Cross-neutralizing antibody against emerging Omicron subvariants of SARS-CoV-2 in infection-naïve individuals with homologous BNT162b2 or BNT162b2(WT+ BA.4/5) bivalent booster vaccination (preprint)

Since the emergence of SARS-CoV-2, different variants and subvariants successively emerged to dominate global virus circulation as a result of immune evasion, replication fitness or both. COVID-19 vaccines continue to be updated in response to the emergence of antigenically divergent viruses, the first being the bivalent RNA vaccines that encodes for both the Wuhan-like and Omicron BA.5 subvariant spike proteins. Repeated infections and vaccine breakthrough infections have led to complex immune landscapes in populations making it increasingly difficult to assess the intrinsic neutralizing antibody responses elicited by the vaccines. Hong Kong’s intensive COVID-19 containment policy through 2020–2021 permitted us to identify sera from a small number of infection naïve individuals who received 3 doses RNA vaccine BNT162b2 of vaccines encoding the Wuhan-like spike who were boosted with a fourth dose monovalent Wuhan-like (WT) vaccine or the bivalent Wuhan-like and BA.4/5 spike (WT + BA.4/5) expressing vaccine. While neutralizing antibody to wild-type virus was comparable in both vaccine groups, BNT162b2 bivalent vaccine elicited significantly higher plaque neutralizing antibodies to Omicron subvariants BA.5, XBB.1.5, XBB.1.16, XBB.1.9.1, XBB.2.3.2, EG.5.1, HK.3, BA.2.86 and JN.1, compared to BNT162b2 monovalent vaccine. The single amino acid substitution that differentiates the spike of JN.1 from BA.2.86 resulted in a profound antigenic change.

Assessment of the impact of the Vaccine Pass Policy on COVID-19 vaccine hesitancy and uptake among Chinese adults in Hong Kong (preprint)

Background: Recognising the importance of attaining high vaccine coverage to mitigate the COVID-19 impact, a Vaccine Pass scheme was implemented during and after the first large Omicron wave in Hong Kong in early 2022 requiring three doses by June 2022. We evaluated the impact of the Vaccine Pass policy on vaccine uptake in adults. Methods: We analyzed patterns in vaccine uptake and hesitancy using local data from the population vaccine registry and 32 cross-sectional surveys conducted from October 2021 to December 2022. We examined the association of Vaccine Pass phases with vaccine uptake, taking into account covariables including self-risk perception, perceived self-efficacy in preventing COVID-19 and trust in government in pandemic control as well as physical distancing measures and demographics. Findings: The uptake of primary series and third doses was significantly associated with stages of Vaccine Pass implementation, and other statistically significant drivers included age group, chronic condition, higher perceived personal susceptibility to COVID-19, higher trust in government, and higher educational attainment. Older adults ([≥]65y) were less likely to be vaccinated against COVID-19, compared to adults aged 18-44 years. Interpretation: Vaccine uptake in older adults was observed to have increased by a greater extent after the policy announcement and implementation, which occurred during and after a large Omicron wave with high mortality in older ages in early 2022. Since the policy withdrawal the uptake of further booster doses has been very low in all ages. Improving voluntary booster uptake in older adults should be prioritized.

Examining the association of live virus neutralisation activity of capillary microsamples and risk of SARS-CoV-2 infections: a nested case control study within the Virus Watch community cohort (preprint)

Due to the proliferation of new SARS-CoV-2 variants, most COVID-19 cases are now caused by post-vaccine infections and a substantial proportion are reinfections. While prior research on correlates of protection has focused on the role of anti-spike antibodies, the results of the corresponding antibody assays may not accurately predict the risk of infection with new SARS-CoV-2 variants. In this study, we investigated the association between live virus neutralising antibody activity and SARS-CoV-2 infection risk using self-administered capillary microsample blood tests from VirusWatch participants. The study was conducted during the transition between the dominance of the B.1.617.2 (Delta) and B.1.1.529 (Omicron BA.1) SARS-CoV-2 variants, enabling us to investigate the association between variant-specific virus inhibition and subsequent infections within each dominance period. Greater inhibition of Omicron BA.1 live virus was associated with a reduction in infection risk during both the Delta and Omicron BA.1 dominance periods. Delta virus inhibition was associated with infection risk reduction during the Delta dominance period, but we found no association between Delta inhibition and protection against infection during the Omicron BA.1 dominance period. Our results are consistent with earlier findings and suggest that variant-specific serosurveillance of immunity and protection against SARS-CoV-2 infection at the population level could inform public health policy in near-real time using inexpensive and accessible home-based testing.

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.

