Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in Hospitalized Patients With COVID-19 : A Target Trial Emulation Study.

BACKGROUND: Whether hospitalized patients benefit from COVID-19 oral antivirals is uncertain. OBJECTIVE: To examine the real-world effectiveness of molnupiravir and nirmatrelvir-ritonavir in hospitalized patients with COVID-19 during the Omicron outbreak. DESIGN: Target trial emulation study. SETTING: Electronic health databases in Hong Kong. PARTICIPANTS: The molnupiravir emulated trial included hospitalized patients with COVID-19 aged 18 years or older between 26 February and 18 July 2022 (n = 16 495). The nirmatrelvir-ritonavir emulated trial included hospitalized patients with COVID-19 aged 18 years or older between 16 March and 18 July 2022 (n = 7119). INTERVENTION: Initiation of molnupiravir or nirmatrelvir-ritonavir within 5 days of hospitalization with COVID-19 versus no initiation of molnupiravir or nirmatrelvir-ritonavir. MEASUREMENTS: Effectiveness against all-cause mortality, intensive care unit (ICU) admission, or use of ventilatory support within 28 days. RESULTS: The use of oral antivirals in hospitalized patients with COVID-19 was associated with a lower risk for all-cause mortality (molnupiravir: hazard ratio [HR], 0.87 [95% CI, 0.81 to 0.93]; nirmatrelvir-ritonavir: HR, 0.77 [CI, 0.66 to 0.90]) but no significant risk reduction in terms of ICU admission (molnupiravir: HR, 1.02 [CI, 0.76 to 1.36]; nirmatrelvir-ritonavir: HR, 1.08 [CI, 0.58 to 2.02]) or the need for ventilatory support (molnupiravir: HR, 1.07 [CI, 0.89 to 1.30]; nirmatrelvir-ritonavir: HR, 1.03 [CI, 0.70 to 1.52]). There was no significant interaction between drug treatment and the number of COVID-19 vaccine doses received, thereby supporting the effectiveness of oral antivirals regardless of vaccination status. No significant interaction between nirmatrelvir-ritonavir treatment and age, sex, or Charlson Comorbidity Index was observed, whereas molnupiravir tended to be more effective in older people. LIMITATION: The outcome of ICU admission or need for ventilatory support may not capture all severe COVID-19 cases; unmeasured confounders, such as obesity and health behaviors, may exist. CONCLUSION: Molnupiravir and nirmatrelvir-ritonavir reduced all-cause mortality in both vaccinated and unvaccinated hospitalized patients. No significant reduction in ICU admission or the need for ventilatory support was observed. PRIMARY FUNDING SOURCE: Health and Medical Research Fund Research on COVID-19, Government of the Hong Kong Special Administrative Region; Research Grants Council, Collaborative Research Fund; and Health Bureau, Government of the Hong Kong Special Administrative Region.

Messenger RNA Coronavirus Disease 2019 (COVID-19) Vaccination With BNT162b2 Increased Risk of Bell's Palsy: A Nested Case-Control and Self-Controlled Case Series Study.

BACKGROUND: Observable symptoms of Bell's palsy following vaccinations arouse concern over the safety profiles of novel coronavirus disease 2019 (COVID-19) vaccines. However, there are only inconclusive findings on Bell's palsy following messenger (mRNA) COVID-19 vaccination. This study aims to update the previous analyses on the risk of Bell's palsy following mRNA (BNT162b2) COVID-19 vaccination. METHODS: This study included cases aged ≥16 years with a new diagnosis of Bell's palsy within 28 days after BNT162b2 vaccinations from the population-based electronic health records in Hong Kong. Nested case-control and self-controlled case series (SCCS) analyses were used, where the association between Bell's palsy and BNT162b2 was evaluated using conditional logistic and Poisson regression, respectively. RESULTS: Totally 54 individuals were newly diagnosed with Bell's palsy after BNT162b2 vaccinations. The incidence of Bell's palsy was 1.58 (95% confidence interval [CI], 1.19-2.07) per 100 000 doses administered. The nested case-control analysis showed significant association between BNT162b2 vaccinations and Bell's palsy (adjusted odds ratio [aOR], 1.543; 95% CI, 1.123-2.121), with up to 1.112 excess events per 100 000 people who received 2 doses of BNT162b2. An increased risk of Bell's palsy was observed during the first 14 days after the second dose of BNT162b2 in both nested case-control (aOR, 2.325; 95% CI, 1.414-3.821) and SCCS analysis (adjusted incidence rate ratio, 2.44; 95% CI, 1.32-4.50). CONCLUSIONS: There was an overall increased risk of Bell's palsy following BNT162b2 vaccination, particularly within the first 14 days after the second dose, but the absolute risk was very low.

