Efficacy and effectiveness of inactivated vaccines against symptomatic COVID-19, severe COVID-19, and COVID-19 clinical outcomes in the general population: a systematic review and meta-analysis

BACKGROUND: Inactivated, whole-virion vaccines have been used extensively in the SARS-CoV-2 pandemic. Its efficacy and effectiveness across regions have not been systematically evaluated. Efficacy refers to how well a vaccine performs in a controlled environment. Effectiveness refers to how well it performs in real world settings. METHODS: This systematic review and meta-analysis reviewed published, peer-reviewed evidence on all WHO-approved inactivated vaccines and evaluated their efficacy and effectiveness against SARS-CoV-2 infection, symptomatic infection, severe clinical outcomes, and severe COVID-19. We searched Pubmed (including MEDLINE), EMBASE (via OVID), Web of Science Core Collection, Web of Science Chinese Science Citation Database, and Clinicaltrials.gov. FINDINGS: The final pool included 28 studies representing over 32 million individuals reporting efficacy or effectiveness estimates of complete vaccination using any approved inactivated vaccine between January 1, 2019 and June 27, 2022. Evidence was found for efficacy and effectiveness against symptomatic infection (OR 0.21, 95% CI 0.16–0.27, I2 = 28% and OR 0.32, 95% CI 0.16–0.64, I2 = 98%, respectively) and infection (OR 0.53, 95% CI 0.49–0.57, I2 = 90% and OR 0.31, 95% CI 0.24–0.41, I2 = 0%, respectively) for early SARS-CoV-2 variants of concern (VoCs) (Alpha, Delta), and for waning of vaccine effectiveness with more recent VoCs (Gamma, Omicron). Effectiveness remained robust against COVID-related ICU admission (OR 0.21, 95% CI 0.04–1.08, I2 = 99%) and death (OR 0.08, 95% CI 0.00–2.02, I2 = 96%), although effectiveness estimates against hospitalization (OR 0.44, 95% CI 0.37–0.53, I2 = 0%) were inconsistent. INTERPRETATION: This study showed evidence of efficacy and effectiveness of inactivated vaccines for all outcomes, although inconsistent reporting of key study parameters, high heterogeneity of observational studies, and the small number of studies of particular designs for most outcomes undermined the reliability of the findings. Findings highlight the need for additional research to address these limitations so that more definitive conclusions can be drawn to inform SARS-CoV-2 vaccine development and vaccination policies. FUNDING: Health and Medical Research Fund on COVID-19, Health Bureau of the Government of the Hong Kong SAR

Global antiplatelet sales trend: A focus on P2Y12 inhibitors from 2008 to 2018

BACKGROUND: P2Y12 inhibitors are an important component of dual antiplatelet therapy. Yet, their accessibility and affordability across countries stratified by income levels have not been studied. METHODS: Sales data were retrieved from the IQVIA Multinational Integrated Data Analysis System for the description of P2Y12 inhibitors global sales. Countries were stratified into 38 high-income countries and 27 middle-income countries. RESULTS: Global sales of P2Y12 inhibitors increased from 0.80 SU per year per person in 2008 to 1.79 in 2018. Growth in sales of P2Y12 inhibitors was greater in middle-income countries compared to high-income countries. Clopidogrel had the highest sales volume in both high-income and middle-income countries from 2008 to 2018, while ticagrelor sales volume increased mainly in high-income countries. CONCLUSIONS: Despite current guideline recommendations favoring ticagrelor and prasugrel for the prevention of atherothrombotic complications in patients with an acute coronary syndrome, clopidogrel retained the highest sales volume among the P2Y12 inhibitors from 2008 to 2018

Hospitalization and Mortality in Patients With Heart Failure Treated With Sacubitril/Valsartan vs. Enalapril: A Real-World, Population-Based Study

