Relative role of border restrictions, case finding and contact tracing in controlling SARS-CoV-2 in the presence of undetected transmission: a mathematical modelling study.

BACKGROUND: Understanding the overall effectiveness of non-pharmaceutical interventions to control the COVID-19 pandemic and reduce the burden of disease is crucial for future pandemic planning. However, quantifying the effectiveness of specific control measures and the extent of missed infections, in the absence of early large-scale serological surveys or random community testing, has remained challenging. METHODS: Combining data on notified local COVID-19 cases with known and unknown sources of infections in Singapore with a branching process model, we reconstructed the incidence of missed infections during the early phase of the wild-type SARS-CoV-2 and Delta variant transmission. We then estimated the relative effectiveness of border control measures, case finding and contact tracing when there was no or low vaccine coverage in the population. We compared the risk of ICU admission and death between the wild-type SARS-CoV-2 and the Delta variant in notified cases and all infections. RESULTS: We estimated strict border control measures were associated with 0.2 (95% credible intervals, CrI 0.04-0.8) missed imported infections per notified case between July and December 2020, a decline from around 1 missed imported infection per notified case in the early phases of the pandemic. Contact tracing was estimated to identify 78% (95% CrI 62-93%) of the secondary infections generated by notified cases before the partial lockdown in Apr 2020, but this declined to 63% (95% CrI 56-71%) during the lockdown and rebounded to 78% (95% CrI 58-94%) during reopening in Jul 2020. The contribution of contact tracing towards overall outbreak control also hinges on ability to find cases with unknown sources of infection: 42% (95% CrI 12-84%) of such cases were found prior to the lockdown; 10% (95% CrI 7-15%) during the lockdown; 47% (95% CrI 17-85%) during reopening, due to increased testing capacity and health-seeking behaviour. We estimated around 63% (95% CrI 49-78%) of the wild-type SARS-CoV-2 infections were undetected during 2020 and around 70% (95% CrI 49-91%) for the Delta variant in 2021. CONCLUSIONS: Combining models with case linkage data enables evaluation of the effectiveness of different components of outbreak control measures, and provides more reliable situational awareness when some cases are missed. Using such approaches for early identification of the weakest link in containment efforts could help policy makers to better redirect limited resources to strengthen outbreak control.

Contrasting SARS-CoV-2 epidemics in Singapore: cohort studies in migrant workers and the general population.

IMPORTANCE: Since January 2020, Singapore has implemented comprehensive measures to suppress SARS-CoV-2. Despite this, the country has experienced contrasting epidemics, with limited transmission in the community and explosive outbreaks in migrant worker dormitories. OBJECTIVE: To estimate SARS-CoV-2 infection incidence among migrant workers and the general population in Singapore. DESIGN: Prospective serological cohort studies. SETTING: Two cohort studies - in a migrant worker dormitory and in the general population in Singapore. PARTICIPANTS: 478 residents of a SARS-CoV-2-affected migrant worker dormitory were followed up between May and July 2020, with blood samples collected on recruitment and after 2 and 6 weeks. In addition, 937 community-dwelling adult Singapore residents, for whom pre-pandemic sera were available, were recruited. These individuals also provided a serum sample on recruitment in November/December 2020. EXPOSURE: Exposure to SARS-CoV-2 in a densely populated migrant worker dormitory and in the general population. MAIN OUTCOMES AND MEASURES: The main outcome measures were the incidences of SARS-CoV-2 infection in migrant workers and in the general population, as determined by the detection of neutralizing antibodies against SARS-CoV-2, and adjusting for assay sensitivity and specificity using a Bayesian modeling framework. RESULTS: No evidence of community SARS-CoV-2 exposure was found in Singapore prior to September 2019. It was estimated that < 2 per 1000 adult residents in the community were infected with SARS-CoV-2 in 2020 (cumulative seroprevalence: 0.16%; 95% CrI: 0.008-0.72%). Comparison with comprehensive national case notification data suggested that around 1 in 4 infections in the general population were associated with symptoms. In contrast, in the migrant worker cohort, almost two-thirds had been infected by July 2020 (cumulative seroprevalence: 63.8%; 95% CrI: 57.9-70.3%); no symptoms were reported in almost all of these infections. CONCLUSIONS AND RELEVANCE: Our findings demonstrate that SARS-CoV-2 suppression is possible with strict and rapid implementation of border restrictions, case isolation, contact tracing, quarantining, and social-distancing measures. However, the risk of large-scale epidemics in densely populated environments requires specific consideration in preparedness planning. Prioritization of these settings in vaccination strategies should minimize the risk of future resurgences and potential spillover of transmission to the wider community.

