Immunogenicity of mRNA vs. BBV152 vaccine boosters against Omicron subvariants: Final results from Phase B of the PRIBIVAC study, a randomized clinical trial.

BACKGROUND: BBV152 (Covaxin™) is a whole-virion inactivated SARS-CoV-2 vaccine mixed with an immune adjuvant. We aimed to compare immune responses after booster vaccination with heterologous BBV152 versus homologous mRNA vaccine. METHODS: We conducted a randomized, participant-blinded, controlled trial. Fifty mRNA-vaccinated participants were enrolled and randomized to receive an mRNA booster (n = 26) or BBV152 (n = 24). Blood samples were collected pre-vaccination, and at Day 7, 28, 180 and 360 post-booster for analysis of humoral and cellular immune responses. Primary end point was the SARS-CoV-2 anti-spike antibody titer at day 28. RESULTS: Recruitment began in January 2022 and was terminated early due to the BBV152 group meeting pre-specified criteria for futility. At Day 28 post-boost, mean SARS-CoV-2 spike antibody titers were lower with BBV152 (2004 IU/mL; 95 % confidence interval [CI], 1132-3548) vs mRNA (26,669 IU/mL; 95 % CI, 21,330-33,266; p < 0.0001), but comparable levels of spike-specific CD4 and cytotoxic T-cells were observed. Anti-spike antibody titers remained significantly different at Day 180: BBV152 4467 IU/mL (95 % CI, 1959-10,186) vs mRNA 20,749 IU/mL (95 % CI, 12,303-35,075; p = 0.0017). Levels of surrogate virus neutralizing antibodies against ancestral and Omicron subvariants BA.1 and BA.2 were significantly higher among mRNA recipients at Day 180, including after adjusting for intercurrent infection. By Day 360, anti-spike antibody titers and neutralizing antibody levels against Omicron subvariants became similar between vaccine groups. By the end of the study, 16 in each arm (mRNA 64 % and BBV152 69.6 %) had breakthrough infections and time to COVID-19 infection between vaccine groups were similar (p = 0.63). CONCLUSIONS: Wild-type SARS-CoV-2 anti-spike antibody titer and surrogate virus neutralizing test levels against wild-type SARS-CoV-2 and Omicron subvariants BA.1/BA.2/BA.5 were significantly higher at Day 28 and 180 in individuals who received booster vaccination with an mRNA vaccine compared with BBV152. CLINICAL TRIAL REGISTRATION NUMBER: NCT05142319.

Risk of death and cardiovascular events following COVID-19 vaccination or positive SARS-CoV-2 test amongst adult Singaporeans during omicron transmission.

IMPORTANCE: Assessing population-wide risk-benefit ratio of COVID-19 vaccination remains relevant in the current era of Omicron endemicity and boosting. Assessments of mortality risk and cardiovascular events post-vaccination/infection were generally made prior to emergence of milder Omicron and booster rollout. METHODS: Retrospective cohort study from 6th January to 31st December 2022 (Omicron-predominant transmission), amongst adult Singaporeans aged ≥18 years. Cox regression models adjusted for demographics/comorbidities were used to estimate risk of all-cause mortality and cardiovascular events 0-180 days post-mRNA vaccination/SARS-CoV-2 infection, compared to >180 days post-mRNA vaccination. Risk periods post-vaccination were further stratified by presence/absence of SARS-CoV-2 infection in the preceding 180 days; similarly, risk periods post-infection were further stratified by vaccination in the 180 days preceding infection. RESULTS: 3,137,210 adults participated, with 2,047,008 vaccine doses administered (99 % being booster doses) and 1,189,846 infections. 23,028 deaths and 54,017 cardiac events were recorded. No elevated risk of all-cause mortality/cardiovascular events was observed across all age strata post-vaccination. Conversely, all-cause mortality post-infection remained elevated up to >180 days in older adults (≥60 years), compared to person-time > 180 days post-vaccination. For vaccine-breakthrough SARS-CoV-2 infection in older adults vaccinated <180 days prior, risk of mortality was only elevated up to 60 days post-infection, but not beyond. Elevated risk of cardiovascular events 1-2 months after any SARS-CoV-2 infection was observed across all age strata, with elevated risk observed in older adults >180 days post-infection (adjusted-hazards-ratio, aHR = 1.18, 95 %CI = 1.04-1.34). Preceding vaccination within 180 days prior to infection attenuated this risk, with no significantly elevated post-acute risk of cardiovascular events (>180 days: aHR = 1.10, 95 %CI = 0.95-1.07). CONCLUSION: No increased risk of all-cause mortality or cardiovascular events was observed up to 180 days after any mRNA vaccination dose in the Omicron era; vaccination attenuated post-acute cardiovascular risk in older adults. The risk-benefit ratio of vaccination remained positive during Omicron.

