Limited impact of lifting universal masks on SARS-COV-2 transmission in schools: The crucial role of outcome measurements (preprint)

As the pandemic's dynamics changed, many municipalities lifted face wearing requirement in school which was initially implemented to mitigate the transmission of COVID-19. This study examines the effects of lifting mask mandates on COVID-19 transmission within Massachusetts school districts. We first replicated previous research by Cowger et al. (2022) utilizing a Difference-in-Difference (DID) model. Then, we back project the case infection and calculate the Rt value to redo the DID analysis. However, when shifting the outcome measurement to the reproductive number (Rt), our findings suggest that lifting mask mandates can only significantly influence the Rt first two weeks post-intervention. This implies that while mask mandate plays a role in mitigation, its lifting does not drastically influence COVID-19 transmissibility in the long term.

Comparison of control and transmission of COVID-19 across epidemic waves in Hong Kong: an observational study (preprint)

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. 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 non-pharmaceutical and pharmaceutical interventions implemented from January 2020 through to 30 December 2022. We estimated the daily effective reproductive number (Rt) 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.

Revisiting assumptions in test-negative studies for estimating vaccine effectiveness: the need for a clinical case definition (preprint)

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.

Viral shedding among symptomatic COVID-19 cases infected with the ancestral strain and Omicron BA.2 (preprint)

Assessment of viral kinetics of SARS-CoV-2 may inform host immune responses to and transmission potential of the virus. We analyzed longitudinal data of RT-PCR tests conducted for symptomatic COVID-19 patients at confirmation and during hospital isolation in Hong Kong during three major epidemic waves, and modeled the temporal trajectories of viral burden in these patients. Our analysis demonstrated that a longer duration of viral shedding appeared in more severe and older cases. Vaccinated individuals with a breakthrough infection of Omicron BA.2 exhibited a lower viral burden than non-vaccinated Omicron cases in early days following onset and a shorter duration of viral shedding particularly in more recently vaccinated patients. The viral kinetics characterized in our study provided insight into further studies on host immune responses to SARS-CoV-2 infection, prognosis of COVID-19 patients as well as possible protective mechanisms of vaccination against infection and severe outcomes.

Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative study: A systematic review and meta-analysis (preprint)

Background: Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. In settings with high pre-existing immunity, vaccine effectiveness (VE) should decrease with higher levels of immunity among unvaccinated individuals. Here, we conducted a systematic review and meta-analysis to understand the influence of prior infection on VE. Methods: We included test-negative design (TND) studies that examined VE against infection or severe disease (hospitalization, ICU admission, or death) for primary vaccination series. To determine the impact of prior infections on VE estimates, we compared studies that excluded or included people with prior COVID-19 infection. We also compared VE estimates by the cumulative incidence of cases before the start of and incidence rates during each study in the study locations, as further measures of prior infections in the community. Findings: We identified 67 studies that met inclusion criteria. Pooled VE among studies that included people with prior COVID-19 infection was lower against infection (pooled VE: 77%; 95% confidence interval (CI): 72%, 81%) and severe disease (pooled VE: 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 the cumulative incidence of cases before the start of the study and VE estimates against infection (spearman correlation ({rho}) = -0.32; 95% CI: -0.45, -0.18) and severe disease ({rho} = -0.49; 95% CI: -0.64, -0.30). There was also a negative correlation between the incidence rates of cases during the study period and VE estimates against infection ({rho} = -0.48; 95% CI: -0.59, -0.34) and severe disease ({rho} = -0.42; 95% CI: -0.58, -0.23). Interpretation: Based on a review of published VE estimates we found clear empirical evidence that higher levels of pre-existing immunity in a population were associated with lower VE estimates. Excluding previously infected individuals from VE studies may result in higher VE estimates with limited generalisability to the wider population. Prior infections should be treated as confounder and effect modificatory when the policies were targeted to whole population or stratified by infection history, respectively.

