Impact of a delayed second dose of mRNA vaccine (BNT162b2) and inactivated SARS-CoV-2 vaccine (CoronaVac) on risks of all-cause mortality, emergency department visit, and unscheduled hospitalization

BACKGROUND: Safety after the second dose of the SARS-CoV-2 vaccine remains to be elucidated, especially among individuals reporting adverse events after their first dose. This study aims to evaluate the impact of a delayed second dose on all-cause mortality and emergency services. METHODS: A territory-wide, retrospective cohort of people who had completed two doses of mRNA (BNT162b2) or inactivated SARS-CoV-2 (CoronaVac) vaccine between February 23 and July 3, 2021, in Hong Kong was analyzed, with linkage to electronic health records retrieved from the Hong Kong Hospital Authority. Vaccine recipients were classified as receiving a second dose within recommended intervals (21-28 days for BNT162b2; 14-28 days for CoronaVac) or delayed. Study outcomes were all-cause mortality, emergency department (ED) visits, and unscheduled hospitalizations within 28 days after the second dose of vaccination. RESULTS: Among 417,497 BNT162b2 and 354,283 CoronaVac second dose recipients, 3.8% and 28.5% received the second dose beyond the recommended intervals (mean 34.4 and 31.8 days), respectively. During the study period, there were < 5 daily new cases of COVID-19 infections in the community. Delaying the second dose was not associated with all-cause mortality (hazard ratio [HR] = 1.185, 95% CI 0.478-2.937, P = 0.714), risk of ED visit (HR = 0.966, 95% CI 0.926-1.008, P = 0.113), and risk of unscheduled hospitalization (HR = 0.956, 95% CI 0.878-1.040, P = 0.294) compared to that within the recommended interval for CoronaVac recipients. No statistically significant differences in all-cause mortality (HR = 4.438, 95% CI 0.951-20.701, P = 0.058), ED visit (HR = 1.037, 95% CI 0.951-1.130, P = 0.411), and unscheduled hospitalization (HR = 1.054, 95% CI 0.867-1.281, P = 0.597) were identified between people who received a second dose of BNT162b2 within and beyond the recommended intervals. CONCLUSIONS: No significant association between delayed second dose of BNT162b2 or CoronaVac and all-cause mortality, ED visit, and unscheduled hospitalization was observed in the present cohort. Regardless of the recommended or delayed schedule for SARS-CoV-2 vaccination, a second dose of both vaccines should be administered to obtain better protection against infection and serious disease. The second dose should be administered within the recommended interval following the manufacturer's product information, until further studies support the benefits of delaying vaccination outweighing the risks

Age-specific Multimorbidity Patterns and Burden on All-Cause Mortality and Public Direct Medical Expenditure:A Retrospective Cohort Study

Objective To evaluate age-specific multimorbidity patterns and morbidity burden on mortality and healthcare expenditure across age groups. Patients and Methods Retrospective observational study between January 1, 2009 to December 31, 2017 using electronic health records in Hong Kong: Individuals were stratified by age (< 50, 50–64, 65–79, ≥ 80), and sub-classified by number of morbidities (0, 1, 2, 3, ≥ 4) out of 21 common chronic conditions. Clustering analyses were conducted to identify specific patterns of multimorbidity. Association between the number as well as combinations of morbidities and all-cause mortality and public expenditure was examined. Results 4,562,832 individuals with a median follow-up of 7 years were included. Mental disorders were the top morbidities among young individuals, while cardiovascular diseases were prevalent in the elderly. An increased number of morbidities was associated with a greater relative risk for mortality and medical expenditure, and this relationship was stronger among younger patients. Compared to individuals in the same age group without morbidity, the hazard ratios (HR; 95% CI) of all-cause mortality in patients aged < 50 and ≥ 80 with two comorbidities 3.81 (3.60–4.03) and 1.38 (1.36–1.40), respectively, which increased to 14.22 (9.87–20.47) and 2.20 (2.13–2.26), respectively, as the number of morbidities increased to ≥ 4. The stroke-hypertension cluster was shown to be associated with the highest HR of mortality 2.48 (2.43–2.53) among all identified clusters arising from the clustering analysis. Conclusion Given the stronger association between multimorbidity and all-cause mortality and greater opportunity costs in younger populations, prevention and management of early-onset multimorbidity are warranted. (248 words

Association of antipsychotic use with breast cancer:a systematic review and meta-analysis of observational studies with over 2 million individuals-CORRIGENDUM

