COVID-19 vaccine update: vaccine effectiveness, SARS-CoV-2 variants, boosters, adverse effects, and immune correlates of protection.

Coronavirus Disease 2019 (COVID-19) has been the most severe public health challenge in this century. Two years after its emergence, the rapid development and deployment of effective COVID-19 vaccines have successfully controlled this pandemic and greatly reduced the risk of severe illness and death associated with COVID-19. However, due to its ability to rapidly evolve, the SARS-CoV-2 virus may never be eradicated, and there are many important new topics to work on if we need to live with this virus for a long time. To this end, we hope to provide essential knowledge for researchers who work on the improvement of future COVID-19 vaccines. In this review, we provided an up-to-date summary for current COVID-19 vaccines, discussed the biological basis and clinical impact of SARS-CoV-2 variants and subvariants, and analyzed the effectiveness of various vaccine booster regimens against different SARS-CoV-2 strains. Additionally, we reviewed potential mechanisms of vaccine-induced severe adverse events, summarized current studies regarding immune correlates of protection, and finally, discussed the development of next-generation vaccines.

Outcomes in patients with and without disability admitted to hospital with COVID-19: a retrospective cohort study.

BACKGROUND: Disability-related considerations have largely been absent from the COVID-19 response, despite evidence that people with disabilities are at elevated risk for acquiring COVID-19. We evaluated clinical outcomes in patients who were admitted to hospital with COVID-19 with a disability compared with patients without a disability. METHODS: We conducted a retrospective cohort study that included adults with COVID-19 who were admitted to hospital and discharged between Jan. 1, 2020, and Nov. 30, 2020, at 7 hospitals in Ontario, Canada. We compared in-hospital death, admission to the intensive care unit (ICU), hospital length of stay and unplanned 30-day readmission among patients with and without a physical disability, hearing or vision impairment, traumatic brain injury, or intellectual or developmental disability, overall and stratified by age (≤ 64 and ≥ 65 yr) using multivariable regression, controlling for sex, residence in a long-term care facility and comorbidity. RESULTS: Among 1279 admissions to hospital for COVID-19, 22.3% had a disability. We found that patients with a disability were more likely to die than those without a disability (28.1% v. 17.6%), had longer hospital stays (median 13.9 v. 7.8 d) and more readmissions (17.6% v. 7.9%), but had lower ICU admission rates (22.5% v. 28.3%). After adjustment, there were no statistically significant differences between those with and without disabilities for in-hospital death or admission to ICU. After adjustment, patients with a disability had longer hospital stays (rate ratio 1.36, 95% confidence interval [CI] 1.19-1.56) and greater risk of readmission (relative risk 1.77, 95% CI 1.14-2.75). In age-stratified analyses, we observed longer hospital stays among patients with a disability than in those without, in both younger and older subgroups; readmission risk was driven by younger patients with a disability. INTERPRETATION: Patients with a disability who were admitted to hospital with COVID-19 had longer stays and elevated readmission risk than those without disabilities. Disability-related needs should be addressed to support these patients in hospital and after discharge.

Aging-related cell type-specific pathophysiologic immune responses that exacerbate disease severity in aged COVID-19 patients.

