publications | Tim K Tsang

2026

Nat Health

Frequent presymptomatic household transmission of influenza A but not influenza B virus

Chengyao Zhang, Xiaotong Huang, Vicky J Fang, Kwok-Hung Chan, Gabriel M Leung, Dennis K M Ip, J S Malik Peiris, Benjamin J Cowling, Simon Cauchemez, and Tim K Tsang

Nature Health, 2026

DOI Bib

@article{zhang2026natHealth,
  title = {Frequent presymptomatic household transmission of influenza A but not influenza B virus},
  author = {Zhang, Chengyao and Huang, Xiaotong and Fang, Vicky J and Chan, Kwok-Hung and Leung, Gabriel M and Ip, Dennis K M and Peiris, J S Malik and Cowling, Benjamin J and Cauchemez, Simon and Tsang, Tim K},
  journal = {Nature Health},
  year = {2026},
  doi = {10.1038/s44360-025-00049-y}
}

Euro Surveill
Population immunity, post-vaccine and post-infection antibody responses to influenza A (H3N2) subclade J.2 and K (J.2.4.1) viruses, Hong Kong, 2025.

Samuel Ms Cheng, Nancy Hl Leung, Eunice Y Shiu, Ricky Wk Wong, Niki Ym Au, Xiaotong Huang, Natalie Km Kwok, Coco Hc Chan, John Kc Li, Leo Ch Tsang, Tsz Chun Kwan, Tim K Tsang, Leo Lm Poon, Benjamin J Cowling, and Malik Peiris

Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin, 2026

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We assessed haemagglutination inhibition (HAI) antibody titres against 2025 influenza A(H3N2) J.2 vaccine reference viruses and the novel subclade K (J.2.4.1) in age-stratified Hong Kong sera (collected May-July 2025), vaccine recipients and sera from virologically confirmed subclade J.2.2 or K infections. In contrast to mono-specific ferret sera, human sera with high J.2 HAI titres cross-reacted strongly with subclade K. Recombinant haemagglutinin- or egg-based standard dose J.2 A(H3N2) vaccines boosted geometric mean titres to K virus 5.6-fold and 2.6-fold, respectively.
@article{cheng2026p41822984, title = {Population immunity, post-vaccine and post-infection antibody responses to influenza A (H3N2) subclade J.2 and K (J.2.4.1) viruses, Hong Kong, 2025.}, author = {Cheng, Samuel Ms and Leung, Nancy Hl and Shiu, Eunice Y and Wong, Ricky Wk and Au, Niki Ym and Huang, Xiaotong and Kwok, Natalie Km and Chan, Coco Hc and Li, John Kc and Tsang, Leo Ch and Kwan, Tsz Chun and Tsang, Tim K and Poon, Leo Lm and Cowling, Benjamin J and Peiris, Malik}, journal = {Euro surveillance : bulletin Europeen sur les maladies transmissibles = European communicable disease bulletin}, year = {2026}, volume = {31}, number = {10}, doi = {10.2807/1560-7917.ES.2026.31.10.2600185}, }
J Infect Dis
Comparative Analysis of Flight Volume Effects on COVID-19 and Influenza Transmission Across Variable Control Intensities, 2019-2024.

Yanfang Xu, Mingwei Li, Liping Peng, Can Wang, Qichang Wan, Chengyao Zhang, Weijia Xiong, Bingyi Yang, and Tim K Tsang

The Journal of infectious diseases, 2026

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BACKGROUND: Air travel has played a critical role in the global spread of infectious diseases, facilitating rapid movement of pathogens across continents. This study quantifies the effects of intercontinental flight volumes on both influenza and COVID-19 transmission patterns across countries with varying intensities of public health interventions. METHODS: We analyzed monthly global passenger numbers from January 2019 to July 2024, coupled with comprehensive surveillance data on both pathogens. Using a hierarchical Bayesian linear mixture modeling framework, we examined the relationship between flight volumes and disease activity while accounting for heterogeneity in public health and social measures. RESULTS: Our analysis reveals that increased flight volumes were significantly associated with both influenza activity and COVID-19 case and mortality rates, with Asian flight spreading rate demonstrating the strongest association with influenza transmission and COVID-19 case rates. These effects were consistently stronger for COVID-19 than influenza and more pronounced in countries with less stringent control measures. CONCLUSIONS: The comparative approach provides unique insights into how different respiratory pathogens respond to aviation-mediated exposures, demonstrating that targeted travel restrictions can effectively impede disease transmission when implemented alongside appropriate public health interventions. These findings have important implications for the development of pathogen-specific strategies for mitigating the international spread of emerging respiratory threats.
@article{xu2026p41144637, title = {Comparative Analysis of Flight Volume Effects on COVID-19 and Influenza Transmission Across Variable Control Intensities, 2019-2024.}, author = {Xu, Yanfang and Li, Mingwei and Peng, Liping and Wang, Can and Wan, Qichang and Zhang, Chengyao and Xiong, Weijia and Yang, Bingyi and Tsang, Tim K}, journal = {The Journal of infectious diseases}, year = {2026}, volume = {233}, number = {3}, pages = {e791-e801}, doi = {10.1093/infdis/jiaf545}, }

2025

Epidemiol Infect
Waning in influenza vaccine effectiveness against influenza A(H1N1)pdm09-associated hospitalization in children in 2012/2013.

Hui Ying Chua, Tim K Tsang, So-Lun Lee, and 6 more authors

Epidemiology and infection, 2025

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Measuring waning in vaccine effectiveness (VE) is challenging due to potential depletion-of-susceptibles bias. Some SARS-CoV-2 studies excluded individuals with prior infection and adjusted for the probability of remaining uninfected. We applied this approach to assess waning influenza VE in Hong Kong during the 2012/2013 season. First, we estimated the infection risk for unvaccinated children using published serological and surveillance data. Next, we derived infection risk for vaccinated children, assuming VE against infection of 57%. Uncorrected VE from 14 to 270 days post-vaccination was estimated from hospitalized children. We calculated the rate of depletion of susceptibles given infection risk and VE corrected for depletion-of-susceptibles bias. Waning rates for uncorrected and bias-corrected VE were measured by comparing VE at day 270 versus day 14. Bias was assessed as the absolute difference between two waning rates in percentage points. Waning rate of uncorrected VE was overestimated by 5.9 percentage points or 1.3 percentage points when assessed up to day 120. Bias was substantial when assuming 80% unvaccinated, and all vaccinated children were initially uninfected, but minimal when these proportions were similar. The observed waning in 2012/2013 was unlikely due to depletion-of-susceptibles bias. Further studies across various conditions are needed to confirm our findings.
@article{chua2025p41277042, title = {Waning in influenza vaccine effectiveness against influenza A(H1N1)pdm09-associated hospitalization in children in 2012/2013.}, author = {Chua, Hui Ying and Tsang, Tim K and Lee, So-Lun and Chan, Eunice L Y and Kwan, Mike Y W and Wong, Joshua S C and Peiris, Malik and Sullivan, Sheena G and Cowling, Benjamin J}, journal = {Epidemiology and infection}, year = {2025}, volume = {153}, pages = {e137}, doi = {10.1017/S0950268825100770}, }
Interface Focus
Optimization of school closures during an Omicron epidemic in Hong Kong: a modelling study.

Benjamin R Young, Faith Ho, Yun Lin, Eric H Y Lau, Peng Wu, Benjamin J Cowling, and Tim K Tsang

Interface focus, 2025

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Closing schools has been a prominent public health control measure for respiratory virus pandemics. However, during the COVID-19 pandemic, they were more contentious, as children were at a lower risk of severe disease while prolonged closures could have affected children’s development. Hong Kong experienced a large Omicron epidemic in the spring of 2022, and face-to-face classes were halted and reopened after the peak with daily rapid-antigen test screening. Using counterfactual simulations, we developed a susceptible-exposed-infectious-recovered model calibrated to severe disease data to estimate the impact of the school closures and screening measures. We estimated that the school closures and screening measures prevented an excess of 35.0% (33.2%, 38.8%) more deaths and 17.4% (15.0%, 19.9%) more hospitalizations in a counterfactual scenario without those interventions. In terms of the impact on disease burden, the closure of primary schools outperformed both the closure of secondary schools and rapid antigen testing. Rapid-antigen screening alone was also an effective measure while minimizing the disruption associated with school closures. This demonstrates that implementing school-non-pharmaceutical intervention requires input from community priorities, balancing the population-wide burden of disease (infections, hospitalizations or mortalities) or educational disruptions (missed school days) and economic repercussions (e.g. the cost of daily rapid-antigen screening).
@article{young2025p41017902, title = {Optimization of school closures during an Omicron epidemic in Hong Kong: a modelling study.}, author = {Young, Benjamin R and Ho, Faith and Lin, Yun and Lau, Eric H Y and Wu, Peng and Cowling, Benjamin J and Tsang, Tim K}, journal = {Interface focus}, year = {2025}, volume = {15}, number = {4}, pages = {20250016}, doi = {10.1098/rsfs.2025.0016}, }
J Infect PH
Retrospective assessment of vaccination policy optimizations during an Omicron BA.2 epidemic in Hong Kong: A modelling study.

Benjamin R Young, Faith Ho, Yun Lin, Eric H Y Lau, Peng Wu, Benjamin J Cowling, and Tim K Tsang

Journal of infection and public health, 2025

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BACKGROUND: Suboptimal COVID-19 vaccine distribution hampers their potential disease protection impact. The 2022 BA.2 epidemic in Hong Kong, occurring over a year into vaccination efforts, resulted in one of the highest daily mortality rates of the pandemic. METHODS: We developed an age- and dose-structured SEIR model to describe the transmission dynamics in this epidemic. Then we fitted the model to severe disease data to estimate the transmission dynamics of the epidemics by Bayesian inference. After that, we conducted extensive counterfactual simulations based on the fitted transmission dynamics and considered varying age-specific vaccination coverages and timing to estimate the impact on severe disease across scenarios. RESULTS: If individuals over 80 had primary series coverage similar to the adult population, 27.6 % (95 % posterior predictive interval [PPI]: 24.7 %, 31.1 %) of deaths could have been averted. High primary series coverage in 40-49-year-olds averted 32.6 % (95 % PPI: 30.0 %, 35.5 %) more hospitalisations. Advancing the adult or senior vaccination campaign by two weeks significantly reduced deaths by 498 (95 % PPI: 309, 688) and 601 (95 % PPI: 412, 792), respectively. Earlier vaccination of children had no significant impact on population-wide deaths. CONCLUSIONS: Low elderly primary series coverage led to the most preventable deaths, while high coverage in middle-aged groups significantly averted excess hospitalisations. Our study underscores the importance of targeting COVID-19 vaccinations in high-risk and transmission-driving groups, as well as vaccination time-sensitivity, where each week difference, averts or abets morbidity and mortality.
@article{young2025p40966820, title = {Retrospective assessment of vaccination policy optimizations during an Omicron BA.2 epidemic in Hong Kong: A modelling study.}, author = {Young, Benjamin R and Ho, Faith and Lin, Yun and Lau, Eric H Y and Wu, Peng and Cowling, Benjamin J and Tsang, Tim K}, journal = {Journal of infection and public health}, year = {2025}, volume = {18}, number = {12}, pages = {102972}, doi = {10.1016/j.jiph.2025.102972}, }
Nat Commun
Investigating setting-specific superspreading potential and generation intervals of COVID-19 in Hong Kong.

Dongxuan Chen, Dillon C Adam, Yiu-Chung Lau, Dong Wang, Wey Wen Lim, Faith Ho, Tim K Tsang, Eric H Y Lau, Peng Wu, Jacco Wallinga, Benjamin J Cowling, and Sheikh Taslim Ali

Nature communications, 2025

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Superspreading is an important feature of COVID-19 transmission dynamics, but few studies have investigated this feature stratified by transmission setting. Using detailed clustering data comprising 8647 COVID-19 cases confirmed in Hong Kong between 2020 and 2021, we estimated the mean number of new infections expected in a transmission cluster ( CZ ) and the degree of overdispersion (k) by setting. Estimates of CZ ranged within 0.4-7.1 across eight settings, with highest CZ in the close-social indoor setting that an average of seven new infections per cluster was expected. Transmission was most heterogeneous (k = 0.05) in retail setting and least heterogeneous (k = 1.1) in households, where smaller k indicates greater overdispersion and superspreading potential. Point-estimates of the mean generation interval (GI) ranged within 4.4-7.0, and settings with shorter mean realized GIs were associated with smaller cluster sizes. Here, we show that superspreading potential and generation intervals can vary across settings, strengthening the need for setting-specific interventions.
@article{chen2025p40593551, title = {Investigating setting-specific superspreading potential and generation intervals of COVID-19 in Hong Kong.}, author = {Chen, Dongxuan and Adam, Dillon C and Lau, Yiu-Chung and Wang, Dong and Lim, Wey Wen and Ho, Faith and Tsang, Tim K and Lau, Eric H Y and Wu, Peng and Wallinga, Jacco and Cowling, Benjamin J and Ali, Sheikh Taslim}, journal = {Nature communications}, year = {2025}, volume = {16}, number = {1}, pages = {5816}, doi = {10.1038/s41467-025-60591-x}, }
Int J Epidemiol
Bias in control selection associated with the use of rapid tests in influenza vaccine effectiveness studies.

Eero Poukka, Caitriona Murphy, Loretta Mak, Samuel M S Cheng, Malik Peiris, Tim K Tsang, Sheena G Sullivan, and Benjamin J Cowling

International journal of epidemiology, 2025

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BACKGROUND: In test-negative design (TND) studies that use rapid tests to estimate influenza vaccine effectiveness (VE), a common concern is case-control misclassification due to imperfect diagnostic accuracy. An imperfect test can also fail to exclude from the control group people infected with other influenza types or other vaccine-preventable respiratory viruses. We investigated these biases while evaluating VE for the 2023/24 seasonal influenza vaccination. METHODS: A TND study was conducted among outpatients aged >/=6 months of age who visited an outpatient clinic in Hong Kong between 15 December 2023 and 13 August 2024. VE was estimated for polymerase chain reaction (PCR)- and rapid-test-confirmed influenza A and B with exclusions of other types of influenza and SARS-CoV-2 based on either PCR or rapid test. Alternatively, for the exclusion of SARS-CoV-2, we adjusted the analysis with COVID-19 vaccination. VE was estimated by using logistic regression adjusted for confounders. RESULTS: In a study population of 1691 participants, VE against influenza A by PCR was 49% [95% confidence interval (CI) 26%-65%] after the exclusion of PCR-confirmed influenza B and SARS-CoV-2 controls. The corresponding VE against influenza B was 65% (95% CI 35%-81%). VE estimated by adjusting for COVID-19 vaccination status yielded similar estimates to these. When case-control status and exclusions from test-negative controls were determined by using the rapid test, VE was reduced by 5%age-15%age points. CONCLUSION: In TND studies using rapid tests, reduced sensitivity affects both case-control classification and control group exclusions, potentially causing bias. New methods for these biases could help to adapt participatory cohorts for the monitoring of VE for influenza, COVID-19, and respiratory syncytial virus.
@article{poukka2025p40574484, title = {Bias in control selection associated with the use of rapid tests in influenza vaccine effectiveness studies.}, author = {Poukka, Eero and Murphy, Caitriona and Mak, Loretta and Cheng, Samuel M S and Peiris, Malik and Tsang, Tim K and Sullivan, Sheena G and Cowling, Benjamin J}, journal = {International journal of epidemiology}, year = {2025}, volume = {54}, number = {4}, doi = {10.1093/ije/dyaf089}, }
Nat Microbiol
Breadth of influenza A antibody cross-reactivity varies by virus isolation interval and subtype.

Bingyi Yang, Katelyn M Gostic, Dillon C Adam, Ru Zhang, Tal Einav, Liping Peng, Sook San Wong, Tim K Tsang, Derek A T Cummings, Sheena G Sullivan, Sarah Cobey, and Benjamin J Cowling

Nature microbiology, 2025

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Influenza virus infections generate antibodies that cross-react with antigenically similar viruses. However, the breadth of cross-reactivity is unclear. Here we analysed 200,000 haemagglutination inhibition (HAI) titrations from ferrets singly infected with A(H3N2) or A(H1N1)pdm09. We identified consistent influenza A virus subtype-specific patterns where breadth of HAI antibody cross-reactivity was associated with isolation time between tested and immunizing viruses. This was independent of virus strains, passage history and genetic mutations. A 6-year interval between virus isolation resulted in minimal HAI titres for A(H3N2), while A(H1N1)pdm09 demonstrated broader cross-reactivity with moderate titre reductions over the same interval. Analysis of HA substitutions revealed more amino acid substitutions between viruses for A(H3N2) and a greater reduction in HAI titres per substitution compared with A(H1N1). Longitudinal analysis of human antisera across age groups suggests that repeat A(H3N2) exposure increased HAI responses within the cross-reactivity range, with greater increases for more recent viruses. These results provide a framework for antigenically evolving pathogens such as influenza viruses.
@article{yang2025p40494885, title = {Breadth of influenza A antibody cross-reactivity varies by virus isolation interval and subtype.}, author = {Yang, Bingyi and Gostic, Katelyn M and Adam, Dillon C and Zhang, Ru and Einav, Tal and Peng, Liping and Wong, Sook San and Tsang, Tim K and Cummings, Derek A T and Sullivan, Sheena G and Cobey, Sarah and Cowling, Benjamin J}, journal = {Nature microbiology}, year = {2025}, volume = {10}, number = {7}, pages = {1711-1722}, doi = {10.1038/s41564-025-02033-4}, }
J Infect Dis
Impact of Population Immunity and Public Health Measures on the Transmission of Omicron Subvariants BA.2 and BA.5 in Hong Kong.

Can Wang, Hsiang-Yu Yuan, Eric H Y Lau, Benjamin J Cowling, Dennis K M Ip, and Tim K Tsang

The Journal of infectious diseases, 2025

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BACKGROUND: The rapid evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and population-level vaccine administration have significantly shifted the population immunity. In Hong Kong, these shifts, coupled with the emergence of Omicron BA.5 with a strong ability of immune evasion, necessitate a deeper understanding of how population immunity and public health and social measures (PHSMs) have shaped the epidemic dynamics across age groups within the population. METHODS: We developed an age-structured, multistrain model and estimated key parameters including transmissibility for the emerging BA.5, the effects of PHSMs on transmission, and contributions of natural infection and vaccination to age-specific immunity against infection of each subvariant over time. RESULTS: We found that reactive PHSMs implemented in February 2022 decreased the time-varying effective reproductive number without the effect of immunity (RtWI) by 67% (95% credible interval [CrI], 52%-78%). However, subsequent relaxation of control measures since April 2022, alongside the enhanced transmissibility of BA.5, drove RtWI back to 3.4 (95% CrI, 2.8-4.1) by late May. Prior to the fifth wave, only 15% of the Hong Kong population had immunity and protection against BA.2 infection. Population immunity against BA.2 infection then increased significantly to 55% within 2 months given 47% cumulative infections and >30% vaccination uptake. Subsequently, with the emergence of BA.5, population immunity against BA.5 infection was 15% lower than that against BA.2 during the end of May. CONCLUSIONS: Our findings underscore the dynamic interplay between population immunity, PHSMs, and variant transmissibility and highlight the potential risks posed by immune-evasive variants in the context of waning immunity and control relaxation.
@article{wang2025p40439352, title = {Impact of Population Immunity and Public Health Measures on the Transmission of Omicron Subvariants BA.2 and BA.5 in Hong Kong.}, author = {Wang, Can and Yuan, Hsiang-Yu and Lau, Eric H Y and Cowling, Benjamin J and Ip, Dennis K M and Tsang, Tim K}, journal = {The Journal of infectious diseases}, year = {2025}, volume = {232}, number = {3}, pages = {e476-e485}, doi = {10.1093/infdis/jiaf287}, }
Nat Commun
Comparative duration of neutralizing responses and protections of COVID-19 vaccination and correlates of protection.

Chang Liu, Tim K Tsang, Sheena G Sullivan, and 2 more authors

Nature communications, 2025

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The decline in neutralizing antibody (nAb) titers and vaccine efficacy /effectiveness (VE) for SARS-CoV-2 vaccines has been observed over time and when confronted with emerging variants, two factors that are hard to distinguish. Despite substantial drop in nAb titers against Omicron, VE remains high for severe cases and fatalities, raising questions about the utility of detected nAbs as a correlate of protection for COVID-19 vaccines for varying disease severity. Here, we conducted a systematic comparison of waning dynamics of nAb and VE over time and against variants with varying levels of disease severity. Using Bayesian linear regression models, we found that antigenically-shifted variants, like Omicron, could potentially lead to greater reductions in nAb titers and primary VE against mild infections than associated immunity waning observed over a 180-day period. By comparing model predicted nAb titers and VE on the same time scales, we found that VE against severe and fatal outcomes remained above 75% even when nAb titers reached the detectable limit of assays, despite strong correlations with nAb titers (spearman correlations >/=0.7) across variants over time. This finding suggested detectable nAb titers are not always sensitive enough to fully predict protection against severe disease and death from SARS-CoV-2.
@article{liu2025p40404724, title = {Comparative duration of neutralizing responses and protections of COVID-19 vaccination and correlates of protection.}, author = {Liu, Chang and Tsang, Tim K and Sullivan, Sheena G and Cowling, Benjamin J and Yang, Bingyi}, journal = {Nature communications}, year = {2025}, volume = {16}, number = {1}, pages = {4748}, doi = {10.1038/s41467-025-60024-9}, }
Commun Med
Evaluating the association between COVID-19 transmission and mobility in omicron outbreaks in China.

Liping Peng, Kylie E C Ainslie, Xiaotong Huang, Benjamin J Cowling, Peng Wu, and Tim K Tsang

Communications medicine, 2025

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BACKGROUND: Prior research has suggested a positive correlation between human mobility and COVID-19 transmission at national or provincial levels, assuming constant correlations during outbreaks. However, the correlation strength at finer scales and potential changes in relationships during outbreaks have been scarcely investigated. METHODS: We gathered case and mobility data (within-city movement, inter-city inflow, and inter-city outflow) at the city level from Omicron outbreaks in mainland China between February and November 2022. For each outbreak, we calculated the time-varying effective reproduction number (R(t)). Subsequently, we estimated the cross-correlation and rolling correlation between R(t) and the mobility index, comparing them and identifying potential factors affecting these correlations. RESULTS: We identify 57 outbreaks during Omicron wave 1 (February to June) and 171 outbreaks during Omicron wave 2 (July to December). Cross-correlation estimates vary between waves, with values ranging from 0.64 to 0.71 in wave 1 and 0.45 to 0.46 in wave 2. Oscillation models best fit the rolling correlation for almost all outbreaks, and there are significant differences between extreme values of rolling correlation and cross-correlation. Additionally, we estimate a positive relationship between the GRI and rolling correlation during the pre-peak stage, turning negative during the post-peak stage. CONCLUSIONS: Our findings suggest a positive relationship between Omicron transmission and mobility at the city level. However, significant fluctuations in their relationship, as demonstrated by rolling correlation, indicate that assuming a constant correlation between transmission and mobility may lead to inaccurate predictions or decisions when using mobility as a proxy for transmission intensity.
@article{peng2025p40394170, title = {Evaluating the association between COVID-19 transmission and mobility in omicron outbreaks in China.}, author = {Peng, Liping and Ainslie, Kylie E C and Huang, Xiaotong and Cowling, Benjamin J and Wu, Peng and Tsang, Tim K}, journal = {Communications medicine}, year = {2025}, volume = {5}, number = {1}, pages = {188}, doi = {10.1038/s43856-025-00906-7}, }
Nat Commun
Estimating transmissibility of Zika virus in Colombia in the presence of surveillance bias.