Multi-dimensional epidemiology and informatics data on COVID-19 wave at the end of zero COVID policy in China.

Background: China exited strict Zero-COVID policy with a surge in Omicron variant infections in December 2022. Given China's pandemic policy and population immunity, employing Baidu Index (BDI) to analyze the evolving disease landscape and estimate the nationwide pneumonia hospitalizations in the post Zero COVID period, validated by hospital data, holds informative potential for future outbreaks. Methods: Retrospective observational analyses were conducted at the conclusion of the Zero-COVID policy, integrating internet search data alongside offline records. Methodologies employed were multidimensional, encompassing lagged Spearman correlation analysis, growth rate assessments, independent sample T-tests, Granger causality examinations, and Bayesian structural time series (BSTS) models for comprehensive data scrutiny. Results: Various diseases exhibited a notable upsurge in the BDI after the policy change, consistent with the broader trajectory of the COVID-19 pandemic. Robust connections emerged between COVID-19 and diverse health conditions, predominantly impacting the respiratory, circulatory, ophthalmological, and neurological domains. Notably, 34 diseases displayed a relatively high correlation (r > 0.5) with COVID-19. Among these, 12 exhibited a growth rate exceeding 50% post-policy transition, with myocarditis escalating by 1,708% and pneumonia by 1,332%. In these 34 diseases, causal relationships have been confirmed for 23 of them, while 28 garnered validation from hospital-based evidence. Notably, 19 diseases obtained concurrent validation from both Granger causality and hospital-based data. Finally, the BSTS models approximated approximately 4,332,655 inpatients diagnosed with pneumonia nationwide during the 2 months subsequent to the policy relaxation. Conclusion: This investigation elucidated substantial associations between COVID-19 and respiratory, circulatory, ophthalmological, and neurological disorders. The outcomes from comprehensive multi-dimensional cross-over studies notably augmented the robustness of our comprehension of COVID-19's disease spectrum, advocating for the prospective utility of internet-derived data. Our research highlights the potential of Internet behavior in predicting pandemic-related syndromes, emphasizing its importance for public health strategies, resource allocation, and preparedness for future outbreaks.

Nirmatrelvir/ritonavir treatment and risk for postacute sequelae of COVID-19 in older Singaporeans.