Background: The effect of sacubitril/valsartan on survival and hospitalization risk in older patients with heart failure has not been explored. We aimed to investigate the risk of hospitalization and mortality with the use of sacubitril/valsartan vs. enalapril in patients with heart failure. / Methods: This was a population-based cohort study using the Hong Kong-wide electronic healthcare database. Patients diagnosed with heart failure and newly prescribed sacubitril/valsartan or enalapril between July 2016 and June 2019 were included. The risk of primary composite outcome of cardiovascular mortality or heart failure-related hospitalization, all-cause hospitalization, heart failure-related hospitalization, cardiovascular mortality and all-cause mortality were compared using Cox regression with inverse probability treatment weighting. Additional analysis was conducted by age stratification. / Results: Of the 44,503 patients who received sacubitril/valsartan or enalapril, 3,237 new users (sacubitril/valsartan, n = 1,056; enalapril, n = 2,181) with a diagnosis of heart failure were identified. Compared with enalapril, sacubitril/valsartan users were associated with a lower risk of primary composite outcome [hazard ratio (HR) 0.58; 95% confidence interval (CI), 0.45–0.75], heart failure-related hospitalization (HR 0.59; 95% CI, 0.45–0.77), all-cause mortality (HR 0.51; 95% CI, 0.36–0.74) and borderline non-significant reductions in all-cause hospitalization (HR 0.85; 95% CI, 0.70–1.04) and cardiovascular mortality (HR 0.63; 95% CI, 0.39–1.02). The treatment effect of sacubitril/valsartan remains unaltered in the patient subgroup age ≥ 65 years (73%). / Conclusions: In real-world settings, sacubitril/valsartan was associated with improved survival and reduced heart failure-related hospitalization compared to enalapril in Asian patients with heart failure. The effectiveness remains consistent in the older population

Association Between Non-vitamin K Antagonist Oral Anticoagulants or Warfarin and Liver Injury: A Cohort Study

INTRODUCTION: The risk of liver injury in patients with atrial fibrillation (AF) using nonvitamin K antagonist oral anticoagulants (NOACs) has not been previously examined using liver function tests as the primary outcome in the real-world setting. This study assessed the association between NOACs (dabigatran, rivaroxaban, and apixaban) and warfarin and the risk of liver injury, as defined by laboratory tests. METHODS: Patients newly diagnosed with AF and prescribed NOACs or warfarin between 2010 and 2016, identified using the Hong Kong Clinical Database and Reporting System, were matched on age, sex, health status scores, comorbidities, and medications by propensity score on a 1:1 ratio. Risk of liver injury, defined as laboratory test values >3 times the upper limit of normal of alanine aminotransferase or aspartate aminotransferase and >2 times the upper limit of normal of total bilirubin, was compared between NOAC and warfarin users using Cox proportional hazards regression. RESULTS: After propensity score matching, 13,698 patients were included, of which 141 (2.1%) NOAC users and 232 (3.4%) warfarin users developed liver injury. The hazard ratio (HR) for NOAC vs warfarin users was 0.71 (95% confidence interval: 0.58–0.89). When comparing individual NOACs, only dabigatran (hazard ratio: 0.63; 95% confidence interval: 0.48–0.82) was associated with a lower risk of liver injury. DISCUSSION: Among patients with AF, NOACs as a group, and dabigatran alone were associated with a significantly lower risk of laboratory-based liver injury when compared with warfarin. However, liver injury occurs more frequently in real-world practice than in NOAC randomized controlled trials