Tim K Tsang, Diana P Rojas, Fei Xu, and 5 more authors

Nature communications, 2025

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The 2015-2016 Zika virus outbreak in the Americas presented significant challenges in understanding the transmission dynamics due to substantial reporting biases, as women of reproductive age (15-39 years) were disproportionately represented in the surveillance data when public awareness of relationship between Zika and microcephaly increased. Using national surveillance data from Colombia during July 27, 2015-November 21, 2016, we developed a Bayesian hierarchical modeling framework to reconstruct the true numbers of symptomatic cases and estimate transmission parameters while accounting for differential reporting across age-sex groups. Our model revealed that the detection rate of symptomatic cases among women of reproductive age was 99% (95% CI: 98.7-100), compared to 85.4% (95% CI: 84.7-86.1) in other demographic groups. After correcting for these biases, our results showed that females aged 15-39 years remained 82.8% (95% CI: 80.2-85.2%) more susceptible to Zika symptomatic infection than males of the same age, independent of differential reporting areas. Departments with medium-high altitude, medium-high population density, low coverage of forest, or high dengue incidence from 2011-2015 exhibited greater Zika risk. This study underscores the importance of accounting for surveillance biases in epidemiological studies to better understand factors influencing Zika transmission and to inform disease control and prevention.
@article{tsang2025p40341193, title = {Estimating transmissibility of Zika virus in Colombia in the presence of surveillance bias.}, author = {Tsang, Tim K and Rojas, Diana P and Xu, Fei and Xu, Yanfang and Zhu, Xiaolin and Halloran, M Elizabeth and Longini, Ira M and Yang, Yang}, journal = {Nature communications}, year = {2025}, volume = {16}, number = {1}, pages = {4299}, doi = {10.1038/s41467-025-59655-9}, }
Vaccines
Interplay Between Viral Shedding, Age, and Symptoms in Individual Infectivity of COVID-19 Breakthrough Infections in Households.

Shuaibing Dong, Ying Sun, Shuyu Ni, Yi Tian, Zhaomin Feng, Lei Jia, Xiaoli Wang, Daitao Zhang, Quanyi Wang, Tim K Tsang, and Peng Yang

Vaccines, 2025

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BACKGROUND/OBJECTIVES: Understanding the factors influencing breakthrough infections following COVID-19 vaccination is critical for disease prevention, especially in households where transmission risks are high. Factors such as age, symptoms, living conditions, and viral load contribute to household transmission dynamics. METHODS: To elucidate this complex interplay of these factors, we analyzed a detailed household transmission study of COVID-19 involving 839 households and 1598 vaccinated individuals during the Omicron variant outbreak in Beijing, China, from April to June 2022. Using multivariate logistic regression models, we analyzed the impact of demographic, environmental, clinical, and virological factors on the risk of breakthrough infections. RESULTS: In multivariate analysis. we estimated that index cases aged 45-59 and 60+ years were associated with 80% (95% confidence interval [CI]: 35%, 140%) and 288% (95% CI: 160%, 481%) higher infectivity compared with index cases aged 18-44 years. We estimated that index cases with fever, headache and cough were associated with 43% (95% CI: 11%, 84%), 78% (95% CI: 18%, 168%) and 67% (25%, 123%) higher infectivity compared with those without. Index cases with higher viral loads were associated with higher infectivity in univariate analysis, but this was no longer significant in multivariate analysis. Smaller living space and two-member households were associated with higher odds of breakthrough infections. CONCLUSIONS: Age, symptoms, and living conditions were significant risk factors for breakthrough infections during the Omicron outbreak. Suburban settings, smaller spaces, and two-member households enhance transmission risks. These findings inform targeted interventions to reduce household transmission.
@article{dong2025p40266240, title = {Interplay Between Viral Shedding, Age, and Symptoms in Individual Infectivity of COVID-19 Breakthrough Infections in Households.}, author = {Dong, Shuaibing and Sun, Ying and Ni, Shuyu and Tian, Yi and Feng, Zhaomin and Jia, Lei and Wang, Xiaoli and Zhang, Daitao and Wang, Quanyi and Tsang, Tim K and Yang, Peng}, journal = {Vaccines}, year = {2025}, volume = {13}, number = {3}, doi = {10.3390/vaccines13030329}, }
J Infect Dis
Estimating the Waning Effectiveness of COVID-19 Vaccines From Population-Level Surveillance Data in Hong Kong.

Haoling Chen, Xiaotong Huang, Can Wang, Benjamin J Cowling, and Tim K Tsang

The Journal of infectious diseases, 2025

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Assessing the time-varying effectiveness of coronavirus disease 2019 (COVID-19) vaccines is critical to guiding vaccine strategies and public health policies. We developed a Bayesian framework to estimate the waning vaccine effectiveness of various doses of CoronaVac and Comirnaty based on population-level surveillance data. We applied this framework to data on a large Omicron BA.2 epidemic in Hong Kong from January to May 2022. Our results indicated that despite high vaccination rates during this period, high vaccine uptake mitigated but did not prevent rapid spread of infection.
@article{chen2025p40247690, title = {Estimating the Waning Effectiveness of COVID-19 Vaccines From Population-Level Surveillance Data in Hong Kong.}, author = {Chen, Haoling and Huang, Xiaotong and Wang, Can and Cowling, Benjamin J and Tsang, Tim K}, journal = {The Journal of infectious diseases}, year = {2025}, volume = {232}, number = {2}, pages = {e341-e345}, doi = {10.1093/infdis/jiaf207}, }
J Infect Dis
Effective Real-time Transmission Estimations Incorporating Population Viral Load Distributions Amid SARS-CoV-2 Variants and Preexisting Immunity.

Yu Meng, Yun Lin, Weijia Xiong, Eric H Y Lau, Faith Ho, Jessica Y Wong, Peng Wu, Tim K Tsang, Benjamin J Cowling, and Bingyi Yang

The Journal of infectious diseases, 2025

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BACKGROUND: Population-level cycle threshold (Ct) distribution allows for Rt estimation for SARS-CoV-2 ancestral strain, however, its generalizability under different circulating variants and preexisting immunity remains unclear. METHODS: We obtained the first Ct record of local COVID-19 cases from July 2020 to January 2023 in Hong Kong. The log-linear regression model, fitting on daily Ct mean and skewness to Rt estimated by case count, was trained with data from ancestral-dominated wave (minimal population immunity), and we predicted the Rt for Omicron waves (>70% vaccine coverage). Cross-validation was performed by training on other waves. Stratification analysis was conducted to retrospectively evaluate the impact of the changing severity profiles. RESULTS: Model trained with the ancestral-dominated wave accurately estimated whether Rt was >1, with areas under the receiver operating characteristic curve of 0.98 (95% CI, 0.96-1.00), 0.62 (95% CI, 0.53-0.70), and 0.80 (95% CI, 0.73-0.88) for Omicron-dominated waves, respectively. Models trained on other waves also had discriminative performance. Stratification analysis suggested the potential impact of case severity on model estimation, which coincided with sampling delay. CONCLUSIONS: Incorporating population viral shedding can provide timely and accurate transmission estimation with evolving variants and population immunity, though model application should consider sampling delay.
@article{meng2025p39601277, title = {Effective Real-time Transmission Estimations Incorporating Population Viral Load Distributions Amid SARS-CoV-2 Variants and Preexisting Immunity.}, author = {Meng, Yu and Lin, Yun and Xiong, Weijia and Lau, Eric H Y and Ho, Faith and Wong, Jessica Y and Wu, Peng and Tsang, Tim K and Cowling, Benjamin J and Yang, Bingyi}, journal = {The Journal of infectious diseases}, year = {2025}, volume = {231}, number = {3}, pages = {684-691}, doi = {10.1093/infdis/jiae592}, }
J Infect Dis
Interplay Between Viral Shedding, Age, and Symptoms in Individual Infectiousness of Influenza Cases in Households.

Chengyao Zhang, Vicky J Fang, Kwok-Hung Chan, Gabriel M Leung, Dennis K M Ip, J S Malik Peiris, Benjamin J Cowling, and Tim K Tsang

The Journal of infectious diseases, 2025

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BACKGROUND: Understanding factors affecting the infectiousness of influenza cases is crucial for disease prevention and control. Viral shedding is expected to correlate with infectiousness of cases, but it is strongly associated with age and the presence of symptoms. METHODS: To elucidate this complex interplay, we analyze with an individual-based household transmission model a detailed household transmission study of influenza with 442 households and 1710 individuals from 2008 to 2017 in Hong Kong, to characterize the household transmission dynamics and identify factors affecting transmissions. RESULTS: We estimate that age, fever symptoms, and viral load were all associated with higher infectiousness. However, by model comparison, the best model included age and fever as factors affecting individual infectiousness, and estimates that preschool and school-aged children were 317% (95% credible interval [CrI], 103%, 1042%) and 161% (95% CrI, 33%, 601%) more infectious than adults, respectively, and patients having fever had 146% (95% CrI, 37%, 420%) higher infectiousness. Adding heterogeneity on individual infectiousness of cases does not improve the model fit, suggesting these factors could explain the difference in individual infectiousness. CONCLUSIONS: Our study clarifies the contribution of age, symptoms, and viral shedding to individual infectiousness of influenza cases in households.
@article{zhang2025p39197019, title = {Interplay Between Viral Shedding, Age, and Symptoms in Individual Infectiousness of Influenza Cases in Households.}, author = {Zhang, Chengyao and Fang, Vicky J and Chan, Kwok-Hung and Leung, Gabriel M and Ip, Dennis K M and Peiris, J S Malik and Cowling, Benjamin J and Tsang, Tim K}, journal = {The Journal of infectious diseases}, year = {2025}, volume = {231}, number = {2}, pages = {462-470}, doi = {10.1093/infdis/jiae434}, }

R Package

hhdynamics: Household Transmission Dynamics Analysis

Tim K Tsang

2025

R package

Bib HTML

@misc{tsang2025hhdynamics,
  title = {hhdynamics: Household Transmission Dynamics Analysis},
  author = {Tsang, Tim K},
  year = {2025},
  howpublished = {\url{https://github.com/timktsang/hhdynamics}},
  note = {R package},
}

R Package

seroreconstruct: Serological Data Reconstruction

Tim K Tsang

2025

R package

Bib HTML

@misc{tsang2025seroreconstruct,
  title = {seroreconstruct: Serological Data Reconstruction},
  author = {Tsang, Tim K},
  year = {2025},
  howpublished = {\url{https://github.com/timktsang/seroreconstruct}},
  note = {R package},
}

R Package

ImmuPop: Population Immunity Estimation

Tim K Tsang

2025

R package

Bib HTML

@misc{tsang2025immupop,
  title = {ImmuPop: Population Immunity Estimation},
  author = {Tsang, Tim K},
  year = {2025},
  howpublished = {\url{https://github.com/timktsang/ImmuPop}},
  note = {R package},
}

Vaccines
Impact of Vaccination and Public Health Measures on the Severity of SARS-CoV-2 Omicron Infections in China: A Systematic Review and Meta-Regression Analysis.

Can Wang, Liping Peng, Xiaotong Huang, and Tim K Tsang

Vaccines, 2025

Abs DOI Bib

Background: Starting in early 2022, SARS-CoV-2 Omicron has driven large outbreaks in China, a predominantly infection-naive population with high inactivated vaccine coverage. This unique context provided a substantially less-confounded opportunity to evaluate how vaccination, public health, and social measures influenced severity. Methods: We systematically reviewed 86 studies (224 severity estimates) published from 2022 to 2024, reporting symptom and clinical severity outcomes (fever, cough, and sore throat; symptomatic, severe/critical, and fatal illness) of Omicron infections in China. Using meta-regression, we evaluated the associations of study setting, age group, vaccination status, predominant subvariants, and Oxford COVID-19 Government Response Tracker (OxCGRT) indices, including the Government Response Index (GRI), Containment and Health Index (CHI), and the Stringency Index (SI), with infection outcomes, adjusting for key confounders. Results: We found the primary or booster series of inactivated vaccines conferred strong protection against severe/critical illness (pooled relative risk (RR) 0.17 [95% CI: 0.09-0.33]) but did not reduce symptom frequency (RR 0.99 [95% CI: 0.95-1.02]). Each 10-unit increase in GRI or CHI was associated with 7% (95% CI: 1-12%) and 6% (95% CI: 1-10%) lower odds of symptomatic infection and 3% (95% CI: 1-4%) lower odds of severe/critical illness. Later subvariants (BA.5, BF.7, and XBB) showed 24-38% higher odds of upper respiratory symptoms versus BA.1. Conclusions: The data collection context significantly impacted severity estimates, with higher estimates from emergency hospitals. Overall, inactivated vaccines provided strong protection against severe/critical outcomes while stringent public health measures were associated with lower severity. Our findings underscore the importance of consistent and standardized protocols to produce reliable estimates of SARS-CoV-2 severity in evolving epidemiological contexts.
@article{wang2025p40733725, title = {Impact of Vaccination and Public Health Measures on the Severity of SARS-CoV-2 Omicron Infections in China: A Systematic Review and Meta-Regression Analysis.}, author = {Wang, Can and Peng, Liping and Huang, Xiaotong and Tsang, Tim K}, journal = {Vaccines}, year = {2025}, volume = {13}, number = {7}, doi = {10.3390/vaccines13070747}, }

2024

Nat Commun
An adaptive weight ensemble approach to forecast influenza activity in an irregular seasonality context.

Tim K Tsang, Qiurui Du, Benjamin J Cowling, and 1 more author

Nature communications, 2024

Abs DOI Bib

Forecasting influenza activity in tropical and subtropical regions, such as Hong Kong, is challenging due to irregular seasonality and high variability. We develop a diverse set of statistical, machine learning, and deep learning approaches to forecast influenza activity in Hong Kong 0 to 8 weeks ahead, leveraging a unique multi-year surveillance record spanning 32 epidemics from 1998 to 2019. We consider a simple average ensemble (SAE) of the top two individual models, and develop an adaptive weight blending ensemble (AWBE) that dynamically updates model contribution. All models outperform the baseline constant incidence model, reducing the root mean square error (RMSE) by 23%-29% and weighted interval score (WIS) by 25%-31% for 8-week ahead forecasts. The SAE model performed similarly to individual models, while the AWBE model reduces RMSE by 52% and WIS by 53%, outperforming individual models for forecasts in different epidemic trends (growth, plateau, decline) and during both winter and summer seasons. Using the post-COVID data (2023-2024) as another test period, the AWBE model still reduces RMSE by 39% and WIS by 45%. Our framework contributes to comparing and benchmarking models in ensemble forecasts, enhancing evidence for synthesizing multiple models in disease forecasting for geographies with irregular influenza seasonality.
@article{tsang2024p39366942, title = {An adaptive weight ensemble approach to forecast influenza activity in an irregular seasonality context.}, author = {Tsang, Tim K and Du, Qiurui and Cowling, Benjamin J and Viboud, Cecile}, journal = {Nature communications}, year = {2024}, volume = {15}, number = {1}, pages = {8625}, doi = {10.1038/s41467-024-52504-1}, }
BMC Med
Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Tim K Tsang, Sheena G Sullivan, Yu Meng, and 9 more authors

BMC medicine, 2024

Abs DOI Bib

BACKGROUND: Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. METHODS: We quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022, based on calendar-time proportional hazards models and matching approaches. RESULTS: We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR 1.66; 95% CI 1.07, 2.59; p = 0.02) after the first dose. CONCLUSIONS: Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.
@article{tsang2024p39267060, title = {Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.}, author = {Tsang, Tim K and Sullivan, Sheena G and Meng, Yu and Lai, Francisco Tsz Tsun and Fan, Min and Huang, Xiaotong and Lin, Yun and Peng, Liping and Zhang, Chengyao and Yang, Bingyi and Ainslie, Kylie E C and Cowling, Benjamin J}, journal = {BMC medicine}, year = {2024}, volume = {22}, number = {1}, pages = {384}, doi = {10.1186/s12916-024-03597-4}, }
Res Sq
Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Tim K Tsang, Sheena G Sullivan, Yu Meng, and 9 more authors

Research square, 2024

Abs DOI Bib

Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. Here, we quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022. We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR: 1.66; 95% CI: 1.07, 2.59; p = 0.02) after the first dose. Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.
@article{tsang2024p38947018, title = {Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.}, author = {Tsang, Tim K and Sullivan, Sheena G and Meng, Yu and Lai, Francisco Tsz Tsun and Fan, Min and Huang, Xiaotong and Lin, Yun and Peng, Liping and Zhang, Chengyao and Yang, Bingyi and Ainslie, Kylie E C and Cowling, Benjamin J}, journal = {Research square}, year = {2024}, doi = {10.21203/rs.3.rs-4518813/v1}, }
Nat Commun
Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children.

Janice Z Jia, Carolyn A Cohen, Haogao Gu, and 11 more authors

Nature communications, 2024

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Cross-reactive antibodies with Fc receptor (FcR) effector functions may mitigate pandemic virus impact in the absence of neutralizing antibodies. In this exploratory study, we use serum from a randomized placebo-controlled trial of seasonal trivalent influenza vaccination in children (NCT00792051) conducted at the onset of the 2009 H1N1 pandemic (pH1N1) and monitored for infection. We found that seasonal vaccination increases pH1N1 specific antibodies and FcR effector functions. Furthermore, prospective baseline antibody profiles after seasonal vaccination, prior to pH1N1 infection, show that unvaccinated uninfected children have elevated ADCC effector function, FcgammaR3a and FcgammaR2a binding antibodies to multiple pH1N1 proteins, past seasonal and avian (H5, H7 and H9) strains. Whereas, children that became pH1N1 infected after seasonal vaccination have antibodies focussed to seasonal strains without FcR functions, and greater aggregated HA-specific profiles for IgM and IgG3. Modeling to predict infection susceptibility, ranked baseline hemagglutination antibody inhibition as the highest contributor to lack of pH1N1 infection, in combination with features that include pH1-IgG1, H1-stem responses and FcR binding to seasonal vaccine and pH1 proteins. Thus, seasonal vaccination can have benefits against pandemic influenza viruses, and some children already have broadly reactive antibodies with Fc potential without vaccination and may be considered ’elite influenza controllers’.
@article{jia2024p38615070, title = {Influenza antibody breadth and effector functions are immune correlates from acquisition of pandemic infection of children.}, author = {Jia, Janice Z and Cohen, Carolyn A and Gu, Haogao and McLean, Milla R and Varadarajan, Raghavan and Bhandari, Nisha and Peiris, Malik and Leung, Gabriel M and Poon, Leo L M and Tsang, Tim and Chung, Amy W and Cowling, Benjamin J and Leung, Nancy H L and Valkenburg, Sophie A}, journal = {Nature communications}, year = {2024}, volume = {15}, number = {1}, pages = {3210}, doi = {10.1038/s41467-024-47590-0}, }
Epidemiol Infect
Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.

Tim K Tsang, Richael Q R Du, Vicky J Fang, and 8 more authors

Epidemiology and infection, 2024

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Previous studies suggest that influenza virus infection may provide temporary non-specific immunity and hence lower the risk of non-influenza respiratory virus infection. In a randomized controlled trial of influenza vaccination, 1 330 children were followed-up in 2009-2011. Respiratory swabs were collected when they reported acute respiratory illness and tested against influenza and other respiratory viruses. We used Poisson regression to compare the incidence of non-influenza respiratory virus infection before and after influenza virus infection. Based on 52 children with influenza B virus infection, the incidence rate ratio (IRR) of non-influenza respiratory virus infection after influenza virus infection was 0.47 (95% confidence interval: 0.27-0.82) compared with before infection. Simulation suggested that this IRR was 0.87 if the temporary protection did not exist. We identified a decreased risk of non-influenza respiratory virus infection after influenza B virus infection in children. Further investigation is needed to determine if this decreased risk could be attributed to temporary non-specific immunity acquired from influenza virus infection.
@article{tsang2024p38584132, title = {Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.}, author = {Tsang, Tim K and Du, Richael Q R and Fang, Vicky J and Lau, Eric H Y and Chan, Kwok Hung and Chu, Daniel K W and Ip, Dennis K M and Peiris, J S Malik and Leung, Gabriel M and Cauchemez, Simon and Cowling, Benjamin J}, journal = {Epidemiology and infection}, year = {2024}, volume = {152}, pages = {e60}, doi = {10.1017/S0950268824000542}, }
Epidemiol Infect
Comparative epidemiology of outbreaks caused by SARS-CoV-2 Delta and Omicron variants in China.

Liping Peng, Xiaotong Huang, Can Wang, Hualei Xin, Benjamin J Cowling, Peng Wu, and Tim K Tsang

Epidemiology and infection, 2024

Abs DOI Bib

From 2020 to December 2022, China implemented strict measures to contain the spread of severe acute respiratory syndrome coronavirus 2. However, despite these efforts, sustained outbreaks of the Omicron variants occurred in 2022. We extracted COVID-19 case numbers from May 2021 to October 2022 to identify outbreaks of the Delta and Omicron variants in all provinces of mainland China. We found that omicron outbreaks were more frequent (4.3 vs. 1.6 outbreaks per month) and longer-lasting (mean duration: 13 vs. 4 weeks per outbreak) than Delta outbreaks, resulting in a total of 865,100 cases, of which 85% were asymptomatic. Despite the average Government Response Index being 12% higher (95% confidence interval (CI): 9%, 15%) in Omicron outbreaks, the average daily effective reproduction number (R(t)) was 0.45 higher (95% CI: 0.38, 0.52, p < 0.001) than in Delta outbreaks. Omicron outbreaks were suppressed in 32 days on average (95% CI: 26, 39), which was substantially longer than Delta outbreaks (14 days; 95% CI: 11, 19; p = 0.004). We concluded that control measures effective against Delta could not contain Omicron outbreaks in China. This highlights the need for continuous evaluation of new variants’ epidemiology to inform COVID-19 response decisions.
@article{peng2024p38500342, title = {Comparative epidemiology of outbreaks caused by SARS-CoV-2 Delta and Omicron variants in China.}, author = {Peng, Liping and Huang, Xiaotong and Wang, Can and Xin, Hualei and Cowling, Benjamin J and Wu, Peng and Tsang, Tim K}, journal = {Epidemiology and infection}, year = {2024}, volume = {152}, pages = {e43}, doi = {10.1017/S0950268824000360}, }
Am J Med Sci
The association between circulating fatty acids and stroke in hypertensive patients.

Hao Peng, Xiao-Qin Cai, Juanying Zhen, Jiangshan Jane Shen, Heng-Shan Shen, Xin-Han Wu, Yi-Bin Zhou, Lijie Ren, Jun Wu, Aimin Xu, Tim K Tsang, Bernard Man Yung Cheung, and Chao Li

The American journal of the medical sciences, 2024

Abs DOI Bib

BACKGROUND: Stroke is prevalent in hypertensive population. It has been suggested that unsaturated fatty acids (USFA) have protective effect on stroke. The effect of saturated fatty acids (SFAs) on stroke is still unclear. Therefore, we studied the relationship between circulating fatty acids and acute ischemic stroke (AIS) in hypertensive patients. METHODS: Eighty-nine pairs including 100 men and 78 women matched by sex and age were recruited. Each pair included a hypertensive patient within 48h of AIS onset and a hypertensive patient without stroke. Six circulating fatty acids were methylated before concentration determination which was repeated twice with percent recovery estimated. RESULTS: There were differences in educational level (P = 0.002) and occupation (P < 0.001) between stroke and non-stroke participants. All the 6 fatty acid levels were higher in non-stroke participants (P = 0.017 for palmitoleic acid, 0.001 for palmitic acid, <0.001 for linoleic acid, <0.001 for behenic acid, <0.001 for nervonic acid and 0.002 for lignoceric acid). In logistic regression analysis, AIS was inversely associated with fatty acid levels except for lignoceric acid. After adjustment for education and occupation, the palmitoleic acid and palmitic acid levels were no longer inversely associated with AIS. After further adjustment for systolic blood pressure, smoking, drinking, total cholesterol and triglyceride, the inverse associations of linoleic acid (OR = 0.965, 95%CI = 0.942-0.990, P = 0.005), behenic acid (OR = 0.778, 95%CI = 0.664-0.939, P = 0.009), nervonic acid (OR = 0.323, 95%CI = 0.121-0.860, P = 0.024) with AIS remained significant. CONCLUSIONS: Circulating fatty acids except lignoceric acid were inversely associated with AIS. Both USFAs and SFAs may have beneficial effect on stroke prevention in hypertensive population.
@article{peng2024p38460926, title = {The association between circulating fatty acids and stroke in hypertensive patients.}, author = {Peng, Hao and Cai, Xiao-Qin and Zhen, Juanying and Shen, Jiangshan Jane and Shen, Heng-Shan and Wu, Xin-Han and Zhou, Yi-Bin and Ren, Lijie and Wu, Jun and Xu, Aimin and Tsang, Tim K and Cheung, Bernard Man Yung and Li, Chao}, journal = {The American journal of the medical sciences}, year = {2024}, volume = {368}, number = {1}, pages = {48-54}, doi = {10.1016/j.amjms.2024.02.013}, }
Lancet Reg
Comparison of control and transmission of COVID-19 across epidemic waves in Hong Kong: an observational study.

