key: cord-0783809-x27au1vw
authors: Clapham, Hannah E.; Chia, Wan Ni; Tan, Linda Wei Lin; Kumar, Vishakha; Lim, Jane M.; Shankar, Nivedita; Tun, Zaw Myo; Zahari, Marina; Hsu, Li Yang; Sun, Louisa Jin; Wang, Lin Fa; Tam, Clarence C.
title: Contrasting SARS-CoV-2 epidemics in Singapore: Cohort studies in migrant workers and the general population
date: 2021-12-02
journal: Int J Infect Dis
DOI: 10.1016/j.ijid.2021.11.043
sha: d49834944d1ff75bf20473491c5209a7cf214604
doc_id: 783809
cord_uid: x27au1vw

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 We followed up 478 residents of a SARS-CoV-2 affected migrant worker dormitory between May and July 2020, collecting blood samples at recruitment and after two and six weeks. We also recruited 937 community-dwelling adult Singapore residents for whom pre-pandemic sera were available. These individuals also provided a serum sample at 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 incidence of SARS-CoV-2 infection in migrant workers and in the general population, as determined by the detection of neutralising antibodies against SARS-CoV-2 and adjusting for assay sensitivity and specificity using a Bayesian modelling framework. Results We found no evidence of community SARS-CoV-2 exposure in Singapore prior to September 2019. We 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 suggests that around 1 in 4 infections in the general population is associated with symptoms. In contrast, in the migrant worker cohort, nearly 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. Prioritisation of these settings in vaccination strategies should minimise risk of future resurgences and potential spillover of transmission to the wider community.

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.

To estimate SARS-CoV-2 infection incidence among migrant workers and the general population in Singapore.

Prospective serological cohort studies.

Two cohort studies in a migrant worker dormitory and in the general population in Singapore.

We followed up 478 residents of a SARS-CoV-2 affected migrant worker dormitory between May and July 2020, collecting blood samples at recruitment and after two and six weeks. We also recruited 937 community-dwelling adult Singapore residents for whom pre-pandemic sera were available. These individuals also provided a serum sample at recruitment in November/December 2020.

Exposure to SARS-CoV-2 in a densely populated migrant worker dormitory and in the general population.

The main outcome measures were the incidence of SARS-CoV-2 infection in migrant workers and in the general population, as determined by the detection of neutralising antibodies against SARS-CoV-2 and adjusting for assay sensitivity and specificity using a Bayesian modelling framework.

We found no evidence of community SARS-CoV-2 exposure in Singapore prior to September 2019. We 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 suggests that around 1 in 4 infections in the general population is associated with symptoms. In contrast, in the migrant worker cohort, nearly 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.

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 denselypopulated environments requires specific consideration in preparedness planning. Prioritisation of these settings in vaccination strategies should minimise risk of future resurgences and potential spillover of transmission to the wider community.

Singapore reported its first imported case of Coronavirus Disease 2019 (COVID-19) on 23 January 2020. The first cases of local transmission were recorded on 4 February 2020. Subsequently, Singapore experienced three distinct COVID-19 epidemics, involving imported cases, clusters of community transmission linked mainly to workplaces, social gatherings and nursing homes, and outbreaks among migrant workers (Figure 1 ). The public health response has involved a comprehensive set of control measures, including isolation of COVID-19 cases in hospitals or dedicated government facilities, extensive manual and digital contact tracing, and strict quarantining and testing of incoming travellers and exposed individuals. Gradually expanding border restrictions were implemented from the end of January 2020 leading to border closures to all but essential services at the end of March 2020. Extensive restrictions on social gatherings and universal mask wearing have been in place since April 2020, when an eight-week national lockdown was initiated.