Long-term effects of coronavirus disease 2019 on diabetes complications and mortality in people with diabetes: Two cohorts in the UK and Hong Kong.

AIM: To evaluate the long-term associations between coronavirus disease 2019 (COVID-19) and diabetes complications and mortality, in patients with diabetes. MATERIALS AND METHODS: People with diabetes diagnosed with COVID-19 infection (exposed group), from 16 March 2020 to 31 May 2021 from the UK Biobank (UKB cohort; n = 2456), and from 1 April 2020 to 31 May 2022 from the electronic health records in Hong Kong (HK cohort; n = 80 546), were recruited. Each patient was randomly matched with participants with diabetes but without COVID-19 (unexposed group), based on age and sex (UKB, n = 41 801; HK, n = 391 849). Patients were followed for up to 18 months until 31 August 2021 for UKB, and up to 28 months until 15 August 2022 for HK. Characteristics between cohorts were further adjusted with Inverse Probability Treatment Weighting. Long-term association of COVID-19 with multi-organ disease complications and all-cause mortality after 21 days of diagnosis was evaluated by Cox regression. RESULTS: Compared with uninfected participants, patients with COVID-19 infection with diabetes were consistently associated with higher risks of cardiovascular diseases (coronary heart disease [CHD]: hazard ratio [HR] [UKB]: 1.6 [95% confidence interval {CI}: 1.0, 2.4], HR [HK]: 1.2 [95% CI: 1.0, 1.5]; and stroke: HR [UKB]: 2.0 [95% CI: 1.1, 3.6], HR [HK]: 1.5 [95% CI: 1.3, 1.8]), microvascular disease (end stage renal disease: HR [UKB]: 2.1 [95% CI: 1.1, 4.0], HR [HK]: 1.2 [95% CI: 1.1, 1.4]) and all-cause mortality (HR [UKB]: 4.6 [95% CI: 3.8, 5.5], HR [HK]: 2.6 [95% CI: 2.5, 2.8]), in both cohorts. CONCLUSIONS: COVID-19 infection is associated with long-term increased risks of diabetes complications (especially cardiovascular complications, and mortality) in people with diabetes. Monitoring for signs/symptoms of developing these long-term complications post-COVID-19 infection in the infected patient population of people with diabetes may be beneficial in minimizing their morbidity and mortality.

Booster vaccination with inactivated whole-virus or mRNA vaccines and COVID-19-related deaths among people with multimorbidity: a cohort study.

BACKGROUND: Multimorbidity is a prevalent risk factor for COVID-19-related complications and death. We sought to evaluate the association of homologous booster vaccination using BNT162b2 (Pfizer-BioNTech) or CoronaVac (Sinovac) with COVID-19-related deaths among people with multimorbidity during the initial Omicron wave of the COVID-19 pandemic. METHODS: Using routine clinical records from public health care facilities in Hong Kong, we conducted a territory-wide retrospective cohort study comparing people aged 18 years or older with 2 or more chronic conditions who received a homologous booster (third) dose with those who received only 2 doses, between Nov. 11, 2021, and Mar. 31, 2022. The primary outcome was death related to COVID-19. RESULTS: We included 120 724 BNT162b2 recipients (including 87 289 who received a booster), followed for a median of 34 (interquartile range [IQR] 20-63) days and 127 318 CoronaVac recipients (including 94 977 who received a booster), followed for a median of 38 (IQR 22-77) days. Among BNT162b2 recipients, booster-vaccinated people had fewer COVID-19-related deaths than those who received 2 doses (5 v. 34, incidence rate 1.3 v. 23.4 per million person-days, weighted incidence rate ratio [IRR] 0.05, 95% confidence interval [CI] 0.02-0.16). We observed similar results among recipients of CoronaVac booster vaccination compared with those who received only 2 doses (26 v. 88, incidence rate 5.3 v. 53.1 per million person-days, weighted IRR 0.08, 95% CI 0.05-0.12). INTERPRETATION: Among people with multimorbidity, booster vaccination with BNT162b2 or CoronaVac was associated with reductions of more than 90% in COVID-19-related mortality rates compared with only 2 doses. These results highlight the crucial role of booster vaccination for protecting vulnerable populations as the COVID-19 pandemic continues to evolve.

Association between the risk of seizure and COVID-19 vaccinations: A self-controlled case-series study.