Residential clustering of COVID-19 cases and efficiency of building-wide compulsory testing notices as a transmission control measure in Hong Kong (preprint)

Background: Despite relatively few reports of residential case clusters of COVID-19, building-wide compulsory testing notices on residential apartment blocks are frequently applied in Hong Kong with the aim of identifying cases and reducing transmission. Methods: We aimed to describe the frequency of residential case clusters and the efficiency of compulsory testing notices in identifying cases. The residences of locally infected COVID-19 cases in Hong Kong were grouped to quantify the number of cases per residence. Buildings targeted in compulsory testing notices were matched with the residence of cases to estimate the number of cases identified. Results: We found that most of the residential buildings (4246/7688, 55.2%) with a confirmed COVID-19 case had only one reported case. In the fourth and the fifth epidemic wave in Hong Kong, we estimated that compulsory testing notices detected 29 cases (95% confidence interval: 26, 32) and 46 cases (44, 48) from every 100 buildings tested (each with hundreds of residents), respectively. Approximately 13% of the daily reported cases were identified through compulsory testing notices. Conclusions: Compulsory testing notices can be an essential method when attempting to maintain local elimination (zero covid) and most impactful early in an epidemic when the benefit remains of stemming a new wave. Compulsory testing therefore appears to be a relatively inefficient control measure in response to sustained community transmission in the community.

The effect of variation of individual infectiousness on SARS-CoV-2 transmission in households (preprint)

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: 2.2-4.2 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.

Impact of public health and social measures on hand-foot-mouth disease transmission and prediction of upcoming season after relaxation of COVID-19 control measures (preprint)

Background School based-measures such as school closure and school holidays have been considered a viable intervention during the hand-foot-mouth disease (HFMD) epidemic. However, the impact of public health and social measures (PHSMs) on HFMD transmission and the consequences of the HFMD epidemic after relaxing the PHSMs remains unclear.Methods Korean national surveillance data on HFMD from 2014 to 2019 was used to estimate the temporal changes in HFMD transmissibility (instantaneous reproductive number, \({R}_{t}\)). Furthermore, we used a simulation based stochastic transmission model to predict the future burden of HFMDs after relaxation of COVID-19 PHSMs, assuming all the Korean population was susceptible to HFMD in 2023, the stochastic transmission model simulated the number of HFMD cases in South Korea.Results We found that school holidays and 2015 PHSMs reduced the \({R}_{t}\) by 2–7% and 13%, respectively. Model projections indicated that the peak magnitude for season 2023, after relaxation of COVID-19 PHSMs in late 2022, could be 2·5–8·5 fold larger than that of the HFMD seasons during the pre-pandemic.Conclusions PHSMs likely have a larger impact on HFMD transmission than school-based measures alone (i.e. school holidays). Furthermore, complete relaxation of COVID-19 PHSMs could significantly increase the HFMD infection burden for the upcoming HFMD season. Preventive measures targeting preschoolers could be considered as potential options for reducing the future burden of HFMD.

An observational study on imported COVID-19 cases in Hong Kong during mandatory on-arrival hotel quarantine (preprint)

Background: Hong Kong has enforced stringent travel restrictions particularly for inbound travellers since the emergence of SARS-CoV-2. Understanding the characteristics of imported COVID-19 cases is important for establishing evidence-based control measures. Methods: We conducted a retrospective cohort study to summarise the characteristics of cases classified as imported cases that were detected on or soon after arrival into Hong Kong from 13 November 2020 through to 31 January 2022, when all arriving persons were required to quarantine in a hotel or a designated quarantine facility. We analysed individual demographics, and clinical information including symptoms and disease severity, virus variants, and Ct values. Results: There were 2269 imported COVID-19 cases aged 0-85 years identified in Hong Kong. Almost half (48.6%) of the imported cases were detected on arrival. A shorter median delay from arrival to isolation was observed in Delta and Omicron cases (3 days) than cases infected with the ancestral strain and other variants (12 days; p<0.001) while lower Ct values at isolation were observed in cases infected with Omicron than the ancestral strain or other variants. No Omicron cases were detected beyond 14 days after arrival, and the cases (n=58, 2.6%) detected after 14 days of quarantine more frequently presented without symptoms at isolation and had a higher RT-PCR Ct-value during isolation. At least some of these cases were post-arrival infections. Conclusions: Testing inbound travellers at arrival and during on-arrival quarantine can detect imported cases early although it may not be sufficient to prevent all introductions of COVID-19 into the community. Public health measures should be adjusted in responses to the emergence of new variants of SARS-CoV-2 based on the epidemiologic evidence from continuous surveillance.