Drug Repurposing for the Treatment of COVID-19: A Knowledge Graph Approach

Identifying effective drug treatments for COVID-19 is essential to reduce morbidity and mortality. Although a number of existing drugs have been proposed as potential COVID-19 treatments, effective data platforms and algorithms to prioritize drug candidates for evaluation and application of knowledge graph for drug repurposing have not been adequately explored. A COVID-19 knowledge graph by integrating 14 public bioinformatic databases containing information on drugs, genes, proteins, viruses, diseases, symptoms and their linkages is developed. An algorithm is developed to extract hidden linkages connecting drugs and COVID-19 from the knowledge graph, to generate and rank proposed drug candidates for repurposing as treatments for COVID-19 by integrating three scores for each drug: motif scores, knowledge graph PageRank scores, and knowledge graph embedding scores. The knowledge graph contains over 48 000 nodes and 13 37 000 edges, including 13 563 molecules in the DrugBank database. From the 5624 molecules identified by the motif-discovery algorithms, ranking results show that 112 drug molecules had the top 2% scores, of which 50 existing drugs with other indications approved by health administrations reported. The proposed drug candidates serve to generate hypotheses for future evaluation in clinical trials and observational studies

Global psychotropic medicine consumption in 65 countries and regions from 2008 to 2019

Background: The WHO Comprehensive Mental Health Action Plan 2013–2030 encourages routine collection and reporting of a set of essential mental health indicators, including the availability of psychotropic medicines. The global monitoring of country-level psychotropic medicine consumption trends can provide information on the extent of the availability of psychotropic medicines. The primary objective of this study was to investigate global trends in psychotropic medicines consumption from 2008 to 2019 across 65 countries and regions according to country income level and geographical region. // Methods: In this longitudinal trends study, we used pharmaceutical sales data from the IQVIA-Multinational Integrated Data Analysis System (IQVIA-MIDAS). We analysed monthly sales data of psychotropic medicines between Jan 1, 2008, and Dec 31, 2019. Total psychotropic medicine consumption included sales of antidepressants, antipsychotics, tranquilisers, sedatives or hypnotics, and mood stabilisers. Population estimates of each country or region (eight lower-middle-income countries, 19 upper-middle-income countries, and 38 high-income countries) were based on the UN World Population Prospects 2019 report. Average annual sales trends of psychotropic medicines, expressed as defined daily dose (DDD) per 1000 inhabitants per day, were estimated using a random-effects model adjusted for income level and region. Relative changes in the annual consumption of psychotropic medicines by income, expressed as DDD per 1000 inhabitants per day, were assessed as percentage change for each medicine class. // Findings: Psychotropic medicine sales increased from 28·54 DDD per 1000 inhabitants per day in 2008 to 34·77 DDD per 1000 inhabitants per day in 2019, corresponding to a 4·08% (95% CI 2·96–5·21) relative average increase annually. The absolute annual increase was greater in high-income countries (3·31 DDD per 1000 inhabitants per day, 95% CI 3·01–3·61) compared with upper-middle-income countries (1·94 DDD per 1000 inhabitants per day, 1·45–2·44) and low-middle-income countries (0·88 DDD per 1000 inhabitants per day, 0·62–1·13; p<0·0001). The relative average annual increase in psychotropic medicine sales from 2008 to 2019 was greater in upper-middle-income countries (7·88%, 95% CI 6·99–8·77) than in lower-middle-income countries (2·90%, 2·40–3·39) and high-income countries (1·02%, 0·80–1·24). In 2019, the regional consumption of psychotropic medicines varied greatly, with the highest sales of all psychotropic medicine classes reported in northern America (167·54 DDD per 1000 inhabitants per day) and lowest sales reported in Asia (5·59 DDD per 1000 inhabitants per day). 17 countries had very low consumption of psychotropic medicines in 2019, including high-income countries and countries with a high prevalence of mental disorders. // Interpretation: The consumption of psychotropic medicines has increased over a 12-year period, and although the absolute growth rate was highest in high-income countries, the relative growth is highest in middle-income countries and especially upper-middle-income countries. Disparities in psychotropic medicine consumption of countries can only partly be explained by geographical location and income. Greater efforts are needed to increase the availability of psychotropic medicines in countries with very low consumption, which is probably due to financial or cultural reasons as well as scarcity of trained health-care professionals to prescribe psychotropic medicines