OBJECTIVE: The risk of seizure following BNT162b2 and CoronaVac vaccinations has been sparsely investigated. This study aimed to evaluate this association. METHOD: Patients who had their first seizure-related hospitalization between February 23, 2021 and January 31, 2022, were identified in Hong Kong. All seizure episodes happening on the day of vaccination (day 0) were excluded, since clinicians validated that most of the cases on day 0 were syncopal episodes. Within-individual comparison using a modified self-controlled case series analysis was applied to estimate the incidence rate ratio (IRR) with 95% confidence intervals (CIs) of seizure using conditional Poisson regression. RESULTS: We identified 1656 individuals who had their first seizure-related hospitalization (BNT162b2: 426; CoronaVac: 263; unvaccinated: 967) within the observation period. The incidence of seizure was 1.04 (95% CI .80-1.33) and 1.11 (95% CI .80-1.50) per 100 000 doses of BNT162b2 and CoronaVac administered, respectively. Sixteen and 17 individuals, respectively, received a second dose after having a first seizure within 28 days after the first dose of BNT162b2 and CoronaVac vaccinations. None had recurrent seizures after the second dose. There was no increased risk during day 1-6 after the first (BNT162b2: IRR = 1.39, 95% CI = .75-2.58; CoronaVac: IRR = 1.19, 95% CI = .50-2.83) and second doses (BNT162b2: IRR = 1.36, 95% CI = .72-2.57; CoronaVac: IRR = .71, 95% CI = .22-2.30) of vaccinations. During 7-13, 14-20, and 21-27 days post-vaccination, no association was observed for either vaccine. SIGNIFICANCE: The findings demonstrated no increased risk of seizure following BNT162b2 and CoronaVac vaccinations. Future studies will be warranted to evaluate the risk of seizure following COVID-19 vaccinations in different populations, with subsequent doses to ensure the generalizability.

Real-World Effectiveness and Safety of Tixagevimab-Cilgavimab: A Target Trial Emulation Study.

BACKGROUND: Immunocompromised individuals are at high risk of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and subsequent severe or fatal coronavirus disease 2019 (COVID-19), yet they have suboptimal responses to mRNA and inactivated COVID-19 vaccines. The efficacy of tixagevimab-cilgavimab in reducing symptomatic SARS-CoV-2 infection was demonstrated in phase III clinical trials. Nevertheless, real-world data on the effectiveness and safety of tixagevimab-cilgavimab remain limited. OBJECTIVE: The aim was to evaluate the effectiveness and safety of tixagevimab-cilgavimab among immunocompromised individuals. METHODS: Adults who were immunocompromised or receiving immunosuppressive therapies were included in this target trial emulation using territory-wide electronic health records in Hong Kong. A sequential trial emulation approach was adopted to compare effectiveness and safety outcomes between individuals who received tixagevimab-cilgavimab and individuals who did not. RESULTS: A total of 746 tixagevimab-cilgavimab recipients and 2980 controls were included from 1 May 2022 to 30 November 2022. Tixagevimab-cilgavimab significantly reduced the risk of COVID-19 infection (hazard ratio [HR] 0.708, 95% confidence interval [CI] 0.527-0.951) during a median follow-up of 60 days. No significant difference was observed in the risk of COVID-19-related hospitalisation. Zero versus eight COVID-19 mortality cases and zero versus two severe COVID-19 cases were observed in tixagevimab-cilgavimab recipients and controls, respectively. Notably, significant risk reduction in COVID-19 infection was also observed among immunocompromised individuals who had been previously vaccinated with three or more doses of COVID-19 vaccine, or had no prior COVID-19 infection history. CONCLUSIONS: Tixagevimab-cilgavimab was effective in reducing COVID-19 infection among immunocompromised patients during the Omicron wave. Findings were consistent among individuals who previously received three or more doses of COVID-19 vaccine, or had no previous history of COVID-19 infection.

Effectiveness of Molnupiravir and Nirmatrelvir-Ritonavir in CKD Patients With COVID-19.

