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.

Estimating the transmission dynamics of Omicron in Beijing, November to December 2022 (preprint)

We tracked the effective reproduction number Rt of Omicron BF.7 in Beijing in November – December 2022 by fitting a transmission dynamic model parameterized with real-time mobility data to (i) the daily number of new symptomatic cases on November 1–11 (when the zero-covid interventions were still strictly enforced) and (ii) the proportion of individuals who participated in online polls on December 10–14 and self-reported to have been previously test-positive. After the announcement of “20 measures”, we estimated that Rt increased to 3.42 (95% CrI: 2.79–4.17) on November 18. Infection incidence peaked on December 10, and the cumulative infection attack rate was 42.5% (95% CrI: 20.3–63.9) on December 14. Surveillance programmes should be rapidly set up to monitor the evolving epidemiology and evolution of SARS-CoV-2 across China.

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.

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.

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.

Real-world effectiveness of molnupiravir and nirmatrelvir/ritonavir against mortality, hospitalization, and in-hospital outcomes among community-dwelling, ambulatory COVID-19 patients during the BA.2.2 wave in Hong Kong: an observational study (preprint)

Background Evidence evaluating real-world effectiveness of oral antivirals against Omicron variants is lacking. Methods An unselected, territory-wide cohort of all initially non-hospitalized patients with an officially registered diagnosis of SARS-CoV-2 infection between 26th February and 3rd May 2022 during the Omicron BA.2.2 wave in Hong Kong, was identified. We undertook a retrospective cohort design as primary analysis, and case-control design as sensitivity analysis. Outpatient oral antiviral users were matched with controls using 1:10 propensity-score matching. Study outcomes were mortality, COVID-19-related hospitalization, composite outcome of in-hospital disease progression (in-hospital mortality, invasive mechanical ventilation, or intensive care unit admission) and its individual outcomes. Hazard ratios (HR) were estimated by Cox regression, and odds ratios in oral antiviral users compared with non-users by logistic regression. Subgroup analyses evaluated the associations by vaccination status and age. Findings Among 1,072,004 non-hospitalized COVID-19 patients, 5,257 and 5,663 were initiated molnupiravir and nirmatrelvir/ritonavir in the community setting with a median follow-up of 42 and 38 days, respectively. Molnupiravir use was associated with lower risks of mortality (HR=0·61, 95%CI=0·46-0·82, p<0·001) and in-hospital composite outcome (HR=0·64, 95%CI=0·50-0·83, p<0·001) than non-use, while that of hospitalization was comparable to controls (HR=1·06, 95%CI=0·97-1·16, p=0·191). Nirmatrelvir/ritonavir use was associated with lower risks of mortality (HR=0·25, 95%CI=0·13-0·47, p<0·001), hospitalization (HR=0·69, 95%CI=0·60-0·79, p<0·001), and in-hospital outcome (HR=0·47, 95%CI=0·31-0·71, p<0·001) than non-use. Similar protective effects of nirmatrelvir/ritonavir were observed across vaccination status (fully vaccinated versus otherwise) and age (dichotomized at 65 years), whereas those for molnupiravir were less consistent. Findings from case-control analysis broadly confirmed those of primary analysis. Interpretation Amid the Omicron BA.2.2 wave, early initiation of oral antivirals among non-institutionalised COVID-19 patients was associated with reduced risks of mortality and in-hospital outcomes. Nirmatrelvir/ritonavir use was associated with greater and more consistent protection than molnupiravir. Funding Health and Medical Research Fund, Food and Health Bureau Research in context Evidence before this study Oral antivirals have been initiating in non-hospitalized COVID-19 patients to lower their risks of hospitalization and death, and hence to reduce the burden on healthcare systems. We searched Scopus and PubMed for studies until 25 May 2022 using the search terms “SARS-CoV-2 OR COVID-19” AND “molnupiravir OR Lagevrio OR EIDD-2801” OR “nirmatrelvir OR Paxlovid OR PF-07321332”. Major studies examining the outpatient use of molnupiravir and nirmatrelvir/ritonavir are MOVe-OUT and EPIC-HR trials, respectively. Both have been conducted among unvaccinated, non-hospitalized patients with mild-to-moderate COVID-19 who are at risk of progression to severe disease, during a pandemic wave of SARS-CoV-2 Delta variant. Early initiation of molnupiravir or nirmatrelvir/ritonavir within five days of symptom onset has been associated with relative risk reduction of hospitalization or death by 30% and 88%, respectively. Considering the real-world evaluation of the two oral antivirals against the currently circulating Omicron variant, only one single-center, retrospective review of solid organ transplant recipients with COVID-19 has been conducted; yet their results are unlikely generalizable to other populations given its specific patient group and small sample size. Real-world effectiveness of oral antivirals is urgently needed to inform their clinical use in COVID-19 patients, considering their vaccination status and the variant of concern. Added value of this study To the best of our knowledge, this is one of the first real-world studies exploring the clinical use of oral antivirals during a pandemic wave dominated by SARS-CoV-2 Omicron variant. A territory-wide, retrospective cohort study was conducted to examine the effectiveness of molnupiravir and nirmatrelvir/ritonavir in community-dwelling COVID-19 patients. Early initiation of molnupiravir or nirmatrelvir/ritonavir within five days of symptom onset was associated with significant reduction of all-cause mortality risk by 39% and 75%, respectively, compared to not using any oral antivirals. Nirmatrelvir/ritonavir use was also associated with a reduced risk of COVID-19-related hospitalization by 31%, which was consistently observed across age and vaccination status. In terms of disease progression, both oral antivirals were effective in lowering the risk of in-hospital death, which was again more substantial with nirmatrelvir/ritonavir than molnupiravir. Intriguingly, the need for invasive ventilation might be reduced among molnupiravir users compared to matched controls. Implications of all the available evidence Based on relative efficacy, our findings give support to current guidelines prioritizing nirmatrelvir/ritonavir use over molnupiravir in community-dwelling COVID-19 patients who are at high risk of hospitalization or progression to severe disease, should the former be accessible and clinically appropriate. Amid a pandemic wave of the Omicron variant, real-world effectiveness of oral antivirals in reducing the mortality risk of community-dwelling COVID-19 patients has been demonstrated in this study consisting mostly of the elderly and those who had not been fully vaccinated, extending beyond the evidence demonstrated in clinical trials among those of the Delta variant and who were at risk of severe COVID-19 from being overweight/obese. Several clinical trials (namely RECOVERY and PANORAMIC) and observational studies of the two oral antivirals are ongoing, and further research is needed to confirm our results in other patient populations and healthcare settings.