OBJECTIVES: Significant heterogeneity has been reported in cohort studies evaluating the impact of early oral antiviral treatment on preventing postacute sequelae after COVID-19. We evaluated the impact of early nirmatrelvir/ritonavir on risk of postacute cardiovascular, neurological, respiratory, and autoimmune diagnoses, as well as postacute symptoms amongst older Singaporeans. METHODS: National COVID-19 registries and healthcare claims databases were used to construct a retrospective population-based cohort enrolling all Singaporeans aged ≥60 years diagnosed with SARS-CoV-2 infection in primary care during Omicron transmission (18 March 2022-4 August 2023). The cohort was divided into nirmatrelvir/ritonavir-treated and untreated groups. Between-group differences in baseline characteristics were adjusted using overlap weighting. Risks of postacute cardiovascular, neurological, respiratory, and autoimmune diagnoses and postacute symptoms (31-180 days) after SARS-CoV-2 infection were contrasted in treated/untreated groups using competing risks regressions (adjusted for demographics/vaccination status/comorbidities). RESULTS: A total of 188 532 older Singaporeans were included; 5.8% (10 905/188 532) received nirmatrelvir/ritonavir. No significantly decreased risk of postacute sequelae (any sequelae: adjusted hazards ratio [aHR], 1.06; 0.94-1.19; cardiovascular sequelae: aHR, 1.01; 0.83-1.24; neurological sequelae: aHR, 1.09; 0.95-1.27; respiratory sequelae: aHR, 1.14; 0.84-1.55; autoimmune sequelae: aHR, 0.76; 0.53-1.09; or any postacute symptom: aHR, 0.97; 0.80-1.18) was observed up to 180 days post-infection in nirmatrelvir/ritonavir-treated individuals vs. untreated cases. Across all vaccination and age subgroups, no significantly decreased risk of any postacute diagnosis/symptom or any cardiovascular, neurological, respiratory, and autoimmune complications up to 180 days post-infection was observed. DISCUSSION: Early outpatient receipt of nirmatrelvir/ritonavir did not significantly reduce risk of postacute cardiovascular, neurological, respiratory, and autoimmune sequelae or the risk of postacute symptoms in a boosted cohort of older Singaporeans.

Hospitalised patients as stewards of their own antibiotic therapy: a qualitative analysis informing the strategic design of interventions to encourage shared decision-making in tertiary hospital settings in Singapore.

Background: Shared decision-making (SDM) on antibiotic therapy may improve antibiotic use in tertiary hospitals, but hospitalised patients are apprehensive about being involved in it. Understanding the facilitators and barriers to SDM can inform the design and implementation of interventions to empower these patients to engage in SDM on their antibiotic therapies. Methods: We conducted qualitative interviews with 23 adult patients purposively sampled with maximum variation from the three largest tertiary-care hospitals in Singapore (April 2019─October 2020). Thematic analysis was conducted using the Theoretical Domains Framework and Capability, Opportunity, Motivation, Behaviour (COM-B) model to identify areas for intervention. Results: Hospitalised patients lacked comprehensive knowledge of their antibiotic therapies and the majority did not have the skills to actively query their doctors about them. There was a lack of opportunities to meet and interact with doctors, and patients were less motivated to engage in SDM if they had a self-perceived paternalistic relationship with doctors, trusted their doctors to provide the best treatment, and had self-perceived poor knowledge to engage in SDM. To empower these patients, they should first be educated with antibiotic knowledge. Highlighting potential side effects of antibiotics could motivate them to ask questions about their antibiotic therapies. Environment restructuring, as facilitated by nurses and visual cues to nudge conversations, could create opportunities for interactions and motivating patients into SDM on their antibiotic therapies. Conclusion: Education and environmental restructuring should be explored to empower hospitalised patients to engage in SDM on their antibiotic therapies.

Effects of Recent Prior Dengue Infection on Risk and Severity of Subsequent SARS-CoV-2 Infection: A Retrospective Cohort Study.

Background and Aims: Elucidating whether prior dengue potentially confers cross-protection against COVID-19 is of public health importance in tropical countries at risk of overlapping dengue and COVID-19 epidemics. However, studies to date have yielded conflicting results. We aimed to assess effects of recent prior dengue infection on risk and severity of subsequent SARS-CoV-2 infection among adult Singaporeans. Methods: A retrospective cohort study including all adult Singaporeans aged ≥18 years was conducted from 1 July 2021 through 31 October 2022, when a dengue outbreak driven by the DENV3 serotype preceded subsequent waves of SARS-CoV-2 Delta/Omicron transmission in Singapore. SARS-CoV-2 and dengue infection status were classified using national registries. Cox regression models adjusted for demographics, COVID-19 vaccination status, comorbidity, and socioeconomic-status were used to assess risks and severity (hospitalization, severe illness) of SARS-CoV-2 infection occurring after previous recorded dengue infection. Results: A total of 3 366 399 individuals were included, contributing 1 399 696 530 person-days of observation. A total of 13 434 dengue infections and 1 253 520 subsequent SARS-CoV-2 infections were recorded; with an average of 94.7 days (standard deviation = 83.8) between dengue infection and SARS-CoV-2 infection. Preceding dengue infection was associated with a modest increase in risk of subsequent SARS-CoV-2 infection (adjusted hazards ratio [aHR] = 1.13; 95% confidence interval [CI], 1.08-1.17), and significantly elevated risk of subsequent COVID-19 hospitalization (aHR = 3.25; 95% CI, 2.78-3.82) and severe COVID-19 (aHR = 3.39; 95% CI, 2.29-5.03). Conclusions: Increased risk of SARS-CoV-2 infection and adverse COVID-19 outcomes were observed following preceding dengue infection in a national population-based cohort of adult Singaporeans. This observation is of significance in tropical countries with overlapping dengue and COVID-19 outbreaks.