Introduction: Even with effective vaccines, patients with CKD have a higher risk of hospitalization and death subsequent to COVID-19 infection than those without CKD. Molnupiravir and nirmatrelvir-ritonavir have been approved for emergency use, but their effectiveness for the CKD population is still unknown. This study was conducted to determine the effectiveness of these drugs in reducing mortality and severe COVID-19 in the CKD population. Methods: This was a target trial emulation study using electronic health databases in Hong Kong. Patients with CKD aged 18 years or older who were hospitalized with COVID-19 were included. The per-protocol average treatment effect among COVID-19 oral antiviral initiators, including all-cause mortality, intensive care unit (ICU) admission, and ventilatory support within 28 days, were compared to noninitiators. Results: Antivirals have been found to lower the risk of all-cause mortality, with Molnupiravir at a hazard ratio (HR) of 0.85 (95% confidence interval [CI], 0.77 to 0.95] and nirmatrelvir-ritonavir at an HR of 0.78 [95% CI, 0.60 to 1.00]. However, they do not significantly reduce the risk of ICU admission (molnupiravir: HR, 0.88 [95% CI, 0.59 to 1.30]; nirmatrelvir-ritonavir: HR, 0.86 [95% CI, 0.56 to 1.32]) or ventilatory support (molnupiravir: HR, 1.00 [95% CI, 0.76 to 1.33]; nirmatrelvir-ritonavir: HR, 1.01 [95% CI, 0.74 to 1.37]). There was a greater risk reduction in males and those with higher Charlson Comorbidity Index (CCI). The nirmatrelvir-ritonavir trial also showed reduced risk for those who had antiviral treatment and received 3 or more vaccine doses. Conclusion: Both molnupiravir and nirmatrelvir-ritonavir reduced mortality rates for hospitalized COVID-19 patients with CKD.

Vaccine Effectiveness of BNT162b2 and CoronaVac against SARS-CoV-2 Omicron BA.2 in CKD.

BACKGROUND: The ongoing coronavirus disease 2019 (COVID-19) pandemic has posed increased risks of hospitalization and mortality in patients with underlying CKD. Current data on vaccine effectiveness of COVID-19 vaccines are limited to patients with CKD on dialysis and seroconversion in the non-dialysis population. METHODS: A case-control study was conducted of adults with CKD using data extracted from the electronic health record database in Hong Kong. Adults with CKD and COVID-19 confirmed by PCR were included in the study. Each case was matched with up to ten controls attending Hospital Authority services without a diagnosis of COVID-19 on the basis of age, sex, and index date (within three calendar days). The vaccine effectiveness of BNT162b2 and CoronaVac in preventing COVID-19 infection, hospitalizations, and all-cause mortality was estimated using conditional logistic regression adjusted by patients' comorbidities and medication history during the outbreak from January to March 2022. RESULTS: A total of 20,570 COVID-19 cases, 6604 COVID-19-related hospitalizations, and 2267 all-cause mortality were matched to 81,092, 62,803, and 21,348 controls, respectively. Compared with the unvaccinated group, three doses of BNT162b2 or CoronaVac were associated with a reduced risk of infection (BNT162b2: 64% [95% confidence interval (CI), 60 to 67], CoronaVac: 42% [95% CI, 38 to 47]), hospitalization (BNT162b2: 82% [95% CI, 77 to 85], CoronaVac: 80% [95% CI, 76 to 84]), and mortality (BNT162b2: 94% [95% CI, 88 to 97], CoronaVac: 93% [95% CI, 88 to 96]). Vaccines were less effective in preventing infection and hospitalization in the eGFR <15 and 15-29 ml/min per 1.73 m 2 subgroups as compared with higher GFR subgroups. However, receipt of vaccine, even for one dose, was effective in preventing all-cause mortality, with estimates similar to the higher eGFR subgroups, as compared with unvaccinated. CONCLUSIONS: A dose-response relationship was observed between the number of BNT162b2 or CoronaVac doses and the effectiveness against COVID-19 infection and related comorbidity in the CKD population.

COVID-19 vaccine effectiveness against the Omicron variant of SARS-CoV-2 in multimorbidity: A territory-wide case-control study.

Multimorbidity entails a higher risk of SARS-CoV-2 infection and COVID-19 complications. We examined vaccine effectiveness (VE) stratified by multimorbidity using a case-control study of territory-wide electronic health records in Hong Kong. Cases of infection (testing positive), hospitalization, and mortality were identified from January to March 2022. Controls were matched by age, sex, outpatient attendance/hospitalization date, and Charlson Comorbidity Index. We demonstrated a consistently good VE among people with increased multimorbidity burden; even more so than among those with minimal such burden. There was also a significantly greater VE after a third dose of BNT162b2 or CoronaVac against infection. The difference in VE between those with multimorbidity and those without was less pronounced for hospitalization, and such difference for COVID-19-related mortality was negligible. In conclusion, VE of both examined vaccines against SARS-CoV-2 infection among people with more complex multimorbidity burden is significant. Further vaccine roll-out should prioritize people with multimorbidity.

Association of COVID-19 with short- and long-term risk of cardiovascular disease and mortality: a prospective cohort in UK Biobank.

