series of questionnaires held within the app. Questionnaires will ask about HRQoL, productivity and symptoms of long COVID. Participants will be asked to fill in the questionnaires once a month, for 90 days. Questionnaire responses will be linked, where possible, to participants' existing health records from primary care, secondary care, and COVID testing and vaccination data. Analysis will take place using the OpenSAFELY data platform and will estimate the impact of long COVID on HRQoL, productivity and cost to the NHS. ETHICS AND DISSEMINATION: The Proportionate Review Sub-Committee of the South Central-Berkshire B Research Ethics Committee has reviewed and approved the study and have agreed that we can ask people to take part (22/SC/0198). Our results will provide information to support long-term care, and make recommendations for prevention of long COVID in the future. TRIAL REGISTRATION NUMBER: NCT05552612.

Immunogenicity, effectiveness, and safety of COVID-19 vaccines among children and adolescents aged 2-18 years: an updated systematic review and meta-analysis.

BACKGROUND: During the coronavirus disease 2019 (COVID-19) pandemic, there is an urgent need for safe and effective COVID-19 vaccines to protect children and adolescents. This study aims to provide scientific evidence and recommendations for the application of COVID-19 vaccines in children and adolescents by analyzing the latest studies. METHODS: We systematically searched MEDLINE (accessed through PubMed), Embase, and Web of Science from January 1, 2020, to October 8, 2022. Eligible clinical trials, cohort studies, case‒control studies, and cross-sectional studies with extractable data were included in immunogenicity, effectiveness, and safety analyses. According to the heterogeneity, we chose a fixed-effect model (when I2 ≤ 50) or a random-effects model (when I2 > 50) to pool effect values. RESULTS: A total of 88 articles were included. The seroconversion rates after the first, second, and third doses of the vaccines were 86.10%, 96.52%, and 99.87%, respectively. After the first and second doses, vaccine effectiveness (VE) against severe acute respiratory syndrome coronavirus 2 infection was 42.87% [95% confidence interval (CI) = 27.09%-58.65%] and 63.33% (95% CI = 52.09%-74.56%), respectively. After the first and second doses, VE against COVID-19 was 60.65% (95% CI = 44.80%-76.50%) and 75.77% (95% CI = 63.99%-87.56%), respectively. VE against hospitalization due to COVID-19 after the first and second doses was 72.74% (95% CI = 51.48%-94.01%) and 82.78% (95% CI = 75.78%-89.78%), respectively. The most common adverse events were injection site pain, fatigue/asthenia/tiredness, headache, myalgia/muscle pain, and chills. The incidence rate of myocarditis or pericarditis was 2.42/100,000 people. In addition, the subgroup analysis showed that children aged ≤ 5 years had the lowest incidence of adverse events, and the incidence rate of adverse events was higher for mRNA vaccines than for inactivated vaccines. CONCLUSIONS: COVID-19 vaccines have good immunogenicity, effectiveness, and safety among children and adolescents. We recommend that children and adolescents be vaccinated as soon as possible to protect them and slow the spread of COVID-19.

Safety and immunogenicity of a mosaic vaccine booster against Omicron and other SARS-CoV-2 variants: a randomized phase 2 trial.

An ongoing randomized, double-blind, controlled phase 2 trial was conducted to evaluate the safety and immunogenicity of a mosaic-type recombinant vaccine candidate, named NVSI-06-09, as a booster dose in subjects aged 18 years and older from the United Arab Emirates (UAE), who had administered two or three doses of inactivated vaccine BBIBP-CorV at least 6 months prior to enrollment. The participants were randomly assigned with 1:1 to receive a booster dose of NVSI-06-09 or BBIBP-CorV. The primary outcomes were immunogenicity and safety against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Omicron variant, and the exploratory outcome was cross-immunogenicity against other circulating strains. Between May 25 and 30, 2022, 516 adults received booster vaccination with 260 in NVSI-06-09 group and 256 in BBIBP-CorV group. Interim results showed a similar safety profile between two booster groups, with low incidence of adverse reactions of grade 1 or 2. For immunogenicity, by day 14 post-booster, the fold rises in neutralizing antibody geometric mean titers (GMTs) from baseline elicited by NVSI-06-09 were remarkably higher than those by BBIBP-CorV against the prototype strain (19.67 vs 4.47-fold), Omicron BA.1.1 (42.35 vs 3.78-fold), BA.2 (25.09 vs 2.91-fold), BA.4 (22.42 vs 2.69-fold), and BA.5 variants (27.06 vs 4.73-fold). Similarly, the neutralizing GMTs boosted by NVSI-06-09 against Beta and Delta variants were also 6.60-fold and 7.17-fold higher than those by BBIBP-CorV. Our findings indicated that a booster dose of NVSI-06-09 was well-tolerated and elicited broad-spectrum neutralizing responses against divergent SARS-CoV-2 variants, including Omicron and its sub-lineages.