Autoimmune Sequelae After Delta or Omicron Variant SARS-CoV-2 Infection in a Highly Vaccinated Cohort.

Importance: Studies have reported increased risk of autoimmune sequelae after SARS-CoV-2 infection. However, risk may potentially be attenuated by milder Omicron (B.1.1.529) variant infection and availability of booster vaccination. Objective: To estimate the 300-day risk of new-incident autoimmune sequelae after SARS-CoV-2 Delta or Omicron BA.1 or BA.2 variant infection in adults who received COVID-19 vaccines and boosters, compared with a contemporary control group without infection. Design, Setting, and Participants: This cohort study in Singapore enrolled adults from September 1, 2021, to March 7, 2022, and followed up for 300 days. Participants were adults aged 18 years or older with SARS-CoV-2 infection during the predominance of the Delta and Omicron BA.1 or BA.2 variants and were still alive at 30 days after COVID-19 diagnosis. Exposure: The national SARS-CoV-2 testing registry was used to construct cohorts of adults with SARS-CoV-2 Delta or Omicron BA.1 or BA.2 variant infection (hereafter, cases) and a contemporaneous group with negative polymerase chain reaction or rapid antigen test results (hereafter, controls). Main Outcomes and Measures: New-incident autoimmune diagnoses after SARS-CoV-2 infection. This information was recorded in the MediClaims national health care claims database and identified 31 to 300 days after index date of infection. Risks and excess burdens were estimated using Cox proportional hazards regression model with overlap weights applied. Results: In total, 1 766 036 adults (915 096 females [51.9%]; mean [SD] age, 49 [18] years) were included in the study population, with 480 082 (27.2%) categorized as cases and 1 285 954 (72.8%) as controls. Of these adults, 73.1% had Chinese, 13.7% Malay, and 9.9% Indian ethnicity. There were 104 179 cases and 666 575 controls included during the Delta variant-predominance transmission, while 375 903 cases and 619 379 controls were included during the Omicron variant-predominance transmission. During the Delta variant period, 81.1% of cases had completed primary vaccination; during the Omicron variant period, 74.6% of cases received boosters. No significantly elevated risk of 12 prespecified autoimmune sequelae was recorded across the Omicron and Delta variant cohorts. Elevated risks of inflammatory bowel disease (adjusted hazard ratio [AHR], 2.23; 95% CI, 1.45-3.46; P < .001) and bullous skin disorders (AHR, 4.88; 95% CI, 2.47-9.66; P < .001) were observed only in the subset of COVID-19 cases requiring hospitalization during the predominance of the Omicron variant. While elevated risk of vasculitis (AHR, 5.74; 95% CI, 1.48-22.23; P = .01) was observed in vaccine-breakthrough Omicron variant infections, no increased risk of vasculitis was observed in the corresponding subgroup who received boosters. Conclusions and Relevance: This cohort study observed no significantly elevated long-term risk of autoimmune sequelae after SARS-CoV-2 Delta and Omicron BA.1 or BA.2 variant infection, except for a modestly increased risk of inflammatory bowel disease and bullous skin disorders in the hospitalized subgroup during the predominance of the Omicron variant. Booster vaccination appeared to mitigate the risk of long-term autoimmune sequelae.

Long-term cardiovascular, cerebrovascular, and thrombotic complications after SARS-CoV-2-Omicron infection: a retrospective cohort study.