AIMS: This study aims to evaluate the short- and long-term associations between COVID-19 and development of cardiovascular disease (CVD) outcomes and mortality in the general population. METHODS AND RESULTS: A prospective cohort of patients with COVID-19 infection between 16 March 2020 and 30 November 2020 was identified from UK Biobank, and followed for up to 18 months, until 31 August 2021. Based on age (within 5 years) and sex, each case was randomly matched with up to 10 participants without COVID-19 infection from two cohorts-a contemporary cohort between 16 March 2020 and 30 November 2020 and a historical cohort between 16 March 2018 and 30 November 2018. The characteristics between groups were further adjusted with propensity score-based marginal mean weighting through stratification. To determine the association of COVID-19 with CVD and mortality within 21 days of diagnosis (acute phase) and after this period (post-acute phase), Cox regression was employed. In the acute phase, patients with COVID-19 (n = 7584) were associated with a significantly higher short-term risk of CVD {hazard ratio (HR): 4.3 [95% confidence interval (CI): 2.6- 6.9]; HR: 5.0 (95% CI: 3.0-8.1)} and all-cause mortality [HR: 81.1 (95% CI: 58.5-112.4); HR: 67.5 (95% CI: 49.9-91.1)] than the contemporary (n = 75 790) and historical controls (n = 75 774), respectively. Regarding the post-acute phase, patients with COVID-19 (n = 7139) persisted with a significantly higher risk of CVD in the long-term [HR: 1.4 (95% CI: 1.2-1.8); HR: 1.3 (95% CI: 1.1- 1.6)] and all-cause mortality [HR: 5.0 (95% CI: 4.3-5.8); HR: 4.5 (95% CI: 3.9-5.2) compared to the contemporary (n = 71 296) and historical controls (n = 71 314), respectively. CONCLUSIONS: COVID-19 infection, including long-COVID, is associated with increased short- and long-term risks of CVD and mortality. Ongoing monitoring of signs and symptoms of developing these cardiovascular complications post diagnosis and up till at least a year post recovery may benefit infected patients, especially those with severe disease.

Post-acute sequelae of COVID-19 in older persons: multi-organ complications and mortality.

INTRODUCTION: Evidence on long-term associations between coronavirus disease 2019 (COVID-19) and risks of multi-organ complications and mortality in older population is limited. This study evaluates these associations. RESEARCH DESIGN AND METHODS: The cohorts included patients aged ≥60 year diagnosed with COVID-19 infection (cases), between 16 March 2020 and 31 May 2021 from the UK Biobank; and between 01 April 2020 and 31 May 2022 from the electronic health records in Hong Kong. Each patient was randomly matched with individuals without COVID-19 infection based on year of birth and sex and were followed for up to 18 months until 31 August 2021 for UKB, and up to 28 months until 15 August 2022 for HK cohort. Patients with COVID-19 infection over 6 months after the date of last dose of vaccination and their corresponding controls were excluded from our study. Characteristics between cohorts were further adjusted with Inverse Probability Treatment Weighting. For evaluating long-term association of COVID-19 with multi-organ disease complications and mortality after 21-days of diagnosis, Cox regression was employed. RESULT: 10,759 (UKB) and 165,259 (HK) older adults with COVID-19 infection with matched 291,077 (UKB) and 1,100,394 (HK) non-COVID-19-diagnosed older adults were recruited. Older adults with COVID-19 were associated with a significantly higher risk of cardiovascular outcomes [major cardiovascular disease (stroke, heart failure and coronary heart disease): hazard ratio(UKB): 1.4 (95% Confidence interval: 1.1,1.6), HK:1.2 (95% CI: 1.1,1.3)]; myocardial infarction: HR(UKB): 1.8 (95% CI: 1.3,2.4), HK:1.2 (95% CI: 1.0,1.4)]; respiratory outcomes [interstitial lung disease: HR(UKB: 3.4 (95% CI: 2.5,4.5), HK: 4.0 (95% CI: 1.3,12.8); chronic pulmonary disease: HR(UKB): 1.7 (95% CI: 1.3,2.2), HK:1.6 (95% CI: 1.3,2.1)]; neuropsychiatric outcomes [seizure: HR(UKB): 2.6 (95% CI: 1.7,4.1), HK: 1.6 (95% CI: 1.2,2.1)]; and renal outcomes [acute kidney disease: HR(UKB): 1.4 (95% CI: 1.1,1.6), HK:1.6 (95% CI: 1.3,2.1)]; and all-cause mortality [HR(UKB): 4.9 (95% CI: 4.4,5.4), HK:2.5 (95% CI: 2.5,2.6)]. CONCLUSION: COVID-19 is associated with long-term risks of multi-organ complications in older adults (aged ≥ 60). Infected patients in this age-group may benefit from appropriate monitoring of signs/symptoms for developing these complications.

Neuropsychiatric events associated with montelukast in patients with asthma: a systematic review.