Epidemiology of infections with SARS-CoV-2 Omicron BA.2 variant in Hong Kong, January-March 2022 (preprint)

Hong Kong reported 12,631 confirmed COVID-19 cases and 213 deaths in the first two years of the pandemic but experienced a major wave predominantly of Omicron BA.2.2 in early 2022 with over 1.1 million reported SARS-CoV-2 infections and more than 7900 deaths. Our data indicated a shorter incubation period, serial interval, and generation time of infections with Omicron than other SARS-CoV-2 variants. Omicron BA.2.2 cases without a complete primary vaccination series appeared to face a similar fatality risk to those infected in earlier waves with the ancestral strain.

Time-varying transmission heterogeneity of SARS and COVID-19 in Hong Kong (preprint)

Transmission heterogeneity is a notable feature of the severe acute respiratory syndrome (SARS) and coronavirus disease 2019 (COVID-19) epidemics, though previous efforts to estimate how heterogeneity changes over time are limited. Using contact tracing data, we compared the epidemiology of SARS and COVID-19 infection in Hong Kong in 2003 and 2020-21 and estimated time-varying transmission heterogeneity (kt) by fitting negative binomial models to offspring distributions generated across variable observation windows. kt fluctuated over time for both COVID-19 and SARS on a continuous scale though SARS exhibited significantly greater (p < 0.001) heterogeneity compared to COVID-19 overall and in-time. For COVID-19, kt declined over time and was significantly associated with increasingly stringent non-pharmaceutical interventions though similar evidence for SARS was inconclusive. Underdetection of sporadic COVID-19 cases led to a moderate overestimation of kt, indicating COVID-19 heterogeneity of could be greater than observed. Time-varying or real-time estimates of transmission heterogeneity could become a critical indicator for epidemic intelligence in the future.