Coronavirus disease 2019 (COVID-19) is especially severe in aged patients, defined as 65 years or older, for reasons that are currently unknown. To investigate the underlying basis for this vulnerability, we performed multimodal data analyses on immunity, inflammation, and COVID-19 incidence and severity as a function of age. Our analysis leveraged age-specific COVID-19 mortality and laboratory testing from a large COVID-19 registry, along with epidemiological data of ~3.4 million individuals, large-scale deep immune cell profiling data, and single-cell RNA-sequencing data from aged COVID-19 patients across diverse populations. We found that decreased lymphocyte count and elevated inflammatory markers (C-reactive protein, D-dimer, and neutrophil-lymphocyte ratio) are significantly associated with age-specific COVID-19 severities. We identified the reduced abundance of naïve CD8 T cells with decreased expression of antiviral defense genes (i.e., IFITM3 and TRIM22) in aged severe COVID-19 patients. Older individuals with severe COVID-19 displayed type I and II interferon deficiencies, which is correlated with SARS-CoV-2 viral load. Elevated expression of SARS-CoV-2 entry factors and reduced expression of antiviral defense genes (LY6E and IFNAR1) in the secretory cells are associated with critical COVID-19 in aged individuals. Mechanistically, we identified strong TGF-beta-mediated immune-epithelial cell interactions (i.e., secretory-non-resident macrophages) in aged individuals with critical COVID-19. Taken together, our findings point to immuno-inflammatory factors that could be targeted therapeutically to reduce morbidity and mortality in aged COVID-19 patients.

Multimodal single-cell omics analysis identifies epithelium-immune cell interactions and immune vulnerability associated with sex differences in COVID-19.

Sex differences in the susceptibility of SARS-CoV-2 infection and severity have been controversial, and the underlying mechanisms of COVID-19 in a sex-specific manner remain understudied. Here we inspected sex differences in SARS-CoV-2 infection, hospitalization, admission to the intensive care unit (ICU), sera inflammatory biomarker profiling, and single-cell RNA-sequencing (scRNA-seq) profiles across nasal, bronchoalveolar lavage fluid (BALF), and peripheral blood mononuclear cells (PBMCs) from COVID-19 patients with varying degrees of disease severities. Our propensity score-matching observations revealed that male individuals have a 29% elevated likelihood of SARS-CoV-2 positivity, with a hazard ratio (HR) 1.32 (95% confidence interval [CI] 1.18-1.48) for hospitalization and HR 1.51 (95% CI 1.24-1.84) for admission to ICU. Sera from male patients at hospital admission had elevated neutrophil-lymphocyte ratio and elevated expression of inflammatory markers (C-reactive protein and procalcitonin). We found that SARS-CoV-2 entry factors, including ACE2, TMPRSS2, FURIN, and NRP1, have elevated expression in nasal squamous cells from male individuals with moderate and severe COVID-19. We observed male-biased transcriptional activation in SARS-CoV-2-infected macrophages from BALF and sputum samples, which offers potential molecular mechanism for sex-biased susceptibility to viral infection. Cell-cell interaction network analysis reveals potential epithelium-immune cell interactions and immune vulnerability underlying male-elevated disease severity and mortality in COVID-19. Mechanistically, monocyte-elevated expression of Toll-like receptor 7 (TLR7) and Bruton tyrosine kinase (BTK) is associated with severe outcomes in males with COVID-19. In summary, these findings provide basis to decipher immune responses underlying sex differences and designing sex-specific targeted interventions and patient care for COVID-19.

Caractéristiques et issues des hospitalisations pour les cas de COVID-19 et d'influenza dans la région de Toronto.