BACKGROUND: The United States Food and Drug Administration issued a black box warning on the mental health adverse effects of montelukast in 2020. Age-related effects on the risk of developing specific neuropsychiatric events in montelukast users remain largely unknown. OBJECTIVE: To describe the risk of neuropsychiatric events associated with montelukast in adults and children with asthma. METHODS: A systematic search of all studies investigating neuropsychiatric events in montelukast users was performed in PubMed, the Cochrane Library and Embase from inception to 7 September 2022. Animal studies and conference abstracts were excluded. RESULTS: 59 studies (21 pharmacovigilance studies, four reviews from 172 randomised controlled trials, 20 observational studies, 10 case reports and four case series) evaluating neuropsychiatric events in patients with asthma on montelukast were reviewed. No significant association was shown between montelukast and suicide-related events in six of the observational studies. No association was found for depression as defined by the International Classification of Diseases 10th revision codes in three observational studies and a review of randomised clinical trials. However, findings from four studies using antidepressant prescriptions as the outcome identified significant associations. Consistent with nine pharmacovigilance studies, two large-scale observational studies revealed possible associations of montelukast with anxiety and sleeping disorders in adult patients with asthma, respectively. However, the results were not replicated in two observational studies on children. CONCLUSION: Montelukast is not associated with suicide- and depression-related events in asthma patients. Older adults may be particularly susceptible to anxiety and sleeping disorders.

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.

Association between BNT162b2 and CoronaVac vaccination and risk of CVD and mortality after COVID-19 infection: A population-based cohort study.

It is unknown if vaccination affects the risk of post-COVID-19 cardiovascular diseases (CVDs). Therefore, this retrospective cohort study examines the short-term and long-term risks of post-infection CVD among COVID-19 patients with different vaccination status utilizing data from electronic health databases in Hong Kong. Cox proportional hazards regression adjusted with inverse probability of treatment weighting is used to evaluate the risks of incident CVD (coronary heart disease, stroke, heart failure) and all-cause mortality in COVID-19 patients. Compared with unvaccinated patients, vaccinated patients have a lower risk of CVD and all-cause mortality, and the lowest risk is observed in those who completed three doses of vaccine. Similar patterns in the subgroups of different vaccine platforms, age, gender, Charlson comorbidity index, and disease severity are observed. These findings highlight a positive dose-response relationship between overall CVD risk reduction and the number of vaccine doses received.

Waning effectiveness against COVID-19-related hospitalization, severe complications, and mortality with two to three doses of CoronaVac and BNT162b2: a case-control study.

BACKGROUND: This study aims to evaluate waning effectiveness against severe and fatal COVID-19 with two to three doses of CoronaVac/BNT162b2, where data are limited. METHODS: A case-control study included individuals aged ≥18 years, unvaccinated or received two to three doses of CoronaVac/BNT162b2, using electronic healthcare databases in Hong Kong. Those with first COVID-19-related hospitalization, severe complications, or mortality between 1 January and 15 August 2022 were defined as cases and matched with up-to-10 controls by age, sex, index date, and Charlson Comorbidity Index. Vaccine effectiveness (VE) against COVID-19-related outcomes was estimated at different time intervals from second and third-dose vaccination (0-13 up-to 210-240 days) using conditional logistic regression adjusted for comorbidities and medications. RESULTS: By 211-240 days after second dose, VE against COVID-19-related hospitalization reduced to 46.6% (40.7-51.8%) for BNT162b2 and 36.2% (28.0-43.4%) for CoronaVac, and VE against COVID-19-related mortality were 73.8% (55.9-84.4%) and 76.6% (60.8-86.0%). After third dose, VE against COVID-19-related hospitalization decreased from 91.2% (89.5-92.6%) for BNT162b2 and 76.7% (73.7-79.4%) for CoronaVac at 0-13 days, to 67.1% (60.4-72.6%) and 51.3% (44.2-57.5%) at 91-120 days. VE against COVID-19-related mortality for BNT162b2 remained high from 0-13 days [98.2% (95.0-99.3%)] to 91-120 days [94.6% (77.7-98.7%)], and for CoronaVac reduced from 0-13 days [96.7% (93.2-98.4%)] to 91-120 days [86.4% (73.3-93.1%)]. CONCLUSIONS: Significant risk reduction against COVID-19-related hospitalization and mortality after CoronaVac or BNT162b2 vaccination was observed for >240 and >120 days after second and third doses compared to unvaccinated, despite significant waning over time. Timely administration of booster doses could provide higher levels of protection.