Circulating microRNAs as emerging regulators of COVID-19.

Coronavirus disease 2019 (COVID-19), an infectious disease caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a global pandemic that has high incidence rates, spreads rapidly, and has caused more than 6.5 million deaths globally to date. Currently, several drugs have been used in the clinical treatment of COVID-19, including antivirals (e.g., molnupiravir, baricitinib, and remdesivir), monoclonal antibodies (e.g., etesevimab and tocilizumab), protease inhibitors (e.g., paxlovid), and glucocorticoids (e.g., dexamethasone). Increasing evidence suggests that circulating microRNAs (miRNAs) are important regulators of viral infection and antiviral immune responses, including the biological processes involved in regulating COVID-19 infection and subsequent complications. During viral infection, both viral genes and host cytokines regulate transcriptional and posttranscriptional steps affecting viral replication. Virus-encoded miRNAs are a component of the immune evasion repertoire and function by directly targeting immune functions. Moreover, several host circulating miRNAs can contribute to viral immune escape and play an antiviral role by not only promoting nonstructural protein (nsp) 10 expression in SARS coronavirus, but among others inhibiting NOD-like receptor pyrin domain-containing (NLRP) 3 and IL-1ß transcription. Consequently, understanding the expression and mechanism of action of circulating miRNAs during SARS-CoV-2 infection will provide unexpected insights into circulating miRNA-based studies. In this review, we examined the recent progress of circulating miRNAs in the regulation of severe inflammatory response, immune dysfunction, and thrombosis caused by SARS-CoV-2 infection, discussed the mechanisms of action, and highlighted the therapeutic challenges involving miRNA and future research directions in the treatment of COVID-19.

Using Text Mining and Data Visualization Approaches for Investigating Mental Illness from the Perspective of Traditional Chinese Medicine.

Background and Objectives. Anxiety and depressive disorders are the most prevalent mental disorders, and due to the COVID-19 pandemic, more people are suffering from anxiety and depressive disorders, and a considerable fraction of COVID-19 survivors have a variety of persistent neuropsychiatric problems after the initial infection. Traditional Chinese Medicine (TCM) offers a different perspective on mental disorders from Western biomedicine. Effective management of mental disorders has become an increasing concern in recent decades due to the high social and economic costs involved. This study attempts to express and ontologize the relationships between different mental disorders and physical organs from the perspective of TCM, so as to bridge the gap between the unique terminology used in TCM and a medical professional. Materials and Methods. Natural language processing (NLP) is introduced to quantify the importance of different mental disorder descriptions relative to the five depots and two palaces, stomach and gallbladder, through the classical medical text Huangdi Neijing and construct a mental disorder ontology based on the TCM classic text. Results. The results demonstrate that our proposed framework integrates NLP and data visualization, enabling clinicians to gain insights into mental health, in addition to biomedicine. According to the results of the relationship analysis of mental disorders, depots, palaces, and symptoms, the organ/depot most related to mental disorders is the heart, and the two most important emotion factors associated with mental disorders are anger and worry & think. The mental disorders described in TCM are related to more than one organ (depot/palace). Conclusion. This study complements recent research delving into co-relations or interactions between mental status and other organs and systems.

Towards a global One Health index: a potential assessment tool for One Health performance.