OBJECTIVES: Evidence suggests that some COVID-19 survivors experience a wide range of post-COVID-19 sequelae; however, the majority of studies were conducted before the emergence of the milder Omicron variant. We examined the post-acute risk of new-incident cardiovascular complications after SARS-CoV-2 infection in a multi-ethnic Asian population, during Omicron predominance. METHODS: This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals with confirmed SARS-CoV-2 infection during Omicron BA.1/2 transmission and a contemporaneous test-negative group. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular complications using doubly robust competing-risks survival analysis. Risks were reported using two measures: hazard ratio and excess burden. RESULTS: We included 375 903 test-positive, infected individuals (mean age 48 years) and 619 379 test-negative controls (mean age 47 years). The majority (97.5%, 366 593/375 903) of infected individuals had mild infection not requiring hospitalization. There was no overall increased risk of new-incident cardiovascular complications, (adjusted hazards ratio, aHR = 1.01 [0.97-1.07]) amongst COVID-19 survivors when compared against test-negatives. A modestly increased risk and excess burden of dysrhythmias amongst COVID-19 survivors (aHR = 1.09 [1.01-1.19]) was observed. Risk and burdens of new-incident cardiovascular complications predominantly accrued in hospitalized (aHR = 2.81 [2.26-3.50]) and severe COVID-19 cases (aHR = 5.52 [3.76-8.10]). DISCUSSION: No significantly increased overall risk of any cardiovascular complication was observed in the 300 days following COVID-19 infection during the Omicron-dominant period when compared against test-negatives, with the exception of a small increased occurrence of dysrhythmias.

A Nationwide Cohort Study of Delta and Omicron SARS-CoV-2 Outcomes in Vaccinated Individuals With Chronic Lung Disease.

BACKGROUND: Individuals with chronic lung disease (CLD) are more susceptible to respiratory viral infections; however, significant heterogeneity exists in the literature on CLD and COVID-19 outcomes. Data are lacking on outcomes with newer variants (eg, Omicron) and in vaccinated and boosted populations. RESEARCH QUESTION: What are the outcomes of SARS-CoV-2 infection in individuals with CLD during Delta and Omicron transmission in a highly vaccinated and boosted population-based cohort? STUDY DESIGN AND METHODS: Outcomes of Delta and Omicron SARS-CoV-2 infection in a highly vaccinated and boosted cohort of adult Singaporeans with CLD (including asthma, COPD, bronchiectasis, and pulmonary fibrosis) were contrasted against matched population control participants. Calendar time-scale Cox regressions were used to compare risk of infection, COVID-19-related hospitalizations, and severe COVID-19 disease, adjusting for sociodemographic factors and comorbidities. RESULTS: Overall, 68,782 individual patients with CLD and 534,364 matched population control participants were included. By the end of the Omicron wave, 92.7% of patients with CLD were boosted. Compared with control participants, patients with CLD showed higher risk of SARS-CoV-2 infection, COVID-19-related hospitalization, and severe COVID-19 during both the Delta wave (infection: adjusted hazards ratio [aHR], 1.22 [95% CI, 1.17-1.28]; hospitalization: aHR, 1.76 [95% CI, 1.61-1.92]; severe COVID-19: aHR, 1.75 [95% CI, 1.50-2.05]) and Omicron wave (infection: aHR, 1.15 [95% CI, 1.14-1.17]; hospitalization: aHR, 1.82 [95% CI, 1.74-1.91]; severe COVID-19: aHR, 2.39 [95% CI, 2.18-2.63]). During Omicron, significantly higher risk of infection, hospitalization, and severe COVID-19 was observed among patients with asthma (severe COVID-19: aHR, 1.31 [95% CI, 1.10-1.55]) and COPD (severe COVID-19: aHR, 1.36 [95% CI, 1.12-1.66]) compared with control participants. Severe exacerbation (requiring hospitalization) in the preceding year was associated with higher risk of poorer outcomes (Delta, severe COVID-19: aHR, 9.84 [95% CI, 6.33-15.28]; Omicron, severe COVID-19: aHR, 19.22 [95% CI, 15.35-24.06]). Risk was attenuated in the boosted group, with numerically lower HRs against hospitalization and severe COVID-19 in the four-dose group compared with the three-dose group. INTERPRETATION: Increased risk of COVID-19-related hospitalization and severe COVID-19 was observed among patients with CLD compared with matched population control participants during Delta and Omicron predominance. Boosting attenuated serious COVID-19 outcomes.