Effectiveness of BNT162b2 and CoronaVac vaccines in preventing SARS-CoV-2 Omicron infections, hospitalizations, and severe complications in the pediatric population in Hong Kong: a case-control study.

Severe COVID-19 appears to be disproportionately more common in children and adolescents since the emergence of Omicron. More evidence regarding vaccine effectiveness (VE) is urgently needed to assist policymakers in making decisions and minimize vaccine hesitancy among the public. This was a case-control study in the pediatric population using data extracted from the electronic health records database in Hong Kong. Individuals aged 3-17 with COVID-19 confirmed by polymerase chain reaction were included in the study. Each case was matched with up to 10 controls based on age, gender, and index date (within 3 calendar days). The VE of BNT162b2 and CoronaVac in preventing COVID-19, hospitalizations, and severe outcomes were estimated using conditional logistic regression adjusted by patients' comorbidities and medication history during the outbreak from January to August 2022. A total of 36,434 COVID-19 cases, 2231 COVID-19-related hospitalizations, and 1918 severe COVID-19 cases were matched to 109,004, 21,788, and 18,823 controls, respectively. Compared to the unvaccinated group, three doses of BNT162b2 or CoronaVac was associated with reduced risk of infection [VE: BNT162b2: 56.0% (95% CI: 49.6-61.6), CoronaVac: 39.4% (95% CI: 25.6-50.6)], hospitalization [VE: BNT162b2: 58.9% (95% CI: 36.1-73.6), CoronaVac: 51.7% (11.6-73.6)], and severe outcomes [VE: BNT162b2: 60.2% (95% CI: 33.7-76.1), CoronaVac: 42.2% (95% CI: -6.2-68.6)]. Our findings showed that three doses of BNT162b2 or CoronaVac was effective in preventing COVID-19, hospitalizations, and severe outcomes among the pediatric population during Omicron-dominant pandemic, which was further enhanced after a booster dose.

Effectiveness of molnupiravir vs nirmatrelvir-ritonavir in non-hospitalised and hospitalised patients with COVID-19: a target trial emulation study.

Background: Molnupiravir and nirmatrelvir-ritonavir have emerged as promising options for COVID-19 treatment, but direct comparisons of their effectiveness have been limited. This study aimed to compare the effectiveness of these two oral antiviral drugs in non-hospitalised and hospitalised patients with COVID-19. Methods: In this target trial emulation study, we used data from a territory-wide electronic health records database on eligible patients aged ≥18 years infected with COVID-19 who were prescribed either molnupiravir or nirmatrelvir-ritonavir within five days of infection between 16 March 2022 and 31 December 2022 in the non-hospitalised and hospitalised settings in Hong Kong. A sequence trial approach and 1:1 propensity score matching was applied based on age, sex, number of COVID-19 vaccine doses received, Charlson comorbidity index, comorbidities, and drug use within past 90 days. Cox regression adjusted with patients' characteristics was used to compare the risk of effectiveness outcomes (all-cause mortality, intensive care unit (ICU) admission or ventilatory support and hospitalisation) between groups. Subgroup analyses included age (<70; ≥70 years); sex, Charlson comorbidity index (<4; ≥4), and number of COVID-19 vaccine doses received (0-1; ≥2 doses). Findings: A total of 63,522 non-hospitalised (nirmatrelvir-ritonavir: 31,761; molnupiravir: 31,761) and 11,784 hospitalised (nirmatrelvir-ritonavir: 5892; molnupiravir: 5892) patients were included. In non-hospitalised setting, 336 events of all-cause mortality (nirmatrelvir-ritonavir: 71, 0.22%; molnupiravir: 265, 0.83%), 162 events of ICU admission or ventilatory support (nirmatrelvir-ritonavir: 71, 0.22%; molnupiravir: 91, 0.29%), and 4890 events of hospitalisation (nirmatrelvir-ritonavir: 1853, 5.83%; molnupiravir: 3037, 9.56%) were observed. Lower risks of all-cause mortality (absolute risk reduction (ARR) at 28 days: 0.61%, 95% CI: 0.50-0.72; HR: 0.43, 95% CI: 0.33-0.56) and hospital admission (ARR at 28 days: 3.73%, 95% CI: 3.31-4.14; HR: 0.72, 95% CI: 0.67-0.76) were observed in nirmatrelvir-ritonavir users compared to molnupiravir users. In hospitalised setting, 509 events of all-cause mortality (nirmatrelvir-ritonavir: 176, 2.99%; molnupiravir: 333, 5.65%), and 50 events of ICU admission or ventilatory support (nirmatrelvir-ritonavir: 26, 0.44%; molnupiravir: 24, 0.41%) were observed. Risk of all-cause mortality was lower for nirmatrelvir-ritonavir users than for molnupiravir users (ARR at 28 days: 2.66%, 95% CI: 1.93-3.40; HR: 0.59, 95% CI: 0.49-0.71). In both settings, there was no difference in the risk of intensive care unit admission or ventilatory support between groups. The findings were consistent across all subgroup's analyses. Interpretation: Our analyses suggest that nirmatrelvir-ritonavir was more effective than molnupiravir in reducing the risk of all-cause mortality in both non-hospitalised and hospitalised patients. When neither drug is contraindicated, nirmatrelvir-ritonavir may be considered the more effective option. Funding: HMRF Research on COVID-19, The Hong Kong Special Administrative Region (HKSAR) Government; Collaborative Research Fund, University Grants Committee, the HKSAR Government; and Research Grant from the Food and Health Bureau, the HKSAR Government; the Laboratory of Data Discovery for Health (D24H) funded by the AIR@InnoHK administered by Innovation and Technology Commission.