Safety of an inactivated, whole-virion COVID-19 vaccine (CoronaVac) in people aged 60 years or older in Hong Kong: a modified self-controlled case series

BACKGROUND: Because evidence on the safety of COVID-19 vaccines in older adults is scarce, we aimed to evaluate the incidence and risk of adverse events after CoronaVac (Sinovac Biotech) vaccination in adults aged 60 years or older. METHODS: In this modified self-controlled case series, we enrolled adults aged 60 years or older who had received at least one dose of CoronaVac in Hong Kong between Feb 23, 2021, and Jan 31, 2022. We extracted population-based, electronic health record data from the clinical management system of the Hospital Authority on adverse events of special interest (from Jan 1, 2005, to Feb 23, 2022) and patients' demographic information (from Jan 1, 2018, to Jan 31, 2022), previous diagnoses (from Jan 1, 2018, to Jan 31, 2022), medication history (from Jan 1, 2018, to Jan 31, 2022), and laboratory tests, including those for SARS-CoV-2 infection (from Jan 1, 2018, to Jan 31, 2022). Details of vaccination status were provided by the Department of Health of the Hong Kong Government and were linked to data from the Hospital Authority with identity card numbers or passport numbers. Our outcomes were the overall incidence of any adverse event of special interest and the incidence rates of 30 adverse events of special interest, as suggested by the WHO Global Advisory Committee on Vaccine Safety, in the inpatient setting within 21 days (2 days for anaphylaxis) of either the first, second, or third CoronaVac dose compared with a baseline period. Individuals who had a history of a particular event between Jan 1, 2005, and Feb 23, 2021, were excluded from the corresponding analysis. We evaluated the risk of an adverse event of special interest using conditional Poisson regression, adjusting for seasonal effects. FINDINGS: Of 1 253 497 individuals who received at least one dose of CoronaVac during the study period, 622 317 (49·6%) were aged at least 60 years and were included in the analysis. Our analysis sample received 1 229 423 doses of CoronaVac and had a mean age of 70·40 years (SD 8·10). 293 086 (47·1%) of 622 317 participants were men and 329 231 (52·9%) were women. The incidence of individual adverse events of interest ranged from 0·00 per 100 000 people to 57·49 per 100 000 people (thromboembolism). The first and third doses of CoronaVac were not associated with a significant excess risk of an adverse event of special interest within 21 days (or 2 days for anaphylaxis) of vaccination. After the second dose, the only significantly increased risk was for anaphylaxis (adjusted incidence rate ratio 2·61, 95% CI 1·08–6·31; risk difference per 100 000 people 0·61, 95% CI 0·03–1·81). INTERPRETATION: Because older age is associated with poor outcomes after SARS-CoV-2 infection, the benefits of CoronaVac vaccination in older adults outweigh the risks in regions where COVID-19 is prevalent. Ongoing monitoring of vaccine safety is warranted. FUNDING: The Food and Health Bureau of the Government, Hong Kong Special Administrative Region, China and AIR@InnoHK, administered by the Innovation and Technology Commission. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section

Association between BNT162b2 or CoronaVac COVID-19 vaccines and major adverse cardiovascular events among individuals with cardiovascular disease