Determining quarantine length and testing frequency for international border opening during the COVID-19 pandemic.

BACKGROUND: The COVID-19 pandemic has resulted in the closure or partial closure of international borders in almost all countries. Here, we investigate the efficacy of imported case detection considering quarantine length and different testing measures for travellers on arrival. METHODS: We examine eight broad border control strategies from utilizing quarantine alone, pre-testing, entry and exit testing, and testing during quarantine. In comparing the efficacy of these strategies, we calculate the probability of detecting travellers who have been infected up to 2 weeks pre-departure according to their estimated incubation and infectious period. We estimate the number of undetected infected travellers permitted entry for these strategies across a prevalence range of 0.1-2% per million travellers. RESULTS: At 14-day quarantine, on average 2.2% (range: 0.5-8.2%) of imported infections are missed across the strategies, leading to 22 (5-82) imported cases at 0.1% prevalence per million travellers, increasing up to 430 (106-1641) at 2%. The strategy utilizing exit testing results in 3.9% (3.1-4.9%) of imported cases being missed at 7-day quarantine, down to 0.4% (0.3-0.7%) at 21-day quarantine, and the introduction of daily testing, as the most risk averse strategy, reduces the proportion further to 2.5-4.2% at day 7 and 0.1-0.2% at day 21 dependent on the tests used. Rapid antigen testing every 3 days in quarantine leads to 3% being missed at 7 days and 0.7% at 14 days, which is comparable to PCR testing with a 24-hour turnaround. CONCLUSIONS: Mandatory testing, at a minimal of pre-testing and on arrival, is strongly recommended where the length of quarantining should then be determined by the destination country's level of risk averseness, pandemic preparedness and origin of travellers. Repeated testing during quarantining should also be utilized to mitigate case importation risk and reduce the quarantining duration required.

Lives saved with vaccination for 10 pathogens across 112 countries in a pre-COVID-19 world.

Background: Vaccination is one of the most effective public health interventions. We investigate the impact of vaccination activities for Haemophilus influenzae type b, hepatitis B, human papillomavirus, Japanese encephalitis, measles, Neisseria meningitidis serogroup A, rotavirus, rubella, Streptococcus pneumoniae, and yellow fever over the years 2000-2030 across 112 countries. Methods: Twenty-one mathematical models estimated disease burden using standardised demographic and immunisation data. Impact was attributed to the year of vaccination through vaccine-activity-stratified impact ratios. Results: We estimate 97 (95%CrI[80, 120]) million deaths would be averted due to vaccination activities over 2000-2030, with 50 (95%CrI[41, 62]) million deaths averted by activities between 2000 and 2019. For children under-5 born between 2000 and 2030, we estimate 52 (95%CrI[41, 69]) million more deaths would occur over their lifetimes without vaccination against these diseases. Conclusions: This study represents the largest assessment of vaccine impact before COVID-19-related disruptions and provides motivation for sustaining and improving global vaccination coverage in the future. Funding: VIMC is jointly funded by Gavi, the Vaccine Alliance, and the Bill and Melinda Gates Foundation (BMGF) (BMGF grant number: OPP1157270 / INV-009125). Funding from Gavi is channelled via VIMC to the Consortium's modelling groups (VIMC-funded institutions represented in this paper: Imperial College London, London School of Hygiene and Tropical Medicine, Oxford University Clinical Research Unit, Public Health England, Johns Hopkins University, The Pennsylvania State University, Center for Disease Analysis Foundation, Kaiser Permanente Washington, University of Cambridge, University of Notre Dame, Harvard University, Conservatoire National des Arts et Métiers, Emory University, National University of Singapore). Funding from BMGF was used for salaries of the Consortium secretariat (authors represented here: TBH, MJ, XL, SE-L, JT, KW, NMF, KAMG); and channelled via VIMC for travel and subsistence costs of all Consortium members (all authors). We also acknowledge funding from the UK Medical Research Council and Department for International Development, which supported aspects of VIMC's work (MRC grant number: MR/R015600/1).JHH acknowledges funding from National Science Foundation Graduate Research Fellowship; Richard and Peggy Notebaert Premier Fellowship from the University of Notre Dame. BAL acknowledges funding from NIH/NIGMS (grant number R01 GM124280) and NIH/NIAID (grant number R01 AI112970). The Lives Saved Tool (LiST) receives funding support from the Bill and Melinda Gates Foundation.This paper was compiled by all coauthors, including two coauthors from Gavi. Other funders had no role in study design, data collection, data analysis, data interpretation, or writing of the report. All authors had full access to all the data in the study and had final responsibility for the decision to submit for publication.