CONTEXTE: Les caractéristiques des patients, les soins cliniques, l'utilisation des ressources et les issues cliniques des personnes atteintes de la maladie à coronavirus 2019 (COVID-19) hospitalisées au Canada ne sont pas bien connus. MÉTHODES: Nous avons recueilli des données sur tous les adultes hospitalisés atteints de la COVID-19 ou de l'influenza ayant obtenu leur congé d'unités médicales ou d'unités de soins intensifs médicaux et chirurgicaux entre le 1er novembre 2019 et le 30 juin 2020 dans 7 centres hospitaliers de Toronto et de Mississauga (Ontario). Nous avons comparé les issues cliniques des patients à l'aide de modèles de régression multivariée, en tenant compte des facteurs sociodémographiques et de l'intensité des comorbidités. Nous avons validé le degré d'exactitude de 7 scores de risque mis au point à l'externe pour déterminer leur capacité à prédire le risque de décès chez les patients atteints de la COVID-19. RÉSULTATS: Parmi les hospitalisations retenues, 1027 patients étaient atteints de la COVID-19 (âge médian de 65 ans, 59,1 % d'hommes) et 783 étaient atteints de l'influenza (âge médian de 68 ans, 50,8 % d'hommes). Les patients âgés de moins de 50 ans comptaient pour 21,2 % de toutes les hospitalisations dues à la COVID-19 et 24,0 % des séjours aux soins intensifs. Comparativement aux patients atteints de l'influenza, les patients atteints de la COVID-19 présentaient un taux de mortalité perhospitalière (mortalité non ajustée 19,9 % c. 6,1 %; risque relatif [RR] ajusté 3,46 %, intervalle de confiance [IC] à 95 % 2,56­4,68) et un taux d'utilisation des ressources des unités de soins intensifs (taux non ajusté 26,4 % c. 18,0 %; RR ajusté 1,50, IC à 95 % 1,25­1,80) significativement plus élevés, ainsi qu'une durée d'hospitalisation (durée médiane non ajustée 8,7 jours c. 4,8 jours; rapport des taux d'incidence ajusté 1,45; IC à 95 % 1,25­1,69) significativement plus longue. Le taux de réhospitalisation dans les 30 jours n'était pas significativement différent (taux non ajusté 9,3 % c. 9,6 %; RR ajusté 0,98 %, IC à 95 % 0,70­1,39). Trois scores de risque utilisant un pointage pour prédire la mortalité perhospitalière ont montré une bonne discrimination (aire sous la courbe [ASC] de la fonction d'efficacité du récepteur [ROC] 0,72­0,81) et une bonne calibration. INTERPRÉTATION: Durant la première vague de la pandémie, l'hospitalisation des patients atteints de la COVID-19 était associée à des taux de mortalité et d'utilisation des ressources des unités de soins intensifs et à une durée d'hospitalisation significativement plus importants que les hospitalisations des patients atteints de l'influenza. De simples scores de risque peuvent prédire avec une bonne exactitude le risque de mortalité perhospitalière des patients atteints de la COVID-19.

Genomic Epidemiology of SARS-CoV-2 Infection During the Initial Pandemic Wave and Association With Disease Severity.

Importance: Understanding of SARS-CoV-2 variants that alter disease outcomes are important for clinical risk stratification and may provide important clues to the complex virus-host relationship. Objective: To examine the association of identified SARS-CoV-2 variants, virus clades, and clade groups with disease severity and patient outcomes. Design, Setting, and Participants: In this cross-sectional study, viral genome analysis of clinical specimens obtained from patients at the Cleveland Clinic infected with SARS-CoV-2 during the initial wave of infection (March 11 to April 22, 2020) was performed. Identified variants were matched with clinical outcomes. Data analysis was performed from April to July 2020. Main Outcomes and Measures: Hospitalization, intensive care unit (ICU) admission, mortality, and laboratory outcomes were matched with SARS-CoV-2 variants. Results: Specimens sent for viral genome sequencing originated from 302 patients with SARS-CoV-2 infection (median [interquartile range] age, 52.6 [22.8 to 82.5] years), of whom 126 (41.7%) were male, 195 (64.6%) were White, 91 (30.1%) required hospitalization, 35 (11.6%) needed ICU admission, and 17 (5.6%) died. From these specimens, 2531 variants (484 of which were unique) were identified. Six different SARS-CoV-2 clades initially circulated followed by a rapid reduction in clade diversity. Several variants were associated with lower hospitalization rate, and those containing 23403A>G (D614G Spike) were associated with increased survival when the patient was hospitalized (64 of 74 patients [86.5%] vs 10 of 17 patients [58.8%]; χ21 = 6.907; P = .009). Hospitalization and ICU admission were similar regardless of clade. Infection with Clade V variants demonstrated higher creatinine levels (median [interquartile range], 2.6 [-0.4 to 5.5] mg/dL vs 1.0 [0.2 to 2.2] mg/dL; mean creatinine difference, 2.9 mg/dL [95% CI, 0.8 to 5.0 mg/dL]; Kruskal-Wallis P = .005) and higher overall mortality rates (3 of 14 patients [21.4%] vs 17 of 302 patients [5.6%]; χ21 = 5.640; P = .02) compared with other variants. Infection by strains lacking the 23403A>G variant showed higher mortality in multivariable analysis (odds ratio [OR], 22.4; 95% CI, 0.6 to 5.6; P = .01). Increased variants of open reading frame (ORF) 3a were associated with decreased hospitalization frequency (OR, 0.4; 95% CI, 0.2 to 0.96; P = .04), whereas increased variants of Spike (OR, 0.01; 95% CI, <0.01 to 0.3; P = .01) and ORF8 (OR, 0.03; 95% CI, <0.01 to 0.6; P = .03) were associated with increased survival. Conclusions and Relevance: Within weeks of SARS-CoV-2 circulation, a profound shift toward 23403A>G (D614G) specific genotypes occurred. Replaced clades were associated with worse clinical outcomes, including mortality. These findings help explain persistent hospitalization yet decreasing mortality as the pandemic progresses. SARS-CoV-2 clade assignment is an important factor that may aid in estimating patient outcomes.