Immunogenicity, efficacy, and safety of SARS-CoV-2 vaccine dose fractionation: a systematic review and meta-analysis (preprint)

Background: Dose fractionation of 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 reported dose-finding results and estimated the dose-response relationship of neutralizing antibodies (nAbs) of COVID-19 vaccines using 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.Conclusion: Dose fractionation of mRNA and protein subunit vaccines may be safe and effective.

Incorporating temporal distribution of population-level viral load enables real-time estimation of COVID-19 transmissibility (preprint)

Many locations around the world have used real-time estimates of the time-varying effective reproductive number (\({R}_{t}\)) of COVID-19 to provide evidence of transmission intensity to inform control strategies. Estimates of \({R}_{t}\) are typically based on statistical models applied to case counts and typically suffer lags of more than a week because of the incubation 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 cycle threshold values) and estimates of \({R}_{t}\) based on case counts. We demonstrate that cycle threshold values could be used to improve real-time \({R}_{t}\) estimation, enabling more timely tracking of epidemic dynamics.

Pandemic fatigue impedes mitigation of COVID-19 in Hong Kong (preprint)

Community-wide social distancing has been a cornerstone of pandemic control prior to mass vaccinations. The extent to which pandemic fatigue is undermining adherence to such measures and accelerating transmission remains unclear. Using large-scale weekly telephone surveys and mobility data, we characterize the evolution of risk perception and protective behaviours in Hong Kong. We estimate a 1.5% to 5.5% reduction in population compliance with protective policies for the fourth wave (October 2020 to January 2021) versus the third wave (July to August 2020), inducing prolonged disease circulation with increased infections. Mathematical models incorporating population protective behaviours estimates that the fourth wave would have been 14% smaller if not for pandemic fatigue. Mitigating pandemic fatigue is essential in maintaining population protective behaviours for controlling COVID-19.

Universal community nucleic acid testing for COVID-19 in Hong Kong reveals insights into transmission dynamics (preprint)

Background: Testing of an entire community has been used as an approach to control COVID-19. In Hong Kong, a universal community testing programme (UCTP) was implemented at the fadeout phase of a community epidemic in July to September 2020, to determine the prevalence of unrecognised cases and limit any remaining transmission chains. We described the utility of the UCTP in finding unrecognised cases, and analysed data from the UCTP and other sources to characterise 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. We developed a Bayesian model to estimate the age-specific incidence of infection and the proportion of cases detected by clinical diagnosis and public health surveillance.Findings: 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 100,000 samples tested), consisting of 29% of all local cases reported during the two-week UCTP period. Compared with the existing clinical diagnosis and public health surveillance, the UCTP detected a higher proportion of sporadic cases (62% versus 27%, p <0.01) and identified 6 (out of 18) additional transmission chains during that period. We estimated that 27% (95% credible interval: 22%, 34%) of all infections were detected by the existing clinical diagnosis and public health surveillance in the third wave.Interpretation: We reported empirical evidence of the utility of population-wide COVID-19 testing in detecting unrecognised infections and transmission chains. Around three quarters of infections have not been identified through existing surveillance approaches including contact tracing.