Bingyi Yang, Yun Lin, Weijia Xiong, Chang Liu, Huizhi Gao, Faith Ho, Jiayi Zhou, Ru Zhang, Jessica Y Wong, Justin K Cheung, Eric H Y Lau, Tim K Tsang, Jingyi Xiao, Irene O L Wong, Mario Martin-Sanchez, Gabriel M Leung, Benjamin J Cowling, and Peng Wu

The Lancet regional health. Western Pacific, 2024

Abs DOI Bib

BACKGROUND: Hong Kong contained COVID-19 for two years but experienced a large epidemic of Omicron BA.2 in early 2022 and endemic transmission of Omicron subvariants thereafter. We reflected on pandemic preparedness and responses by assessing COVID-19 transmission and associated disease burden in the context of implementation of various public health and social measures (PHSMs). METHODS: We examined the use and impact of pandemic controls in Hong Kong by analysing data on more than 1.7 million confirmed COVID-19 cases and characterizing the temporal changes non-pharmaceutical and pharmaceutical interventions implemented from January 2020 through to 30 December 2022. We estimated the daily effective reproductive number (R(t)) to track changes in transmissibility and effectiveness of community-based measures against infection over time. We examined the temporal changes of pharmaceutical interventions, mortality rate and case-fatality risks (CFRs), particularly among older adults. FINDINGS: Hong Kong experienced four local epidemic waves predominated by the ancestral strain in 2020 and early 2021 and prevented multiple SARS-CoV-2 variants from spreading in the community before 2022. Strict travel-related, case-based, and community-based measures were increasingly tightened in Hong Kong over the first two years of the pandemic. However, even very stringent measures were unable to contain the spread of Omicron BA.2 in Hong Kong. Despite high overall vaccination uptake (>70% with at least two doses), high mortality was observed during the Omicron BA.2 wave due to lower vaccine coverage (42%) among adults >/=65 years of age. Increases in antiviral usage and vaccination uptake over time through 2022 was associated with decreased case fatality risks. INTERPRETATION: Integrated strict measures were able to reduce importation risks and interrupt local transmission to contain COVID-19 transmission and disease burden while awaiting vaccine development and rollout. Increasing coverage of pharmaceutical interventions among high-risk groups reduced infection-related mortality and mitigated the adverse health impact of the pandemic. FUNDING: Health and Medical Research Fund.
@article{yang2024p38076326, title = {Comparison of control and transmission of COVID-19 across epidemic waves in Hong Kong: an observational study.}, author = {Yang, Bingyi and Lin, Yun and Xiong, Weijia and Liu, Chang and Gao, Huizhi and Ho, Faith and Zhou, Jiayi and Zhang, Ru and Wong, Jessica Y and Cheung, Justin K and Lau, Eric H Y and Tsang, Tim K and Xiao, Jingyi and Wong, Irene O L and Martin-Sanchez, Mario and Leung, Gabriel M and Cowling, Benjamin J and Wu, Peng}, journal = {The Lancet regional health. Western Pacific}, year = {2024}, volume = {43}, pages = {100969}, doi = {10.1016/j.lanwpc.2023.100969}, }
J Infect Dis
Estimation of the Time-Varying Effective Reproductive Number of COVID-19 Based on Multivariate Time Series of Severe Health Outcomes.

Benjamin R Young, Faith Ho, Yun Lin, Eric H Y Lau, Benjamin J Cowling, Peng Wu, and Tim K Tsang

The Journal of infectious diseases, 2024

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The time-varying effective reproduction number (Rt at time t) measures the transmissibility of SARS-CoV-2 and is conventionally based on daily case counts, which may suffer from time-varying ascertainment. We analyzed Rt estimates from case counts and severe COVID-19 (intensive care unit admissions, severe or critical cases, and mortality) across 2022 in Hong Kong’s fifth and sixth waves of infection. Within the fifth wave, the severe disease-based Rt (3.5) was significantly higher than the case-based Rt (2.4) but not in the sixth wave. During periods with fluctuating underreporting, data based on severe diseases may provide more reliable Rt estimates.
@article{young2024p37815808, title = {Estimation of the Time-Varying Effective Reproductive Number of COVID-19 Based on Multivariate Time Series of Severe Health Outcomes.}, author = {Young, Benjamin R and Ho, Faith and Lin, Yun and Lau, Eric H Y and Cowling, Benjamin J and Wu, Peng and Tsang, Tim K}, journal = {The Journal of infectious diseases}, year = {2024}, volume = {229}, number = {2}, pages = {502-506}, doi = {10.1093/infdis/jiad445}, }
Am J Epidemiol
Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative studies: a systematic review and meta-analysis.

Tim K Tsang, Sheena G Sullivan, Xiaotong Huang, and 6 more authors

American journal of epidemiology, 2024

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Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. We aimed to determine the impact of preexisting immunity on vaccine effectiveness (VE) estimates. We systematically reviewed and meta-analyzed 66 test-negative design studies that examined VE against infection or severe disease (hospitalization, intensive care unit admission, or death) for primary vaccination series. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (77%; 95% CI, 72-81) and severe disease (86%; 95% CI, 83-89) compared with studies that excluded people with prior COVID-19 infection (pooled VE against infection: 87% [95% CI, 85-89]; pooled VE against severe disease: 93% [95% CI, 91-95]). There was a negative correlation between VE estimates against infection and severe disease, and the cumulative incidence of cases before the start of the study or incidence rates during the study period. We found clear empirical evidence that higher levels of preexisting immunity were associated with lower VE estimates. Prior infections should be treated as both a confounder and effect modificatory when the policies target the whole population or are stratified by infection history, respectively.
@article{tsang2024p38904437, title = {Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative studies: a systematic review and meta-analysis.}, author = {Tsang, Tim K and Sullivan, Sheena G and Huang, Xiaotong and Wang, Can and Wang, Yifan and Nealon, Joshua and Yang, Bingyi and Ainslie, Kylie E C and Cowling, Benjamin J}, journal = {American journal of epidemiology}, year = {2024}, volume = {193}, number = {12}, pages = {1868-1881}, doi = {10.1093/aje/kwae142}, }

2023

Emerg Infect Dis
Influenza Resurgence after Relaxation of Public Health and Social Measures, Hong Kong, 2023.

Weijia Xiong, Benjamin J Cowling, and Tim K Tsang

Emerging infectious diseases, 2023

Abs DOI Bib

Soon after a mask mandate was relaxed (March 1, 2023), the first post-COVID-19 influenza season in Hong Kong lasted 12 weeks. After other preventive measures were accounted for, mask wearing was associated with an estimated 25% reduction in influenza transmission. Influenza resurgence probably resulted from relaxation of mask mandates and other measures.
@article{xiong2023p37885047, title = {Influenza Resurgence after Relaxation of Public Health and Social Measures, Hong Kong, 2023.}, author = {Xiong, Weijia and Cowling, Benjamin J and Tsang, Tim K}, journal = {Emerging infectious diseases}, year = {2023}, volume = {29}, number = {12}, pages = {2556-2559}, doi = {10.3201/eid2912.230937}, }
JAMA NO
COVID-19 Vaccination Willingness and Reasons for Vaccine Refusal.

Phyllis Lun, Ke Ning, Yishan Wang, Tiffany S W Ma, Francis P Flores, Xiao Xiao, Mythily Subramaniam, Edimansyah Abdin, Linwei Tian, Tim K Tsang, Kathy Leung, Joseph T Wu, Benjamin J Cowling, Gabriel M Leung, and Michael Y Ni

JAMA network open, 2023

Abs DOI Bib

IMPORTANCE: Hong Kong was held as an exemplar for pandemic response until it recorded the world’s highest daily COVID-19 mortality, which was likely due to vaccine refusal. To prevent this high mortality in future pandemics, information on underlying reasons for vaccine refusal is necessary. OBJECTIVES: To track the evolution of COVID-19 vaccination willingness and uptake from before vaccine rollout to mass vaccination, to examine factors associated with COVID-19 vaccine refusal and compare with data from Singapore, and to assess the population attributable fraction for vaccine refusal. DESIGN, SETTING, AND PARTICIPANTS: This cohort study used data from randomly sampled participants from 14 waves of population-based studies in Hong Kong (February 2020 to May 2022) and 2 waves of population-based studies in Singapore (May 2020 to June 2021 and October 2021 to January 2022), and a population-wide registry of COVID-19 vaccination appointments. Data were analyzed from February 23, 2021, to May 30, 2022. EXPOSURES: Trust in COVID-19 vaccine information sources (ie, health authorities, physicians, traditional media, and social media); COVID-19 vaccine confidence on effectiveness, safety, and importance; COVID-19 vaccine misconceptions on safety and high-risk groups; political views; and COVID-19 policies (ie, workplace vaccine mandates and vaccine pass). MAIN OUTCOMES AND MEASURES: Primary outcomes were the weighted prevalence of COVID-19 vaccination willingness over the pandemic, adjusted incidence rate ratios, and population attributable fractions of COVID-19 vaccine refusal. A secondary outcome was change in daily COVID-19 vaccination appointments. RESULTS: The study included 28 007 interviews from 20 waves of longitudinal data, with 1114 participants in the most recent wave (median [range] age, 54.2 years [20-92] years; 571 [51.3%] female). Four factors-mistrust in health authorities, low vaccine confidence, vaccine misconceptions, and political views-could jointly account for 82.2% (95% CI, 62.3%-100.0%) of vaccine refusal in adults aged 18 to 59 years and 69.3% (95% CI, 47.2%-91.4%) of vaccine refusal in adults aged 60 years and older. Workplace vaccine mandates were associated with 62.2% (95% CI, 9.9%-139.2%) increases in daily COVID-19 vaccination appointments, and the Hong Kong vaccine pass was associated with 124.8% (95% CI, 65.9%-204.6%) increases in daily COVID-19 vaccination appointments. CONCLUSIONS AND RELEVANCE: These findings suggest that trust in health authorities was fundamental to overcoming vaccine hesitancy. As such, engendering trust in health care professionals, experts, and public health agencies should be incorporated into pandemic preparedness and response.
@article{lun2023p37856125, title = {COVID-19 Vaccination Willingness and Reasons for Vaccine Refusal.}, author = {Lun, Phyllis and Ning, Ke and Wang, Yishan and Ma, Tiffany S W and Flores, Francis P and Xiao, Xiao and Subramaniam, Mythily and Abdin, Edimansyah and Tian, Linwei and Tsang, Tim K and Leung, Kathy and Wu, Joseph T and Cowling, Benjamin J and Leung, Gabriel M and Ni, Michael Y}, journal = {JAMA network open}, year = {2023}, volume = {6}, number = {10}, pages = {e2337909}, doi = {10.1001/jamanetworkopen.2023.37909}, }
Lancet Microbe
Viral kinetics of SARS-CoV-2 following onset of COVID-19 in symptomatic patients infected with the ancestral strain and omicron BA.2 in Hong Kong: a retrospective observational study.

Yun Lin, Peng Wu, Tim K Tsang, and 5 more authors

The Lancet. Microbe, 2023

Abs DOI Bib

BACKGROUND: Assessment of viral kinetics of SARS-CoV-2 can inform on host immune responses to the virus and on the viral transmission potential. We aimed to characterise viral shedding kinetics by age, virus type, and clinical outcome, and to examine the potential effect of vaccination on viral shedding. METHODS: In this retrospective observational study, we analysed longitudinal data on cycle threshold (Ct) values of reverse-transcription quantitative PCR (RT-qPCR) assays of upper respiratory tract samples from symptomatic patients with COVID-19. Patients who were confirmed with COVID-19 with at least one Ct value of the RT-qPCR test available within 28 days after symptom onset, and discharged or died at the time of the analysis, were included in the study. Patients were isolated in hospitals in Hong Kong during three major epidemic waves dominated by the ancestral strain or omicron BA.2. We modelled the temporal trajectories of viral burden in these patients. Electronic medical records of the patients with COVID-19 were retrieved and linked to the patients’ epidemiological information obtained from contact tracing. Patients who were infected outside Hong Kong, infected with variants other than the ancestral strain or omicron BA.2, not reporting any COVID-19 related symptoms, still hospitalised at the time of analysis, missing information on age, time of symptom onset, infection severity, vaccination or clinical outcome, infected more than once, or treated with nirmatrelvir-ritonavir or molnupiravir were excluded from analysis. The main outcome of this study is the temporal change of SARS-CoV-2 viral burden measured by Ct values of RT-qPCR tests in symptomatic patients with COVID-19. FINDINGS: Among 22 461 symptomatic patients with COVID-19 confirmed from July 1, 2020, to May 22, 2022, the estimated viral burden from a random-effects model indicated a longer duration of viral shedding in patients with more severe outcomes of infection (mean difference 13.1 days, 95% CI 12.9-13.3, for fatal vs mild-to-moderate) and in older patients (5.2, 5.0-5.5, for age >/=80 years vs 0-18 years). Vaccinated individuals with a breakthrough infection with the omicron BA.2 variant had a generally lower viral burden and shorter durations of viral shedding (mean difference of 2-4 days) over 4 weeks after onset than unvaccinated individuals infected with omicron BA.2, particularly in patients whose last dose of COVID-19 vaccine was received </=90 days before symptom onset. Marginal differences in viral burden following symptom onset and the duration of viral shedding were observed between unvaccinated individuals infected with the ancestral strain and omicron BA.2. INTERPRETATION: The viral kinetics since symptom onset characterised for symptomatic patients with COVID-19 in our study show that previously vaccinated or younger individuals, or those with a milder infection, shed fewer viruses in a shorter period, implying possible transmission dynamics of SARS-CoV-2 and protective mechanisms of vaccination against infection and severe outcomes. FUNDING: Hong Kong Health and Medical Research Fund and Hong Kong Collaborative Research Fund.
@article{lin2023p37659420, title = {Viral kinetics of SARS-CoV-2 following onset of COVID-19 in symptomatic patients infected with the ancestral strain and omicron BA.2 in Hong Kong: a retrospective observational study.}, author = {Lin, Yun and Wu, Peng and Tsang, Tim K and Wong, Jessica Y and Lau, Eric H Y and Yang, Bingyi and Leung, Gabriel M and Cowling, Benjamin J}, journal = {The Lancet. Microbe}, year = {2023}, volume = {4}, number = {9}, pages = {e722-e731}, doi = {10.1016/S2666-5247(23)00146-5}, }
npj Vaccines
The need for a clinical case definition in test-negative design studies estimating vaccine effectiveness.

Sheena G Sullivan, Arseniy Khvorov, Xiaotong Huang, Can Wang, Kylie E C Ainslie, Joshua Nealon, Bingyi Yang, Benjamin J Cowling, and Tim K Tsang

NPJ vaccines, 2023

Abs DOI Bib

Test negative studies have been used extensively for the estimation of COVID-19 vaccine effectiveness (VE). Such studies are able to estimate VE against medically-attended illness under certain assumptions. Selection bias may be present if the probability of participation is associated with vaccination or COVID-19, but this can be mitigated through use of a clinical case definition to screen patients for eligibility, which increases the likelihood that cases and non-cases come from the same source population. We examined the extent to which this type of bias could harm COVID-19 VE through systematic review and simulation. A systematic review of test-negative studies was re-analysed to identify studies ignoring the need for clinical criteria. Studies using a clinical case definition had a lower pooled VE estimate compared with studies that did not. Simulations varied the probability of selection by case and vaccination status. Positive bias away from the null (i.e., inflated VE consistent with the systematic review) was observed when there was a higher proportion of healthy, vaccinated non-cases, which may occur if a dataset contains many results from asymptomatic screening in settings where vaccination coverage is high. We provide an html tool for researchers to explore site-specific sources of selection bias in their own studies. We recommend all groups consider the potential for selection bias in their vaccine effectiveness studies, particularly when using administrative data.
@article{sullivan2023p37573443, title = {The need for a clinical case definition in test-negative design studies estimating vaccine effectiveness.}, author = {Sullivan, Sheena G and Khvorov, Arseniy and Huang, Xiaotong and Wang, Can and Ainslie, Kylie E C and Nealon, Joshua and Yang, Bingyi and Cowling, Benjamin J and Tsang, Tim K}, journal = {NPJ vaccines}, year = {2023}, volume = {8}, number = {1}, pages = {118}, doi = {10.1038/s41541-023-00716-9}, }
PNAS
Reconstructing household transmission dynamics to estimate the infectiousness of asymptomatic influenza virus infections.

Tim K Tsang, Can Wang, Vicky J Fang, and 7 more authors

Proceedings of the National Academy of Sciences of the United States of America, 2023

Abs DOI Bib

There has long been controversy over the potential for asymptomatic cases of the influenza virus to have the capacity for onward transmission, but recognition of asymptomatic transmission of COVID-19 stimulates further research into this topic. Here, we develop a Bayesian methodology to analyze detailed data from a large cohort of 727 households and 2515 individuals in the 2009 pandemic influenza A(H1N1) outbreak in Hong Kong to characterize household transmission dynamics and to estimate the relative infectiousness of asymptomatic versus symptomatic influenza cases. The posterior probability that asymptomatic cases [36% of cases; 95% credible interval (CrI): 32%, 40%] are less infectious than symptomatic cases is 0.82, with estimated relative infectiousness 0.57 (95% CrI: 0.11, 1.54). More data are required to strengthen our understanding of the contribution of asymptomatic cases to the spread of influenza.
@article{tsang2023p37549267, title = {Reconstructing household transmission dynamics to estimate the infectiousness of asymptomatic influenza virus infections.}, author = {Tsang, Tim K and Wang, Can and Fang, Vicky J and Perera, Ranawaka A P M and So, Hau Chi and Ip, Dennis K M and Leung, Gabriel M and Peiris, J S Malik and Cauchemez, Simon and Cowling, Benjamin J}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, year = {2023}, volume = {120}, number = {33}, pages = {e2304750120}, doi = {10.1073/pnas.2304750120}, }
Emerg Infect Dis
Effects of School-Based Preventive Measures on COVID-19 Incidence, Hong Kong, 2022.

Tim K Tsang, Xiaotong Huang, Min Whui Fong, and 4 more authors

Emerging infectious diseases, 2023

Abs DOI Bib

We show that school closures reduced COVID-19 incidence rates in children by 31%-46% in Hong Kong in 2022. After school reopening accompanied by mask mandates, daily rapid testing, and vaccination requirements, school-reported cases correlated with community incidence rates. Safe school reopening is possible when appropriate preventive measures are used.
@article{tsang2023p37490926, title = {Effects of School-Based Preventive Measures on COVID-19 Incidence, Hong Kong, 2022.}, author = {Tsang, Tim K and Huang, Xiaotong and Fong, Min Whui and Wang, Can and Lau, Eric H Y and Wu, Peng and Cowling, Benjamin J}, journal = {Emerging infectious diseases}, year = {2023}, volume = {29}, number = {9}, pages = {1850-1854}, doi = {10.3201/eid2909.221897}, }
Res Sq
Revisiting assumptions in test-negative studies for estimating vaccine effectiveness: the need for a clinical case definition.

Sheena Sullivan, Arseniy Khvorov, Xiaotong Huang, and 6 more authors

Research square, 2023

Abs DOI Bib

Test negative studies have been used extensively for the estimation of COVID-19 vaccine effectiveness (VE). Such studies are able to estimate VE against medically-attended illness under certain assumptions. Selection bias may be present if the probability of participation is associated with vaccination or COVID-19, but this can be mitigated through use of a clinical case definition to screen patients for eligibility, which increases the likelihood that cases and non-cases come from the same source population. We examined the extent to which this type of bias could harm COVID-19 VE through systematic review and simulation. A systematic review of test-negative studies was re-analysed to identify studies ignoring the need for clinical criteria. Studies using a clinical case definition had a lower pooled VE estimate compared with studies that did not. Simulations varied the probability of selection by case and vaccination status. Positive bias away from the null (i.e., inflated VE consistent with the systematic review) was observed when there was a higher proportion of healthy, vaccinated non-cases, which may occur if a dataset contains many results from asymptomatic screening in settings where vaccination coverage is high. We provide an html tool for researchers to explore site-specific sources of selection bias in their own studies. We recommend all group consider the potential for selection bias in their vaccine effectiveness studies, particularly when using administrative data.
@article{sullivan2023p37205486, title = {Revisiting assumptions in test-negative studies for estimating vaccine effectiveness: the need for a clinical case definition.}, author = {Sullivan, Sheena and Khvorov, Arseniy and Huang, Xiaotong and Wang, Can and Ainslie, Kylie and Nealon, Joshua and Yang, Bingyi and Cowling, Benjamin and Tsang, Tim}, journal = {Research square}, year = {2023}, doi = {10.21203/rs.3.rs-2689147/v1}, }
Nat Commun
Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong.

Ruopeng Xie, Kimberly M Edwards, Dillon C Adam, Kathy S M Leung, Tim K Tsang, Shreya Gurung, Weijia Xiong, Xiaoman Wei, Daisy Y M Ng, Gigi Y Z Liu, Pavithra Krishnan, Lydia D J Chang, Samuel M S Cheng, Haogao Gu, Gilman K H Siu, Joseph T Wu, Gabriel M Leung, Malik Peiris, Benjamin J Cowling, Leo L M Poon, and Vijaykrishna Dhanasekaran

Nature communications, 2023

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Hong Kong experienced a surge of Omicron BA.2 infections in early 2022, resulting in one of the highest per-capita death rates of COVID-19. The outbreak occurred in a dense population with low immunity towards natural SARS-CoV-2 infection, high vaccine hesitancy in vulnerable populations, comprehensive disease surveillance and the capacity for stringent public health and social measures (PHSMs). By analyzing genome sequences and epidemiological data, we reconstructed the epidemic trajectory of BA.2 wave and found that the initial BA.2 community transmission emerged from cross-infection within hotel quarantine. The rapid implementation of PHSMs suppressed early epidemic growth but the effective reproduction number (R(e)) increased again during the Spring festival in early February and remained around 1 until early April. Independent estimates of point prevalence and incidence using phylodynamics also showed extensive superspreading at this time, which likely contributed to the rapid expansion of the epidemic. Discordant inferences based on genomic and epidemiological data underscore the need for research to improve near real-time epidemic growth estimates by combining multiple disparate data sources to better inform outbreak response policy.
@article{xie2023p37105966, title = {Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong.}, author = {Xie, Ruopeng and Edwards, Kimberly M and Adam, Dillon C and Leung, Kathy S M and Tsang, Tim K and Gurung, Shreya and Xiong, Weijia and Wei, Xiaoman and Ng, Daisy Y M and Liu, Gigi Y Z and Krishnan, Pavithra and Chang, Lydia D J and Cheng, Samuel M S and Gu, Haogao and Siu, Gilman K H and Wu, Joseph T and Leung, Gabriel M and Peiris, Malik and Cowling, Benjamin J and Poon, Leo L M and Dhanasekaran, Vijaykrishna}, journal = {Nature communications}, year = {2023}, volume = {14}, number = {1}, pages = {2422}, doi = {10.1038/s41467-023-38201-5}, }
Elife
The effect of variation of individual infectiousness on SARS-CoV-2 transmission in households.

Tim K Tsang, Xiaotong Huang, Can Wang, and 4 more authors

eLife, 2023

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Quantifying variation of individual infectiousness is critical to inform disease control. Previous studies reported substantial heterogeneity in transmission of many infectious diseases including SARS-CoV-2. However, those results are difficult to interpret since the number of contacts is rarely considered in such approaches. Here, we analyze data from 17 SARS-CoV-2 household transmission studies conducted in periods dominated by ancestral strains, in which the number of contacts was known. By fitting individual-based household transmission models to these data, accounting for number of contacts and baseline transmission probabilities, the pooled estimate suggests that the 20% most infectious cases have 3.1-fold (95% confidence interval: 2.2- to 4.2-fold) higher infectiousness than average cases, which is consistent with the observed heterogeneity in viral shedding. Household data can inform the estimation of transmission heterogeneity, which is important for epidemic management.
@article{tsang2023p36880191, title = {The effect of variation of individual infectiousness on SARS-CoV-2 transmission in households.}, author = {Tsang, Tim K and Huang, Xiaotong and Wang, Can and Chen, Sijie and Yang, Bingyi and Cauchemez, Simon and Cowling, Benjamin John}, journal = {eLife}, year = {2023}, volume = {12}, doi = {10.7554/eLife.82611}, }
npj Vaccines
Impact of host genetic polymorphisms on response to inactivated influenza vaccine in children.