AIMS: Concern about the cardiovascular safety of coronavirus disease 2019 (COVID-19) vaccines among individuals with cardiovascular disease (CVD) may lead to vaccine hesitancy. We sought to assess the association between two COVID-19 vaccines, BNT162b2 and CoronaVac, and the risk of major adverse cardiovascular events (MACE) in individuals with established CVD. METHODS AND RESULTS: We identified individuals with a history of CVD before 23 February 2021 and a diagnosis of MACE between 23 February 2021 and 31 January 2022 in Hong Kong. MACE was defined as a composite of myocardial infarction, stroke, revascularization, and cardiovascular death. Electronic health records from the Hong Kong Hospital Authority were linked to vaccination records from the Department of Health. A self-controlled case-series method was used to evaluate the risk of MACE for 0-13 and 14-27 days after two doses of COVID-19 vaccine. We estimated incidence rate ratios (IRRs) to compare the risk of MACE between each risk period and the baseline period. A total of 229 235 individuals with CVD were identified, of which 1764 were vaccinated and had a diagnosis of MACE during the observation period (BNT162b2 = 662; CoronaVac = 1102). For BNT162b2, IRRs were 0.48 [95% confidence interval (CI) 0.23-1.02] for the first dose and 0.87 (95% CI 0.50-1.52) for the second dose during the 0-13 days risk period, 0.40 (95% CI 0.18-0.93) for the first dose and 1.13 (95% CI 0.70-1.84) for the second dose during the 14-27 days risk period. For CoronaVac, the IRRs were 0.43 (95% CI 0.24-0.75) for the first dose and, 0.73 (95% CI 0.46-1.16) for the second dose during the 0-13 days risk period, 0.54 (95% CI 0.33-0.90) for the first dose and 0.83 (95% CI 0.54-1.29) for the second dose during the 14-27 days risk period. Consistent results were found in subgroup analyses for different sexes, age groups and different underlying cardiovascular conditions. CONCLUSION: Our findings showed no evidence of an increased risk of MACE after vaccination with BNT162b2 or CoronaVac in patients with CVD. Future research is required to monitor the risk after the third dose of each vaccine

Herpes zoster related hospitalisation after inactivated (CoronaVac) and mRNA (BNT162b2) SARS-CoV-2 vaccination: a self-controlled case series and nested case-control study

BACKGROUND: Stimulation of immunity by vaccination may elicit adverse events. There is currently inconclusive evidence on the relationship between herpes zoster related hospitalization and COVID-19 vaccination. This study aimed to evaluate the effect of inactivated virus (CoronaVac, Sinovac) and mRNA (BNT162b2, BioNTech/Fosun Pharma) COVID-19 vaccine on the risk of herpes zoster related hospitalization. METHODS: Self-controlled case series (SCCS) analysis was conducted using the data from the electronic health records in Hospital Authority and COVID-19 vaccination records in the Department of Health in Hong Kong. We conducted the SCCS analysis including patients with a first primary diagnosis of herpes zoster in the hospital inpatient setting between February 23 and July 31, 2021. A confirmatory analysis by nested case-control method was also conducted. Each herpes zoster case was randomly matched with ten controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Conditional Poisson regression and logistic regression models were used to assess the potential excess rates of herpes zoster after vaccination. FINDINGS: From February 23 to July 31, 2021, a total of 16 and 27 patients were identified with a first primary hospital diagnosis of herpes zoster within 28 days after CoronaVac and BNT162b2 vaccinations. The incidence of herpes zoster was 7.9 (95% Confidence interval [CI]: 5.2–11.5) for CoronaVac and 7.1 (95% CI: 4.1–11.5) for BNT162b2 per 1,000,000 doses administered. In SCCS analysis, CoronaVac vaccination was associated with significantly higher risk of herpes zoster within 14 days after first dose (adjusted incidence rate ratio [aIRR]=2.67, 95% CI: 1.08–6.59) but not in other periods afterwards compared to the baseline period. Regarding BNT162b2 vaccination, a significantly increased risk of herpes zoster was observed after first dose up to 14 days after second dose (0-13 days after first dose: aIRR=5.23, 95% CI: 1.61–17.03; 14–27 days after first dose: aIRR=5.82, 95% CI: 1.62–20.91; 0-13 days after second dose: aIRR=5.14, 95% CI: 1.29–20.47). Using these relative rates, we estimated that there has been an excess of approximately 5 and 7 cases of hospitalization as a result of herpes zoster after every 1,000,000 doses of CoronaVac and BNT162b2 vaccination, respectively. The findings in the nested case control analysis showed similar results. INTERPRETATION: We identified an increased risk of herpes zoster related hospitalization after CoronaVac and BNT162b2 vaccinations. However, the absolute risks of such adverse event after CoronaVac and BNT162b2 vaccinations were very low. In locations where COVID-19 is prevalent, the protective effects on COVID-19 from vaccinations will greatly outweigh the potential side effects of vaccination. FUNDING: The project was funded by Research Grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (Ref. No.COVID19F01). FTTL (Francisco Tsz Tsun Lai) and ICKW (Ian Chi Kei Wong)’s posts were partly funded by D^{2}4H; hence this work was partly supported by AIR@InnoHK administered by Innovation and Technology Commission