AIMS: Despite reports of an elevated risk of breast cancer associated with antipsychotic use in women, existing evidence remains inconclusive. We aimed to examine existing observational data in the literature and determine this hypothesised association. METHODS: We searched Embase, PubMed and Web of Science™ databases on 27 January 2022 for articles reporting relevant cohort or case-control studies published since inception, supplemented with hand searches of the reference lists of the included articles. Quality of studies was assessed using the Newcastle-Ottawa Scale. We generated the pooled odds ratio (OR) and pooled hazard ratio (HR) using a random-effects model to quantify the association. This study was registered with PROSPERO (CRD42022307913). RESULTS: Nine observational studies, including five cohort and four case-control studies, were eventually included for review (N = 2 031 380) and seven for meta-analysis (N = 1 557 013). All included studies were rated as high-quality (seven to nine stars). Six studies reported a significant association of antipsychotic use with breast cancer, and a stronger association was reported when a greater extent of antipsychotic use, e.g. longer duration, was operationalised as the exposure. Pooled estimates of HRs extracted from cohort studies and ORs from case-control studies were 1.39 [95% confidence interval (CI) 1.11–1.73] and 1.37 (95% CI 0.90–2.09), suggesting a moderate association of antipsychotic use with breast cancer. CONCLUSIONS: Antipsychotic use is moderately associated with breast cancer, possibly mediated by prolactin-elevating properties of certain medications. This risk should be weighed against the potential treatment effects for a balanced prescription decision

Effectiveness of BNT162b2 and CoronaVac vaccinations against SARS-CoV-2 omicron infection in people aged 60 years or above: a case–control study

BACKGROUND: In view of limited evidence that specifically addresses vaccine effectiveness (VE) in the older population, this study aims to evaluate the real-world effectiveness of BNT162b2 and CoronaVac in older adults during the Omicron BA.2 outbreak. METHODS: This case-control study analyzed data available between January and March 2022 from the electronic health databases in Hong Kong and enrolled individuals aged 60 or above. Each case was matched with up to 10 controls by age, sex, index date and Charlson Comorbidity Index for the four outcomes (COVID-19 infection, COVID-19-related hospitalization, severe complications, and all-cause mortality) independently. Conditional logistic regression was conducted to evaluate VE of BNT162b2 and CoronaVac against COVID-19-related outcomes within 28 days after COVID-19 infection among participants stratified by age groups (60-79, ≥80 years old). RESULTS: A dose-response relationship between the number of vaccine doses received and protection against severe or fatal disease was observed. Highest VE (95% CI) against COVID-19 infection was observed in individuals aged ≥80 who received three doses of BNT162b2 [75.5% (73.1-77.7%)] or three doses of CoronaVac [53.9% (51.0-56.5%)] compared to those in the younger age group who received three doses of BNT162b2 [51.1% (49.9-52.4%)] or three doses of CoronaVac [2.0% (-0.1-4.1%)]. VE (95% CI) was higher for other outcomes, reaching 91.9% (89.4-93.8%) and 86.7% (84.3-88.8%) against COVID-19-related hospitalization; 85.8% (61.2-94.8%) and 89.8% (72.4-96.3%) against COVID-19-related severe complications; and 96.4% (92.9-98.2%) and 95.0% (92.1-96.8%) against COVID-19-related mortality after three doses of BNT162b2 and CoronaVac in older vaccine recipients, respectively. A similar dose-response relationship was established in younger vaccine recipients and after stratification by sex and Charlson Comorbidity Index. CONCLUSION: Both BNT162b2 and CoronaVac vaccination were effective in protecting older adults against COVID-19 infection and COVID-19-related severe outcomes amidst the Omicron BA.2 pandemic, and VE increased further with the third dose

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 (CI) 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: 0.80-1.33) and 1.11 (95% CI: 0.80-1.50) per 100,000 doses of BNT162b2 and CoronaVac administered respectively. 16 and 17 individuals received second dose after having first seizure within 28 days after first dose of BNT162b2 and CoronaVac vaccinations, respectively. 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=0.75-2.58; CoronaVac: IRR=1.19, 95% CI=0.50-2.83) and second doses (BNT162b2: IRR=1.36, 95% CI 0.72-2.57; CoronaVac: IRR=0.71, 95% CI=0.22-2.30) of vaccinations. During 7-13, 14-20- and 21-27-days post-vaccination, no association was observed for both vaccines. 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

Adverse events of special interest following the use of BNT162b2 in adolescents: a population-based retrospective cohort study