Tim K Tsang, Can Wang, Nicole N Y Tsang, and 6 more authors

NPJ vaccines, 2023

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In randomized controlled trials of influenza vaccination, 550 children received trivalent-inactivated influenza vaccine, permitting us to explore relationship between vaccine response and host single nucleotide polymorphisms (SNPs) in 23 candidate genes with adjustment of multiple testing. For host SNPs in TLR7-1817G/T (rs5741880), genotype GT was associated with lower odds (OR: 0.22, 95% CI: 0.09, 0.53) of have post-vaccination hemagglutination-inhibiting (HAI) titers >/=40, compared with genotype GG and TT combined under the over-dominant model. For host SNPs in TLR8-129G/C (rs3764879), genotype GT was associated with lower odds (OR: 0.47; 95% CI: 0.28, 0.80) of have post vaccination HAI titers >/=40 compared with genotype GG and AA combined under the over-dominant model. Our results could contribute to the development of better vaccines that may offer improved protection to all recipients.
@article{tsang2023p36804941, title = {Impact of host genetic polymorphisms on response to inactivated influenza vaccine in children.}, author = {Tsang, Tim K and Wang, Can and Tsang, Nicole N Y and Fang, Vicky J and Perera, Ranawaka A P M and Malik Peiris, J S and Leung, Gabriel M and Cowling, Benjamin J and Ip, Dennis K M}, journal = {NPJ vaccines}, year = {2023}, volume = {8}, number = {1}, pages = {21}, doi = {10.1038/s41541-023-00621-1}, }
China CDC
Characterizing Human Collective Behaviors During COVID-19 - Hong Kong SAR, China, 2020.

Zhanwei Du, Xiao Zhang, Lin Wang, Sidan Yao, Yuan Bai, Qi Tan, Xiaoke Xu, Sen Pei, Jingyi Xiao, Tim K Tsang, Qiuyan Liao, Eric H Y Lau, Peng Wu, Chao Gao, and Benjamin J Cowling

China CDC weekly, 2023

Abs DOI Bib

WHAT IS ALREADY KNOWN ABOUT THIS TOPIC? People are likely to engage in collective behaviors online during extreme events, such as the coronavirus disease 2019 (COVID-19) crisis, to express awareness, take action, and work through concerns. WHAT IS ADDED BY THIS REPORT? This study offers a framework for evaluating interactions among individuals’ emotions, perceptions, and online behaviors in Hong Kong Special Administrative Region (SAR) during the first two waves of COVID-19 (February to June 2020). Its results indicate a strong correlation between online behaviors, such as Google searches, and the real-time reproduction numbers. To validate the model’s output of risk perception, this investigation conducted 10 rounds of cross-sectional telephone surveys on 8,593 local adult residents from February 1 through June 20 in 2020 to quantify risk perception levels over time. WHAT ARE THE IMPLICATIONS FOR PUBLIC HEALTH PRACTICE? Compared to the survey results, the estimates of the risk perception of individuals using our network-based mechanistic model capture 80% of the trend of people’s risk perception (individuals who are worried about being infected) during the studied period. We may need to reinvigorate the public by involving people as part of the solution that reduced the risk to their lives.
@article{du2023p36777899, title = {Characterizing Human Collective Behaviors During COVID-19 - Hong Kong SAR, China, 2020.}, author = {Du, Zhanwei and Zhang, Xiao and Wang, Lin and Yao, Sidan and Bai, Yuan and Tan, Qi and Xu, Xiaoke and Pei, Sen and Xiao, Jingyi and Tsang, Tim K and Liao, Qiuyan and Lau, Eric H Y and Wu, Peng and Gao, Chao and Cowling, Benjamin J}, journal = {China CDC weekly}, year = {2023}, volume = {5}, number = {4}, pages = {71-75}, doi = {10.46234/ccdcw2023.014}, }
Epidemiology
Accounting for the Potential of Overdispersion in Estimation of the Time-varying Reproduction Number.

Faith Ho, Kris V Parag, Dillon C Adam, Eric H Y Lau, Benjamin J Cowling, and Tim K Tsang

Epidemiology (Cambridge, Mass.), 2023

Abs DOI Bib

BACKGROUND: The time-varying reproduction number, Rt, is commonly used to monitor the transmissibility of an infectious disease during an epidemic, but standard methods for estimating Rt seldom account for the impact of overdispersion on transmission. METHODS: We developed a negative binomial framework to estimate Rt and a time-varying dispersion parameter (kt). We applied the framework to COVID-19 incidence data in Hong Kong in 2020 and 2021. We conducted a simulation study to compare the performance of our model with the conventional Poisson-based approach. RESULTS: Our framework estimated an Rt peaking around 4 (95% credible interval = 3.13, 4.30), similar to that from the Poisson approach but with a better model fit. Our approach further estimated kt <0.5 at the start of both waves, indicating appreciable heterogeneity in transmission. We also found that kt decreased sharply to around 0.4 when a large cluster of infections occurred. CONCLUSIONS: Our proposed approach can contribute to the estimation of Rt and monitoring of the time-varying dispersion parameters to quantify the role of superspreading.
@article{ho2023p36722802, title = {Accounting for the Potential of Overdispersion in Estimation of the Time-varying Reproduction Number.}, author = {Ho, Faith and Parag, Kris V and Adam, Dillon C and Lau, Eric H Y and Cowling, Benjamin J and Tsang, Tim K}, journal = {Epidemiology (Cambridge, Mass.)}, year = {2023}, volume = {34}, number = {2}, pages = {201-205}, doi = {10.1097/EDE.0000000000001563}, }
Emerg Infect Dis
Epidemiology of SARS-CoV-2 Omicron BA.5 Infections, Macau, June-July 2022.

Weijia Xiong, Liping Peng, Tim K Tsang, and 1 more author

Emerging infectious diseases, 2023

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A SARS-CoV-2 Omicron BA.5 outbreak occurred in Macau from mid-June through July 2022. Out of >1,800 laboratory-confirmed cases, most were mild or asymptomatic; only 6 deaths were recorded. The outbreak was controlled through stringent public health and social measures, such as repeated universal testing and a stay-at-home order lasting 2 weeks.
@article{xiong2023p36648122, title = {Epidemiology of SARS-CoV-2 Omicron BA.5 Infections, Macau, June-July 2022.}, author = {Xiong, Weijia and Peng, Liping and Tsang, Tim K and Cowling, Benjamin J}, journal = {Emerging infectious diseases}, year = {2023}, volume = {29}, number = {2}, pages = {453-456}, doi = {10.3201/eid2902.221243}, }
J Infect Dis
Investigation of the Impact of Childhood Immune Imprinting on Birth Year-Specific Risk of Clinical Infection During Influenza A Virus Epidemics in Hong Kong.

Tim K Tsang, Katelyn M Gostic, Sijie Chen, and 5 more authors

The Journal of infectious diseases, 2023

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Influenza imprinting reduces risks of influenza A virus clinical infection by 40%-90%, estimated from surveillance data in western countries. We analyzed surveillance data from 2010 to 2019 in Hong Kong. Based on the best model, which included hemagglutinin group-level imprinting, we estimated that individuals imprinted to H1N1 or H2N2 had a 17% (95% confidence interval [CI], 3%-28%) lower risk of H1N1 clinical infection, and individuals imprinted to H3N2 would have 12% (95% CI, -3% to 26%) lower risk of H3N2 clinical infection. These estimated imprinting protections were weaker than estimates in western countries. Identifying factors affecting imprinting protections is important for control policies and disease modeling.
@article{tsang2023p36637115, title = {Investigation of the Impact of Childhood Immune Imprinting on Birth Year-Specific Risk of Clinical Infection During Influenza A Virus Epidemics in Hong Kong.}, author = {Tsang, Tim K and Gostic, Katelyn M and Chen, Sijie and Wang, Yifan and Arevalo, Philip and Lau, Eric H Y and Cobey, Sarah and Cowling, Benjamin J}, journal = {The Journal of infectious diseases}, year = {2023}, volume = {228}, number = {2}, pages = {169-172}, doi = {10.1093/infdis/jiad009}, }
OFID
Association Between Population-Level Factors and Household Secondary Attack Rate of SARS-CoV-2: A Systematic Review and Meta-analysis.

Can Wang, Xiaotong Huang, Eric H Y Lau, Benjamin J Cowling, and Tim K Tsang

Open forum infectious diseases, 2023

Abs DOI Bib

BACKGROUND: Accurate estimation of household secondary attack rate (SAR) is crucial to understand the transmissibility of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The impact of population-level factors, such as transmission intensity in the community, on SAR estimates is rarely explored. METHODS: In this study, we included articles with original data to compute the household SAR. To determine the impact of transmission intensity in the community on household SAR estimates, we explored the association between SAR estimates and the incidence rate of cases by country during the study period. RESULTS: We identified 163 studies to extract data on SARs from 326 031 cases and 2 009 859 household contacts. The correlation between the incidence rate of cases during the study period and SAR estimates was 0.37 (95% CI, 0.24-0.49). We found that doubling the incidence rate of cases during the study period was associated with a 1.2% (95% CI, 0.5%-1.8%) higher household SAR. CONCLUSIONS: Our findings suggest that the incidence rate of cases during the study period is associated with higher SAR. Ignoring this factor may overestimate SARs, especially for regions with high incidences, which further impacts control policies and epidemiological characterization of emerging variants.
@article{wang2023p36655186, title = {Association Between Population-Level Factors and Household Secondary Attack Rate of SARS-CoV-2: A Systematic Review and Meta-analysis.}, author = {Wang, Can and Huang, Xiaotong and Lau, Eric H Y and Cowling, Benjamin J and Tsang, Tim K}, journal = {Open forum infectious diseases}, year = {2023}, volume = {10}, number = {1}, pages = {ofac676}, doi = {10.1093/ofid/ofac676}, }
JMIR PH
Monitoring School Absenteeism for Influenza-Like Illness Surveillance: Systematic Review and Meta-analysis.

Tim K Tsang, Xiaotong Huang, Yiyang Guo, and 3 more authors

JMIR public health and surveillance, 2023

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BACKGROUND: Influenza causes considerable disease burden each year, particularly in children. Monitoring school absenteeism has long been proposed as a surveillance tool of influenza activity in the community, but the practice of school absenteeism could be varying, and the potential of such usage remains unclear. OBJECTIVE: The aim of this paper is to determine the potential of monitoring school absenteeism as a surveillance tool of influenza. METHODS: We conducted a systematic review of the published literature on the relationship between school absenteeism and influenza activity in the community. We categorized the types of school absenteeism and influenza activity in the community to determine the correlation between these data streams. We also extracted this correlation with different lags in community surveillance to determine the potential of using school absenteeism as a leading indicator of influenza activity. RESULTS: Among the 35 identified studies, 22 (63%), 12 (34%), and 8 (23%) studies monitored all-cause, illness-specific, and influenza-like illness (ILI)-specific absents, respectively, and 16 (46%) used quantitative approaches and provided 33 estimates on the temporal correlation between school absenteeism and influenza activity in the community. The pooled estimate of correlation between school absenteeism and community surveillance without lag, with 1-week lag, and with 2-week lag were 0.44 (95% CI 0.34, 0.53), 0.29 (95% CI 0.15, 0.42), and 0.21 (95% CI 0.11, 0.31), respectively. The correlation between influenza activity in the community and ILI-specific absenteeism was higher than that between influenza activity in community all-cause absenteeism. Among the 19 studies that used qualitative approaches, 15 (79%) concluded that school absenteeism was in concordance with, coincided with, or was associated with community surveillance. Of the 35 identified studies, only 6 (17%) attempted to predict influenza activity in the community from school absenteeism surveillance. CONCLUSIONS: There was a moderate correlation between school absenteeism and influenza activity in the community. The smaller correlation between school absenteeism and community surveillance with lag, compared to without lag, suggested that careful application was required to use school absenteeism as a leading indicator of influenza epidemics. ILI-specific absenteeism could monitor influenza activity more closely, but the required resource or school participation willingness may require careful consideration to weight against the associated costs. Further development is required to use and optimize the use of school absenteeism to predict influenza activity. In particular, the potential of using more advanced statistical models and validation of the predictions should be explored.
@article{tsang2023p36630159, title = {Monitoring School Absenteeism for Influenza-Like Illness Surveillance: Systematic Review and Meta-analysis.}, author = {Tsang, Tim K and Huang, Xiaotong and Guo, Yiyang and Lau, Eric H Y and Cowling, Benjamin J and Ip, Dennis K M}, journal = {JMIR public health and surveillance}, year = {2023}, volume = {9}, pages = {e41329}, doi = {10.2196/41329}, }

2022

Nat Commun
Inferring time-varying generation time, serial interval, and incubation period distributions for COVID-19.

Dongxuan Chen, Yiu-Chung Lau, Xiao-Ke Xu, Lin Wang, Zhanwei Du, Tim K Tsang, Peng Wu, Eric H Y Lau, Jacco Wallinga, Benjamin J Cowling, and Sheikh Taslim Ali

Nature communications, 2022

Abs DOI Bib

The generation time distribution, reflecting the time between successive infections in transmission chains, is a key epidemiological parameter for describing COVID-19 transmission dynamics. However, because exact infection times are rarely known, it is often approximated by the serial interval distribution. This approximation holds under the assumption that infectors and infectees share the same incubation period distribution, which may not always be true. We estimated incubation period and serial interval distributions using 629 transmission pairs reconstructed by investigating 2989 confirmed cases in China in January-February 2020, and developed an inferential framework to estimate the generation time distribution that accounts for variation over time due to changes in epidemiology, sampling biases and public health and social measures. We identified substantial reductions over time in the serial interval and generation time distributions. Our proposed method provides more reliable estimation of the temporal variation in the generation time distribution, improving assessment of transmission dynamics.
@article{chen2022p36513688, title = {Inferring time-varying generation time, serial interval, and incubation period distributions for COVID-19.}, author = {Chen, Dongxuan and Lau, Yiu-Chung and Xu, Xiao-Ke and Wang, Lin and Du, Zhanwei and Tsang, Tim K and Wu, Peng and Lau, Eric H Y and Wallinga, Jacco and Cowling, Benjamin J and Ali, Sheikh Taslim}, journal = {Nature communications}, year = {2022}, volume = {13}, number = {1}, pages = {7727}, doi = {10.1038/s41467-022-35496-8}, }
PNAS
Pandemic fatigue impedes mitigation of COVID-19 in Hong Kong.

Zhanwei Du, Lin Wang, Songwei Shan, Dickson Lam, Tim K Tsang, Jingyi Xiao, Huizhi Gao, Bingyi Yang, Sheikh Taslim Ali, Sen Pei, Isaac Chun-Hai Fung, Eric H Y Lau, Qiuyan Liao, Peng Wu, Lauren Ancel Meyers, Gabriel M Leung, and Benjamin J Cowling

Proceedings of the National Academy of Sciences of the United States of America, 2022

Abs DOI Bib

Hong Kong has implemented stringent public health and social measures (PHSMs) to curb each of the four COVID-19 epidemic waves since January 2020. The third wave between July and September 2020 was brought under control within 2 m, while the fourth wave starting from the end of October 2020 has taken longer to bring under control and lasted at least 5 mo. Here, we report the pandemic fatigue as one of the potential reasons for the reduced impact of PHSMs on transmission in the fourth wave. We contacted either 500 or 1,000 local residents through weekly random-digit dialing of landlines and mobile telephones from May 2020 to February 2021. We analyze the epidemiological impact of pandemic fatigue by using the large and detailed cross-sectional telephone surveys to quantify risk perception and self-reported protective behaviors and mathematical models to incorporate population protective behaviors. Our retrospective prediction suggests that an increase of 100 daily new reported cases would lead to 6.60% (95% CI: 4.03, 9.17) more people worrying about being infected, increase 3.77% (95% CI: 2.46, 5.09) more people to avoid social gatherings, and reduce the weekly mean reproduction number by 0.32 (95% CI: 0.20, 0.44). Accordingly, the fourth wave would have been 14% (95% CI%: -53%, 81%) smaller if not for pandemic fatigue. This indicates the important role of mitigating pandemic fatigue in maintaining population protective behaviors for controlling COVID-19.
@article{du2022p36417445, title = {Pandemic fatigue impedes mitigation of COVID-19 in Hong Kong.}, author = {Du, Zhanwei and Wang, Lin and Shan, Songwei and Lam, Dickson and Tsang, Tim K and Xiao, Jingyi and Gao, Huizhi and Yang, Bingyi and Ali, Sheikh Taslim and Pei, Sen and Fung, Isaac Chun-Hai and Lau, Eric H Y and Liao, Qiuyan and Wu, Peng and Meyers, Lauren Ancel and Leung, Gabriel M and Cowling, Benjamin J}, journal = {Proceedings of the National Academy of Sciences of the United States of America}, year = {2022}, volume = {119}, number = {48}, pages = {e2213313119}, doi = {10.1073/pnas.2213313119}, }
Viruses
Indirect Protection from Vaccinating Children against Influenza A Virus Infection in Households.

Tim K Tsang, Can Wang, Vicky J Fang, and 7 more authors

Viruses, 2022

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Influenza vaccination is an important intervention to prevent influenza virus infection. Our previous analysis suggested that indirect protection is limited in an influenza B epidemic in Hong Kong. We further analyzed six influenza A epidemics to determine such potential. We applied a statistical model to estimate household transmission dynamics in the 3 influenza A(H3N2) and 3 pandemic influenza A(H1N1) epidemics. Then, we estimated the reduction in infection risk among unvaccinated household members when all children in households are vaccinated, with different assumptions on vaccine efficacy (VE). In the optimal scenario that VE was 70%, the reduction to the total probability of infection was only marginal, with relative probabilities ranged from 0.91-0.94 when all children in households were vaccinated because community was by far the main source of infection during the six epidemics in our study. The proportion of cases attributed to household transmission was 10% (95% CrI: 7%, 13%). Individual influenza vaccination is important even when other household members are vaccinated, given the degree of indirect protection is small.
@article{tsang2022p36298653, title = {Indirect Protection from Vaccinating Children against Influenza A Virus Infection in Households.}, author = {Tsang, Tim K and Wang, Can and Fang, Vicky J and Perera, Ranawaka A P M and So, Hau Chi and Ip, Dennis K M and Peiris, J S Malik and Leung, Gabriel M and Cauchemez, Simon and Cowling, Benjamin J}, journal = {Viruses}, year = {2022}, volume = {14}, number = {10}, doi = {10.3390/v14102097}, }
Lancet GH
Prediction of upcoming global infection burden of influenza seasons after relaxation of public health and social measures during the COVID-19 pandemic: a modelling study.

Sheikh Taslim Ali, Yiu Chung Lau, Songwei Shan, Sukhyun Ryu, Zhanwei Du, Lin Wang, Xiao-Ke Xu, Dongxuan Chen, Jiaming Xiong, Jungyeon Tae, Tim K Tsang, Peng Wu, Eric H Y Lau, and Benjamin J Cowling

The Lancet. Global health, 2022

Abs DOI Bib

BACKGROUND: The transmission dynamics of influenza were affected by public health and social measures (PHSMs) implemented globally since early 2020 to mitigate the COVID-19 pandemic. We aimed to assess the effect of COVID-19 PHSMs on the transmissibility of influenza viruses and to predict upcoming influenza epidemics. METHODS: For this modelling study, we used surveillance data on influenza virus activity for 11 different locations and countries in 2017-22. We implemented a data-driven mechanistic predictive modelling framework to predict future influenza seasons on the basis of pre-COVID-19 dynamics and the effect of PHSMs during the COVID-19 pandemic. We simulated the potential excess burden of upcoming influenza epidemics in terms of fold rise in peak magnitude and epidemic size compared with pre-COVID-19 levels. We also examined how a proactive influenza vaccination programme could mitigate this effect. FINDINGS: We estimated that COVID-19 PHSMs reduced influenza transmissibility by a maximum of 17.3% (95% CI 13.3-21.4) to 40.6% (35.2-45.9) and attack rate by 5.1% (1.5-7.2) to 24.8% (20.8-27.5) in the 2019-20 influenza season. We estimated a 10-60% increase in the population susceptibility for influenza, which might lead to a maximum of 1-5-fold rise in peak magnitude and 1-4-fold rise in epidemic size for the upcoming 2022-23 influenza season across locations, with a significantly higher fold rise in Singapore and Taiwan. The infection burden could be mitigated by additional proactive one-off influenza vaccination programmes. INTERPRETATION: Our results suggest the potential for substantial increases in infection burden in upcoming influenza seasons across the globe. Strengthening influenza vaccination programmes is the best preventive measure to reduce the effect of influenza virus infections in the community. FUNDING: Health and Medical Research Fund, Hong Kong.
@article{ali2022p36240828, title = {Prediction of upcoming global infection burden of influenza seasons after relaxation of public health and social measures during the COVID-19 pandemic: a modelling study.}, author = {Ali, Sheikh Taslim and Lau, Yiu Chung and Shan, Songwei and Ryu, Sukhyun and Du, Zhanwei and Wang, Lin and Xu, Xiao-Ke and Chen, Dongxuan and Xiong, Jiaming and Tae, Jungyeon and Tsang, Tim K and Wu, Peng and Lau, Eric H Y and Cowling, Benjamin J}, journal = {The Lancet. Global health}, year = {2022}, volume = {10}, number = {11}, pages = {e1612-e1622}, doi = {10.1016/S2214-109X(22)00358-8}, }
J Infect Dis
Effectiveness of CoronaVac and BNT162b2 Vaccines Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.2 Infections in Hong Kong.

Bingyi Yang, Irene O L Wong, Jingyi Xiao, Tim K Tsang, Qiuyan Liao, and Benjamin J Cowling

The Journal of infectious diseases, 2022

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There is limited evidence on vaccine effectiveness against asymptomatic or mild Omicron infections. We estimated that recent third doses of messenger RNA or inactivated vaccines reduced the risk of self-reported infection by 52% (95% confidence interval, 17%-73%) among randomly sampled adults during the Omicron BA.2-dominated surge in Hong Kong.
@article{yang2022p36054016, title = {Effectiveness of CoronaVac and BNT162b2 Vaccines Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.2 Infections in Hong Kong.}, author = {Yang, Bingyi and Wong, Irene O L and Xiao, Jingyi and Tsang, Tim K and Liao, Qiuyan and Cowling, Benjamin J}, journal = {The Journal of infectious diseases}, year = {2022}, volume = {226}, number = {8}, pages = {1382-1384}, doi = {10.1093/infdis/jiac360}, }

JAMA NO

Association Between the Relaxation of Public Health and Social Measures and Transmission of the SARS-CoV-2 Omicron Variant in South Korea.

Sukhyun Ryu, Changhee Han, Dasom Kim, Tim K Tsang, Benjamin J Cowling, and Sunmi Lee

JAMA network open, 2022

Abs DOI Bib

@article{ryu2022p35960524,
  title = {Association Between the Relaxation of Public Health and Social Measures and Transmission of the SARS-CoV-2 Omicron Variant in South Korea.},
  author = {Ryu, Sukhyun and Han, Changhee and Kim, Dasom and Tsang, Tim K and Cowling, Benjamin J and Lee, Sunmi},
  journal = {JAMA network open},
  year = {2022},
  volume = {5},
  number = {8},
  pages = {e2225665},
  doi = {10.1001/jamanetworkopen.2022.25665},
}

BMC Med
Investigation of CD4 and CD8 T cell-mediated protection against influenza A virus in a cohort study.