COVID-19 and Cardiovascular Disease: From Bench to Bedside.

A pandemic of historic impact, coronavirus disease 2019 (COVID-19) has potential consequences on the cardiovascular health of millions of people who survive infection worldwide. Severe acute respiratory syndrome-coronavirus 2 (SARS-CoV-2), the etiologic agent of COVID-19, can infect the heart, vascular tissues, and circulating cells through ACE2 (angiotensin-converting enzyme 2), the host cell receptor for the viral spike protein. Acute cardiac injury is a common extrapulmonary manifestation of COVID-19 with potential chronic consequences. This update provides a review of the clinical manifestations of cardiovascular involvement, potential direct SARS-CoV-2 and indirect immune response mechanisms impacting the cardiovascular system, and implications for the management of patients after recovery from acute COVID-19 infection.

Characteristics and outcomes of hospital admissions for COVID-19 and influenza in the Toronto area.

BACKGROUND: Patient characteristics, clinical care, resource use and outcomes associated with admission to hospital for coronavirus disease 2019 (COVID-19) in Canada are not well described. METHODS: We described all adults with COVID-19 or influenza discharged from inpatient medical services and medical-surgical intensive care units (ICUs) between Nov. 1, 2019, and June 30, 2020, at 7 hospitals in Toronto and Mississauga, Ontario. We compared patient outcomes using multivariable regression models, controlling for patient sociodemographic factors and comorbidity level. We validated the accuracy of 7 externally developed risk scores to predict mortality among patients with COVID-19. RESULTS: There were 1027 hospital admissions with COVID-19 (median age 65 yr, 59.1% male) and 783 with influenza (median age 68 yr, 50.8% male). Patients younger than 50 years accounted for 21.2% of all admissions for COVID-19 and 24.0% of ICU admissions. Compared with influenza, patients with COVID-19 had significantly greater in-hospital mortality (unadjusted 19.9% v. 6.1%, adjusted relative risk [RR] 3.46, 95% confidence interval [CI] 2.56-4.68), ICU use (unadjusted 26.4% v. 18.0%, adjusted RR 1.50, 95% CI 1.25-1.80) and hospital length of stay (unadjusted median 8.7 d v. 4.8 d, adjusted rate ratio 1.45, 95% CI 1.25-1.69). Thirty-day readmission was not significantly different (unadjusted 9.3% v. 9.6%, adjusted RR 0.98, 95% CI 0.70-1.39). Three points-based risk scores for predicting in-hospital mortality showed good discrimination (area under the receiver operating characteristic curve [AUC] ranging from 0.72 to 0.81) and calibration. INTERPRETATION: During the first wave of the pandemic, admission to hospital for COVID-19 was associated with significantly greater mortality, ICU use and hospital length of stay than influenza. Simple risk scores can predict in-hospital mortality in patients with COVID-19 with good accuracy.