These measures have largely been effective at curtailing community transmission of SARS-CoV-2. However, from March 2020, Singapore experienced a series of large epidemics in densely populated migrant worker dormitories. (Tan et al., 2021) There are over 320,000 migrant workers residing in around 50 dormitories nationwide. In response to the epidemic, workers were confined to dormitories during the lockdown period and movement within dormitories was restricted. Medical teams were deployed in all dormitories to provide testing and refer suspected COVID-19 cases to healthcare facilities, leading to the eventual interruption of transmission in September 2020. As of 31 August 2021, 67,459 confirmed COVID-19 cases have been reported nationally. Of these, >80% have been among male foreign migrant workers living in dormitories. Here, we report on the contrasting SARS-CoV-2 epidemics among migrant workers and the community in Singapore, based on two longitudinal serological studies.

Between May and July 2020, we conducted a longitudinal serology study among 541 male residents of a migrant worker dormitory in Singapore. At the start of the epidemic, the dormitory housed over 4000 residents of primarily Indian, Bangladeshi and Chinese origin working mainly in the construction, shipping, manufacturing and processing sectors. The dormitory consisted of 10 multi-storey residential blocks, with rooms typically housing 10-14 residents. At the time of the study, clinical management and testing of suspected COVID-19 cases within the dormitory was provided by a mobile medical team. PCR-confirmed COVID-19 cases were referred to acute care hospitals or community isolation facilities, depending on medical need.

We recruited participants from randomly selected rooms within each residential block (~5 rooms per block, see Supplementary Information for sampling methodology). Consenting participants provided a 5ml venous blood sample at enrollment and after two and six weeks. We collected information on participants' demographics, country of origin, work sector, pre-existing health conditions and smoking history at enrollment. Additionally, we asked participants whether they had experienced any symptoms compatible with COVID-19 in the month prior to enrollment and in the intervening periods between follow-up visits. COVID-19 compatible symptoms included fever, cough, shortness of breath, sore throat, runny nose, anosmia, muscle ache, fatigue and diarrhoea.

Participants were recruited from among individuals taking part in the Singapore Population Health Studies (SPHS), which comprises 50,000 adult Singaporeans and longterm residents followed up over multiple waves to monitor risk factors for common health conditions. Individuals in SPHS were eligible to take part in this study if they were Singapore Citizens or Permanent Residents aged >=21 years and had a stored serum sample collected prior to September 2019 available for serological testing. Participants were recruited between November and December 2020. Trained interviewers conducted an interview by telephone to collect demographic details and information on potential risk factors for SARS-CoV-2 infection, including occupation, travel history, contact with suspected or confirmed COVID-19 cases, and co-morbidities. An in-person visit was subsequently arranged, at which participants provided a 5ml venous blood sample for serological testing.

We tested for the presence of SARS-CoV-2 neutralising antibodies in pre-pandemic sera and sera collected in November/December 2020 from all community cohort participants, and in sera collected at baseline, two and six weeks from the migrant worker cohort. Sera were extracted from fresh blood samples within 24 hours of collection. We tested for SARS-CoV-2 neutralising antibodies (NAb) using the cPass SARS-CoV-2 Neutralization Antibody Detection Kit (GenScript). An inhibition threshold of 30% was used to define a positive result, as per the manufacturer's instructions.

We estimated cumulative seroprevalence in November/December 2020 in the community cohort using a Bayesian approach accounting for test sensitivity and specificity, as described by Larremore et al. (Larremore et al., 2021) We obtained 5000 samples from the posterior parameter distributions Markov Chain Monte Carlo (MCMC) methods, after a burn-in of 1000 iterations.

For the migrant worker cohort, we estimated cumulative seroprevalence at baseline, two and six weeks of follow-up using a Bayesian random effects logistic model as described by Stringhini et al.(Stringhini et al., 2020) (Supplementary Information), which additionally accounts for the clustering of observations from residents sampled from the same room. In addition, we estimated the risk of seroconversion during the follow-up period among individuals who were seronegative at baseline. We obtained 6000 samples from the posterior parameter distributions using four MCMC chains, each with a burn-in of 750 iterations. We checked for model convergence using the R-hat statistic and through visual inspection of trace plots to ensure good mixing of MCMC chains.

Information on false positivity and false negativity for the cPass assay were obtained from a validation study by Meyer et al., (Meyer et al., 2020) which estimated a sensitivity 80.3% and specificity of 99.3% respectively.