Tim K Tsang, Kwok-Tai Lam, Yinping Liu, and 7 more authors

BMC medicine, 2022

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BACKGROUND: The protective effect of T cell-mediated immunity against influenza virus infections in natural settings remains unclear, especially in seasonal epidemics. METHODS: To explore the potential of such protection, we analyzed the blood samples collected longitudinally in a community-based study and covered the first wave of pandemic H1N1 (pH1N1), two subsequent pH1N1 epidemics, and three seasonal H3N2 influenza A epidemics (H3N2) for which we measured pre-existing influenza virus-specific CD4 and CD8 T cell responses by intracellular IFN-gamma staining assay for 965 whole blood samples. RESULTS: Based on logistic regression, we found that higher pre-existing influenza virus-specific CD4 and CD8 T cell responses were associated with lower infection odds for corresponding subtypes. Every fold increase in H3N2-specific CD4 and CD8 T cells was associated with 28% (95% CI 8%, 44%) and 26% (95% CI 8%, 41%) lower H3N2 infection odds, respectively. Every fold increase in pre-existing seasonal H1N1 influenza A virus (sH1N1)-specific CD4 and CD8 T cells was associated with 28% (95% CI 11%, 41%) and 22% (95% CI 8%, 33%) lower pH1N1 infection odds, respectively. We observed the same associations for individuals with pre-epidemic hemagglutination inhibition (HAI) titers < 40. There was no correlation between pre-existing influenza virus-specific CD4 and CD8 T cell response and HAI titer. CONCLUSIONS: We demonstrated homosubtypic and cross-strain protection against influenza infections was associated with T cell response, especially CD4 T cell response. These protections were independent of the protection associated with HAI titer. Therefore, T cell response could be an assessment of individual and population immunity for future epidemics and pandemics, in addition to using HAI titer.
@article{tsang2022p35858844, title = {Investigation of CD4 and CD8 T cell-mediated protection against influenza A virus in a cohort study.}, author = {Tsang, Tim K and Lam, Kwok-Tai and Liu, Yinping and Fang, Vicky J and Mu, Xiaofeng and Leung, Nancy H L and Peiris, J S Malik and Leung, Gabriel M and Cowling, Benjamin J and Tu, Wenwei}, journal = {BMC medicine}, year = {2022}, volume = {20}, number = {1}, pages = {230}, doi = {10.1186/s12916-022-02429-7}, }
Emerg Infect Dis
Determining Existing Human Population Immunity as Part of Assessing Influenza Pandemic Risk.

Jonathan Tin Lai Cheung, Tim K Tsang, Hui-Ling Yen, and 5 more authors

Emerging infectious diseases, 2022

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Zoonotic influenza infections continue to threaten human health. Ongoing surveillance and risk assessment of animal viruses are needed for pandemic preparedness, and population immunity is an important component of risk assessment. We determined age-stratified hemagglutinin inhibition seroprevalence against 5 swine influenza viruses circulating in Hong Kong and Guangzhou in China. Using hemagglutinin inhibition seroprevalence and titers, we modeled the effect of population immunity on the basic reproduction number (R(0)) if each virus were to become transmissible among humans. Among 353 individual serum samples, we reported low seroprevalence for triple-reassortant H1N2 and Eurasian avian-like H1N1 influenza viruses, which would reduce R(0) by only 18%-20%. The smallest R(0) needed to cause a pandemic was 1.22-1.24, meaning existing population immunity would be insufficient to block the spread of these H1N1 or H1N2 variants. For human-origin H3N2, existing population immunity could suppress R(0) by 47%, thus reducing pandemic risk.
@article{cheung2022p35447069, title = {Determining Existing Human Population Immunity as Part of Assessing Influenza Pandemic Risk.}, author = {Cheung, Jonathan Tin Lai and Tsang, Tim K and Yen, Hui-Ling and Perera, Ranawaka A P M and Mok, Chris Ka Pun and Lin, Yong Ping and Cowling, Benjamin J and Peiris, Malik}, journal = {Emerging infectious diseases}, year = {2022}, volume = {28}, number = {5}, pages = {977-985}, doi = {10.3201/eid2805.211965}, }
J Infect Dis
Biphasic Waning of Hemagglutination Inhibition Antibody Titers After Influenza Vaccination in Children.

Weijia Xiong, Tim K Tsang, Ranawaka A P M Perera, and 5 more authors

The Journal of infectious diseases, 2022

Abs DOI Bib

We explored the potential for a biphasic pattern in waning of antibody titers after influenza vaccination. We collected blood samples in a randomized controlled trial of influenza vaccination in children and tested them with hemagglutination inhibition assays for influenza A(H3N2) and influenza B/Victoria lineage. Using piecewise log-linear mixed-effects models, we found evidence for a faster initial waning of antibody titers for the first 1-2 years after vaccination and then slower longer-term declines. Children with higher postvaccination titers had faster antibody decay.
@article{xiong2022p35380689, title = {Biphasic Waning of Hemagglutination Inhibition Antibody Titers After Influenza Vaccination in Children.}, author = {Xiong, Weijia and Tsang, Tim K and Perera, Ranawaka A P M and Leung, Nancy H L and Fang, Vicky J and Barr, Ian G and Malik Peiris, J S and Cowling, Benjamin J}, journal = {The Journal of infectious diseases}, year = {2022}, volume = {226}, number = {6}, pages = {1022-1026}, doi = {10.1093/infdis/jiac117}, }
Nat Commun
Reconstructing antibody dynamics to estimate the risk of influenza virus infection.

Tim K Tsang, Ranawaka A P M Perera, Vicky J Fang, and 8 more authors

Nature communications, 2022

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For >70 years, a 4-fold or greater rise in antibody titer has been used to confirm influenza virus infections in paired sera, despite recognition that this heuristic can lack sensitivity. Here we analyze with a novel Bayesian model a large cohort of 2353 individuals followed for up to 5 years in Hong Kong to characterize influenza antibody dynamics and develop an algorithm to improve the identification of influenza virus infections. After infection, we estimate that hemagglutination-inhibiting (HAI) titers were boosted by 16-fold on average and subsequently decrease by 14% per year. In six epidemics, the infection risks for adults were 3%-19% while the infection risks for children were 1.6-4.4 times higher than that of younger adults. Every two-fold increase in pre-epidemic HAI titer was associated with 19%-58% protection against infection. Our inferential framework clarifies the contributions of age and pre-epidemic HAI titers to characterize individual infection risk.
@article{tsang2022p35322048, title = {Reconstructing antibody dynamics to estimate the risk of influenza virus infection.}, author = {Tsang, Tim K and Perera, Ranawaka A P M and Fang, Vicky J and Wong, Jessica Y and Shiu, Eunice Y and So, Hau Chi and Ip, Dennis K M and Malik Peiris, J S and Leung, Gabriel M and Cowling, Benjamin J and Cauchemez, Simon}, journal = {Nature communications}, year = {2022}, volume = {13}, number = {1}, pages = {1557}, doi = {10.1038/s41467-022-29310-8}, }
Epidemics
Variability in transmission risk of SARS-CoV-2 in close contact settings: A contact tracing study in Shandong Province, China.

Tim K Tsang, Li-Qun Fang, Anran Zhang, and 6 more authors

Epidemics, 2022

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BACKGROUND: Understanding the relative transmissibility of SARS-CoV-2 virus across different contact settings and the possibility of superspreading events is important for prioritizing disease control. Such assessment requires proper consideration of individual level exposure history, which is made possible by contact tracing. METHODS: The case-ascertained study in Shandong, China including 97 laboratory-confirmed index cases and 3158 close contacts. All close contacts were quarantined after their last exposure of index cases. Contacts were tested for COVID-19 regularly by PCR to identify both symptomatic and asymptomatic infections. We developed a Bayesian transmission model to the contact tracing data to account for different duration of exposure among individuals to transmission risk in different settings, and the heterogeneity of infectivity of cases. RESULTS: We estimate secondary attack rates (SAR) to be 39% (95% credible interval (CrI): 20-64%) in households, 30% (95% CrI: 11-67%) in healthcare facilities, 23% (95% CrI: 7-51%) at workplaces, and 4% (95% CrI: 1-17%) during air travel. Models allowing heterogeneity of infectivity of cases provided a better goodness-of-fit. We estimated that 64% (95% CrI: 55-72%) of cases did not generate secondary transmissions, and 20% (95% CrI: 15-26%) cases explained 80% of secondary transmissions. CONCLUSIONS: Household, healthcare facilities and workplaces are efficient setting for transmission. Timely identification of potential superspreaders in most transmissible settings remains crucial for containing the pandemic.
@article{tsang2022p35287110, title = {Variability in transmission risk of SARS-CoV-2 in close contact settings: A contact tracing study in Shandong Province, China.}, author = {Tsang, Tim K and Fang, Li-Qun and Zhang, Anran and Jiang, Fa-Chun and Ruan, Shi-Man and Liu, Lan-Zheng and Cowling, Benjamin J and Liu, Wei and Yang, Yang}, journal = {Epidemics}, year = {2022}, volume = {39}, pages = {100553}, doi = {10.1016/j.epidem.2022.100553}, }
Nat Commun
Incorporating temporal distribution of population-level viral load enables real-time estimation of COVID-19 transmission.

Yun Lin, Bingyi Yang, Sarah Cobey, Eric H Y Lau, Dillon C Adam, Jessica Y Wong, Helen S Bond, Justin K Cheung, Faith Ho, Huizhi Gao, Sheikh Taslim Ali, Nancy H L Leung, Tim K Tsang, Peng Wu, Gabriel M Leung, and Benjamin J Cowling

Nature communications, 2022

Abs DOI Bib

Many locations around the world have used real-time estimates of the time-varying effective reproductive number ([Formula: see text]) of COVID-19 to provide evidence of transmission intensity to inform control strategies. Estimates of [Formula: see text] are typically based on statistical models applied to case counts and typically suffer lags of more than a week because of the latent period and reporting delays. Noting that viral loads tend to decline over time since illness onset, analysis of the distribution of viral loads among confirmed cases can provide insights into epidemic trajectory. Here, we analyzed viral load data on confirmed cases during two local epidemics in Hong Kong, identifying a strong correlation between temporal changes in the distribution of viral loads (measured by RT-qPCR cycle threshold values) and estimates of [Formula: see text] based on case counts. We demonstrate that cycle threshold values could be used to improve real-time [Formula: see text] estimation, enabling more timely tracking of epidemic dynamics.
@article{lin2022p35241662, title = {Incorporating temporal distribution of population-level viral load enables real-time estimation of COVID-19 transmission.}, author = {Lin, Yun and Yang, Bingyi and Cobey, Sarah and Lau, Eric H Y and Adam, Dillon C and Wong, Jessica Y and Bond, Helen S and Cheung, Justin K and Ho, Faith and Gao, Huizhi and Ali, Sheikh Taslim and Leung, Nancy H L and Tsang, Tim K and Wu, Peng and Leung, Gabriel M and Cowling, Benjamin J}, journal = {Nature communications}, year = {2022}, volume = {13}, number = {1}, pages = {1155}, doi = {10.1038/s41467-022-28812-9}, }
Emerg Infect Dis
Restaurant-Based Measures to Control Community Transmission of COVID-19, Hong Kong.

Faith Ho, Tim K Tsang, Huizhi Gao, and 6 more authors

Emerging infectious diseases, 2022

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Controlling transmission in restaurants is an important component of public health and social measures for coronavirus disease. We examined the effects of restaurant measures in Hong Kong. Our findings indicate that shortening operating hours did not have an effect on time-varying effective reproduction number when capacity was already reduced.
@article{ho2022p35202535, title = {Restaurant-Based Measures to Control Community Transmission of COVID-19, Hong Kong.}, author = {Ho, Faith and Tsang, Tim K and Gao, Huizhi and Xiao, Jingyi and Lau, Eric H Y and Wong, Jessica Y and Wu, Peng and Leung, Gabriel M and Cowling, Benjamin J}, journal = {Emerging infectious diseases}, year = {2022}, volume = {28}, number = {3}, pages = {759-761}, doi = {10.3201/eid2803.211015}, }
Clin Infect Dis
Universal Community Nucleic Acid Testing for Coronavirus Disease 2019 (COVID-19) in Hong Kong Reveals Insights Into Transmission Dynamics: A Cross-Sectional and Modeling Study.

Bingyi Yang, Tim K Tsang, Huizhi Gao, and 10 more authors

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022

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BACKGROUND: Testing of an entire community has been used as an approach to control coronavirus disease 2019 (COVID-19). In Hong Kong, a universal community testing program (UCTP) was implemented at the fadeout phase of a community epidemic in July to September 2020. We described the utility of the UCTP in finding unrecognized infections and analyzed data from the UCTP and other sources to characterize transmission dynamics. METHODS: We described the characteristics of people participating in the UCTP and compared the clinical and epidemiological characteristics of COVID-19 cases detected by the UCTP versus those detected by clinical diagnosis and public health surveillance (CDPHS). We developed a Bayesian model to estimate the age-specific incidence of infection and the proportion of cases detected by CDPHS. RESULTS: In total, 1.77 million people, 24% of the Hong Kong population, participated in the UCTP from 1 to 14 September 2020. The UCTP identified 32 new infections (1.8 per 100000 samples tested), consisting of 29% of all local cases reported during the two-week UCTP period. Compared with the CDPHS, the UCTP detected a higher proportion of sporadic cases (62% vs 27%, P<.01) and identified 6 (out of 18) additional clusters during that period. We estimated that 27% (95% credible interval: 22%, 34%) of all infections were detected by the CDPHS in the third wave. CONCLUSIONS: We reported empirical evidence of the utility of population-wide COVID-19 testing in detecting unrecognized infections and clusters. Around three quarters of infections have not been identified through existing surveillance approaches including contact tracing.
@article{yang2022p34718464, title = {Universal Community Nucleic Acid Testing for Coronavirus Disease 2019 (COVID-19) in Hong Kong Reveals Insights Into Transmission Dynamics: A Cross-Sectional and Modeling Study.}, author = {Yang, Bingyi and Tsang, Tim K and Gao, Huizhi and Lau, Eric H Y and Lin, Yun and Ho, Faith and Xiao, Jingyi and Wong, Jessica Y and Adam, Dillon C and Liao, Qiuyan and Wu, Peng and Cowling, Benjamin J and Leung, Gabriel M}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2022}, volume = {75}, number = {1}, pages = {e216-e223}, doi = {10.1093/cid/ciab925}, }
Emerg Infect Dis
Effectiveness of International Travel Controls for Delaying Local Outbreaks of COVID-19.

Bingyi Yang, Sheena G Sullivan, Zhanwei Du, Tim K Tsang, and Benjamin J Cowling

Emerging infectious diseases, 2022

Abs DOI Bib

During the coronavirus disease pandemic, international travel controls have been widely adopted. To determine the effectiveness of these measures, we analyzed data from 165 countries and found that early implementation of international travel controls led to a mean delay of 5 weeks in the first epidemic peak of cases.
@article{yang2022p34647863, title = {Effectiveness of International Travel Controls for Delaying Local Outbreaks of COVID-19.}, author = {Yang, Bingyi and Sullivan, Sheena G and Du, Zhanwei and Tsang, Tim K and Cowling, Benjamin J}, journal = {Emerging infectious diseases}, year = {2022}, volume = {28}, number = {1}, pages = {251-253}, doi = {10.3201/eid2801.211944}, }
Clin Infect Dis
Estimating the Latent Period of Coronavirus Disease 2019 (COVID-19).

Hualei Xin, Yu Li, Peng Wu, Zhili Li, Eric H Y Lau, Ying Qin, Liping Wang, Benjamin J Cowling, Tim K Tsang, and Zhongjie Li

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2022

Abs DOI Bib

Using detailed exposure information on COVID-19 cases, we estimated the mean latent period to be 5.5 (95% CI: 5.1-5.9) days, shorter than the mean incubation period (6.9 days). Laboratory testing may allow shorter quarantines since 95% of COVID-19 cases shed virus within 10.6 (95% CI: 9.6-11.6) days of infection.
@article{xin2022p34453527, title = {Estimating the Latent Period of Coronavirus Disease 2019 (COVID-19).}, author = {Xin, Hualei and Li, Yu and Wu, Peng and Li, Zhili and Lau, Eric H Y and Qin, Ying and Wang, Liping and Cowling, Benjamin J and Tsang, Tim K and Li, Zhongjie}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2022}, volume = {74}, number = {9}, pages = {1678-1681}, doi = {10.1093/cid/ciab746}, }
BMC Med
Immunogenicity, efficacy, and safety of SARS-CoV-2 vaccine dose fractionation: a systematic review and meta-analysis.

Bingyi Yang, Xiaotong Huang, Huizhi Gao, Nancy H Leung, Tim K Tsang, and Benjamin J Cowling

BMC medicine, 2022

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BACKGROUND: Dose fractionation of a coronavirus disease 2019 (COVID-19) vaccine could effectively accelerate global vaccine coverage, while supporting evidence of efficacy, immunogenicity, and safety are unavailable, especially with emerging variants. METHODS: We systematically reviewed clinical trials that reported dose-finding results and estimated the dose-response relationship of neutralizing antibodies (nAbs) of COVID-19 vaccines using a generalized additive model. We predicted the vaccine efficacy against both ancestral and variants, using previously reported correlates of protection and cross-reactivity. We also reviewed and compared seroconversion to nAbs, T cell responses, and safety profiles between fractional and standard dose groups. RESULTS: We found that dose fractionation of mRNA and protein subunit vaccines could induce SARS-CoV-2-specific nAbs and T cells that confer a reasonable level of protection (i.e., vaccine efficacy > 50%) against ancestral strains and variants up to Omicron. Safety profiles of fractional doses were non-inferior to the standard dose. CONCLUSIONS: Dose fractionation of mRNA and protein subunit vaccines may be safe and effective, which would also vary depending on the characteristics of emerging variants and updated vaccine formulations.
@article{yang2022p36284331, title = {Immunogenicity, efficacy, and safety of SARS-CoV-2 vaccine dose fractionation: a systematic review and meta-analysis.}, author = {Yang, Bingyi and Huang, Xiaotong and Gao, Huizhi and Leung, Nancy H and Tsang, Tim K and Cowling, Benjamin J}, journal = {BMC medicine}, year = {2022}, volume = {20}, number = {1}, pages = {409}, doi = {10.1186/s12916-022-02600-0}, }

2021

BMJ Open
Pandemic fatigue and attenuated impact of avoidance behaviours against COVID-19 transmission in Hong Kong by cross-sectional telephone surveys.

Huizhi Gao, Zhanwei Du, Tim K Tsang, and 6 more authors

BMJ open, 2021

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OBJECTIVES: This study aims to explore the attenuated impact of reported avoidance behaviours adherence on the transmission of COVID-19 through cross-sectional surveys in Hong Kong, in order to make up for the lack of research on avoidance behaviours fatigue. DESIGN: 40 cross-sectional telephone surveys. SETTING: All districts in Hong Kong. PARTICIPANTS: 31 332 Cantonese or English-speaking participants at age of 18 years or above. METHODS: We collected data on behaviours and estimated the average effective reproduction number ([Formula: see text]) among the Hong Kong adult population during the COVID-19 epidemic wave in November-December 2020 and compared with the preceding epidemic in June-July 2020. RESULTS: We observed a reduction in adherence to voluntary avoidance behaviours due to pandemic fatigue, but continued adherence to regulated avoidance behaviours. The average [Formula: see text] during the post-work from home period was higher in November-December wave with estimated [Formula: see text] of 0.81 (95% CI: 0.75 to 0.87) compared with the June-July wave with an [Formula: see text] of 0.67 (95% CI: 0.60 to 0.75). CONCLUSIONS: The declined effectiveness of social distancing interventions in reducing COVID-19 transmission was associated with fatigue with voluntary avoidance behaviours in Hong Kong population, implying a need for the government to reinvigorate the public to maintain effective pandemic control.
@article{gao2021p34930744, title = {Pandemic fatigue and attenuated impact of avoidance behaviours against COVID-19 transmission in Hong Kong by cross-sectional telephone surveys.}, author = {Gao, Huizhi and Du, Zhanwei and Tsang, Tim K and Xiao, Jingyi and Shan, Songwei and Liao, Qiuyan and Wu, Peng and Leung, Gabriel M and Cowling, Benjamin J}, journal = {BMJ open}, year = {2021}, volume = {11}, number = {12}, pages = {e055909}, doi = {10.1136/bmjopen-2021-055909}, }
Nat Commun
Using secondary cases to characterize the severity of an emerging or re-emerging infection.

Tim K Tsang, Can Wang, Bingyi Yang, and 2 more authors

Nature communications, 2021

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The methods to ascertain cases of an emerging infectious disease are typically biased toward cases with more severe disease, which can bias the average infection-severity profile. Here, we conducted a systematic review to extract information on disease severity among index cases and secondary cases identified by contact tracing of index cases for COVID-19. We identified 38 studies to extract information on measures of clinical severity. The proportion of index cases with fever was 43% higher than for secondary cases. The proportion of symptomatic, hospitalized, and fatal illnesses among index cases were 12%, 126%, and 179% higher than for secondary cases, respectively. We developed a statistical model to utilize the severity difference, and estimate 55% of index cases were missed in Wuhan, China. Information on disease severity in secondary cases should be less susceptible to ascertainment bias and could inform estimates of disease severity and the proportion of missed index cases.
@article{tsang2021p34737277, title = {Using secondary cases to characterize the severity of an emerging or re-emerging infection.}, author = {Tsang, Tim K and Wang, Can and Yang, Bingyi and Cauchemez, Simon and Cowling, Benjamin J}, journal = {Nature communications}, year = {2021}, volume = {12}, number = {1}, pages = {6372}, doi = {10.1038/s41467-021-26709-7}, }
J Infect Dis
Joint Estimation of Generation Time and Incubation Period for Coronavirus Disease 2019.

Yiu Chung Lau, Tim K Tsang, Lee Kennedy-Shaffer, and 7 more authors

The Journal of infectious diseases, 2021

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BACKGROUND: Coronavirus disease 2019 (COVID-19) has caused a heavy disease burden globally. The impact of process and timing of data collection on the accuracy of estimation of key epidemiological distributions are unclear. Because infection times are typically unobserved, there are relatively few estimates of generation time distribution. METHODS: We developed a statistical framework to jointly estimate generation time and incubation period from human-to-human transmission pairs, accounting for sampling biases. We applied the framework on 80 laboratory-confirmed human-to-human transmission pairs in China. We further inferred the infectiousness profile, serial interval distribution, proportions of presymptomatic transmission, and basic reproduction number (R0) for COVID-19. RESULTS: The estimated mean incubation period was 4.8 days (95% confidence interval [CI], 4.1-5.6), and mean generation time was 5.7 days (95% CI, 4.8-6.5). The estimated R0 based on the estimated generation time was 2.2 (95% CI, 1.9-2.4). A simulation study suggested that our approach could provide unbiased estimates, insensitive to the width of exposure windows. CONCLUSIONS: Properly accounting for the timing and process of data collection is critical to have correct estimates of generation time and incubation period. R0 can be biased when it is derived based on serial interval as the proxy of generation time.
@article{lau2021p34423821, title = {Joint Estimation of Generation Time and Incubation Period for Coronavirus Disease 2019.}, author = {Lau, Yiu Chung and Tsang, Tim K and Kennedy-Shaffer, Lee and Kahn, Rebecca and Lau, Eric H Y and Chen, Dongxuan and Wong, Jessica Y and Ali, Sheikh Taslim and Wu, Peng and Cowling, Benjamin J}, journal = {The Journal of infectious diseases}, year = {2021}, volume = {224}, number = {10}, pages = {1664-1671}, doi = {10.1093/infdis/jiab424}, }
Lancet Reg
The differential importation risks of COVID-19 from inbound travellers and the feasibility of targeted travel controls: A case study in Hong Kong.