Universal Community Nucleic Acid Testing for COVID-19 in Hong Kong Reveals Insights into Transmission Dynamics (preprint)

Background: Testing of an entire community has been used as an approach to control COVID-19. In Hong Kong, a universal community testing programme (UCTP) was implemented at the fadeout phase of a community epidemic in July to September 2020, to determine the prevalence of unrecognised cases and limit any remaining transmission chains. We described the utility of the UCTP in finding unrecognised cases, and analysed data from the UCTP and other sources to characterise 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. We developed a Bayesian model to estimate the age-specific incidence of infection and the proportion of cases detected by clinical diagnosis and public health surveillance.Findings: 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 100,000 samples tested), consisting of 29% of all local cases reported during the two-week UCTP period. Compared with the existing clinical diagnosis and public health surveillance, the UCTP detected a higher proportion of sporadic cases (62% versus 27%, p <0.01) and identified 6 (out of 18) additional transmission chains during that period. We estimated that 27% (95% credible interval: 22%, 34%) of all infections were detected by the existing clinical diagnosis and public health surveillance in the third wave.Interpretation: We reported empirical evidence of the utility of population-wide COVID-19 testing in detecting unrecognised infections and transmission chains. Around three quarters of infections have not been identified through existing surveillance approaches including contact tracing.Funding Statement: This project was supported by the Health and Medical Research Fund, Food and Health Bureau, Government of the Hong Kong Special Administrative Region (grant no. COVID190118).Declaration of Interests: BJC consults for Roche, Sanofi Pasteur, GSK and Moderna. The authors report no other potential conflicts of interest.Ethics Approval Statement: Our project was approved by the Institutional Review Board of the University of Hong Kong/Hospital Authority Hong Kong West Cluster (HKU/HA HKW IRB).

Confidence, Acceptance and Willingness to Pay for the COVID-19 Vaccine Among Migrants in Shanghai, China: A Cross-Sectional Study (preprint)

Background: Vaccine hesitancy became one of the top ten threats to global health. This study aimed to assess the acceptance and willingness to pay (WTP) for COVID-19 vaccine among migrants in Shanghai, China.Methods: A cross-sectional study was conducted among 2,126 migrants in Shanghai during November 1-20th, 2020. A questionnaire was used to measure confidence in, acceptance of and WTP for COVID-19 vaccine. Multivariable (ordered) logistic regressions were used to examine factors associated with acceptance and WTP of COVID-19 vaccine.Findings: Most (89.1%) migrants stated that they would accept COVID-19 vaccination. Over 90.0% migrants perceived COVID-19 vaccine as important, while only 75.0% and 77.7% perceived vaccines safe and effective. Socio-demographic factors were not significantly associated with vaccine acceptance, but confidence in the importance, safety and effectiveness of COVID-19 vaccine was significantly associated with vaccine acceptance. The top reasons for vaccine hesitancy were lack of vaccine information and confidence. Proportion of those definitely willing to get COVID-19 vaccine was 20% lower if paid by themselves than free vaccination. Migrants were willing to pay a median amount of US$ 46 for COVID-19 vaccine.Interpretation: A high acceptance of COVID-19 vaccine was universal among migrants in Shanghai, China. Concerns about vaccine safety and effectiveness as well as high costs of the COVID-19 vaccine may hinder their uptake in the future. Effective health communication to build confidence in the COVID-19 vaccine and subsidies toward the prohibitive costs of these vaccines are needed to improve uptake.Funding: National Natural Science Foundation of China (No. 71874034).Declaration of Interests: We declare no competing interests.Ethics Approval Statement: This study was approved by Ethics Committee at the Fudan University School of Public Health [IRB#2020-12-0861].

International risk of the new variant COVID-19 importations originating in the United Kingdom (preprint)

A fast-spreading SARS-CoV-2 variant identified in the United Kingdom in December 2020 has raised international alarm. We estimate that, in all 15 countries analyzed, there is at least a 50% chance the variant was imported by travelers from the United Kingdom by December 7th.

Effect of specific non-pharmaceutical intervention policies on SARS-CoV-2 transmission in the counties of the United States (preprint)

Non-pharmaceutical interventions (NPIs) remain the only widely available tool for controlling the ongoing SARS-CoV-2 pandemic. We estimated weekly values of the effective basic reproductive number (Reff) using a mechanistic metapopulation model and associated these with county-level characteristics and NPIs in the United States (US). Interventions that included school and leisure activities closure and nursing home visiting bans were all associated with an Reff below 1 when combined with either stay at home orders (median Reff 0.97, 95% confidence interval (CI) 0.58-1.39)* or face masks (median Reff 0.97, 95% CI 0.58-1.39)*. While direct causal effects of interventions remain unclear, our results suggest that relaxation of some NPIs will need to be counterbalanced by continuation and/or implementation of others.