Analyses were conducted in R software version 4.1.(R Core Team (2020), n.d.) Bayesian random effects models were fitted in Stan using the rstan package.(Stan Development Team (2020), n.d.) We summarised the posterior parameter distributions using the median and central 95% of the posterior distribution.

Of 551 individuals approached, we recruited 541 (98.2%) participants in the male migrant worker cohort. Of these, 478 (88.4%) provided 3 blood samples at recruitment, two and six weeks, and were included in this analysis. The mean age was 35 years (range: 19-59 years). Among the participants, 51.4% originated from India, 34.9% from Bangladesh and 9.4% from China. Nearly a third of participants were current smokers, but underlying medical conditions were uncommon (Table 1 ).

In the community cohort, we approached 2608 individuals of whom 701 (26.9%) were not contactable after three attempts and three (0.1%) were no longer in Singapore or had passed away. Of the remaining 1904 individuals, 937 (49.2%) agreed to participate and completed the baseline assessment. Participants had a mean age of 52 years (range: 23-83 years) and 480 (51.2%) were female. The most common underlying conditions were high blood pressure (23.2%), diabetes (15.0%) and chronic respiratory conditions (6.5%); 9.7% were current smokers (Table 1 ). In comparison with the census population, cohort participants were generally younger, with an over-representation of those of Indian ethnicity, married individuals and those living in larger public housing apartments, and an under-representation of individuals of Malay ethnicity, unmarried individuals and those living in private condominiums or landed property (Supplementary Information Table S1 ).

Recruitment summaries for the two cohorts are shown in Supplementary Information Figures S1 and S2 .

In the migrant worker cohort, 117 (24.5%) were positive for SARS-CoV-2 neutralising antibodies at baseline. This rose to 178 (37.2%) after two weeks and 245 (51.3%) after six weeks. After accounting for test characteristics, the cumulative seroprevalence was estimated to be 30.4% (95% credible interval, CrI: 26.1% -35.9%) at baseline, 46.5% (95% CrI: 41.4% -51.9%) after two weeks and 63.8% (95% CrI: 57.9% -70.3%) after six weeks. Among initially seronegative migrant workers, the risk of seroconversion was 22.9% (95% CrI: 18.5% -27.8%) by two weeks and 54.3% (95% CrI: 48.3% -60.7%) by week six of follow-up (Figure 2 ).

There was statistical and epidemiological evidence that infections clustered strongly by room (household random effect at baseline, σh = 3.0, 95% CrI: 1. 93 -5.27 ). This clustering effect decreased over time as seroprevalence increased over the six-week follow-up period (σh = 1.74, 95% CrI: 1.11 -2.86 at six weeks). Additionally, among 16 initially seronegative rooms widely heterogeneous trajectories were observed (Multimedia File), with attack rates over the six-week follow-up ranging from 0% to 85% (Supplementary Information Figure S3 ).

The vast majority of migrant worker infections were asymptomatic. Among those seropositive at baseline, five (4.3%) reported experiencing any symptom compatible with COVID-19 in the previous four weeks, and 3.8% (6/160) of seroconverters reported symptoms during the six week follow-up period. We found no association between seropositivity at baseline or seroconversion and age, country of origin, work sector, occurrence of symptoms or smoking status.

In the community cohort, no pre-pandemic serum samples were positive for SARS-CoV-2 neutralising antibodies. Among samples collected in November/December 2020, 0.21% (2/937) tested positive. Both positive samples were non-reactive against SARS virus spike protein. After accounting for test characteristics, we estimated the cumulative seroprevalence in 2020 to be 0.16% (95% CrI: 0.008% -0.72%).

A total of 2272 community cases of COVID-19 were reported in Singapore up to the end of December 2020, corresponding to a cumulative incidence of 0.042%.(COVID-19 Situation Report, n.d.) This indicates a most likely value for the infection:case ratio of 3.8:1.