Intravenous fluid therapy in hospitalized adult dengue patients without shock: Impact on subsequent severe dengue and potential adverse effects.

There is a lack of evidence on the optimal administration of intravenous (IV) fluids in hospitalized adult dengue patients without compensated and hypotensive shock. This study utilized a well-established cohort of dengue patients to compare risks of progressing to severe dengue (SD) over time for patients who were administered IV fluid versus others who were not. We included adult patients (n = 4781) who were hospitalized for dengue infection from 2005 to 2008. Cases were patients who developed SD (n = 689) and controls were patients who did not up until discharge (n = 4092). We estimated the hazard ratios (HRs) and risk of SD over time between groups administered different volumes of IV fluids versus the no IV fluid comparison group using Cox models with time-dependent covariates. The doubly-robust estimation approach was used to control for the propensity of fluid administration given clinical characteristics of patients. Subgroup analyses by age, sex, and dengue warning signs before IV fluid administration were conducted. High (>2000 mL/day) IV fluids volume was associated with a higher risk of development of SD for those who had warning signs (HR: 1.77 [1.05-2.97], p: 0.0713) and for those below 55 years old (HR: 1.53 [1.04-2.25], p: 0.0713). Low (<1000 mL/day) IV fluids volume was protective against SD for patients without warning signs (HR: 0.757 [0.578-0.990], p: 0.0883), no lethargy (HR: 0.770 [0.600-0.998], p: 0.0847), and females (HR: 0.711 [0.516-0.980], p: 0.0804). Over the course of hospitalization, there were no significant differences in IV fluid administration and SD risk in most subgroups, except in those who experienced lethargy and were administered IV fluid volume or quantity. Administering high volumes of IV fluids may be associated with an increased risk of SD during hospitalization for adult dengue patients without shock. Judicious use of IV fluids as supportive therapy is warranted.

Dengue versus COVID-19: comparing the incidence of cardiovascular, neuropsychiatric and autoimmune complications.

BACKGROUND: While persistence of chronic symptoms following dengue infection has been documented in small prospective cohorts, population-based studies are limited. The post-acute risk of new-incident multi-systemic complications following dengue infection was contrasted against that following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a multi-ethnic adult Asian population. METHODS: National testing and healthcare claims that databases in Singapore were utilized to build a retrospective population-based adult cohort with laboratory-confirmed infection during overlapping waves of SARS-CoV-2 and dengue transmission (1 July 2021 to 31 October 2022). Risks of new-incident cardiovascular/neuropsychiatric/autoimmune complications 31-300 days of post-dengue infection, contrasted with SARS-CoV-2 infection, were estimated using Cox regression with overlap weights. Risks were reported in terms of adjusted hazard ratio (aHR) and excess burden per 1000 persons. RESULTS: 11 707 dengue-infected individuals and 1 248 326 contemporaneous coronavirus disease 2019 (COVID-19) cases were included; the majority had mild initial infection not requiring hospitalization. Amongst dengue-infected individuals, there was 21% [aHR = 1.21 (1.06-1.38)] increased risk of any sequelae, with 55% [aHR = 1.55 (1.27-1.89)] increased risk of cardiovascular sequelae. Specifically, increased risk of dysrhythmias [aHR = 1.79(1.35-2.37)], ischemic heart disease [aHR = 1.45(1.12-1.89)], other cardiac disorders [aHR = 2.21(1.54-3.16)] and thrombotic disorders [aHR = 2.55(1.50-4.35)] was noted. Elevated risk of individual neuropsychiatric sequelae, including cerebrovascular disorders [aHR = 1.49(1.09-2.13)], cognition/memory disorders [aHR = 2.13(1.55-2.93)], extrapyramidal/movement disorders [aHR = 1.98(1.33-2.94)] and anxiety disorders [aHR = 1.61(1.01-2.56)], was observed in dengue-infected individuals compared to COVID-19 cases. Elevated risks of post-acute sequelae in dengue survivors were observed when contrasted against COVID-19 survivors infected during Delta/Omicron predominance, as well as across vaccination strata. CONCLUSION: Increased risk of post-acute cardiovascular/neuropsychiatric complications was observed in dengue survivors, when contrasted against COVID-19 survivors infected during Delta/Omicron predominance.