The usefulness of SARS-CoV-2 test positive proportion as a surveillance tool (preprint)

Comparison of COVID-19 case numbers over time and between locations is complicated by limits to virologic testing confirm SARS-CoV-2 infection, leading to under-reporting of incidence, and by variations in testing capacity between locations and over time. The proportion of tested individuals who have tested positive (test positive proportion, TPP) can potentially be used to qualitatively assess the testing capacity of a location; a high TPP could provide evidence that too few people are tested, leading to more under-reporting. In this study we propose a simple model for testing in a population experiencing an epidemic of COVID-19, and derive an expression for TPP in terms of well-defined parameters in the model, related to testing and presence of other pathogens causing COVID-19 like symptoms. We use simulations to show situations in which the TPP is higher or lower than we expect based on these parameters, and the effect of testing strategies on the TPP. In our simulations, we find in the absence of dramatic shifts of testing practices in time or between spatial locations, the TPP is positively correlated with the incidence of infection. As a corollary, the TPP can be used to distinguish between a decline in confirmed cases due to decline in incidence (in which case TPP should decline) and a decline in confirmed cases due to testing constraints (in which case TPP should remain constant). We show that the proportion of tested individuals who present COVID-19 like symptoms (test symptomatic proportion, TSP) encodes similar information to the TPP but has different relationships with the testing parameters, and can thus provide additional information regarding dynamic changes in TPP and incidence. Finally, we compare data on confirmed cases and TPP from US states. We conjecture why states may have higher or lower TPP than average. We suggest that collection of symptom status and age/risk category of tested individuals can aid interpretation of changes in TPP and increase the utility of TPP in assessing the state of the pandemic in different locations and times. SummaryO_LIKey question: when can we use the proportion of tests that are positive (test positive proportion, TPP) as an indicator of the burden of infection in a state? C_LIO_LIIf testing strategies are broadly similar between locations and over time, the TPP is positively correlated with incidence rates. C_LIO_LIHowever, changes in testing practices over time and between locations can affect the TPP independently of the number of cases. C_LIO_LIMore testing of asymptomatic individuals, e.g. through population-level testing, lowers the TPP. C_LIO_LIWe can identify locations that have a lower or higher TPP than expected, given how many cases they are reporting. C_LIO_LIEfficient transmission increases detected cases exponentially, resulting in large changes in confirmed cases compared to factors that change linearly. C_LIO_LIData that could aid interpretability of the TPP include: age of individuals who test positive and negative, and other data on testing performed in high-prevalence settings; and symptom status of tested individuals. C_LI

A systematic review of antibody mediated immunity to coronaviruses: antibody kinetics, correlates of protection, and association of antibody responses with severity of disease (preprint)

The duration and nature of immunity generated in response to SARS-CoV-2 infection is unknown. Many public health responses and modeled scenarios for COVID-19 outbreaks caused by SARS-CoV-2 assume that infection results in an immune response that protects individuals from future infections or illness for some amount of time. The timescale of protection is a critical determinant of the future impact of the pathogen. The presence or absence of protective immunity due to infection or vaccination (when available) will affect future transmission and illness severity. The dynamics of immunity and nature of protection are relevant to discussions surrounding therapeutic use of convalescent sera as well as efforts to identify individuals with protective immunity. Here, we review the scientific literature on antibody immunity to coronaviruses, including SARS-CoV-2 as well as the related SARS-CoV-1, MERS-CoV and human endemic coronaviruses (HCoVs). We reviewed 1281 abstracts and identified 322 manuscripts relevant to 5 areas of focus: 1) antibody kinetics, 2) correlates of protection, 3) immunopathogenesis, 4) antigenic diversity and cross-reactivity, and 5) population seroprevalence. While studies of SARS-CoV-2 are necessary to determine immune responses to it, evidence from other coronaviruses can provide clues and guide future research.