Highly functional virus-specific cellular immune response in asymptomatic SARS-CoV-2 infection.

The efficacy of virus-specific T cells in clearing pathogens involves a fine balance between antiviral and inflammatory features. SARS-CoV-2-specific T cells in individuals who clear SARS-CoV-2 without symptoms could reveal nonpathological yet protective characteristics. We longitudinally studied SARS-CoV-2-specific T cells in a cohort of asymptomatic (n = 85) and symptomatic (n = 75) COVID-19 patients after seroconversion. We quantified T cells reactive to structural proteins (M, NP, and Spike) using ELISpot and cytokine secretion in whole blood. Frequencies of SARS-CoV-2-specific T cells were similar between asymptomatic and symptomatic individuals, but the former showed an increased IFN-γ and IL-2 production. This was associated with a proportional secretion of IL-10 and proinflammatory cytokines (IL-6, TNF-α, and IL-1ß) only in asymptomatic infection, while a disproportionate secretion of inflammatory cytokines was triggered by SARS-CoV-2-specific T cell activation in symptomatic individuals. Thus, asymptomatic SARS-CoV-2-infected individuals are not characterized by weak antiviral immunity; on the contrary, they mount a highly functional virus-specific cellular immune response.

Strategies at points of entry to reduce importation risk of COVID-19 cases and reopen travel.

BACKGROUND: With more countries exiting lockdown, public health safety requires screening measures at international travel entry points that can prevent the reintroduction or importation of the severe acute respiratory syndrome-related coronavirus-2. Here, we estimate the number of cases captured, quarantining days averted and secondary cases expected to occur with screening interventions. METHODS: To estimate active case exportation risk from 153 countries with recorded coronavirus disease-2019 cases and deaths, we created a simple data-driven framework to calculate the number of infectious and upcoming infectious individuals out of 100 000 000 potential travellers from each country, and assessed six importation risk reduction strategies; Strategy 1 (S1) has no screening on entry, S2 tests all travellers and isolates test-positives where those who test negative at 7 days are permitted entry, S3 the equivalent but for a 14 day period, S4 quarantines all travellers for 7 days where all are subsequently permitted entry, S5 the equivalent for 14 days and S6 the testing of all travellers and prevention of entry for those who test positive. RESULTS: The average reduction in case importation across countries relative to S1 is 90.2% for S2, 91.7% for S3, 55.4% for S4, 91.2% for S5 and 77.2% for S6. An average of 79.6% of infected travellers are infectious upon arrival. For the top 100 exporting countries, an 88.2% average reduction in secondary cases is expected through S2 with the 7-day isolation of test-positives, increasing to 92.1% for S3 for 14-day isolation. A substantially smaller reduction of 30.0% is expected for 7-day all traveller quarantining, increasing to 84.3% for 14-day all traveller quarantining. CONCLUSIONS: The testing and isolation of test-positives should be implemented provided good testing practices are in place. If testing is not feasible, quarantining for a minimum of 14 days is recommended with strict adherence measures in place.

Effectiveness of Containment Measures Against COVID-19 in Singapore: Implications for Other National Containment Efforts.

BACKGROUND: We hypothesize that comprehensive surveillance of COVID-19 in Singapore has facilitated early case detection and prompt contact tracing and, with community-based measures, contained spread. We assessed the effectiveness of containment measures by estimating transmissibility (effective reproduction number, (Equation is included in full-text article.)) over the course of the outbreak. METHODS: We used a Bayesian data augmentation framework to allocate infectors to infectees with no known infectors and determine serial interval distribution parameters via Markov chain Monte Carlo sampling. We fitted a smoothing spline to the number of secondary cases generated by each infector by respective onset dates to estimate (Equation is included in full-text article.)and evaluated increase in mean number of secondary cases per individual for each day's delay in starting isolation or quarantine. RESULTS: As of April 1, 2020, 1000 COVID-19 cases were reported in Singapore. We estimated a mean serial interval of 4.6 days [95% credible interval (CI) = 4.2, 5.1] with a SD of 3.5 days (95% CI = 3.1, 4.0). The posterior mean (Equation is included in full-text article.)was below one for most of the time, peaking at 1.1 (95% CI = 1.0, 1.3) on week 9 of 2020 due to a spreading event in one of the clusters. Eight hundred twenty-seven (82.7%) of cases infected less than one person on average. Over an interval of 7 days, the incremental mean number of cases generated per individual for each day's delay in starting isolation or quarantine was 0.03 cases (95% CI = 0.02, 0.05). CONCLUSIONS: We estimate that robust surveillance, active case detection, prompt contact tracing, and quarantine of close contacts kept (Equation is included in full-text article.)below one.