Public defibrillator accessibility and mobility trends during the COVID-19 pandemic in Canada.

INTRODUCTION: The COVID-19 pandemic has led to closures of non-essential businesses and buildings. The impact of such closures on automated external defibrillator (AED) accessibility compared to changes in foot traffic levels is unknown. METHODS: We identified all publicly available online AED registries in Canada last updated May 1, 2019 or later. We mapped AED locations to location types and classified each location type as completely inaccessible, partially inaccessible, or unaffected based on government-issued closure orders as of May 1, 2020. Using location and mobility data from Google's COVID-19 Community Mobility Reports, we identified the change in foot traffic levels between February 15-May 1, 2020 (excluding April 10-12) compared to the baseline of January 3-February 1, 2020, and determined the discrepancy between foot traffic levels and AED accessibility. RESULTS: We identified four provincial and two municipal AED registries containing a total of 5848 AEDs. Of those, we estimated that 69.9% were completely inaccessible, 18.8% were partially inaccessible, and 11.3% were unaffected. Parks, retail and recreation locations, and workplaces experienced the greatest reduction in AED accessibility. The greatest discrepancies between foot traffic levels and AED accessibility occurred in parks, retail and recreation locations, and transit stations. CONCLUSION: A majority of AEDs became inaccessible during the COVID-19 pandemic due to government-mandated closures. In a substantial number of locations across Canada, the reduction in AED accessibility was far greater than the reduction in foot traffic.

A Network Medicine Approach to Investigation and Population-based Validation of Disease Manifestations and Drug Repurposing for COVID-19.

The global Coronavirus Disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of co-existing medical conditions while the underlying mechanisms remain unclear. Furthermore, there are no proven effective therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, diseases manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measure revealed underlying pathogenesis for broad COVID-19-associated manifestations. Multi-modal analyses of single-cell RNA-sequencing data showed that co-expression of ACE2 and TMPRSS2 was elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn's disease patients compared to uninflamed tissues, revealing shared pathobiology by COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicated that COVID-19 shared intermediate inflammatory endophenotypes with asthma (including IRAK3 and ADRB2). To prioritize potential treatment, we combined network-based prediction and propensity score (PS) matching observational study of 18,118 patients from a COVID-19 registry. We identified that melatonin (odds ratio (OR) = 0.36, 95% confidence interval (CI) 0.22-0.59) was associated with 64% reduced likelihood of a positive laboratory test result for SARS-CoV-2. Using PS-matching user active comparator design, melatonin was associated with 54% reduced likelihood of SARS-CoV-2 positive test result compared to angiotensin II receptor blockers or angiotensin-converting enzyme inhibitors (OR = 0.46, 95% CI 0.24-0.86).

A network medicine approach to investigation and population-based validation of disease manifestations and drug repurposing for COVID-19.