Inpatient Antibacterial Drug Prescribing for Patients with COVID-19 in Hong Kong (preprint)

Background: Hong Kong experienced four epidemic waves caused by the ancestral strain of SARS-CoV-2 in 2020-2021 and a large Omicron wave in 2022. Few studies have assessed antibacterial drug prescribing for COVID-19 inpatients throughout the pandemic. Objectives: To describe inpatient antibacterial drug prescribing for COVID-19 patients throughout the pandemic and to determine factors associated with their prescription. Methods: This cohort study used electronic health records of COVID-19 cases admitted to public hospitals in Hong Kong from 21 January 2020 to 30 September 2022. We assessed the prevalence and rates of inpatient antibacterial drug use, using days of therapy/1000 patient days (DOT/1000PD), and examined the association of baseline factors and disease severity with receipt of an inpatient antibacterial drug prescription. Results: Among 65,810 inpatients, 54.0% were prescribed antibacterial drugs at a rate of 550.5 DOT/1000PD. Antibacterial use was lowest during wave 4 (28.0%; 246.9 DOT/1000PD), peaked in early wave 5 (64.6%; 661.2 DOT/1000PD), and then modestly declined in late wave 5 (43.2%; 464.1 DOT/1000PD) starting on 23 May 2022. Older age, increased disease severity, and residing in an elderly care home were strongly associated with increased odds of prescription, while receiving [≥] 2 doses of COVID-19 vaccines and pre-admission use of coronavirus antivirals were associated with lower odds. Conclusions: The rate of inpatient antibacterial prescribing initially declined during the pandemic, but increased during the Omicron wave when hospital capacity was overwhelmed. Despite the availability of COVID-19 vaccines and antiviral drugs, antibacterial drug use among COVID-19 inpatients remained high into late 2022.

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.

The public health impact of Paxlovid COVID-19 treatment in the United States (preprint)

The antiviral drug Paxlovid has been shown to rapidly reduce viral load. Coupled with vaccination, timely administration of safe and effective antivirals could provide a path towards managing COVID-19 without restrictive non-pharmaceutical measures. Here, we estimate the population-level impacts of expanding treatment with Paxlovid in the US using a multi-scale mathematical model of SARS-CoV-2 transmission that incorporates the within-host viral load dynamics of the Omicron variant. We find that, under a low transmission scenario (Re~1.2) treating 20% of symptomatic cases with Paxlovid would be life and cost saving, leading to an estimated 0.26 (95% CrI:0.03, 0.59) million hospitalizations averted, 30.61 (95% CrI:1.69, 71.15) thousand deaths averted, and US$52.16 (95% CrI:2.62, 122.63) billion reduction in the US. Rapid and broad use of the antiviral Paxlovid could substantially reduce COVID-19 morbidity and mortality, while averting socioeconomic hardship.

Key challenges for the surveillance of respiratory viruses: transitioning out of the acute phase of the SARS-CoV-2 pandemic (preprint)

To support the ongoing management of viral respiratory diseases, many countries are moving towards an integrated model of surveillance for SARS-CoV-2, influenza, and other respiratory pathogens. While many surveillance approaches catalysed by the COVID-19 pandemic provide novel epidemiological insight, continuing them as implemented during the pandemic is unlikely to be feasible for non-emergency surveillance, and many have already been scaled back. Furthermore, given anticipated co-circulation of SARS-CoV-2 and influenza, surveillance activities in place prior to the pandemic require review and adjustment to ensure their ongoing value for public health. In this perspective, we highlight key challenges for the development of integrated models of surveillance. We discuss the relative strengths and limitations of different surveillance practices and studies, their contribution to epidemiological assessment, forecasting, and public health decision making.

Intrinsic and effective severity of COVID-19 cases infected with the ancestral strain and Omicron BA.2 variant in Hong Kong (preprint)

Background: Understanding severity of infections with SARS-CoV-2 and its variants is crucial to inform public health measures. Here we used COVID-19 patient data from Hong Kong to characterise the severity profile of COVID-19 and to examine factors associated with fatality of infection. Methods: Time-varying and age-specific effective severity measured by case-hospitalization risk and hospitalization risk was estimated with all individual COVID-19 case data collected in Hong Kong from 23 January 2020 through to 26 October 2022 over six epidemic waves, in comparison with estimates of influenza A(H1N1)pdm09 during the 2009 pandemic. The intrinsic severity of Omicron BA.2 was compared with the estimate for the ancestral strain with the data from unvaccinated patients without previous infections. Factors potentially associated with the fatality risk of hospitalized Omicron patients were also examined. Results: With 32,222 COVID-19 hospitalizations and 9,669 deaths confirmed over 6 epidemic waves in Hong Kong, the time-varying hospitalization fatality risk dramatically increased from below 10% before the largest fifth wave of Omicron BA.2, to 41% during the peak of the fifth wave when hospital resources were severely constrained. The age-specific fatality risk in unvaccinated hospitalized Omicron cases was comparable to the estimates for unvaccinated cases with the ancestral strain. During epidemics predominated by Omicron BA.2, the highest fatality risk was amongst unvaccinated patients aged [≥]80 years and the risk was inversely associated with the number of vaccination doses received. Conclusions: Omicron has comparable intrinsic severity to the ancestral Wuhan strain although the effective severity is substantially lower in Omicron cases due to vaccination. With a moderate-to-high coverage of vaccination, hospitalized COVID-19 patients caused by Omicron subvariants appeared to have similar age-specific risks of fatality to patients hospitalized with influenza A(H1N1)pdm09.