Comparative effectiveness of allocation strategies of COVID-19 vaccines and antivirals against emerging SARS-CoV-2 variants of concern in East Asia and Pacific region (preprint)

Background We aimed to evaluate the impact of various allocation strategies of COVID-19 vaccines and antiviral such that the pandemic exit strategy could be tailored to risks and preferences of jurisdictions in the East Asia and Pacific region (EAP) to improve its efficiency and effectiveness. Methods Vaccine efficacies were estimated from the titre distributions of 50% plaque reduction neutralization test (PRNT50), assuming that PRNT50 titres of primary vaccination decreased by 2-10 folds due to antibody waning and emergence of VOCs, and an additional dose of vaccine would increase PRNT50 titres by 3- or 9-fold. We then used an existing SARS-CoV-2 transmission model to assess the outcomes of vaccine allocation strategies with and without the use of antivirals for symptomatic patients in Japan, Hong Kong and Vietnam. Findings Increasing primary vaccination coverage was the most important contributing factor in reducing the total and peak number of COVID-19 hospitalizations, especially when population vaccine coverage or vaccine uptake among older adults was low. Providing antivirals to 50% of symptomatic infections only further reduced total and peak hospitalizations by 10-13%. The effectiveness of an additional dose of vaccine was highly dependent on the immune escape potential of VOCs and antibody waning, but less dependent on the boosting efficacy of the additional dose. Interpretation Increasing primary vaccination coverage should be prioritised in the design of allocation strategies of COVID-19 vaccines and antivirals in the EAP region. Heterologous vaccination with any available vaccine as the additional dose could be considered when planning pandemic exit strategies tailored to the circumstances of EAP jurisdictions. Funding Health and Medical Research Fund, General Research Fund, AIR@InnoHK

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.

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).

Clustering and superspreading potential of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections in Hong Kong (preprint)

Superspreading events have characterised previous epidemics of severe acute respiratory syndrome coronavirus (SARS-CoV) and Middle East respiratory syndrome coronavirus (MERS-CoV) infections. Using contact tracing data, we identified and characterized SARS-CoV-2 clusters in Hong Kong. Given a superspreading threshold of 6-8 secondary cases, we identified 5-7 probable superspreading events and evidence of substantial overdispersion in transmissibility, and estimated that 20% of cases were responsible for 80% of local transmission. Among terminal cluster cases, 27% (45/167) ended in quarantine. Social exposures produced a greater number of secondary cases compared to family or work exposures (p<0.001) while delays between symptom onset and isolation did not reliably predict the number of individual secondary cases or resulting cluster sizes. Public health authorities should focus on rapid tracing and quarantine of contacts, along with physical distancing to prevent superspreading events in high-risk social environments. 

Estimating clinical severity of COVID-19 from the transmission dynamics in Wuhan, China (preprint)

As of February 13, 2020, there have been 59,863 laboratory-confirmed cases of COVID-19 infections in mainland China, including 1,367 deaths. A key public health priority during the emergence of a novel pathogen is estimating clinical severity. Here we estimated the symptomatic case-fatality risk (sCFR; the probability of dying from the infection after developing symptoms) of COVID-19 in Wuhan using public and published information. We estimated that sCFR was 0.5% (0.1%-1.3%), 0.5% (0.2%-1.1%) and 2.7% (1.5%-4.7%) for those aged 15-44, 45-64 and >64 years. The overall sCFR among those aged ≥15 years was 1.4% (0.8%-2.0%). Authors Joseph T Wu and Kathy Leung contributed equally to this work