Feasibility of wastewater-based detection of emergent pandemics through a global network of airports.

Wastewater-based surveillance has been put into practice during the pandemic. Persistence of SARS-CoV-2 in faeces of infected individuals, and high volume of passengers travelling by air, make it possible to detect virus from aircraft wastewater, lending itself to the potential identification of a novel pathogen prior to clinical diagnosis. In this study, we estimated the likelihood of detecting the virus through aircraft wastewater from the probabilities of air travel, viral shedding, defecation, testing sensitivity, and sampling. We considered various hypothetical scenarios, with diverse sampling proportions of inbound flights, surveillance airports, and sources of outbreaks. Our calculations showed that the probability of detecting SARS-CoV-2 would increase exponentially against time in the early phase of the pandemic, and would be much higher if the 20 major airports in Asia, Europe, and North America cooperated to perform aircraft wastewater surveillance. We also found other contributors to early detection, including high sampling proportion of inbound flight at destination airports, small population size of the epicentre relative to the travel volume, and large volume of outbound travelers to major airports around the globe. We concluded that routine aircraft wastewater monitoring could be a feasible approach for early identification and tracking of an emerging pathogen with high faecal shedding rates, particularly when implemented through a global surveillance network of major airports.

Long-term Cardiovascular, Cerebrovascular, and Other Thrombotic Complications in COVID-19 Survivors: A Retrospective Cohort Study.

BACKGROUND: Growing evidence suggests that some coronavirus disease 2019 (COVID-19) survivors experience a wide range of long-term postacute sequelae. We examined the postacute risk and burden of new-incident cardiovascular, cerebrovascular, and other thrombotic complications after severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection in a highly vaccinated multiethnic Southeast Asian population, during Delta predominance. METHODS: This cohort study used national testing and healthcare claims databases in Singapore to build a cohort of individuals who had a positive SARS-CoV-2 test between 1 September and 30 November 2021 when Delta predominated community transmission. Concurrently, we constructed a test-negative control group by enrolling individuals between 13 April 2020 and 31 December 2022 with no evidence of SARS-CoV-2 infection. Participants in both groups were followed up for a median of 300 days. We estimated risks of new-incident cardiovascular, cerebrovascular, and other thrombotic complications using doubly robust competing-risks survival analysis. Risks were reported using 2 measures: hazard ratio (HR) and excess burden (EB) with 95% confidence intervals. RESULTS: We included 106 012 infected cases and 1 684 085 test-negative controls. Compared with the control group, individuals with COVID-19 exhibited increased risk (HR, 1.157 [1.069-1.252]) and excess burden (EB, 0.70 [.53-.88]) of new-incident cardiovascular and cerebrovascular complications. Risks decreased in a graded fashion for fully vaccinated (HR, 1.11 [1.02-1.22]) and boosted (HR, 1.10 [.92-1.32]) individuals. Conversely, risks and burdens of subsequent cardiovascular/cerebrovascular complications increased for hospitalized and severe COVID-19 cases (compared to nonhospitalized cases). CONCLUSIONS: Increased risks and excess burdens of new-incident cardiovascular/cerebrovascular complications were reported among infected individuals; risks can be attenuated with vaccination and boosting.

Long-term neuropsychiatric sequelae of Delta versus Omicron SARS-CoV-2 infection.