Importations of COVID-19 into African countries and risk of onward spread.

BACKGROUND: The emergence of a novel coronavirus (SARS-CoV-2) in Wuhan, China, at the end of 2019 has caused widespread transmission around the world. As new epicentres in Europe and America have arisen, of particular concern is the increased number of imported coronavirus disease 2019 (COVID-19) cases in Africa, where the impact of the pandemic could be more severe. We aim to estimate the number of COVID-19 cases imported from 12 major epicentres in Europe and America to each African country, as well as the probability of reaching 10,000 cases in total by the end of March, April, May, and June following viral introduction. METHODS: We used the reported number of cases imported from the 12 major epicentres in Europe and America to Singapore, as well as flight data, to estimate the number of imported cases in each African country. Under the assumption that Singapore has detected all the imported cases, the estimates for Africa were thus conservative. We then propagated the uncertainty in the imported case count estimates to simulate the onward spread of the virus, until 10,000 cases are reached or the end of June, whichever is earlier. Specifically, 1,000 simulations were run separately under four different combinations of parameter values to test the sensitivity of our results. RESULTS: We estimated Morocco, Algeria, South Africa, Egypt, Tunisia, and Nigeria as having the largest number of COVID-19 cases imported from the 12 major epicentres. Based on our 1,000 simulation runs, Morocco and Algeria's estimated probability of reaching 10,000 cases by end of March was close to 100% under all scenarios. In particular, we identified countries with less than 1,000 cases in total reported by end of June whilst the estimated probability of reaching 10,000 cases by then was higher than 50% even under the most optimistic scenario. CONCLUSIONS: Our study highlights particular countries that are likely to reach (or have reached) 10,000 cases far earlier than the reported data suggest, calling for the prioritization of resources to mitigate the further spread of the epidemic.

Estimating the Size of a COVID-19 Epidemic from Surveillance Systems.

Public health policy makers in countries with Coronavirus Disease 2019 (COVID-19) outbreaks face the decision of when to switch from measures that seek to contain and eliminate the outbreak to those designed to mitigate its effects. Estimates of epidemic size are complicated by surveillance systems that cannot capture all cases, and by the need for timely estimates as the epidemic is ongoing. This article provides a Bayesian methodology to estimate outbreak size from one or more surveillance systems such as virologic testing of pneumonia cases or samples from a network of general practitioners.

Investigation of three clusters of COVID-19 in Singapore: implications for surveillance and response measures.

BACKGROUND: Three clusters of coronavirus disease 2019 (COVID-19) linked to a tour group from China, a company conference, and a church were identified in Singapore in February, 2020. METHODS: We gathered epidemiological and clinical data from individuals with confirmed COVID-19, via interviews and inpatient medical records, and we did field investigations to assess interactions and possible modes of transmission of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Open source reports were obtained for overseas cases. We reported the median (IQR) incubation period of SARS-CoV-2. FINDINGS: As of Feb 15, 2020, 36 cases of COVID-19 were linked epidemiologically to the first three clusters of circumscribed local transmission in Singapore. 425 close contacts were quarantined. Direct or prolonged close contact was reported among affected individuals, although indirect transmission (eg, via fomites and shared food) could not be excluded. The median incubation period of SARS-CoV-2 was 4 days (IQR 3-6). The serial interval between transmission pairs ranged between 3 days and 8 days. INTERPRETATION: SARS-CoV-2 is transmissible in community settings, and local clusters of COVID-19 are expected in countries with high travel volume from China before the lockdown of Wuhan and institution of travel restrictions. Enhanced surveillance and contact tracing is essential to minimise the risk of widespread transmission in the community. FUNDING: None.