Bingyi Yang, Tim K Tsang, Jessica Y Wong, and 7 more authors

The Lancet regional health. Western Pacific, 2021

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BACKGROUND: Many countries/regions implemented strict border measures (e.g., 14-day quarantines) as a blanket policy to prevent COVID-19 importations, while proposed "travel bubbles" as an alternative to reduce the impact of border controls. We aim to examine the differential importation risks with departure origins and post-arrival controls. METHODS: We developed a Bayesian framework to model disease progress of COVID-19 and the effectiveness of travel measures and inferred the origin-specific disease prevalence among inbound travellers, using data on passengers arriving in Hong Kong and laboratory-confirmed imported cases. We estimated the origin-specific risks of releasing infectious travellers under different control strategies and traveller volumes. We also estimated the risk of having released infectious travellers when a resurgence occurs in departure locations with no imported cases during a certain period. FINDINGS: Under the then strict controls of 14-day quarantine and testing on day 12, the Philippines imposed the greatest importation risk among the studied countries/regions (95.8% of releasing at least one infectious traveller, 95% credible interval (CrI), 94.8-96.6%). This was higher than that from low prevalence countries/regions (e.g., 23.4%, 95% CrI, 21.6-25.3% for Taiwan) if controls relaxed (i.e., 7-day quarantine and test on day 5). Increased traveller volumes and resurgence in departure locations with low prevalence under relaxed controls did not impose a greater importation risk than high prevalence locations under stricter controls. INTERPRETATION: Moderate relaxation of control measures for travellers arriving from low prevalence locations did not impose higher risks of community outbreaks than strict controls on travellers from high prevalence locations. FUNDING: Health and Medical Research Fund, Hong Kong.
@article{yang2021p34179860, title = {The differential importation risks of COVID-19 from inbound travellers and the feasibility of targeted travel controls: A case study in Hong Kong.}, author = {Yang, Bingyi and Tsang, Tim K and Wong, Jessica Y and He, Yinan and Gao, Huizhi and Ho, Faith and Lau, Eric H Y and Wu, Peng and Sullivan, Sheena G and Cowling, Benjamin J}, journal = {The Lancet regional health. Western Pacific}, year = {2021}, volume = {13}, pages = {100184}, doi = {10.1016/j.lanwpc.2021.100184}, }
J Infect Dis
Accounting for Imported Cases in Estimating the Time-Varying Reproductive Number of Coronavirus Disease 2019 in Hong Kong.

Tim K Tsang, Peng Wu, Eric H Y Lau, and 1 more author

The Journal of infectious diseases, 2021

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Estimating the time-varying reproductive number, Rt, is critical for monitoring transmissibility of an infectious disease. The impact of imported cases on the estimation is rarely explored. We developed a model to estimate separately the Rt for local cases and imported cases, accounting for imperfect contact tracing of cases. We applied this framework to data on coronavirus disease 2019 outbreaks in Hong Kong. The estimated Rt for local cases rose above 1 in late March 2020, which was undetected by other commonly used methods. When imported cases account for a considerable proportion of all cases, their impact on estimating Rt is critical.
@article{tsang2021p34086944, title = {Accounting for Imported Cases in Estimating the Time-Varying Reproductive Number of Coronavirus Disease 2019 in Hong Kong.}, author = {Tsang, Tim K and Wu, Peng and Lau, Eric H Y and Cowling, Benjamin J}, journal = {The Journal of infectious diseases}, year = {2021}, volume = {224}, number = {5}, pages = {783-787}, doi = {10.1093/infdis/jiab299}, }
Clin Infect Dis
Assessing Asymptomatic, Presymptomatic, and Symptomatic Transmission Risk of Severe Acute Respiratory Syndrome Coronavirus 2.

Peng Wu, Fengfeng Liu, Zhaorui Chang, Yun Lin, Minrui Ren, Canjun Zheng, Yu Li, Zhibin Peng, Yin Qin, Jianxing Yu, Mengjie Geng, Xiaokun Yang, Hongting Zhao, Zhili Li, Sheng Zhou, Lu Ran, Benjamin J Cowling, Shengjie Lai, Qiulan Chen, Liping Wang, Tim K Tsang, and Zhongjie Li

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021

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BACKGROUND: The relative contributions of asymptomatic, presymptomatic, and symptomatic transmission of severe acute respiratory syndrome coronavirus 2 have not been clearly measured, although control measures may differ in response to the risk of spread posed by different types of cases. METHODS: We collected detailed information on transmission events and symptom status based on laboratory-confirmed patient data and contact tracing data from 4 provinces and 1 municipality in China. We estimated the variation in risk of transmission over time and the severity of secondary infections by symptomatic status of the infector. RESULTS: There were 393 symptomatic index cases with 3136 close contacts and 185 asymptomatic index cases with 1078 close contacts included in the study. The secondary attack rates among close contacts of symptomatic and asymptomatic index cases were 4.1% (128 of 3136) and 1.1% (12 of 1078), respectively, corresponding to a higher transmission risk from symptomatic cases than from asymptomatic cases (odds ratio, 3.79; 95% confidence interval, 2.06-6.95). Approximately 25% (32 of 128) and 50% (6 of 12) of the infected close contacts were asymptomatic from symptomatic and asymptomatic index cases, respectively, while more than one third (38%) of the infections in the close contacts of symptomatic cases were attributable to exposure to the index cases before symptom onset. CONCLUSIONS: Asymptomatic and presymptomatic transmissions play an important role in spreading infection, although asymptomatic cases pose a lower risk of transmission than symptomatic cases. Early case detection and effective test-and-trace measures are important to reduce transmission.
@article{wu2021p33772573, title = {Assessing Asymptomatic, Presymptomatic, and Symptomatic Transmission Risk of Severe Acute Respiratory Syndrome Coronavirus 2.}, author = {Wu, Peng and Liu, Fengfeng and Chang, Zhaorui and Lin, Yun and Ren, Minrui and Zheng, Canjun and Li, Yu and Peng, Zhibin and Qin, Yin and Yu, Jianxing and Geng, Mengjie and Yang, Xiaokun and Zhao, Hongting and Li, Zhili and Zhou, Sheng and Ran, Lu and Cowling, Benjamin J and Lai, Shengjie and Chen, Qiulan and Wang, Liping and Tsang, Tim K and Li, Zhongjie}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2021}, volume = {73}, number = {6}, pages = {e1314-e1320}, doi = {10.1093/cid/ciab271}, }
Emerg Infect Dis
Risk for International Importations of Variant SARS-CoV-2 Originating in the United Kingdom.

Zhanwei Du, Lin Wang, Bingyi Yang, Sheikh Taslim Ali, Tim K Tsang, Songwei Shan, Peng Wu, Eric H Y Lau, Benjamin J Cowling, and Lauren Ancel Meyers

Emerging infectious diseases, 2021

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A fast-spreading severe acute respiratory syndrome coronavirus 2 variant identified in the United Kingdom in December 2020 has raised international alarm. We analyzed data from 15 countries and estimated that the chance that this variant was imported into these countries by travelers from the United Kingdom by December 7 is >50%.
@article{du2021p33760727, title = {Risk for International Importations of Variant SARS-CoV-2 Originating in the United Kingdom.}, author = {Du, Zhanwei and Wang, Lin and Yang, Bingyi and Ali, Sheikh Taslim and Tsang, Tim K and Shan, Songwei and Wu, Peng and Lau, Eric H Y and Cowling, Benjamin J and Meyers, Lauren Ancel}, journal = {Emerging infectious diseases}, year = {2021}, volume = {27}, number = {5}, pages = {1527-1529}, doi = {10.3201/eid2705.210050}, }
Clin Infect Dis
Changing Disparities in Coronavirus Disease 2019 (COVID-19) Burden in the Ethnically Homogeneous Population of Hong Kong Through Pandemic Waves: An Observational Study.

Bingyi Yang, Peng Wu, Eric H Y Lau, Jessica Y Wong, Faith Ho, Huizhi Gao, Jingyi Xiao, Dillon C Adam, Tiffany W Y Ng, Jianchao Quan, Tim K Tsang, Qiuyan Liao, Benjamin J Cowling, and Gabriel M Leung

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2021

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BACKGROUND: Disparities were marked in previous pandemics, usually with higher attack rates reported for those in lower socioeconomic positions and for ethnic minorities. METHODS: We examined characteristics of laboratory-confirmed coronavirus disease 2019 (COVID-19) cases in Hong Kong, assessed associations between incidence and population-level characteristics at the level of small geographic areas, and evaluated relations between socioeconomics and work-from-home (WFH) arrangements. RESULTS: The largest source of COVID-19 importations switched from students studying overseas in the second wave to foreign domestic helpers in the third. The local cases were mostly individuals not in formal employment (retirees and homemakers) and production workers who were unable to WFH. For every 10% increase in the proportion of population employed as executives or professionals in a given geographic region, there was an 84% (95% confidence interval [CI], 1-97%) reduction in the incidence of COVID-19 during the third wave. In contrast, in the first 2 waves, the same was associated with 3.69 times (95% CI, 1.02-13.33) higher incidence. Executives and professionals were more likely to implement WFH and experienced frequent changes in WFH practice compared with production workers. CONCLUSIONS: Consistent findings on the reversed socioeconomic patterning of COVID-19 burden between infection waves in Hong Kong in both individual- and population-level analyses indicated that risks of infections may be related to occupations involving high exposure frequency and WFH flexibility. Contextual determinants should be taken into account in policy planning aiming at mitigating such disparities.
@article{yang2021p33406238, title = {Changing Disparities in Coronavirus Disease 2019 (COVID-19) Burden in the Ethnically Homogeneous Population of Hong Kong Through Pandemic Waves: An Observational Study.}, author = {Yang, Bingyi and Wu, Peng and Lau, Eric H Y and Wong, Jessica Y and Ho, Faith and Gao, Huizhi and Xiao, Jingyi and Adam, Dillon C and Ng, Tiffany W Y and Quan, Jianchao and Tsang, Tim K and Liao, Qiuyan and Cowling, Benjamin J and Leung, Gabriel M}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2021}, volume = {73}, number = {12}, pages = {2298-2305}, doi = {10.1093/cid/ciab002}, }

2020

Nat Med
Clustering and superspreading potential of SARS-CoV-2 infections in Hong Kong.

Dillon C Adam, Peng Wu, Jessica Y Wong, Eric H Y Lau, Tim K Tsang, Simon Cauchemez, Gabriel M Leung, and Benjamin J Cowling

Nature medicine, 2020

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Superspreading events (SSEs) have characterized previous epidemics of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) infections(1-6). For SARS-CoV-2, the degree to which SSEs are involved in transmission remains unclear, but there is growing evidence that SSEs might be a typical feature of COVID-19(7,8). Using contact tracing data from 1,038 SARS-CoV-2 cases confirmed between 23 January and 28 April 2020 in Hong Kong, we identified and characterized all local clusters of infection. We identified 4-7 SSEs across 51 clusters (n = 309 cases) and estimated that 19% (95% confidence interval, 15-24%) of cases seeded 80% of all local transmission. Transmission in social settings was associated with more secondary cases than households when controlling for age (P = 0.002). Decreasing the delay between symptom onset and case confirmation did not result in fewer secondary cases (P = 0.98), although the odds that an individual being quarantined as a contact interrupted transmission was 14.4 (95% CI, 1.9-107.2). Public health authorities should focus on rapidly tracing and quarantining contacts, along with implementing restrictions targeting social settings to reduce the risk of SSEs and suppress SARS-CoV-2 transmission.
@article{adam2020p32943787, title = {Clustering and superspreading potential of SARS-CoV-2 infections in Hong Kong.}, author = {Adam, Dillon C and Wu, Peng and Wong, Jessica Y and Lau, Eric H Y and Tsang, Tim K and Cauchemez, Simon and Leung, Gabriel M and Cowling, Benjamin J}, journal = {Nature medicine}, year = {2020}, volume = {26}, number = {11}, pages = {1714-1719}, doi = {10.1038/s41591-020-1092-0}, }
Lancet PH
Effect of changing case definitions for COVID-19 on the epidemic curve and transmission parameters in mainland China: a modelling study.

Tim K Tsang, Peng Wu, Yun Lin, and 3 more authors

The Lancet. Public health, 2020

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BACKGROUND: When a new infectious disease emerges, appropriate case definitions are important for clinical diagnosis and for public health surveillance. Tracking case numbers over time is important to establish the speed of spread and the effectiveness of interventions. We aimed to assess whether changes in case definitions affected inferences on the transmission dynamics of coronavirus disease 2019 (COVID-19) in China. METHODS: We examined changes in the case definition for COVID-19 in mainland China during the first epidemic wave. We used exponential growth models to estimate how changes in the case definitions affected the number of cases reported each day. We then inferred how the epidemic curve would have appeared if the same case definition had been used throughout the epidemic. FINDINGS: From Jan 15 to March 3, 2020, seven versions of the case definition for COVID-19 were issued by the National Health Commission in China. We estimated that when the case definitions were changed, the proportion of infections being detected as cases increased by 7.1 times (95% credible interval [CrI] 4.8-10.9) from version 1 to 2, 2.8 times (1.9-4.2) from version 2 to 4, and 4.2 times (2.6-7.3) from version 4 to 5. If the fifth version of the case definition had been applied throughout the outbreak with sufficient testing capacity, we estimated that by Feb 20, 2020, there would have been 232 000 (95% CrI 161 000-359 000) confirmed cases in China as opposed to the 55 508 confirmed cases reported. INTERPRETATION: The case definition was initially narrow and was gradually broadened to allow detection of more cases as knowledge increased, particularly milder cases and those without epidemiological links to Wuhan, China, or other known cases. These changes should be taken into account when making inferences on epidemic growth rates and doubling times, and therefore on the reproductive number, to avoid bias. FUNDING: Health and Medical Research Fund, Hong Kong.
@article{tsang2020p32330458, title = {Effect of changing case definitions for COVID-19 on the epidemic curve and transmission parameters in mainland China: a modelling study.}, author = {Tsang, Tim K and Wu, Peng and Lin, Yun and Lau, Eric H Y and Leung, Gabriel M and Cowling, Benjamin J}, journal = {The Lancet. Public health}, year = {2020}, volume = {5}, number = {5}, pages = {e289-e296}, doi = {10.1016/S2468-2667(20)30089-X}, }
Lancet PH
Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study.

Benjamin J Cowling, Sheikh Taslim Ali, Tiffany W Y Ng, Tim K Tsang, Julian C M Li, Min Whui Fong, Qiuyan Liao, Mike Yw Kwan, So Lun Lee, Susan S Chiu, Joseph T Wu, Peng Wu, and Gabriel M Leung

The Lancet. Public health, 2020

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BACKGROUND: A range of public health measures have been implemented to suppress local transmission of coronavirus disease 2019 (COVID-19) in Hong Kong. We examined the effect of these interventions and behavioural changes of the public on the incidence of COVID-19, as well as on influenza virus infections, which might share some aspects of transmission dynamics with COVID-19. METHODS: We analysed data on laboratory-confirmed COVID-19 cases, influenza surveillance data in outpatients of all ages, and influenza hospitalisations in children. We estimated the daily effective reproduction number (R(t)) for COVID-19 and influenza A H1N1 to estimate changes in transmissibility over time. Attitudes towards COVID-19 and changes in population behaviours were reviewed through three telephone surveys done on Jan 20-23, Feb 11-14, and March 10-13, 2020. FINDINGS: COVID-19 transmissibility measured by R(t) has remained at approximately 1 for 8 weeks in Hong Kong. Influenza transmission declined substantially after the implementation of social distancing measures and changes in population behaviours in late January, with a 44% (95% CI 34-53%) reduction in transmissibility in the community, from an estimated R(t) of 1.28 (95% CI 1.26-1.30) before the start of the school closures to 0.72 (0.70-0.74) during the closure weeks. Similarly, a 33% (24-43%) reduction in transmissibility was seen based on paediatric hospitalisation rates, from an R(t) of 1.10 (1.06-1.12) before the start of the school closures to 0.73 (0.68-0.77) after school closures. Among respondents to the surveys, 74.5%, 97.5%, and 98.8% reported wearing masks when going out, and 61.3%, 90.2%, and 85.1% reported avoiding crowded places in surveys 1 (n=1008), 2 (n=1000), and 3 (n=1005), respectively. INTERPRETATION: Our study shows that non-pharmaceutical interventions (including border restrictions, quarantine and isolation, distancing, and changes in population behaviour) were associated with reduced transmission of COVID-19 in Hong Kong, and are also likely to have substantially reduced influenza transmission in early February, 2020. FUNDING: Health and Medical Research Fund, Hong Kong.
@article{cowling2020p32311320, title = {Impact assessment of non-pharmaceutical interventions against coronavirus disease 2019 and influenza in Hong Kong: an observational study.}, author = {Cowling, Benjamin J and Ali, Sheikh Taslim and Ng, Tiffany W Y and Tsang, Tim K and Li, Julian C M and Fong, Min Whui and Liao, Qiuyan and Kwan, Mike Yw and Lee, So Lun and Chiu, Susan S and Wu, Joseph T and Wu, Peng and Leung, Gabriel M}, journal = {The Lancet. Public health}, year = {2020}, volume = {5}, number = {5}, pages = {e279-e288}, doi = {10.1016/S2468-2667(20)30090-6}, }
Clin Infect Dis
Association Between the Respiratory Microbiome and Susceptibility to Influenza Virus Infection.

Tim K Tsang, Kyu Han Lee, Betsy Foxman, and 8 more authors

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2020

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BACKGROUND: Previous studies suggest that the nose/throat microbiome may play an important role in shaping host immunity and modifying the risk of respiratory infection. Our aim is to quantify the association between the nose/throat microbiome and susceptibility to influenza virus infection. METHODS: In this household transmission study, index cases with confirmed influenza virus infection and their household contacts were followed for 9-12 days to identify secondary influenza infections. Respiratory swabs were collected at enrollment to identify and quantify bacterial species via high-performance sequencing. Data were analyzed by an individual hazard-based transmission model that was adjusted for age, vaccination, and household size. RESULTS: We recruited 115 index cases with influenza A(H3N2) or B infection and 436 household contacts. We estimated that a 10-fold increase in the abundance in Streptococcus spp. and Prevotella salivae was associated with 48% (95% credible interval [CrI], 9-69%) and 25% (95% CrI, 0.5-42%) lower susceptibility to influenza A(H3N2) infection, respectively. In contrast, for influenza B infection, a 10-fold increase in the abundance in Streptococcus vestibularis and Prevotella spp. was associated with 63% (95% CrI, 17-83%) lower and 83% (95% CrI, 15-210%) higher susceptibility, respectively. CONCLUSIONS: Susceptibility to influenza infection is associated with the nose/throat microbiome at the time of exposure. The effects of oligotypes on susceptibility differ between influenza A(H3N2) and B viruses. Our results suggest that microbiome may be a useful predictor of susceptibility, with the implication that microbiome could be modulated to reduce influenza infection risk, should these associations be causal.
@article{tsang2020p31562814, title = {Association Between the Respiratory Microbiome and Susceptibility to Influenza Virus Infection.}, author = {Tsang, Tim K and Lee, Kyu Han and Foxman, Betsy and Balmaseda, Angel and Gresh, Lionel and Sanchez, Nery and Ojeda, Sergio and Lopez, Roger and Yang, Yang and Kuan, Guillermina and Gordon, Aubree}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2020}, volume = {71}, number = {5}, pages = {1195-1203}, doi = {10.1093/cid/ciz968}, }

2019

Nat Commun
Effects of infection history on dengue virus infection and pathogenicity.

Tim K Tsang, Samson L Ghebremariam, Lionel Gresh, and 10 more authors

Nature communications, 2019

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The understanding of immunological interactions among the four dengue virus (DENV) serotypes and their epidemiological implications is often hampered by the lack of individual-level infection history. Using a statistical framework that infers full infection history, we analyze a prospective pediatric cohort in Nicaragua to characterize how infection history modulates the risks of DENV infection and subsequent clinical disease. After controlling for age, one prior infection is associated with 54% lower, while two or more are associated with 91% higher, risk of a new infection, compared to DENV-naive children. Children >8 years old have 55% and 120% higher risks of infection and subsequent disease, respectively, than their younger peers. Among children with >/=1 prior infection, intermediate antibody titers increase, whereas high titers lower, the risk of subsequent infection, compared with undetectable titers. Such complex dependency needs to be considered in the design of dengue vaccines and vaccination strategies.
@article{tsang2019p30886145, title = {Effects of infection history on dengue virus infection and pathogenicity.}, author = {Tsang, Tim K and Ghebremariam, Samson L and Gresh, Lionel and Gordon, Aubree and Halloran, M Elizabeth and Katzelnick, Leah C and Rojas, Diana Patricia and Kuan, Guillermina and Balmaseda, Angel and Sugimoto, Jonathan and Harris, Eva and Longini, Ira M Jr and Yang, Yang}, journal = {Nature communications}, year = {2019}, volume = {10}, number = {1}, pages = {1246}, doi = {10.1038/s41467-019-09193-y}, }
Nat Commun
Indirect protection from vaccinating children against influenza in households.

Tim K Tsang, Vicky J Fang, Dennis K M Ip, and 6 more authors

Nature communications, 2019

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Vaccination is an important intervention to prevent influenza virus infection, but indirect protection of household members of vaccinees is not fully known. Here, we analyze a cluster household randomized controlled trial, with one child in each household randomized to receive influenza vaccine or placebo, for an influenza B epidemic in Hong Kong. We apply statistical models to estimate household transmission dynamics and quantify the direct and indirect protection of vaccination. Direct vaccine efficacy was 71%. The infection probability of unvaccinated household members in vaccinated households was only 5% lower than in control households, because only 10% of infections are attributed to household transmission. Even when that proportion rises to 30% and all children are vaccinated, we predict that the infection probability for unvaccinated household members would only be reduced by 20%. This suggests that benefits of individual vaccination remain important even when other household members are vaccinated.
@article{tsang2019p30631062, title = {Indirect protection from vaccinating children against influenza in households.}, author = {Tsang, Tim K and Fang, Vicky J and Ip, Dennis K M and Perera, Ranawaka A P M and So, Hau Chi and Leung, Gabriel M and Peiris, J S Malik and Cowling, Benjamin J and Cauchemez, Simon}, journal = {Nature communications}, year = {2019}, volume = {10}, number = {1}, pages = {106}, doi = {10.1038/s41467-018-08036-6}, }
Clin Infect Dis
Assessment of Human-to-Human Transmissibility of Avian Influenza A(H7N9) Virus Across 5 Waves by Analyzing Clusters of Case Patients in Mainland China, 2013-2017.

Xiling Wang, Peng Wu, Yao Pei, Tim K Tsang, Dantong Gu, Wei Wang, Juanjuan Zhang, Peter W Horby, Timothy M Uyeki, Benjamin J Cowling, and Hongjie Yu

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2019

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BACKGROUND: The 2016-17 epidemic of human infections with avian influenza A(H7N9) virus was alarming, due to the surge in reported cases across a wide geographic area and the emergence of highly-pathogenic A(H7N9) viruses. Our study aimed to assess whether the human-to-human transmission risk of A(H7N9) virus has changed across the 5 waves since 2013. METHODS: Data on human cases and clusters of A(H7N9) virus infection were collected from the World Health Organization, open access national and provincial reports, informal online sources, and published literature. We compared the epidemiological characteristics of sporadic and cluster cases, estimated the relative risk (RR) of infection in blood relatives and non-blood relatives, and estimated the bounds on the effective reproductive number (Re) across waves from 2013 through September 2017. RESULTS: We identified 40 human clusters of A(H7N9) virus infection, with a median cluster size of 2 (range 2-3). The overall RR of infection in blood relatives versus non-blood relatives was 1.65 (95% confidence interval [CI]: 0.88, 3.09), and was not significantly different across waves (chi2 = 2.66, P = .617). The upper limit of Re for A(H7N9) virus was 0.12 (95% CI: 0.10, 0.14) and was not significantly different across waves (chi2 = 1.52, P = .822). CONCLUSIONS: The small cluster size and low Re suggest that human-to-human transmissibility of A(H7N9) virus has not changed over time and remains limited to date. Continuous assessment of A(H7N9) virus infections and human case clusters is of crucial importance for public health.
@article{wang2019p29961834, title = {Assessment of Human-to-Human Transmissibility of Avian Influenza A(H7N9) Virus Across 5 Waves by Analyzing Clusters of Case Patients in Mainland China, 2013-2017.}, author = {Wang, Xiling and Wu, Peng and Pei, Yao and Tsang, Tim K and Gu, Dantong and Wang, Wei and Zhang, Juanjuan and Horby, Peter W and Uyeki, Timothy M and Cowling, Benjamin J and Yu, Hongjie}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2019}, volume = {68}, number = {4}, pages = {623-631}, doi = {10.1093/cid/ciy541}, }

2018

Emerg Infect Dis
Influenza Transmission Dynamics in Urban Households, Managua, Nicaragua, 2012-2014.