OBJECTIVES: Studies have reported increased rates of long-term neuropsychiatric sequelae after SARS-CoV-2 infection using electronic health-record (EHR) data; however, the majority were conducted before Omicron and booster rollout. We estimated the long-term risks and excess burdens of pre-specified new-incident neuropsychiatric diagnoses after Delta versus Omicron BA.1/2 infection in a highly-vaccinated and boosted cohort of adult Singaporeans. METHODS: The national SARS-CoV-2 testing registry was used to construct cohorts of Singaporean adults infected during periods of Delta and Omicron BA.1/2 predominance and a contemporaneous test-negative control group. New-incident neuropsychiatric diagnoses recorded in the national health care claims database were identified up to 300 days postinfection. Risks and excess burden were estimated using a doubly robust competing-risks survival analysis. RESULTS: 104 179 and 375 903 infected cases were assigned to Delta and Omicron cohorts and compared against test-negative controls (Delta: N = 666 575 and Omicron: N = 619 379). Elevated risk of cognition or memory disorders was consistently reported across Omicron (Adjusted hazards ratio [aHR], 1.24; 95% CI, 1.12-1.38) and Delta cohorts (aHR, 1.63; 95% CI, 1.39-1.92). Delta-variant infection was associated with an increased risk of anosmia or dysgeusia (aHR, 4.53; 95% CI, 2.78-7.41) and psychosis (aHR, 1.65; 95% CI, 1.22-2.22). By contrast, Omicron-variant infection was associated with a risk of abnormal involuntary movements (aHR, 1.93; 95% CI, 1.32-2.83). Risks of neuropsychiatric sequelae predominantly accrued in hospitalized individuals. DISCUSSIONS: A modestly increased risk of cognition and memory disorders at 300 days after SARS-CoV-2 infection was observed among adult Singaporeans infected during the Delta/Omicron BA.1/2 transmission. There was no overall increased risk of neuropsychiatric sequelae observed across other domains. Variant-specific differences were also observed in individual neuropsychiatric sequelae, including an elevated risk of anosmia or dysgeusia after Delta-variant infection.

Effectiveness of Monovalent mRNA Vaccines Against Omicron XBB Infection in Singaporean Children Younger Than 5 Years.

Importance: Literature on vaccine effectiveness of SARS-CoV-2 messenger RNA (mRNA) vaccines for children younger than 5 years is limited. Objective: To report the effectiveness of monovalent mRNA vaccines against SARS-CoV-2 infection among Singaporean children aged 1 through 4 years during a COVID-19 pandemic wave of the Omicron XBB variant. Design, Setting, and Participants: This was a population-based cohort study, conducted over a 6-month study period from October 1, 2022, through March 31, 2023, after the implementation of community vaccination among all Singaporean children aged 1 through 4 years. The study period was dominated by the Omicron XBB subvariant. Exposure: Receipt of SARS-CoV-2 mRNA vaccines. Main Outcome Measure: Vaccine effectiveness against confirmed SARS-CoV-2 infection. The adjusted incidence rate ratio for confirmed infections using Poisson regression was reported, with the reference group being those who were unvaccinated. Analyses were stratified by prior documented SARS-CoV-2 infection. Results: A total of 121 628 children (median [IQR] age, 3.1 [2.2-3.9] years; 61 925 male [50.9%]) were included in the study, contributing 21 015 956 person-days of observation. The majority of children (11 294 of 11 705 [96.5%]) received the mRNA-1273 COVID-19 vaccine (Moderna). Vaccine effectiveness against confirmed infection was 45.2% (95% CI, 24.7%-60.2%) in partially vaccinated, infection-naive children and 63.3% (95% CI, 40.6%-77.3%) in fully vaccinated, infection-naive children compared with the unvaccinated group. Among previously infected children, vaccine effectiveness against reinfections in those with at least 1 vaccine dose was estimated at 74.6% (95% CI, 38.7%-89.5%). Conclusions and Relevance: Study results suggest that completion of a primary mRNA vaccine series provided protection against SARS-CoV-2 infection in children aged 1 through 4 years. Although incidence of hospitalization and severe illness is low in this age group, there is potential benefit of vaccination in preventing infection and potential sequelae.