Effectiveness of BNT162b2 after extending the primary series dosing interval in children and adolescents aged 5-17.

Extended intervals between the first and second doses of mRNA Covid-19 vaccines may reduce the risk of myocarditis in children and adolescents. However, vaccine effectiveness after this extension remains unclear. To examine this potential variable effectiveness, we conducted a population-based nested case-control study of children and adolescents aged 5-17 years who had received two doses of BNT162b2 in Hong Kong. From January 1 to August 15, 2022, 5396 Covid-19 cases and 202 Covid-19 related hospitalizations were identified and matched with 21,577 and 808 controls, respectively. For vaccine recipients with extended intervals [≥28 days, adjusted odds ratio 0.718, 95% Confidence Interval: 0.619, 0.833] there was a 29.2%-reduced risk of Covid-19 infection compared to those with regular intervals (21-27 days). If the threshold was set at eight weeks, the risk reduction was estimated at 43.5% (aOR 0.565, 95% CI: 0.456, 0.700). In conclusion, longer dosing intervals for children and adolescents should be considered.

Transcriptome-wide summary data-based Mendelian randomization analysis reveals 38 novel genes associated with severe COVID-19.

Severe COVID-19 has a poor prognosis, while the genetic mechanism underlying severe COVID-19 remains largely unknown. We aimed to identify genes that are potentially causally associated with severe COVID-19. We conducted a summary data-based Mendelian randomization (SMR) analysis using expression quantitative trait loci (eQTL) data from 49 different tissues as the exposure and three COVID-19-phenotypes (very severe respiratory confirmed COVID-19 [severe COVID-19], hospitalized COVID-19, and SARS-CoV-2 infection) as the outcomes. SMR using multiple SNPs was used as a sensitivity analysis to reduce false positive rate. Multiple testing was corrected using the false discovery rate (FDR) q-value. We identified 309 significant gene-trait associations (FDR q value < 0.05) across 46 tissues for severe COVID-19, which mapped to 64 genes, of which 38 are novel. The top five most associated protein-coding genes were Interferon Alpha and Beta Receptor Subunit 2 (IFNAR2), 2'-5'-Oligoadenylate Synthetase 3 (OAS3), mucin 1 (MUC1), Interleukin 10 Receptor Subunit Beta (IL10RB), and Napsin A Aspartic Peptidase (NAPSA). The potential causal genes were enriched in biological processes related to type I interferons, interferon-gamma inducible protein 10 production, and chemokine (C-X-C motif) ligand 2 production. In addition, we further identified 23 genes and 5 biological processes which are unique to hospitalized COVID-19, as well as 13 genes that are unique to SARS-CoV-2 infection. We identified several genes that are potentially causally associated with severe COVID-19. These findings improve our limited understanding of the mechanism of COVID-19 and shed light on the development of therapeutic agents for treating severe COVID-19.

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.

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.

Prognosis of Myocarditis Developing After mRNA COVID-19 Vaccination Compared With Viral Myocarditis.

BACKGROUND: Association between messenger RNA (mRNA) COVID-19 vaccines and myocarditis has aroused public concern over vaccine safety. OBJECTIVES: The goal of this study was to compare the prognosis of this condition with viral infection-related myocarditis over 180 days. METHODS: A territory-wide electronic public health care database in Hong Kong linked with population-based vaccination records was used to conduct a retrospective cohort study. Since the roll-out of BNT162b2 (Pfizer-BioNTech), patients aged ≥12 years hospitalized with myocarditis within 28 days after BNT162b2 vaccination were compared against viral infection-related myocarditis recorded before the pandemic (2000-2019), over a 180-day follow-up period (starting from diagnosis of myocarditis). All-cause mortality, heart failure, dilated cardiomyopathy, heart transplant, and postdischarge health care utilization were examined with Cox proportional hazards models. RESULTS: A total of 866 patients were included for analysis. Over the follow-up period, 1 death (1.0%) of 104 patients with postvaccination myocarditis and 84 deaths (11.0%) of 762 patients with viral infection-related myocarditis were identified. One case (1.0%) of dilated cardiomyopathy and 2 cases (1.9%) of heart failure were identified in the postvaccination group, compared with 28 (3.7%) and 93 (12.2%) in the viral infection-related myocarditis group, respectively. Adjusted analysis showed that the postvaccination myocarditis group had a 92% lower mortality risk (adjusted HR: 0.08; 95% CI: 0.01-0.57). No significant differences in other prognostic outcomes were seen. CONCLUSIONS: This study found a significantly lower rate of mortality among individuals with myocarditis after mRNA vaccination compared with those with viral infection-related myocarditis. Prognosis of this iatrogenic condition may be less severe than naturally acquired viral infection-related myocarditis.