Accruing evidence suggests an increased risk of myocarditis in adolescents from messenger RNA COVID-19 vaccines. However, other potential adverse events remain under-researched. We conducted a retrospective cohort study of adolescents aged 12–18 with a territory-wide electronic healthcare database of the Hong Kong population linked with population-based vaccination records and supplemented with age- and sex-specific population numbers. Two age- and sex-matched retrospective cohorts were formed to observe 28 days following the first and second doses of BNT162b2 and estimate the age- and sex-adjusted incidence rate ratios between the vaccinated and unvaccinated. Thirty AESIs adapted from the World Health Organization’s Global Advisory Committee on Vaccine Safety were examined. Eventually, the first-dose cohort comprised 274,881 adolescents (50.25% received the first dose) and the second-dose cohort 237,964 (50.29% received the second dose). Ninety-four (34.2 per 100,000 persons) adolescents in the first-dose cohort and 130 (54.6 per 100,000 persons) in the second-dose cohort experienced ≥1 AESIs. There were no statistically significant differences in the risk of any AESI associated with BNT162b2 except myocarditis [first-dose cohort: incidence rate ratio (IRR) = 9.15, 95% confidence interval (CI) 1.14–73.16; second-dose cohort: IRR = 29.61, 95% CI 4.04–217.07] and sleeping disturbances/disorders after the second dose (IRR = 2.06, 95% CI 1.01–4.24). Sensitivity analysis showed that, with myocarditis excluded as AESIs, no significantly elevated risk of AESIs as a composite outcome associated with vaccination was observed (P = 0.195). To conclude, the overall absolute risk of AESIs was low with no evidence of an increased risk of AESIs except myocarditis and sleeping disturbances/disorders

Medium-term Outcomes of Myocarditis and Pericarditis following BNT162b2 Vaccination among Adolescents in Hong Kong

In this study, we examined the clinical and electrophysiological outcomes of adolescents in Hong Kong who developed myocarditis or pericarditis following BNT162b2 vaccination for COVID-19, and followed-up for 60 to 180 days after their initial diagnosis. Clinical assessments included electrocardiogram (ECG) and echocardiogram at the initial admission and follow-up were compared. Treadmill testing was also performed in some cases. Between 14 June 2021 and 16 February 2022, 53 subjects were approached to participate in this follow-up study, of which 28 patients were followed up for >60 days with a median follow-up period of 100 days (range, 61-178 days) and were included in this study. On admission, 23 patients had ECG abnormalities but no high-grade atrioventricular block. Six patients had echocardiogram abnormalities, including reduced contractility, small rim pericardial effusions, and hyperechoic ventricular walls. All patients achieved complete recovery on follow-up. After discharge, 10 patients (35.7%) reported symptoms, including occasional chest pain, shortness of breath, reduced exercise tolerance, and recurrent vasovagal near-syncope. At follow-up, assessments, including ECGs, were almost all normal. Among the three patients with possible ECG abnormalities, all their echocardiograms or treadmill testings were normal. Sixteen patients (57.1%) underwent treadmill testing at a median of 117 days post-admission, which were also normal. However, at follow-up, there was a significant mean bodyweight increase of 1.81kg (95%CI 0.47-3.1 kg, p=0.01), possibly due to exercise restriction. In conclusion, most adolescents experiencing myocarditis and pericarditis following BNT162b2 vaccination achieved complete recovery. Some patients developed non-specific persistent symptoms, and bodyweight changes shall be monitored

Risk of carditis among adolescents after extending the interdose intervals of BNT162b2

Previous studies indicate an increased carditis risk among adolescents following the two-dose messenger RNA COVID-19 vaccine. Several jurisdictions have extended the interdose interval between the first and second doses to reduce the risk. However, the effectiveness of such an extension policy remains inconclusive. Using the territory-wide vaccine record-linked electronic health records in Hong Kong, we conducted a nested case-control study from February 23, 2021 to August 15, 2022. Adolescents aged between 12 and 17 who received two-dose BNT162b2 were included for comparing risks between standard interdose interval (21-27 days) versus extended interdose interval ( ≥ 56 days). The carditis cumulative incidence within 28 days following the second dose was calculated. The adjusted odds ratio was estimated from multivariable conditional logistic regression. We identified 49 adolescents with newly diagnosed carditis within 28 days following the second dose. The crude cumulative incidence is 37.41 [95% confidence interval (CI): 27.68-49.46] per million vaccinated adolescents. Compared to the standard interdose interval group, adolescents with an extended interval had a significantly lower risk of carditis [adjusted odds ratio (aOR) 0.34 (95% CI: 0.16-0.73)]. Sensitivity analysis of carditis occurring within 14 days following the second dose yielded a similar estimate [aOR 0.30 (95% CI: 0.13-0.73)]. Extending the interdose interval of the BNT162b2 vaccine from 21 to 27 days to 56 days or longer is associated with 66% lower risk of incident carditis among adolescents. Our findings contribute towards an evidence-based vaccination strategy for a vulnerable population and potentially informs product label updates

Waning effectiveness against COVID-19-related hospitalisation, 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 2-3 doses of CoronaVac/BNT162b2, where data is limited. METHODS: A case-control study included individuals aged ≥18 years, unvaccinated or received 2-3 doses of CoronaVac/BNT162b2, using electronic healthcare databases in Hong Kong. Those with first COVID-19-related hospitalisation, 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 hospitalisation 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 hospitalisation 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 hospitalisation and mortality after CoronaVac or BNT162b2 vaccination was observed for >240 and >120 days after second and third dose compared to unvaccinated, despite significant waning over time. Timely administration of booster doses could provide higher levels of protection