The global coronavirus disease 2019 (COVID-19) pandemic, caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has led to unprecedented social and economic consequences. The risk of morbidity and mortality due to COVID-19 increases dramatically in the presence of coexisting medical conditions, while the underlying mechanisms remain unclear. Furthermore, there are no approved therapies for COVID-19. This study aims to identify SARS-CoV-2 pathogenesis, disease manifestations, and COVID-19 therapies using network medicine methodologies along with clinical and multi-omics observations. We incorporate SARS-CoV-2 virus-host protein-protein interactions, transcriptomics, and proteomics into the human interactome. Network proximity measurement revealed underlying pathogenesis for broad COVID-19-associated disease manifestations. Analyses of single-cell RNA sequencing data show that co-expression of ACE2 and TMPRSS2 is elevated in absorptive enterocytes from the inflamed ileal tissues of Crohn disease patients compared to uninflamed tissues, revealing shared pathobiology between COVID-19 and inflammatory bowel disease. Integrative analyses of metabolomics and transcriptomics (bulk and single-cell) data from asthma patients indicate that COVID-19 shares an intermediate inflammatory molecular profile with asthma (including IRAK3 and ADRB2). To prioritize potential treatments, we combined network-based prediction and a propensity score (PS) matching observational study of 26,779 individuals from a COVID-19 registry. We identified that melatonin usage (odds ratio [OR] = 0.72, 95% CI 0.56-0.91) is significantly associated with a 28% reduced likelihood of a positive laboratory test result for SARS-CoV-2 confirmed by reverse transcription-polymerase chain reaction assay. Using a PS matching user active comparator design, we determined that melatonin usage was associated with a reduced likelihood of SARS-CoV-2 positive test result compared to use of angiotensin II receptor blockers (OR = 0.70, 95% CI 0.54-0.92) or angiotensin-converting enzyme inhibitors (OR = 0.69, 95% CI 0.52-0.90). Importantly, melatonin usage (OR = 0.48, 95% CI 0.31-0.75) is associated with a 52% reduced likelihood of a positive laboratory test result for SARS-CoV-2 in African Americans after adjusting for age, sex, race, smoking history, and various disease comorbidities using PS matching. In summary, this study presents an integrative network medicine platform for predicting disease manifestations associated with COVID-19 and identifying melatonin for potential prevention and treatment of COVID-19.

Modelling resource requirements and physician staffing to provide virtual urgent medical care for residents of long-term care homes: a cross-sectional study.

BACKGROUND: The coronavirus disease 2019 (COVID-19) outbreak increases the importance of strategies to enhance urgent medical care delivery in long-term care (LTC) facilities that could potentially reduce transfers to emergency departments. The study objective was to model resource requirements to deliver virtual urgent medical care in LTC facilities. METHODS: We used data from all general medicine inpatient admissions at 7 hospitals in the Greater Toronto Area, Ontario, Canada, over a 7.5-year period (Apr. 1, 2010, to Oct. 31, 2017) to estimate historical patterns of hospital resource use by LTC residents. We estimated an upper bound of potentially avoidable transfers by combining data on short admissions (≤ 72 h) with historical data on the proportion of transfers from LTC facilities for which patients were discharged from the emergency department without admission. Regression models were used to extrapolate future resource requirements, and queuing models were used to estimate physician staffing requirements to perform virtual assessments. RESULTS: There were 235 375 admissions to general medicine wards, and residents of LTC facilities (age 16 yr or older) accounted for 9.3% (n = 21 948) of these admissions. Among the admissions of residents of LTC facilities, short admissions constituted 24.1% (n = 5297), and for 99.8% (n = 5284) of these admissions, the patient received laboratory testing, for 86.9% (n = 4604) the patient received plain radiography, for 41.5% (n = 2197) the patient received computed tomography and for 81.2% (n = 4300) the patient received intravenous medications. If all patients who have short admissions and are transferred from the emergency department were diverted to outpatient care, the average weekly demand for outpatient imaging per hospital would be 2.6 ultrasounds, 11.9 computed tomographic scans and 23.9 radiographs per week. The average daily volume of urgent medical virtual assessments would range from 2.0 to 5.8 per hospital. A single centralized virtual assessment centre staffed by 2 or 3 physicians would provide services similar in efficiency (measured by waiting time for physician assessment) to 7 separate centres staffed by 1 physician each. INTERPRETATION: The provision of acute medical care to LTC residents at their facility would probably require rapid access to outpatient diagnostic imaging, within-facility access to laboratory services and intravenous medication and virtual consultations with physicians. The results of this study can inform efforts to deliver urgent medical care in LTC facilities in light of a potential surge in COVID-19 cases.