Risk of thyroid dysfunction associated with mRNA and inactivated COVID-19 vaccines: a population-based study of 2.3 million vaccine recipients.

BACKGROUND: In view of accumulating case reports of thyroid dysfunction following COVID-19 vaccination, we evaluated the risks of incident thyroid dysfunction following inactivated (CoronaVac) and mRNA (BNT162b2) COVID-19 vaccines using a population-based dataset. METHODS: We identified people who received COVID-19 vaccination between 23 February and 30 September 2021 from a population-based electronic health database in Hong Kong, linked to vaccination records. Thyroid dysfunction encompassed anti-thyroid drug (ATD)/levothyroxine (LT4) initiation, biochemical picture of hyperthyroidism/hypothyroidism, incident Graves' disease (GD), and thyroiditis. A self-controlled case series design was used to estimate the incidence rate ratio (IRR) of thyroid dysfunction in a 56-day post-vaccination period compared to the baseline period (non-exposure period) using conditional Poisson regression. RESULTS: A total of 2,288,239 people received at least one dose of COVID-19 vaccination (57.8% BNT162b2 recipients and 42.2% CoronaVac recipients). 94.3% of BNT162b2 recipients and 92.2% of CoronaVac recipients received the second dose. Following the first dose of COVID-19 vaccination, there was no increase in the risks of ATD initiation (BNT162b2: IRR 0.864, 95% CI 0.670-1.114; CoronaVac: IRR 0.707, 95% CI 0.549-0.912), LT4 initiation (BNT162b2: IRR 0.911, 95% CI 0.716-1.159; CoronaVac: IRR 0.778, 95% CI 0.618-0.981), biochemical picture of hyperthyroidism (BNT162b2: IRR 0.872, 95% CI 0.744-1.023; CoronaVac: IRR 0.830, 95% CI 0.713-0.967) or hypothyroidism (BNT162b2: IRR 1.002, 95% CI 0.838-1.199; CoronaVac: IRR 0.963, 95% CI 0.807-1.149), GD, and thyroiditis. Similarly, following the second dose of COVID-19 vaccination, there was no increase in the risks of ATD initiation (BNT162b2: IRR 0.972, 95% CI 0.770-1.227; CoronaVac: IRR 0.879, 95%CI 0.693-1.116), LT4 initiation (BNT162b2: IRR 1.019, 95% CI 0.833-1.246; CoronaVac: IRR 0.768, 95% CI 0.613-0.962), hyperthyroidism (BNT162b2: IRR 1.039, 95% CI 0.899-1.201; CoronaVac: IRR 0.911, 95% CI 0.786-1.055), hypothyroidism (BNT162b2: IRR 0.935, 95% CI 0.794-1.102; CoronaVac: IRR 0.945, 95% CI 0.799-1.119), GD, and thyroiditis. Age- and sex-specific subgroup and sensitivity analyses showed consistent neutral associations between thyroid dysfunction and both types of COVID-19 vaccines. CONCLUSIONS: Our population-based study showed no evidence of vaccine-related increase in incident hyperthyroidism or hypothyroidism with both BNT162b2 and CoronaVac.

Thromboembolic events and hemorrhagic stroke after mRNA (BNT162b2) and inactivated (CoronaVac) covid-19 vaccination: A self-controlled case series study.

Background: This study aims to evaluate the association between thromboembolic events and hemorrhagic stroke following BNT162b2 and CoronaVac vaccination. Methods: Patients with incident thromboembolic events or hemorrhagic stroke within 28 days of covid-19 vaccination or SARS-CoV-2 positive test during 23 February to 30 September 2021 were included. The incidence per 100,000 covid-19 vaccine doses administered and SARS-CoV-2 test positive cases were estimated. A modified self-controlled case series (SCCS) analysis using the data from the Hong Kong territory-wide electronic health and vaccination records. Seasonal effect was adjusted by month. Findings: A total of 5,526,547 doses of BNT162b2 and 3,146,741 doses of CoronaVac were administered. A total of 334 and 402 thromboembolic events, and 57 and 49 hemorrhagic stroke cases occurred within 28 days after BNT162b2 and CoronaVac vaccination, respectively. The crude incidence of thromboembolic events and hemorrhagic stroke per 100,000 doses administered for both covid-19 vaccines were smaller than that per 100,000 SARS-CoV-2 test positive cases. The modified SCCS detected an increased risk of hemorrhagic stroke in BNT162b2 14-27 days after first dose with adjusted IRR of 2.53 (95% CI 1.48-4.34), and 0-13 days after second dose with adjusted IRR 2.69 (95% CI 1.54-4.69). No statistically significant risk was observed for thromboembolic events for both vaccines. Interpretation: We detected a possible safety signal for hemorrhagic stroke following BNT162b2 vaccination. The incidence of thromboembolic event or hemorrhagic stroke following vaccination is lower than that among SARS-CoV-2 test positive cases; therefore, vaccination against covid-19 remains an important public health intervention. Funding: This study was funded by a research grant from the Food and Health Bureau, The Government of the Hong Kong Special Administrative Region (reference COVID19F01).