Our findings highlight the contrasting epidemics in the community and in migrant worker populations in Singapore, based on serological evidence from two longitudinal studies. These studies demonstrate the continuing effectiveness of nationally-implemented, wideranging control measures for minimising community transmission of SARS-CoV-2, while emphasising the challenges to mitigating risk in densely populated settings. We also documented evidence of high rates of asymptomatic infection in migrant workers.

To our knowledge, this is the first study to report on SARS-CoV-2 cross-reactivity in prepandemic sera from a large, systematic, general population cohort. We found no evidence of population exposure to SARS-CoV-2 prior to September 2019. Since January 2020, Singapore has implemented a multi-pronged strategy for SARS-CoV-2 containment and suppression, including extensive testing and contact tracing, strictly enforced case isolation and quarantining, and risk-based border restrictions, social distancing measures and maskwearing policies. Early modelling work in Singapore emphasised the important role of case isolation, contact tracing, quarantining and workplace distancing measures in controlling SARS-CoV-2 transmission, (Koo et al., 2020) which is evidenced by the comparatively small number of community COVID-19 cases notified to date and the extremely low seroprevalence observed in this study. In comparison, early seroprevalence studies in European settings indicated that between 5%-10% of the population had evidence of SARS-CoV-2 exposure after the first epidemic wave. (Pollán et al., 2020; Stringhini et al., 2020) Initial measures in Singapore, however, were unable to prevent large epidemics in densely populated migrant worker dormitories. More than 49,000 COVID-19 cases were reported among dormitory residents between April and July 2020, corresponding to an incidence of 1526 cases per 10,000 residents. This compares with 1760 cases, or 3 per 10,000 population, in the community. Data from our study indicated that around two-thirds of dormitory residents had been infected between April and early July, in line with seroprevalence estimates reported from other migrant worker populations. (Tan et al., 2021) Moreover, our data suggest extremely high infection risks in these settings, with more than half of initially immunologically naive individuals becoming infected over the six-week follow-up period. Crowded, poorly ventilated indoor spaces are known to be highrisk environments for SARS-CoV-2 transmission, and have been associated with large outbreaks among processing plant workers. (Günther et al., 2020; Middleton et al., 2020; Steinberg et al., 2020) Despite this, the vast majority of infections were asymptomatic. This finding should be interpreted in the context of prevailing control measures in migrant worker dormitories. Individuals at higher risk of severe COVID-19, including older individuals and those with underlying medical conditions, were moved to alternative housing early on in the epidemic. Additionally, universal mask-wearing was mandatory during the study period, which is likely to have contributed to reducing droplet exposure from infectious individuals and, hence, viral inoculum. (Spinelli et al., 2021) Although it is possible that participants may have under-reported symptoms, we believe this is an unlikely explanation for the high fraction of asymptomatic infections. At the time of the study, dormitory residents were required to report their temperature every day and were asked to report to a medical post within the dormitory in the event of symptoms for testing and referral to medical services where necessary. All but essential work had been suspended and residents were confined to the dormitory. The Singapore government set up a compensation scheme so that workers continued to be paid during this period. It is thus unlikely that there were strong disincentives to report symptoms.

Based on a comparison of cumulative seroprevalence in our community cohort to officially reported COVID-19 cases in the community up to the end of 2020, we estimate a likely value for the infection:case ratio of around 4:1, although uncertainty is high because of the very small number of seroconversions. Importantly, Singapore has employed extensive testing, case identification and contact tracing since the start of the pandemic, and ascertainment of community COVID-19 cases during the study period is likely to be near complete. Our estimate for the infection:case ratio is in agreement with analyses of the Diamond Princess cruise ship outbreak, in which an estimated three-quarters of infections were asymptomatic. (Emery et al., 2020) Data from extensive investigations of the wider outbreak in migrant workers also identified 5 times as many infections as symptomatic cases, (Tan et al., 2021) although there may have been some under-ascertainment of symptomatic cases among migrant workers early in the epidemic.