Aubree Gordon, Tim K Tsang, Benjamin J Cowling, and 7 more authors

Emerging infectious diseases, 2018

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During August 2012-November 2014, we conducted a case ascertainment study to investigate household transmission of influenza virus in Managua, Nicaragua. We collected up to 5 respiratory swab samples from each of 536 household contacts of 133 influenza virus-infected persons and assessed for evidence of influenza virus transmission. The overall risk for influenza virus infection of household contacts was 15.7% (95% CI 12.7%-19.0%). Oseltamivir treatment of index patients did not appear to reduce household transmission. The mean serial interval for within-household transmission was 3.1 (95% CI 1.6-8.4) days. We found the transmissibility of influenza B virus to be higher than that of influenza A virus among children. Compared with households with <4 household contacts, those with >4 household contacts appeared to have a reduced risk for infection. Further research is needed to model household influenza virus transmission and design interventions for these settings.
@article{gordon2018p30226161, title = {Influenza Transmission Dynamics in Urban Households, Managua, Nicaragua, 2012-2014.}, author = {Gordon, Aubree and Tsang, Tim K and Cowling, Benjamin J and Kuan, Guillermina and Ojeda, Sergio and Sanchez, Nery and Gresh, Lionel and Lopez, Roger and Balmaseda, Angel and Harris, Eva}, journal = {Emerging infectious diseases}, year = {2018}, volume = {24}, number = {10}, pages = {1882-1888}, doi = {10.3201/eid2410.161258}, }
Epidemiology
Transmissibility of Norovirus in Urban Versus Rural Households in a Large Community Outbreak in China.

Tim K Tsang, Tian-Mu Chen, Ira M Jr Longini, and 3 more authors

Epidemiology (Cambridge, Mass.), 2018

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BACKGROUND: Norovirus is a leading cause of outbreaks of acute infectious gastroenteritis worldwide, yet its transmissibility within households and associated risk factors remain unknown in developing countries. METHODS: Household, demographic, and clinical data were collected from a semi-urban area in south China where an outbreak occurred in the winter of 2014. Using a Bayesian modeling framework, we assessed the transmissibility and potential risk modifiers in both urban and rural households. RESULTS: In urban apartment buildings, the secondary attack rates were 84% (95% credible interval [CI] = 60%, 96%) among households of size two and 29% (95% CI = 9.6%, 53%) in larger households. In the rural village, secondary attack rate estimates were lower than the urban setting, 13% (0.51%, 54%) for households of size two and 7.3% (0.38%, 27%) for larger households. Males were 31% (95% CI = 3%, 50%) less susceptible to the disease than female. Water disinfection with chlorine was estimated to reduce environmental risk of infection by 60% (95% CI = 26%, 82%), and case isolation was estimated to reduce person-to-person transmission by 65% (95% CI = 15%, 93%). Nausea and vomiting were not associated with household transmission. CONCLUSIONS: Norovirus is highly contagious within households, in particular in small households in urban communities. Our results suggest that water disinfection and case isolation are associated with reduction of outbreaks in resource-limited communities.
@article{tsang2018p29847497, title = {Transmissibility of Norovirus in Urban Versus Rural Households in a Large Community Outbreak in China.}, author = {Tsang, Tim K and Chen, Tian-Mu and Longini, Ira M Jr and Halloran, M Elizabeth and Wu, Ying and Yang, Yang}, journal = {Epidemiology (Cambridge, Mass.)}, year = {2018}, volume = {29}, number = {5}, pages = {675-683}, doi = {10.1097/EDE.0000000000000855}, }
Sci Rep
Evaluation of animal-to-human and human-to-human transmission of influenza A (H7N9) virus in China, 2013-15.

Victor Virlogeux, Luzhao Feng, Tim K Tsang, and 11 more authors

Scientific reports, 2018

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A novel avian-origin influenza A(H7N9) virus emerged in China in March 2013 and by 27 September 2017 a total of 1533 laboratory-confirmed cases have been reported. Occurrences of animal-to-human and human-to-human transmission have been previously identified, and the force of human-to-human transmission is an important component of risk assessment. In this study, we constructed an ecological model to evaluate the animal-to-human and human-to-human transmission of H7N9 during the first three epidemic waves in spring 2013, winter/spring 2013-2014 and winter/spring 2014-2015 in China based on 149 laboratory-confirmed urban cases. Our analysis of patterns in incidence in major cities allowed us to estimate a mean incubation period in humans of 2.6 days (95% credibility interval, CrI: 1.4-3.1) and an effective reproduction number Re of 0.23 (95% CrI: 0.05-0.47) for the first wave, 0.16 (95% CrI: 0.01-0.41) for the second wave, and 0.16 (95% CrI: 0.01-0.45) for the third wave without a significant difference between waves. There was a significant decrease in the incidence of H7N9 cases after live poultry market closures in various major cities. Our analytic framework can be used for continued assessment of the risk of human to human transmission of A(H7N9) virus as human infections continue to occur in China.
@article{virlogeux2018p29323268, title = {Evaluation of animal-to-human and human-to-human transmission of influenza A (H7N9) virus in China, 2013-15.}, author = {Virlogeux, Victor and Feng, Luzhao and Tsang, Tim K and Jiang, Hui and Fang, Vicky J and Qin, Ying and Wu, Peng and Wang, Xiling and Zheng, Jiandong and Lau, Eric H Y and Peng, Zhibin and Yang, Juan and Cowling, Benjamin J and Yu, Hongjie}, journal = {Scientific reports}, year = {2018}, volume = {8}, number = {1}, pages = {552}, doi = {10.1038/s41598-017-17335-9}, }

2017

Clin Infect Dis
Preliminary Epidemiologic Assessment of Human Infections With Highly Pathogenic Avian Influenza A(H5N6) Virus, China.

Hui Jiang, Peng Wu, Timothy M Uyeki, Jianfeng He, Zhihong Deng, Wen Xu, Qiang Lv, Jin Zhang, Yang Wu, Tim K Tsang, Min Kang, Jiandong Zheng, Lili Wang, Bingyi Yang, Ying Qin, Luzhao Feng, Vicky J Fang, George F Gao, Gabriel M Leung, Hongjie Yu, and Benjamin J Cowling

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2017

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BACKGROUND: Since 2014, 17 human cases of infection with the newly emerged highly pathogenic avian influenza A(H5N6) virus have been identified in China to date. The epidemiologic characteristics of laboratory-confirmed A(H5N6) cases were compared to A(H5N1) and A(H7N9) cases in mainland China. METHODS: Data on laboratory-confirmed H5N6, H5N1, and H7N9 cases identified in mainland China were analyzed to compare epidemiologic characteristics and clinical severity. Severity of confirmed H5N6, H5N1 and H7N9 cases was estimated based on the risk of severe outcomes in hospitalized cases. RESULTS: H5N6 cases were older than H5N1 cases with a higher prevalence of underlying medical conditions but younger than H7N9 cases. Epidemiological time-to-event distributions were similar among cases infected with the 3 viruses. In comparison to a fatality risk of 70% (30/43) for hospitalized H5N1 cases and 41% (319/782) for hospitalized H7N9 cases, 12 (75%) out of the 16 hospitalized H5N6 cases were fatal, and 15 (94%) required mechanical ventilation. CONCLUSION: Similar epidemiologic characteristics and high severity were observed in cases of H5N6 and H5N1 virus infection, whereas severity of H7N9 virus infections appeared lower. Continued surveillance of human infections with avian influenza A viruses remains an essential component of pandemic influenza preparedness.
@article{jiang2017p28407105, title = {Preliminary Epidemiologic Assessment of Human Infections With Highly Pathogenic Avian Influenza A(H5N6) Virus, China.}, author = {Jiang, Hui and Wu, Peng and Uyeki, Timothy M and He, Jianfeng and Deng, Zhihong and Xu, Wen and Lv, Qiang and Zhang, Jin and Wu, Yang and Tsang, Tim K and Kang, Min and Zheng, Jiandong and Wang, Lili and Yang, Bingyi and Qin, Ying and Feng, Luzhao and Fang, Vicky J and Gao, George F and Leung, Gabriel M and Yu, Hongjie and Cowling, Benjamin J}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2017}, volume = {65}, number = {3}, pages = {383-388}, doi = {10.1093/cid/cix334}, }

2016

Emerg Infect Dis
Human Infection with Influenza A(H7N9) Virus during 3 Major Epidemic Waves, China, 2013-2015.

Peng Wu, Zhibin Peng, Vicky J Fang, Luzhao Feng, Tim K Tsang, Hui Jiang, Eric H Y Lau, Juan Yang, Jiandong Zheng, Ying Qin, Zhongjie Li, Gabriel M Leung, Hongjie Yu, and Benjamin J Cowling

Emerging infectious diseases, 2016

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Since March 2013, a novel influenza A(H7N9) virus has caused 3 epidemic waves of human infection in mainland China. We analyzed data from patients with laboratory-confirmed influenza A(H7N9) virus infection to estimate the risks for severe outcomes after hospitalization across the 3 waves. We found that hospitalized patients with confirmed infections in waves 2 and 3 were younger and more likely to be residing in small cities and rural areas than were patients in wave 1; they also had a higher risk for death, after adjustment for age and underlying medical conditions. Risk for death among hospitalized patients during waves 2 and 3 was lower in Jiangxi and Fujian Provinces than in eastern and southern provinces. The variation in risk for death among hospitalized case-patients in different areas across 3 epidemic waves might be associated with differences in case ascertainment, changes in clinical management, or virus genetic diversity.
@article{wu2016p27191934, title = {Human Infection with Influenza A(H7N9) Virus during 3 Major Epidemic Waves, China, 2013-2015.}, author = {Wu, Peng and Peng, Zhibin and Fang, Vicky J and Feng, Luzhao and Tsang, Tim K and Jiang, Hui and Lau, Eric H Y and Yang, Juan and Zheng, Jiandong and Qin, Ying and Li, Zhongjie and Leung, Gabriel M and Yu, Hongjie and Cowling, Benjamin J}, journal = {Emerging infectious diseases}, year = {2016}, volume = {22}, number = {6}, pages = {964-72}, doi = {10.3201/eid2206.151752}, }
PLoS One
Individual Correlates of Infectivity of Influenza A Virus Infections in Households.

Tim K Tsang, Vicky J Fang, Kwok-Hung Chan, and 5 more authors

PloS one, 2016

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BACKGROUND: Identifying individual correlates of infectivity of influenza virus is important for disease control and prevention. Viral shedding is used as a proxy measure of infectivity in many studies. However, the evidence for this is limited. METHODS: In a detailed study of influenza virus transmission within households in 2008-12, we recruited index cases with confirmed influenza infection from outpatient clinics, and followed up their household contacts for 7-10 days to identify secondary infections. We used individual-based hazard models to characterize the relationship between individual viral shedding and individual infectivity. RESULTS: We analyzed 386 households with 1147 household contacts. Index cases were separated into 3 groups according to their estimated level of viral shedding at symptom onset. We did not find a statistically significant association of virus shedding with transmission. Index cases in medium and higher viral shedding groups were estimated to have 21% (95% CI: -29%, 113%) and 44% (CI: -16%, 167%) higher infectivity, compared with those in the lower viral shedding group. CONCLUSIONS: Individual viral load measured by RT-PCR in the nose and throat was at most weakly correlated with individual infectivity in households. Other correlates of infectivity should be examined in future studies.
@article{tsang2016p27153194, title = {Individual Correlates of Infectivity of Influenza A Virus Infections in Households.}, author = {Tsang, Tim K and Fang, Vicky J and Chan, Kwok-Hung and Ip, Dennis K M and Leung, Gabriel M and Peiris, J S Malik and Cowling, Benjamin J and Cauchemez, Simon}, journal = {PloS one}, year = {2016}, volume = {11}, number = {5}, pages = {e0154418}, doi = {10.1371/journal.pone.0154418}, }
PLoS One
Association between the Severity of Influenza A(H7N9) Virus Infections and Length of the Incubation Period.

Victor Virlogeux, Juan Yang, Vicky J Fang, Luzhao Feng, Tim K Tsang, Hui Jiang, Peng Wu, Jiandong Zheng, Eric H Y Lau, Ying Qin, Zhibin Peng, J S Malik Peiris, Hongjie Yu, and Benjamin J Cowling

PloS one, 2016

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BACKGROUND: In early 2013, a novel avian-origin influenza A(H7N9) virus emerged in China, and has caused sporadic human infections. The incubation period is the delay from infection until onset of symptoms, and varies from person to person. Few previous studies have examined whether the duration of the incubation period correlates with subsequent disease severity. METHODS AND FINDINGS: We analyzed data of period of exposure on 395 human cases of laboratory-confirmed influenza A(H7N9) virus infection in China in a Bayesian framework using a Weibull distribution. We found a longer incubation period for the 173 fatal cases with a mean of 3.7 days (95% credibility interval, CrI: 3.4-4.1), compared to a mean of 3.3 days (95% CrI: 2.9-3.6) for the 222 non-fatal cases, and the difference in means was marginally significant at 0.47 days (95% CrI: -0.04, 0.99). There was a statistically significant correlation between a longer incubation period and an increased risk of death after adjustment for age, sex, geographical location and underlying medical conditions (adjusted odds ratio 1.70 per day increase in incubation period; 95% credibility interval 1.47-1.97). CONCLUSIONS: We found a significant association between a longer incubation period and a greater risk of death among human H7N9 cases. The underlying biological mechanisms leading to this association deserve further exploration.
@article{virlogeux2016p26885816, title = {Association between the Severity of Influenza A(H7N9) Virus Infections and Length of the Incubation Period.}, author = {Virlogeux, Victor and Yang, Juan and Fang, Vicky J and Feng, Luzhao and Tsang, Tim K and Jiang, Hui and Wu, Peng and Zheng, Jiandong and Lau, Eric H Y and Qin, Ying and Peng, Zhibin and Peiris, J S Malik and Yu, Hongjie and Cowling, Benjamin J}, journal = {PloS one}, year = {2016}, volume = {11}, number = {2}, pages = {e0148506}, doi = {10.1371/journal.pone.0148506}, }
Epidemiology
Interpreting Seroepidemiologic Studies of Influenza in a Context of Nonbracketing Sera.

Tim K Tsang, Vicky J Fang, Ranawaka A P M Perera, and 5 more authors

Epidemiology (Cambridge, Mass.), 2016

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BACKGROUND: In influenza epidemiology, analysis of paired sera collected from people before and after influenza seasons has been used for decades to study the cumulative incidence of influenza virus infections in populations. However, interpretation becomes challenging when sera are collected after the start or before the end of an epidemic, and do not neatly bracket the epidemic. METHODS: Serum samples were collected longitudinally in a community-based study. Most participants provided their first serum after the start of circulation of influenza A(H1N1)pdm09 virus in 2009. We developed a Bayesian hierarchical model to correct for nonbracketing sera and estimate the cumulative incidence of infection from the serological data and surveillance data in Hong Kong. RESULTS: We analyzed 4,843 sera from 2,097 unvaccinated participants in the study, collected from April 2009 to December 2010. After accounting for nonbracketing, we estimated that the cumulative incidence of H1N1pdm09 virus infection was 45% (95% credible interval [CI] = 40%, 49%), 17% (95% CI = 13%, 20%), and 11% (95% CI = 6%, 18%) for children ages 0-18 years, adults 19-50 years, and older adults >50 years, respectively. Including all available data substantially increased precision compared with a simpler analysis based only on sera collected at 6-month intervals in a subset of participants. CONCLUSIONS: We developed a framework for the analysis of antibody titers that accounted for the timing of sera collection with respect to influenza activity and permitted robust estimation of the cumulative incidence of infection during an epidemic.
@article{tsang2016p26427725, title = {Interpreting Seroepidemiologic Studies of Influenza in a Context of Nonbracketing Sera.}, author = {Tsang, Tim K and Fang, Vicky J and Perera, Ranawaka A P M and Ip, Dennis K M and Leung, Gabriel M and Peiris, J S Malik and Cauchemez, Simon and Cowling, Benjamin J}, journal = {Epidemiology (Cambridge, Mass.)}, year = {2016}, volume = {27}, number = {1}, pages = {152-8}, doi = {10.1097/EDE.0000000000000408}, }
Lancet ID
Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data.

Shengjie Lai, Ying Qin, Benjamin J Cowling, Xiang Ren, Nicola A Wardrop, Marius Gilbert, Tim K Tsang, Peng Wu, Luzhao Feng, Hui Jiang, Zhibin Peng, Jiandong Zheng, Qiaohong Liao, Sa Li, Peter W Horby, Jeremy J Farrar, George F Gao, Andrew J Tatem, and Hongjie Yu

The Lancet. Infectious diseases, 2016

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Avian influenza A H5N1 viruses have caused many, typically severe, human infections since the first human case was reported in 1997. However, no comprehensive epidemiological analysis of global human cases of H5N1 from 1997 to 2015 exists. Moreover, few studies have examined in detail the changing epidemiology of human H5N1 cases in Egypt, especially given the outbreaks since November, 2014, which have the highest number of cases ever reported worldwide in a similar period. Data on individual patients were collated from different sources using a systematic approach to describe the global epidemiology of 907 human H5N1 cases between May, 1997, and April, 2015. The number of affected countries rose between 2003 and 2008, with expansion from east and southeast Asia, then to west Asia and Africa. Most cases (67.2%) occurred from December to March, and the overall case-fatality risk was 483 (53.5%) of 903 cases which varied across geographical regions. Although the incidence in Egypt has increased dramatically since November, 2014, compared with the cases beforehand, there were no significant differences in the fatality risk, history of exposure to poultry, history of patient contact, and time from onset to hospital admission in the recent cases.
@article{lai2016p27211899, title = {Global epidemiology of avian influenza A H5N1 virus infection in humans, 1997-2015: a systematic review of individual case data.}, author = {Lai, Shengjie and Qin, Ying and Cowling, Benjamin J and Ren, Xiang and Wardrop, Nicola A and Gilbert, Marius and Tsang, Tim K and Wu, Peng and Feng, Luzhao and Jiang, Hui and Peng, Zhibin and Zheng, Jiandong and Liao, Qiaohong and Li, Sa and Horby, Peter W and Farrar, Jeremy J and Gao, George F and Tatem, Andrew J and Yu, Hongjie}, journal = {The Lancet. Infectious diseases}, year = {2016}, volume = {16}, number = {7}, pages = {e108-e118}, doi = {10.1016/S1473-3099(16)00153-5}, }
Trends Microbiol
Household Transmission of Influenza Virus.

Tim K Tsang, Lincoln L H Lau, Simon Cauchemez, and 1 more author

Trends in microbiology, 2016

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Human influenza viruses cause regular epidemics and occasional pandemics with a substantial public health burden. Household transmission studies have provided valuable information on the dynamics of influenza transmission. We reviewed published studies and found that once one household member is infected with influenza, the risk of infection in a household contact can be up to 38%, and the delay between onset in index and secondary cases is around 3 days. Younger age was associated with higher susceptibility. In the future, household transmission studies will provide information on transmission dynamics, including the correlation of virus shedding and symptoms with transmission, and the correlation of new measures of immunity with protection against infection.
@article{tsang2016p26612500, title = {Household Transmission of Influenza Virus.}, author = {Tsang, Tim K and Lau, Lincoln L H and Cauchemez, Simon and Cowling, Benjamin J}, journal = {Trends in microbiology}, year = {2016}, volume = {24}, number = {2}, pages = {123-133}, doi = {10.1016/j.tim.2015.10.012}, }

2015

Am J Epidemiol
Estimating the Distribution of the Incubation Periods of Human Avian Influenza A(H7N9) Virus Infections.

Victor Virlogeux, Ming Li, Tim K Tsang, and 11 more authors

American journal of epidemiology, 2015

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A novel avian influenza virus, influenza A(H7N9), emerged in China in early 2013 and caused severe disease in humans, with infections occurring most frequently after recent exposure to live poultry. The distribution of A(H7N9) incubation periods is of interest to epidemiologists and public health officials, but estimation of the distribution is complicated by interval censoring of exposures. Imputation of the midpoint of intervals was used in some early studies, resulting in estimated mean incubation times of approximately 5 days. In this study, we estimated the incubation period distribution of human influenza A(H7N9) infections using exposure data available for 229 patients with laboratory-confirmed A(H7N9) infection from mainland China. A nonparametric model (Turnbull) and several parametric models accounting for the interval censoring in some exposures were fitted to the data. For the best-fitting parametric model (Weibull), the mean incubation period was 3.4 days (95% confidence interval: 3.0, 3.7) and the variance was 2.9 days; results were very similar for the nonparametric Turnbull estimate. Under the Weibull model, the 95th percentile of the incubation period distribution was 6.5 days (95% confidence interval: 5.9, 7.1). The midpoint approximation for interval-censored exposures led to overestimation of the mean incubation period. Public health observation of potentially exposed persons for 7 days after exposure would be appropriate.
@article{virlogeux2015p26409239, title = {Estimating the Distribution of the Incubation Periods of Human Avian Influenza A(H7N9) Virus Infections.}, author = {Virlogeux, Victor and Li, Ming and Tsang, Tim K and Feng, Luzhao and Fang, Vicky J and Jiang, Hui and Wu, Peng and Zheng, Jiandong and Lau, Eric H Y and Cao, Yu and Qin, Ying and Liao, Qiaohong and Yu, Hongjie and Cowling, Benjamin J}, journal = {American journal of epidemiology}, year = {2015}, volume = {182}, number = {8}, pages = {723-9}, doi = {10.1093/aje/kwv115}, }
Am J Epidemiol
Comparative Epidemiology of Influenza B Yamagata- and Victoria-Lineage Viruses in Households.

Cuiling Xu, Kwok-Hung Chan, Tim K Tsang, and 7 more authors

American journal of epidemiology, 2015

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Influenza B viruses split into 2 distinct lineages in the early 1980s, commonly named the Victoria and Yamagata lineages. There are few data on the comparative epidemiology of Victoria- and Yamagata-lineage viruses. In 2007-2011, we enrolled 75 and 34 households containing index patients with acute respiratory illness who tested positive for Yamagata- and Victoria-lineage viruses, respectively, from outpatient clinics in Hong Kong, China. These index patients and their household contacts were followed up for 7-10 days. We examined overall risk of polymerase chain reaction-confirmed infection among household contacts and the risk of secondary infection within households using an individual-based hazard model that accounted for tertiary transmission and infections occurring outside the household. We found that for Victoria-lineage viruses, the risk of within-household infection among household contacts aged </=15 years was significantly higher (risk ratio = 12.9, 95% credibility interval: 4.2, 43.6) than that for older household contacts, while for Yamagata-lineage viruses, the risk of within-household infection for household contacts did not differ by age. Influenza B Yamagata- and Victoria-lineage viruses have similar characteristics in terms of viral shedding and clinical illness. The mechanisms underlying these epidemiologic differences deserve further investigation.
@article{xu2015p26400854, title = {Comparative Epidemiology of Influenza B Yamagata- and Victoria-Lineage Viruses in Households.}, author = {Xu, Cuiling and Chan, Kwok-Hung and Tsang, Tim K and Fang, Vicky J and Fung, Rita O P and Ip, Dennis K M and Cauchemez, Simon and Leung, Gabriel M and Peiris, J S Malik and Cowling, Benjamin J}, journal = {American journal of epidemiology}, year = {2015}, volume = {182}, number = {8}, pages = {705-13}, doi = {10.1093/aje/kwv110}, }
Clin Infect Dis
Differences in the Epidemiology of Human Cases of Avian Influenza A(H7N9) and A(H5N1) Viruses Infection.