COVID-19 and Thyroid Function: A Bi-Directional Two-Sample Mendelian Randomization Study.

Background: Thyroid dysfunction has been observed among some patients with coronavirus disease (COVID-19). It is unclear whether severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection (or its severity) leads to the development of thyroid dysfunction, or vice versa. In this study, we examined the bi-directional causal relationship between host genetic liability to three COVID-19 phenotypes (including SARS-CoV-2 infection, hospitalized and severe COVID-19) and three thyroid dysfunction traits (including hyperthyroidism, hypothyroidism, and autoimmune thyroid disease [AITD]) and three continuous traits of thyroid hormones (including thyrotropin [TSH] and free thyroxine [fT4] within reference range, and TSH in full range). Methods: Summary statistics from the largest available meta-analyses of human genome-wide association studies were retrieved for the following variables: SARS-CoV-2 infection (n = 1,348,701), COVID-19 hospitalization (n = 1,557,411), severe COVID-19 (n = 1,059,456), hyperthyroidism (n = 51,823), hypothyroidism (n = 53,423), AITD (n = 755,406), TSH within reference range (n = 54,288), fT4 within reference range (n = 49,269), and TSH in full range (n = 119,715). Using a two-sample Mendelian randomization (MR) approach, the inverse-variance weighted (IVW) method was adopted as the main MR analysis. Weighted median, contamination mixture, MR-Egger, and MR pleiotropy residual sum and outlier (MR-PRESSO) methods were applied as sensitivity analyses. Results: Host genetic susceptibility to SARS-CoV-2 infection was causally associated with hypothyroidism in the main IVW analysis (per doubling in prevalence of SARS-CoV-2 infection, odds ratio [OR] = 1.335; 95% confidence interval [CI]: 1.167-1.526; p = 2.4 × 10-5, surpassing the Bonferroni multiple-testing threshold). Similar causal estimates were observed in the sensitivity analyses (weighted median: OR = 1.296; CI: 1.066-1.575; p = 9 × 10-3; contamination mixture: OR = 1.356; CI: 1.095-1.818; p = 0.013; MR-Egger: OR = 1.712; CI: 1.202-2.439; p = 2.92 × 10-3, and MR-PRESSO: OR = 1.335; CI: 1.156-1.542; p = 5.73 × 10-4). Host genetic liability to hospitalized or severe COVID-19 was not associated with thyroid dysfunction or thyroid hormone levels. In the reverse direction, there was no evidence to suggest that genetic predisposition to thyroid dysfunction or genetically determined thyroid hormone levels altered the risk of the COVID-19 outcomes. Conclusions: This bi-directional MR study supports that host response to SARS-CoV-2 viral infection plays a role in the causal association with increased risk of hypothyroidism. Long-term follow-up studies are needed to confirm the expected increased hypothyroidism risk.

COVID-19 and platelet traits: A bidirectional Mendelian randomization study.

This study aimed to evaluate the host genetic liability of coronavirus disease 2019 (covid-19) with platelet traits using the Mendelian randomization (MR) approach. We conducted a bidirectional two-sample MR using summary statistics from the largest genome-wide association study of three variables, covid-19 severity (severe acute respiratory syndrome coronavirus 2 [SARS-CoV-2] infection, covid-19 hospitalization, and severe covid-19, N = ~1 059 456-1 557 411) and four platelet traits (mean platelet volume [MPV], plateletcrit, platelet distribution width, and platelet count; N = 408 112). Inverse-variance weighted (IVW), median weighted, MR-Egger, and contamination mixture methods were used to estimate the causal association. Null and inconsistent associations in the IVW and sensitivity analyses were observed for SARS-CoV-2 infection and covid-19 hospitalization with platelet traits. For severe covid-19, significant associations with MPV and platelet count were observed in the IVW and sensitivity analyses, with the betaIVW of 0.01 (95% confidence interval [CI]: 0.005-0.016, p = 3.51 × 10-4 ) and -0.009 (95% CI: -0.015 to -0.002, p = 0.008) per doubling in odds of severe covid-19, respectively. Conversely, null associations were observed for platelet traits with covid-19 traits. In conclusion, host genetic liability to severe covid-19 was causally associated with increased MPV and reduced platelet count, which may provide insights into evaluating hypercoagulability and thromboembolic events in covid-19 patients.