Bell's palsy following vaccination with mRNA (BNT162b2) and inactivated (CoronaVac) SARS-CoV-2 vaccines: a case series and nested case-control study

BACKGROUND: Bell's palsy is a rare adverse event reported in clinical trials of COVID-19 vaccines. However, to our knowledge no population-based study has assessed the association between the inactivated SARS-CoV-2 vaccines and Bell's palsy. The aim of this study was to evaluate the risk of Bell's palsy after BNT162b2 and CoronaVac vaccination. METHODS: In this case series and nested case-control study done in Hong Kong, we assessed the risk of Bell's palsy within 42 days following vaccination with BNT162b2 (Fosun–BioNTech [equivalent to Pfizer–BioNTech]) or CoronaVac (from Sinovac Biotech, Hong Kong) using data from voluntary surveillance reporting with the Hospital Authority, the COVID-19 Vaccine Adverse Event Online Reporting system for all health-care professionals, and the Hospital Authority's territory-wide electronic health records from the Clinical Data Analysis and Reporting System. We described reported cases of Bell's palsy among vaccine recipients (aged 18–110 years for CoronaVac and aged 16–110 years for BNT162b2). We compared the estimated age-standardised incidence of clinically confirmed cases among individuals who had received the CoronaVac or BNT162b2 vaccination (up to 42 days before presentation) with the background incidence in the population. A nested case-control study was also done using conditional logistic regression to estimate the odds ratio (OR) for risk of Bell's palsy and vaccination. Cases and controls were matched (1:4) by age, sex, admission setting, and admission date. FINDINGS: Between February 23 and May 4, 2021, 451 939 individuals received the first dose of CoronaVac and 537 205 individuals received the first dose of BNT162b2. 28 clinically confirmed cases of Bell's palsy were reported following CoronaVac and 16 cases were reported following BNT162b2. The age-standardised incidence of clinically confirmed Bell's palsy was 66·9 cases per 100 000 person-years (95% CI 37·2 to 96·6) following CoronaVac vaccination and 42·8 per 100 000 person-years (19·4 to 66·1) for BNT162b2 vaccination. The age-standardised difference for the incidence compared with the background population was 41·5 (95% CI 11·7 to 71·4) for CoronaVac and 17·0 (−6·6 to 40·6) for BNT162b2, equivalent to an additional 4·8 cases per 100 000 people vaccinated for CoronaVac and 2·0 cases per 100 000 people vaccinated for BNT162b2. In the nested case-control analysis, 298 cases were matched to 1181 controls, and the adjusted ORs were 2·385 (95% CI 1·415 to 4·022) for CoronaVac and 1·755 (0·886 to 3·477) for BNT162b2. INTERPRETATION: Our findings suggest an overall increased risk of Bell's palsy after CoronaVac vaccination. However, the beneficial and protective effects of the inactivated COVID-19 vaccine far outweigh the risk of this generally self-limiting adverse event. Additional studies are needed in other regions to confirm our findings. FUNDING: The Food and Health Bureau of the Government of the Hong Kong Special Administrative Region, China. TRANSLATION: For the Chinese translation of the abstract see Supplementary Materials section