A number of limitations should be borne in mind when interpreting our findings. First, because of the extensive control measures and movement restrictions implemented within migrant worker dormitories, our study was limited to residents of a single dormitory. Within the dormitory, the sampling protocol had to be designed so as to minimise contact between residents in different floors and residential blocks; it was not possible to implement a sampling scheme that provided a truly representative sample. We accounted for this by using a model that incorporated the dependence of samples, and our infection rates are in line with other estimates from the broader migrant worker population in Singapore. (Tan et al., 2021) Additionally, we did not perform virological detection of SARS-CoV-2 from respiratory samples. Combined use of polymerase chain reaction (PCR) tests and serological assays would have allowed for more precise determination of the timing of infection and more detailed investigation of transmission within the migrant worker dormitory. However, because of limitations on the availability of PCR test kits nationally early on in the pandemic, this was beyond the scope of this study. Due to the lag in the appearance of detectable neutralising antibodies, our infection rate estimates therefore reflect levels of transmission two to three weeks earlier.

Within the broader context of the COVID-19 epidemic in Singapore, our findings demonstrate that suppression of SARS-CoV-2 transmission is possible with strict and rapid implementation of border restrictions, case isolation, contact tracing, quarantining and social distancing measures. However, the potential for large-scale epidemics in denselypopulated environments has proven to be a point of vulnerability in virological containment, requiring special consideration in preparedness, mitigation and control planning. Although we did not specifically investigate routes of transmission within the migrant worker dormitory, strong clustering of infection within rooms highlights the role of crowding in transmission and emphasises the need to reduce density in dormitory settings in order to reduce vulnerability to outbreaks. Consideration and prioritisation of these settings in vaccination strategies should help minimise risk of future resurgences and potential spillover of transmission to the wider community.

Author contributions Drs Tam and Clapham had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Tam, Clapham. Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Tam, Clapham.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Tam, Clapham.

Administrative, technical, or material support: Tan, Lim, Shankar, Zahari, Kumar, Tun.

The community cohort study was approved by the National University of Singapore Institutional Review Board (reference H-20-032). Participants in this study provided signed, informed consent. The migrant worker cohort study was approved by the Singapore Ministry of Health under the Infectious Diseases Act and was exempt from institutional review board approval as it was conducted as part of the national public health response to the COVID-19 pandemic. Under the 2015 Singapore Infectious Diseases Act (Schedule 59A), the Ministry of Health can approve and require research to support the national public health response to an epidemic, as per schedule 59A Participants provided verbal consent to take part. Prior to taking consent, the study team explained the purpose of the study to potential participants and answered any questions about the study. Potential participants were also provided with written study information sheets that were available in English, Chinese, Bengali, Tamil and Burmese. It was made clear to individuals that participation was entirely voluntary and that they could withdraw from the study at any time without providing a reason, and with no penalty or consequences for their access to health care, employment or immigration status. Printed versions of the study questionnaire were also available in the five languages to make sure that participants understood the questions, and the study team included data collectors fluent in English, Chinese, Tamil and Burmese. The study team also had access to a roster of interpreters, who could be contacted by telephone to aid communication with participants where necessary. Participants were informed of their serology results and were provided with information sheets in their language of choice explaining the interpretation of the test results. week period among migrant workers residing in a dormitory, Singapore 2020. Two-week and sixweek seroconversion estimates are based on antibody test results at two and six weeks among individuals initially seronegative at baseline. Four-week seroconversion estimates are based on antibody test results at the six-week follow-up among individuals who were seronegative at the two-week follow-up. 

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Recruitment and data collection for the two cohort studies was made possible by the Singapore Population Health Studies operations team.

The community cohort study is supported by a Wellcome Trust grant (grant number: 221013/Z/20/Z). The migrant worker cohort study is supported by the NUS Efforts Against COVID-19 fund. The serological test development at Duke-NUS was supported by grants from the Singapore National Medical Research Council (STPRG-FY19-001 and COVID19RF-003) .

L-FW and WNC are co-inventors of a patent application for the cPass test kit. The remaining authors declare no competing interests in relation to this work.The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.