COVID-19 vaccines and risks of hematological abnormalities: Nested case-control and self-controlled case series study.

Several studies reported hematological abnormalities after vaccination against the coronavirus disease 2019 (COVID-19). We evaluated the association between COVID-19 vaccines (CoronaVac and BNT162b2) and hematological abnormalities. We conducted nested case-control and self-controlled case series analyses using the data from the Hong Kong Hospital Authority and the Department of Health, HKSAR. Outcomes of interest were thrombocytopenia, leukopenia, and neutropenia. Adjusted odds ratios (aORs), incidence rate ratios (IRRs), and 95% confidence intervals (CIs) were estimated using conditional logistic regression. In total, 1 643 419 people received COVID-19 vaccination (738 609 CoronaVac; 904 810 BNT162b2). We identified 457 and 422 cases after CoronaVac and BNT162b2 vaccination, respectively. For CoronaVac, the incidence of thrombocytopenia, leukopenia, and neutropenia was 2.51, 1.08, and 0.15 per 10 000 doses. For BNT162b2, the corresponding incidence was 1.39, 1.17, and 0.26 per 10 000 doses. The incidence per 10 000 COVID-19 cases were 1254, 2341, and 884, respectively. We only observed an increased risk of leukopenia following the second dose of BNT162b2 (aOR 1.58, 95% CI 1.24-2.02; day 0-14, IRR 2.21; 95% CI 1.59-3.08). There was no increased risk of any hematological abnormalities after CoronaVac vaccination. We observed an increased risk of leukopenia shortly after the second dose of BNT162b2. However, the incidence was much lower than the incidence following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections. There was no association between CoronaVac and hematological abnormalities. The benefits of vaccination against COVID-19 still outweigh the risk of hematological abnormalities.

Education Attainment, Intelligence and COVID-19: A Mendelian Randomization Study.

BACKGROUND: Evidence of socioeconomic inequality in COVID-19-related outcomes is emerging, with a higher risk of infection and mortality observed among individuals with lower education attainment. We aimed to evaluate the potential interventions against COVID-19 from the socioeconomic perspective, including improvement in education and intelligence. METHODS: With a two-sample Mendelian randomization approach using summary statistics from the largest genome-wide association meta-analysis, univariable analysis was adopted to evaluate the total causal effects of genetically determined education attainment and intelligence on COVID-19 outcomes. Multivariable analysis was performed to dissect the potential mechanisms. RESULTS: Genetic predisposition to higher education attainment by 1 SD (4.2 years) was independently associated with reduced risk of COVID-19 severity (OR = 0.508 [95% CI: 0.417-0.617]; p < 0.001). Genetically higher education attainment also lowered the risk of COVID-19 hospitalization (0.685 [0.593-0.791]; p < 0.001), but the association was attenuated after adjustment for beta estimates of intelligence in multivariable analysis. Genetically higher intelligence was associated with reduced risk of COVID-19 hospitalization (0.780 [0.655-0.930]; p = 0.006), with attenuation of association after adjustment for education attainment. Null association was observed for genetically determined education attainment and intelligence with SARS-CoV-2 infection. CONCLUSION: Education may act independently and jointly with intelligence in improving the COVID-19 outcomes. Improving education may potentially alleviate the COVID-19-related health inequality.

Long-term Outcome of Short-course High-dose Glucocorticoids for Severe Acute Respiratory Syndrome (SARS): A 17-Year Follow-up in SARS Survivors.

Use of high-dose glucocorticoids for COVID-19 (caused by SARS-CoV-2) is controversial because of safety concerns. We examined the long-term consequences of glucocorticoid use in severe acute respiratory syndrome (caused by SARS-CoV-1) survivors. Results showed that high-dose glucocorticoids greatly increased the long-term risk of avascular necrosis but not other major diseases.