Ying Qin, Peter W Horby, Tim K Tsang, and 22 more authors

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2015

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BACKGROUND: The pandemic potential of avian influenza viruses A(H5N1) and A(H7N9) remains an unresolved but critically important question. METHODS: We compared the characteristics of sporadic and clustered cases of human H5N1 and H7N9 infection, estimated the relative risk of infection in blood-related contacts, and the reproduction number (R). RESULTS: We assembled and analyzed data on 720 H5N1 cases and 460 H7N9 cases up to 2 November 2014. The severity and average age of sporadic/index cases of H7N9 was greater than secondary cases (71% requiring intensive care unit admission vs 33%, P = .007; median age 59 years vs 31, P < .001). We observed no significant differences in the age and severity between sporadic/index and secondary H5N1 cases. The upper limit of the 95% confidence interval (CI) for R was 0.12 for H5N1 and 0.27 for H7N9. A higher proportion of H5N1 infections occurred in clusters (20%) compared to H7N9 (8%). The relative risk of infection in blood-related contacts of cases compared to unrelated contacts was 8.96 for H5N1 (95% CI, 1.30, 61.86) and 0.80 for H7N9 (95% CI, .32, 1.97). CONCLUSIONS: The results are consistent with an ascertainment bias towards severe and older cases for sporadic H7N9 but not for H5N1. The lack of evidence for ascertainment bias in sporadic H5N1 cases, the more pronounced clustering of cases, and the higher risk of infection in blood-related contacts, support the hypothesis that susceptibility to H5N1 may be limited and familial. This analysis suggests the potential pandemic risk may be greater for H7N9 than H5N1.
@article{qin2015p25940354, title = {Differences in the Epidemiology of Human Cases of Avian Influenza A(H7N9) and A(H5N1) Viruses Infection.}, author = {Qin, Ying and Horby, Peter W and Tsang, Tim K and Chen, Enfu and Gao, Lidong and Ou, Jianming and Nguyen, Tran Hien and Duong, Tran Nhu and Gasimov, Viktor and Feng, Luzhao and Wu, Peng and Jiang, Hui and Ren, Xiang and Peng, Zhibin and Li, Sa and Li, Ming and Zheng, Jiandong and Liu, Shelan and Hu, Shixiong and Hong, Rongtao and Farrar, Jeremy J and Leung, Gabriel M and Gao, George F and Cowling, Benjamin J and Yu, Hongjie}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2015}, volume = {61}, number = {4}, pages = {563-71}, doi = {10.1093/cid/civ345}, }
J Infect Dis
Influenza A Virus Shedding and Infectivity in Households.

Tim K Tsang, Benjamin J Cowling, Vicky J Fang, and 5 more authors

The Journal of infectious diseases, 2015

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BACKGROUND: Viral shedding is often considered to correlate with the infectivity of influenza, but the evidence for this is limited. METHODS: In a detailed study of influenza virus transmission within households in 2008-2012, index case patients with confirmed influenza were identified in outpatient clinics, and we collected nose and throat swab specimens for testing by reverse-transcription polymerase chain reaction from all household members regardless of illness. We used individual-based hazard models to characterize the relationship between viral load (V) and infectivity. RESULTS: Assuming that infectivity was proportional to viral load V gave the worst fit, because it strongly overestimated the proportion of transmission occurring at symptom onset. Alternative models assuming that infectivity was proportional to a various functions of V provided better fits, although they all overestimated the proportion of transmission occurring >3 days after symptom onset. The best fitting model assumed that infectivity was proportion to V(gamma), with estimates of gamma = 0.136 and gamma = 0.156 for seasonal influenza A(H1N1) and A(H3N2) respectively. CONCLUSIONS: All the models we considered that used viral loads to approximate infectivity of a case imperfectly explained the timing of influenza secondary infections in households. Identification of more accurate correlates of infectivity will be important to inform control policies and disease modeling.
@article{tsang2015p25883385, title = {Influenza A Virus Shedding and Infectivity in Households.}, author = {Tsang, Tim K and Cowling, Benjamin J and Fang, Vicky J and Chan, Kwok-Hung and Ip, Dennis K M and Leung, Gabriel M and Peiris, J S Malik and Cauchemez, Simon}, journal = {The Journal of infectious diseases}, year = {2015}, volume = {212}, number = {9}, pages = {1420-8}, doi = {10.1093/infdis/jiv225}, }
J Infect Dis
Association of Oseltamivir Treatment With Virus Shedding, Illness, and Household Transmission of Influenza Viruses.

Doug H Cheung, Tim K Tsang, Vicky J Fang, and 6 more authors

The Journal of infectious diseases, 2015

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In an observational study of 582 patients with laboratory-confirmed influenza virus infections and their household contacts, we found that the initiation of oseltamivir within 24 hours was associated with shorter duration of self-reported illness symptoms (56% reduction in duration; 95% confidence interval, 41%-67%). However, we did not find any association of oseltamivir treatment with duration of viral shedding by polymerase chain reaction or with the risk of household transmission.
@article{cheung2015p25646354, title = {Association of Oseltamivir Treatment With Virus Shedding, Illness, and Household Transmission of Influenza Viruses.}, author = {Cheung, Doug H and Tsang, Tim K and Fang, Vicky J and Xu, Jiajing and Chan, Kwok-Hung and Ip, Dennis K M and Peiris, Joseph Sriyal Malik and Leung, Gabriel M and Cowling, Benjamin J}, journal = {The Journal of infectious diseases}, year = {2015}, volume = {212}, number = {3}, pages = {391-6}, doi = {10.1093/infdis/jiv058}, }

2014

Emerg Infect Dis
Poultry market closures and human infection with influenza A(H7N9) virus, China, 2013-14.

Peng Wu, Hui Jiang, Joseph T Wu, Enfu Chen, Jianfeng He, Hang Zhou, Lan Wei, Juan Yang, Bingyi Yang, Ying Qin, Vicky J Fang, Ming Li, Tim K Tsang, Jiandong Zheng, Eric H Y Lau, Yu Cao, Chengliang Chai, Haojie Zhong, Zhongjie Li, Gabriel M Leung, Luzhao Feng, George F Gao, Benjamin J Cowling, and Hongjie Yu

Emerging infectious diseases, 2014

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Closure of live poultry markets was implemented in areas affected by the influenza virus A(H7N9) outbreak in China during winter, 2013-14. Our analysis showed that closing live poultry markets in the most affected cities of Guangdong and Zhejiang provinces was highly effective in reducing the risk for H7N9 infection in humans.
@article{wu2014p25340354, title = {Poultry market closures and human infection with influenza A(H7N9) virus, China, 2013-14.}, author = {Wu, Peng and Jiang, Hui and Wu, Joseph T and Chen, Enfu and He, Jianfeng and Zhou, Hang and Wei, Lan and Yang, Juan and Yang, Bingyi and Qin, Ying and Fang, Vicky J and Li, Ming and Tsang, Tim K and Zheng, Jiandong and Lau, Eric H Y and Cao, Yu and Chai, Chengliang and Zhong, Haojie and Li, Zhongjie and Leung, Gabriel M and Feng, Luzhao and Gao, George F and Cowling, Benjamin J and Yu, Hongjie}, journal = {Emerging infectious diseases}, year = {2014}, volume = {20}, number = {11}, pages = {1891-4}, doi = {10.3201/eid2011.140556}, }
BMC Med
A clinical prediction rule for diagnosing human infections with avian influenza A(H7N9) in a hospital emergency department setting.

Qiaohong Liao, Dennis K M Ip, Tim K Tsang, and 12 more authors

BMC medicine, 2014

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BACKGROUND: Human infections with avian influenza A(H7N9) virus are associated with severe illness and high mortality. To better inform triage decisions of hospitalization and management, we developed a clinical prediction rule for diagnosing patients with A(H7N9) and determined its predictive performance. METHODS: Clinical details on presentation of adult patients hospitalized with either A(H7N9)(n = 121) in China from March to May 2013 or other causes of acute respiratory infections (n = 2,603) in Jingzhou City, China from January 2010 through September 2012 were analyzed. A clinical prediction rule was developed using a two-step coefficient-based multivariable logistic regression scoring method and evaluated with internal validation by bootstrapping. RESULTS: In step 1, predictors for A(H7N9) included male sex, poultry exposure history, and fever, haemoptysis, or shortness of breath on history and physical examination. In step 2, haziness or pneumonic consolidation on chest radiographs and leukopenia were also associated with a higher probability of A(H7N9). The observed risk of A(H7N9) was 0.3% for those assigned to the low-risk group and 2.5%, 4.3%, and 44.0% for tertiles 1 through 3, respectively, in the high-risk group. This prediction rule achieved good model performance, with an optimism-corrected sensitivity of 0.93, a specificity of 0.80, and an area under the receiver-operating characteristic curve of 0.96. CONCLUSIONS: A simple decision rule based on data readily obtainable in the setting of patients’ first clinical presentations from the first wave of the A/H7N9 epidemic in China has been developed. This prediction rule has achieved good model performance in predicting their risk of A(H7N9) infection and should be useful in guiding important clinical and public health decisions in a timely and objective manner. Data to be gathered with its use in the current evolving second wave of the A/H7N9 epidemic in China will help to inform its performance in the field and contribute to its further refinement.
@article{liao2014p25091477, title = {A clinical prediction rule for diagnosing human infections with avian influenza A(H7N9) in a hospital emergency department setting.}, author = {Liao, Qiaohong and Ip, Dennis K M and Tsang, Tim K and Cao, Bin and Jiang, Hui and Liu, Fengfeng and Zheng, Jiandong and Peng, Zhibin and Wu, Peng and Huai, Yang and Lau, Eric H Y and Feng, Luzhao and Leung, Gabriel M and Yu, Hongjie and Cowling, Benjamin J}, journal = {BMC medicine}, year = {2014}, volume = {12}, pages = {127}, doi = {10.1186/s12916-014-0127-0}, }
BMC Med
Accuracy of epidemiological inferences based on publicly available information: retrospective comparative analysis of line lists of human cases infected with influenza A(H7N9) in China.

Eric H Y Lau, Jiandong Zheng, Tim K Tsang, and 19 more authors

BMC medicine, 2014

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BACKGROUND: Appropriate public health responses to infectious disease threats should be based on best-available evidence, which requires timely reliable data for appropriate analysis. During the early stages of epidemics, analysis of ’line lists’ with detailed information on laboratory-confirmed cases can provide important insights into the epidemiology of a specific disease. The objective of the present study was to investigate the extent to which reliable epidemiologic inferences could be made from publicly-available epidemiologic data of human infection with influenza A(H7N9) virus. METHODS: We collated and compared six different line lists of laboratory-confirmed human cases of influenza A(H7N9) virus infection in the 2013 outbreak in China, including the official line list constructed by the Chinese Center for Disease Control and Prevention plus five other line lists by HealthMap, Virginia Tech, Bloomberg News, the University of Hong Kong and FluTrackers, based on publicly-available information. We characterized clinical severity and transmissibility of the outbreak, using line lists available at specific dates to estimate epidemiologic parameters, to replicate real-time inferences on the hospitalization fatality risk, and the impact of live poultry market closure. RESULTS: Demographic information was mostly complete (less than 10% missing for all variables) in different line lists, but there were more missing data on dates of hospitalization, discharge and health status (more than 10% missing for each variable). The estimated onset to hospitalization distributions were similar (median ranged from 4.6 to 5.6 days) for all line lists. Hospital fatality risk was consistently around 20% in the early phase of the epidemic for all line lists and approached the final estimate of 35% afterwards for the official line list only. Most of the line lists estimated >90% reduction in incidence rates after live poultry market closures in Shanghai, Nanjing and Hangzhou. CONCLUSIONS: We demonstrated that analysis of publicly-available data on H7N9 permitted reliable assessment of transmissibility and geographical dispersion, while assessment of clinical severity was less straightforward. Our results highlight the potential value in constructing a minimum dataset with standardized format and definition, and regular updates of patient status. Such an approach could be particularly useful for diseases that spread across multiple countries.
@article{lau2014p24885692, title = {Accuracy of epidemiological inferences based on publicly available information: retrospective comparative analysis of line lists of human cases infected with influenza A(H7N9) in China.}, author = {Lau, Eric H Y and Zheng, Jiandong and Tsang, Tim K and Liao, Qiaohong and Lewis, Bryan and Brownstein, John S and Sanders, Sharon and Wong, Jessica Y and Mekaru, Sumiko R and Rivers, Caitlin and Wu, Peng and Jiang, Hui and Li, Yu and Yu, Jianxing and Zhang, Qian and Chang, Zhaorui and Liu, Fengfeng and Peng, Zhibin and Leung, Gabriel M and Feng, Luzhao and Cowling, Benjamin J and Yu, Hongjie}, journal = {BMC medicine}, year = {2014}, volume = {12}, pages = {88}, doi = {10.1186/1741-7015-12-88}, }
J Infect Dis
Association between antibody titers and protection against influenza virus infection within households.

Tim K Tsang, Simon Cauchemez, Ranawaka A P M Perera, and 6 more authors

The Journal of infectious diseases, 2014

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BACKGROUND: Previous studies have established that antibody titer measured by the hemagglutination-inhibiting (HAI) assay is correlated with protection against influenza virus infection, with an HAI titer of 1:40 generally associated with 50% protection. METHODS: We recruited index cases with confirmed influenza virus infection from outpatient clinics, and followed up their household contacts for 7-10 days to identify secondary infections. Serum samples collected from a subset of household contacts were tested by HAI and microneutralization (MN) assays against prevalent influenza viruses. We analyzed the data using an individual hazard-based transmission model that adjusted for age and vaccination history. RESULTS: Compared to a reference group with antibody titers <1:10, we found that HAI titers of 1:40 against influenza A(H1N1) and A(H3N2) were associated with 31% (95% confidence interval [CI], 13%-46%) and 31% (CI, 1%-53%) protection against polymerase chain reaction (PCR)-confirmed A(H1N1) and A(H3N2) virus infection, respectively, while an MN titer of 1:40 against A(H3N2) was associated with 49% (95% CI, 7%-81%) protection against PCR-confirmed A(H3N2) virus infection. CONCLUSIONS: An HAI titer of 1:40 was associated with substantially less than 50% protection against PCR-confirmed influenza virus infection within households, perhaps because of exposures of greater duration or intensity in that confined setting.
@article{tsang2014p24676208, title = {Association between antibody titers and protection against influenza virus infection within households.}, author = {Tsang, Tim K and Cauchemez, Simon and Perera, Ranawaka A P M and Freeman, Guy and Fang, Vicky J and Ip, Dennis K M and Leung, Gabriel M and Malik Peiris, Joseph Sriyal and Cowling, Benjamin J}, journal = {The Journal of infectious diseases}, year = {2014}, volume = {210}, number = {5}, pages = {684-92}, doi = {10.1093/infdis/jiu186}, }
Clin Infect Dis
Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1.

Chen Wang, Hongjie Yu, Peter W Horby, Bin Cao, Peng Wu, Shigui Yang, Hainv Gao, Hui Li, Tim K Tsang, Qiaohong Liao, Zhancheng Gao, Dennis K M Ip, Hongyu Jia, Hui Jiang, Bo Liu, Michael Y Ni, Xiahong Dai, Fengfeng Liu, Nguyen Van Kinh, Nguyen Thanh Liem, Tran Tinh Hien, Yu Li, Juan Yang, Joseph T Wu, Yaming Zheng, Gabriel M Leung, Jeremy J Farrar, Benjamin J Cowling, Timothy M Uyeki, and Lanjuan Li

Clinical infectious diseases : an official publication of the Infectious Diseases Society of America, 2014

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BACKGROUND: Influenza A(H7N9) viruses isolated from humans show features suggesting partial adaptation to mammals. To provide insights into the pathogenesis of H7N9 virus infection, we compared risk factors, clinical presentation, and progression of patients hospitalized with H7N9, H5N1, and 2009 pandemic H1N1 (pH1N1) virus infections. METHODS: We compared individual-level data from patients hospitalized with infection by H7N9 (n = 123), H5N1 (n = 119; 43 China, 76 Vietnam), and pH1N1 (n = 3486) viruses. We assessed risk factors for hospitalization after adjustment for age- and sex-specific prevalence of risk factors in the general Chinese population. RESULTS: The median age of patients with H7N9 virus infection was older than other patient groups (63 years; P < .001) and a higher proportion was male (71%; P < .02). After adjustment for age and sex, chronic heart disease was associated with an increased risk of hospitalization with H7N9 (relative risk, 9.68; 95% confidence interval, 5.24-17.9). H7N9 patients had similar patterns of leukopenia, thrombocytopenia, and elevated alanine aminotransferase, creatinine kinase, C-reactive protein, and lactate dehydrogenase to those seen in H5N1 patients, which were all significantly different from pH1N1 patients (P < .005). H7N9 patients had a longer duration of hospitalization than either H5N1 or pH1N1 patients (P < .001), and the median time from onset to death was 18 days for H7N9 (P = .002) vs 11 days for H5N1 and 15 days for pH1N1 (P = .154). CONCLUSIONS: The identification of known risk factors for severe seasonal influenza and the more protracted clinical course compared with that of H5N1 suggests that host factors are an important contributor to H7N9 severity.
@article{wang2014p24488975, title = {Comparison of patients hospitalized with influenza A subtypes H7N9, H5N1, and 2009 pandemic H1N1.}, author = {Wang, Chen and Yu, Hongjie and Horby, Peter W and Cao, Bin and Wu, Peng and Yang, Shigui and Gao, Hainv and Li, Hui and Tsang, Tim K and Liao, Qiaohong and Gao, Zhancheng and Ip, Dennis K M and Jia, Hongyu and Jiang, Hui and Liu, Bo and Ni, Michael Y and Dai, Xiahong and Liu, Fengfeng and Van Kinh, Nguyen and Liem, Nguyen Thanh and Hien, Tran Tinh and Li, Yu and Yang, Juan and Wu, Joseph T and Zheng, Yaming and Leung, Gabriel M and Farrar, Jeremy J and Cowling, Benjamin J and Uyeki, Timothy M and Li, Lanjuan}, journal = {Clinical infectious diseases : an official publication of the Infectious Diseases Society of America}, year = {2014}, volume = {58}, number = {8}, pages = {1095-103}, doi = {10.1093/cid/ciu053}, }

2013

Lancet
Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases.

Benjamin J Cowling, Lianmei Jin, Eric H Y Lau, Qiaohong Liao, Peng Wu, Hui Jiang, Tim K Tsang, Jiandong Zheng, Vicky J Fang, Zhaorui Chang, Michael Y Ni, Qian Zhang, Dennis K M Ip, Jianxing Yu, Yu Li, Liping Wang, Wenxiao Tu, Ling Meng, Joseph T Wu, Huiming Luo, Qun Li, Yuelong Shu, Zhongjie Li, Zijian Feng, Weizhong Yang, Yu Wang, Gabriel M Leung, and Hongjie Yu

Lancet (London, England), 2013

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BACKGROUND: The novel influenza A H7N9 virus emerged recently in mainland China, whereas the influenza A H5N1 virus has infected people in China since 2003. Both infections are thought to be mainly zoonotic. We aimed to compare the epidemiological characteristics of the complete series of laboratory-confirmed cases of both viruses in mainland China so far. METHODS: An integrated database was constructed with information about demographic, epidemiological, and clinical variables of laboratory-confirmed cases of H7N9 (130 patients) and H5N1 (43 patients) that were reported to the Chinese Centre for Disease Control and Prevention until May 24, 2013. We described disease occurrence by age, sex, and geography, and estimated key epidemiological variables. We used survival analysis techniques to estimate the following distributions: infection to onset, onset to admission, onset to laboratory confirmation, admission to death, and admission to discharge. FINDINGS: The median age of the 130 individuals with confirmed infection with H7N9 was 62 years and of the 43 with H5N1 was 26 years. In urban areas, 74% of cases of both viruses were in men, whereas in rural areas the proportions of the viruses in men were 62% for H7N9 and 33% for H5N1. 75% of patients infected with H7N9 and 71% of those with H5N1 reported recent exposure to poultry. The mean incubation period of H7N9 was 3.1 days and of H5N1 was 3.3 days. On average, 21 contacts were traced for each case of H7N9 in urban areas and 18 in rural areas, compared with 90 and 63 for H5N1. The fatality risk on admission to hospital was 36% (95% CI 26-45) for H7N9 and 70% (56-83%) for H5N1. INTERPRETATION: The sex ratios in urban compared with rural cases are consistent with exposure to poultry driving the risk of infection–a higher risk in men was only recorded in urban areas but not in rural areas, and the increased risk for men was of a similar magnitude for H7N9 and H5N1. However, the difference in susceptibility to serious illness with the two different viruses remains unexplained, since most cases of H7N9 were in older adults whereas most cases of H5N1 were in younger people. A limitation of our study is that we compared laboratory-confirmed cases of H7N9 and H5N1 infection, and some infections might not have been ascertained. FUNDING: Ministry of Science and Technology, China; Research Fund for the Control of Infectious Disease and University Grants Committee, Hong Kong Special Administrative Region, China; and the US National Institutes of Health.
@article{cowling2013p23803488, title = {Comparative epidemiology of human infections with avian influenza A H7N9 and H5N1 viruses in China: a population-based study of laboratory-confirmed cases.}, author = {Cowling, Benjamin J and Jin, Lianmei and Lau, Eric H Y and Liao, Qiaohong and Wu, Peng and Jiang, Hui and Tsang, Tim K and Zheng, Jiandong and Fang, Vicky J and Chang, Zhaorui and Ni, Michael Y and Zhang, Qian and Ip, Dennis K M and Yu, Jianxing and Li, Yu and Wang, Liping and Tu, Wenxiao and Meng, Ling and Wu, Joseph T and Luo, Huiming and Li, Qun and Shu, Yuelong and Li, Zhongjie and Feng, Zijian and Yang, Weizhong and Wang, Yu and Leung, Gabriel M and Yu, Hongjie}, journal = {Lancet (London, England)}, year = {2013}, volume = {382}, number = {9887}, pages = {129-37}, doi = {10.1016/S0140-6736(13)61171-X}, }
Lancet
Human infection with avian influenza A H7N9 virus: an assessment of clinical severity.

Hongjie Yu, Benjamin J Cowling, Luzhao Feng, Eric H Y Lau, Qiaohong Liao, Tim K Tsang, Zhibin Peng, Peng Wu, Fengfeng Liu, Vicky J Fang, Honglong Zhang, Ming Li, Lingjia Zeng, Zhen Xu, Zhongjie Li, Huiming Luo, Qun Li, Zijian Feng, Bin Cao, Weizhong Yang, Joseph T Wu, Yu Wang, and Gabriel M Leung

Lancet (London, England), 2013

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BACKGROUND: Characterisation of the severity profile of human infections with influenza viruses of animal origin is a part of pandemic risk assessment, and an important part of the assessment of disease epidemiology. Our objective was to assess the clinical severity of human infections with avian influenza A H7N9 virus, which emerged in China in early 2013. METHODS: We obtained information about laboratory-confirmed cases of avian influenza A H7N9 virus infection reported as of May 28, 2013, from an integrated database built by the Chinese Center for Disease Control and Prevention. We estimated the risk of fatality, mechanical ventilation, and admission to the intensive care unit for patients who required hospital admission for medical reasons. We also used information about laboratory-confirmed cases detected through sentinel influenza-like illness surveillance to estimate the symptomatic case fatality risk. FINDINGS: Of 123 patients with laboratory-confirmed avian influenza A H7N9 virus infection who were admitted to hospital, 37 (30%) had died and 69 (56%) had recovered by May 28, 2013. After we accounted for incomplete data for 17 patients who were still in hospital, we estimated the fatality risk for all ages to be 36% (95% CI 26-45) on admission to hospital. Risks of mechanical ventilation or fatality (69%, 95% CI 60-77) and of admission to an intensive care unit, mechanical ventilation, or fatality (83%, 76-90) were high. With assumptions about coverage of the sentinel surveillance network and health-care-seeking behaviour for patients with influenza-like illness associated with influenza A H7N9 virus infection, and pro-rata extrapolation, we estimated that the symptomatic case fatality risk could be between 160 (63-460) and 2800 (1000-9400) per 100,000 symptomatic cases. INTERPRETATION: Human infections with avian influenza A H7N9 virus seem to be less serious than has been previously reported. Many mild cases might already have occurred. Continued vigilance and sustained intensive control efforts are needed to minimise the risk of human infection. FUNDING: Chinese Ministry of Science and Technology; Research Fund for the Control of Infectious Disease; Hong Kong University Grants Committee; China-US Collaborative Program on Emerging and Re-emerging Infectious Diseases; Harvard Center for Communicable Disease Dynamics; US National Institute of Allergy and Infectious Disease; and the US National Institutes of Health.
@article{yu2013p23803487, title = {Human infection with avian influenza A H7N9 virus: an assessment of clinical severity.}, author = {Yu, Hongjie and Cowling, Benjamin J and Feng, Luzhao and Lau, Eric H Y and Liao, Qiaohong and Tsang, Tim K and Peng, Zhibin and Wu, Peng and Liu, Fengfeng and Fang, Vicky J and Zhang, Honglong and Li, Ming and Zeng, Lingjia and Xu, Zhen and Li, Zhongjie and Luo, Huiming and Li, Qun and Feng, Zijian and Cao, Bin and Yang, Weizhong and Wu, Joseph T and Wang, Yu and Leung, Gabriel M}, journal = {Lancet (London, England)}, year = {2013}, volume = {382}, number = {9887}, pages = {138-45}, doi = {10.1016/S0140-6736(13)61207-6}, }