BACKGROUND: A One Health approach has been increasingly mainstreamed by the international community, as it provides for holistic thinking in recognizing the close links and inter-dependence of the health of humans, animals and the environment. However, the dearth of real-world evidence has hampered application of a One Health approach in shaping policies and practice. This study proposes the development of a potential evaluation tool for One Health performance, in order to contribute to the scientific measurement of One Health approach and the identification of gaps where One Health capacity building is most urgently needed. METHODS: We describe five steps towards a global One Health index (GOHI), including (i) framework formulation; (ii) indicator selection; (iii) database building; (iv) weight determination; and (v) GOHI scores calculation. A cell-like framework for GOHI is proposed, which comprises an external drivers index (EDI), an intrinsic drivers index (IDI) and a core drivers index (CDI). We construct the indicator scheme for GOHI based on this framework after multiple rounds of panel discussions with our expert advisory committee. A fuzzy analytical hierarchy process is adopted to determine the weights for each of the indicators. RESULTS: The weighted indicator scheme of GOHI comprises three first-level indicators, 13 second-level indicators, and 57 third-level indicators. According to the pilot analysis based on the data from more than 200 countries/territories the GOHI scores overall are far from ideal (the highest score of 65.0 out of a maximum score of 100), and we found considerable variations among different countries/territories (31.8-65.0). The results from the pilot analysis are consistent with the results from a literature review, which suggests that a GOHI as a potential tool for the assessment of One Health performance might be feasible. CONCLUSIONS: GOHI-subject to rigorous validation-would represent the world's first evaluation tool that constructs the conceptual framework from a holistic perspective of One Health. Future application of GOHI might promote a common understanding of a strong One Health approach and provide reference for promoting effective measures to strengthen One Health capacity building. With further adaptations under various scenarios, GOHI, along with its technical protocols and databases, will be updated regularly to address current technical limitations, and capture new knowledge.

Nanoformulations targeting immune cells for cancer therapy: mRNA therapeutics

The approved worldwide use of two messenger RNA (mRNA) vaccines (BNT162b2 and mRNA-1273) in late 2020 has proven the remarkable success of mRNA therapeutics together with lipid nanoformulation technology in protecting people against coronaviruses during COVID-19 pandemic. This unprecedented and exciting dual strategy with nanoformulations and mRNA therapeutics in play is believed to be a promising paradigm in targeted cancer immunotherapy in future. Recent advances in nanoformulation technologies play a prominent role in adapting mRNA platform in cancer treatment. In this review, we introduce the biologic principles and advancements of mRNA technology, and chemistry fundamentals of intriguing mRNA delivery nanoformulations. We discuss the latest promising nano-mRNA therapeutics for enhanced cancer immunotherapy by modulation of targeted specific subtypes of immune cells, such as dendritic cells (DCs) at peripheral lymphoid organs for initiating mRNA cancer vaccine-mediated antigen specific immunotherapy, and DCs, natural killer (NK) cells, cytotoxic T cells, or multiple immunosuppressive immune cells at tumor microenvironment (TME) for reversing immune evasion. We highlight the clinical progress of advanced nano-mRNA therapeutics in targeted cancer therapy and provide our perspectives on future directions of this transformative integrated technology toward clinical implementation.

Circular RNAs as emerging regulators in COVID-19 pathogenesis and progression.

Coronavirus disease 2019 (COVID-19), an infectious acute respiratory disease caused by a newly emerging RNA virus, is a still-growing pandemic that has caused more than 6 million deaths globally and has seriously threatened the lives and health of people across the world. Currently, several drugs have been used in the clinical treatment of COVID-19, such as small molecules, neutralizing antibodies, and monoclonal antibodies. In addition, several vaccines have been used to prevent the spread of the pandemic, such as adenovirus vector vaccines, inactivated vaccines, recombinant subunit vaccines, and nucleic acid vaccines. However, the efficacy of vaccines and the onset of adverse reactions vary among individuals. Accumulating evidence has demonstrated that circular RNAs (circRNAs) are crucial regulators of viral infections and antiviral immune responses and are heavily involved in COVID-19 pathologies. During novel coronavirus infection, circRNAs not only directly affect the transcription process and interfere with viral replication but also indirectly regulate biological processes, including virus-host receptor binding and the immune response. Consequently, understanding the expression and function of circRNAs during severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection will provide novel insights into the development of circRNA-based methods. In this review, we summarize recent progress on the roles and underlying mechanisms of circRNAs that regulate the inflammatory response, viral replication, immune evasion, and cytokines induced by SARS-CoV-2 infection, and thus highlighting the diagnostic and therapeutic challenges in the treatment of COVID-19 and future research directions.

Immunoglobulin Y Specific for SARS-CoV-2 Spike Protein Subunits Effectively Neutralizes SARS-CoV-2 Infectivity and Ameliorates Disease Manifestations In Vivo.