Sex-based differences in risk of ischaemic stroke or systemic embolism after BNT162b2 or CoronaVac COVID-19 vaccination in patients with atrial fibrillation: a self-controlled case series and nested case-control study.

AIMS: Patients with atrial fibrillation (AF) have a higher risk of ischaemic stroke or systemic embolism, with a greater risk for female patients. This study aims to evaluate the risk of ischaemic stroke or systemic embolism and bleeding following COVID-19 vaccination in patients with AF and the sex differences. METHODS AND RESULTS: Self-controlled case series (SCCS) analysis was conducted to evaluate the risk of ischaemic stroke or systemic embolism and bleeding following BNT162b2 or CoronaVac in patients with AF, using the territory-wide electronic medical records from the Hospital Authority and vaccination records from the Department of Health in Hong Kong. Patients with a primary diagnosis of ischaemic stroke, systemic embolism, or bleeding in the inpatient setting between 23 February 2021 and 31 March 2022 were included. A nested case-control analysis was also conducted with each case randomly matched with 10 controls according to sex, age, Charlson comorbidity index, and date of hospital admission. Conditional Poisson regression was used in the SCCS analysis, and conditional logistic regression was used in the nested case-control analysis to assess the risks, and all analyses were stratified by sex and type of vaccines. Among 51 158 patients with AF, we identified an increased risk of ischaemic stroke or systemic embolism after the first dose of BNT162b2 in SCCS analysis during 0-13 days [incidence rate ratio 6.60, 95% confidence interval (CI) 1.51-28.77] and 14-27 days (6.53, 95% CI 1.31-32.51), and nested case-control analysis during 0-13 days (adjusted odds ratio 6.21, 95% CI 1.14-33.91) and 14-27 days (5.52, 95% CI 1.12-27.26) only in female patients. The increased risk in female patients following the first dose of CoronaVac was only detected during 0-13 days (3.88, 95% CI 1.67-9.03) in the nested case-control analysis. No increased risk of ischaemic stroke or systemic embolism was identified in male patients, and no increased risk of bleeding was detected in all patients with AF for both vaccines. An increased risk of ischaemic stroke or systemic embolism after COVID-19 was also observed in both females (17.42, 95% CI 5.08-59.73) and males (6.63, 95% CI 2.02-21.79). CONCLUSIONS: The risk of ischaemic stroke or systemic embolism after COVID-19 vaccination was only increased in female patients with AF. However, as the risk after COVID-19 was even higher, proactive uptake of COVID-19 vaccines is recommended to prevent the potential severe outcomes after infection.

Comparing hybrid and regular COVID-19 vaccine-induced immunity against the Omicron epidemic.

Evidence on the effectiveness of COVID-19 vaccines among people who recovered from a previous SARS-CoV-2 infection is warranted to inform vaccination recommendations. Using the territory-wide public healthcare and vaccination records of over 2.5 million individuals in Hong Kong, we examined the potentially differential risk of SARS-CoV-2 infection, hospitalization, and mortality between those receiving two homologous doses of BNT162b2 or CoronaVac versus those with a previous infection receiving only one dose amid the Omicron epidemic. Results show a single dose after a SARS-CoV-2 infection is associated with a lower risk of infection (BNT162b2: adjusted incidence rate ratio [IRR] = 0.475, 95% CI: 0.410-0.550; CoronaVac: adjusted IRR = 0.397, 95% CI: 0.309-0.511) and no significant difference was detected in the risk of COVID-19-related hospitalization or mortality compared with a two-dose vaccination regimen. Findings support clinical recommendations that those with a previous infection could receive a single dose to gain at least similar protection as those who received two doses without a previous infection.