(Background) The coronavirus disease 2019 (COVID-19) that is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) carries high infectivity and mortality. Efficient intervention strategies are urgently needed. Avian immunoglobulin Y (IgY) showed efficacy against viral infection whereas the in vivo efficacy remains unclear. (Methods) We immunized laying hens with S1, S1 receptor-binding domain (S1-RBD), or S2 subunits of the SARS-CoV-2 spike (S) protein. After immunization, IgYs were collected and extracted from the egg yolks. The neutralization potential of IgYs was examined by the plaque reduction neutralization test (PRNT). The bioutility of IgYs was examined in Syrian hamsters in vivo. (Results) IgYs exhibited typical banding patterns in SDS-PAGE and Western blot and were immunoreactive against S1, S1-RBD, and S2 subunits. The plaque reduction neutralization test (PRNT) showed that all purified IgYs potently neutralized different SARS-CoV-2 strains in vitro. In Syrian hamsters, the combination of IgYs for S1-RBD and S2 subunits administered before or after SARS-CoV-2 infection effectively restored body weight loss and reduced intrapulmonary lesions and the amount of immunoreactive N protein-positive cells, which were caused by SARS-CoV-2 infection. (Conclusions) Collectively, IgYs specific for S protein subunits effectively neutralized SARS-CoV-2 in vitro and in vivo and may serve as prophylactic or therapeutic antibodies in the prevention or treatment of COVID-19.

A mosaic-type trimeric RBD-based COVID-19 vaccine candidate induces potent neutralization against Omicron and other SARS-CoV-2 variants.

Large-scale populations in the world have been vaccinated with COVID-19 vaccines, however, breakthrough infections of SARS-CoV-2 are still growing rapidly due to the emergence of immune-evasive variants, especially Omicron. It is urgent to develop effective broad-spectrum vaccines to better control the pandemic of these variants. Here, we present a mosaic-type trimeric form of spike receptor-binding domain (mos-tri-RBD) as a broad-spectrum vaccine candidate, which carries the key mutations from Omicron and other circulating variants. Tests in rats showed that the designed mos-tri-RBD, whether used alone or as a booster shot, elicited potent cross-neutralizing antibodies against not only Omicron but also other immune-evasive variants. Neutralizing antibody ID50 titers induced by mos-tri-RBD were substantially higher than those elicited by homo-tri-RBD (containing homologous RBDs from prototype strain) or the BIBP inactivated COVID-19 vaccine (BBIBP-CorV). Our study indicates that mos-tri-RBD is highly immunogenic, which may serve as a broad-spectrum vaccine candidate in combating SARS-CoV-2 variants including Omicron.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic continues to pose a serious threat to public health and has so far resulted in over six million deaths worldwide. Mass vaccination programs have reduced the risk of serious illness and death in many people, but the virus continues to persist and circulate in communities across the globe. Furthermore, the current vaccines may be less effective against the new variants of the virus, such as Omicron and Delta, which are continually emerging and evolving. Therefore, it is urgent to develop effective vaccines that can provide broad protection against existing and future forms of SARS-CoV-2. There are several different types of SARS-CoV-2 vaccine, but they all work in a similar way. They contain molecules that induce immune responses in individuals to help the body recognize and more effectively fight SARS-CoV-2 if they happen to encounter it in the future. These immune responses may be so specific that new variants of a virus may not be recognized by them. Therefore, a commonly used strategy for producing vaccines with broad protection is to make multiple vaccines that each targets different variants and then mix them together before administering to patients. Here, Zhang et al. took a different approach by designing a new vaccine candidate against SARS-CoV2 that contained three different versions of part of a SARS-CoV2 protein ­ the so-called spike protein ­ all linked together as one molecule. The different versions of the spike protein fragment were designed to include key features of the fragments found in Omicron and several other SARS-CoV-2 variants. The experiments found that this candidate vaccine elicited a much higher immune response against Omicron and other SARS-CoV-2 variants in rats than an existing SARS-CoV-2 vaccine. It was also effective as a booster shot after a first vaccination with the existing SARS-CoV-2 vaccine. These findings demonstrate that the molecule developed by Zhang et al. induces potent and broad immune responses against different variants of SARS-CoV-2 including Omicron in rats. The next steps following on from this work are to evaluate the safety and immunogenicity of this vaccine candidate in clinical trials. In the future, it may be possible to use a similar approach to develop new broad-spectrum vaccines against other viruses.