Comparative Effectiveness of BNT162b2 and NVX-CoV2373 Vaccines in Korean Adults (preprint)

Background: Various types of vaccines against SARS-CoV-2 have reduced the burden of coronavirus diseases 2019 (COVID-19) across the world. We conducted an observational study to evaluate the effectiveness of NVX-CoV2373 and BNT162b2 in providing protection in Korean adults. Methods: This study was a retrospective matched cohort study to emulate a target trial of three doses of NVX-CoV2373 (N-N-N) versus three doses of BNT162b2 (B-B-B) vaccines in presumed immune-naive adults. We used data from the Korea COVID-19 Vaccine Effectiveness (K-COVE) cohort, combining all COVID-19 laboratory-confirmed cases and all COVID-19 immunization registry, between February and November 2022. We calculated 40-week risk differences and risk ratios between the two vaccines. Results: A total of 3,019 recipients of NVX-CoV2373 vaccine and 3,027 recipients of BNT162b2 vaccine were eligible for the study. The 40-week risk ratios for recipients of the NVX-CoV2373 vaccine as compared with recipients of the BNT162b2 vaccine were 1.169 (95% CI, 1.015 to 1.347) for laboratory-confirmed SARS-CoV-2 infection, and 0.504 (95% CI, 0.126 to 2.014) for severe SARS-CoV-2 infection. Estimated risk of severe infection was 0.001 events per 1000 persons (95% CI, 0 to 0.003) for the NVX-CoV2373 vaccine and 0.002 events per 1000 persons (95% CI, 0.001 to 0.006) for BNT162b2 vaccine. Conclusion: This study identifies reduced risk of SARS-CoV-2 infection and severe infection after receipt of three doses of either NVX-CoV2373 or BNT162b2 vaccines in Korean adults. Direct, vaccine-conferred protection may be of importance among high risk persons to mitigate from serious clinical outcome from COVID-19.

Characterizing human collective behaviours of COVID-19 in Hong Kong (preprint)

People are likely to engage in collective behaviour online during extreme events, such as the COVID-19 crisis, to express their awareness, actions and concerns. Hong Kong has implemented stringent public health and social measures (PHSMs) to curb COVID-19 epidemic waves since the first COVID-19 case was confirmed on 22 January 2020. People are likely to engage in collective behaviour online during extreme events, such as the COVID-19 crisis, to express their awareness, actions and concerns. Here, we offer a framework to evaluate interactions among individuals emotions, perception, and online behaviours in Hong Kong during the first two waves (February to June 2020) and found a strong correlation between online behaviours of Google search and the real-time reproduction numbers. To validate the model output of risk perception, we conducted 10 rounds of cross-sectional telephone surveys from February 1 through June 20 in 2020 to quantify risk perception levels over time. Compared with the survey results, the estimates of the risk perception of individuals using our network-based mechanistic model capture 80% of the trend of people risk perception (individuals who worried about being infected) during the studied period. We may need to reinvigorate the public by engaging people as part of the solution to live their lives with reduced risk.

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.

Resurgence of Omicron BA.2 in SARS-CoV-2 infection-naive Hong Kong (preprint)

After keeping infections at bay for two years, Hong Kong experienced a surge of Omicron BA.2 infections in early 2022 that overwhelmed the health care system, isolation facilities, and contact tracing capacity, leading to one of the highest per-capita death rates of COVID-19 in early 2022. The outbreak occurred against a backdrop of 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. Using genome sequences and epidemiological data from this time, we reconstruct the epidemic trajectory of the BA.2 wave, estimate transmission and incidence rates, and evaluate the effectiveness of policy changes. We identify an increase in the effective reproductive rate (Re) to 9.5 in mid-January 2022, which preceded real-time estimates of transmission (Rt), revealing that BA.2 community transmission was under-ascertained weeks before the epidemic appeared to surge in mid-February 2022. Due to this, public health measures were relaxed in early February (Spring Festival) while Re increased and remained > 1 throughout February. An independent estimation of point prevalence and incidence using phylodynamics also indicates extensive superspreading at this time, which likely contributed to the rapid expansion of the epidemic. This study demonstrates that relying on Rt estimation methods dependent on case reporting can misinform epidemic response planning, sometimes with substantial consequences. There is a need for future research and implementation of improved estimates of epidemic growth in near real-time that combine multiple disparate data sources to better inform outbreak response policy.

Insights into COVID-19 epidemiology and control from temporal changes in serial interval distributions in Hong Kong (preprint)

The serial interval distribution is used to approximate the generation time distribution, an essential parameter to predict the effective reproductive number "Rt", a measure of transmissibility. However, serial interval distributions may change as an epidemic progresses rather than remaining constant. Here we show that serial intervals in Hong Kong varied over time, closely associated with the temporal variation in COVID-19 case profiles and public health and social measures that were implemented in response to surges in community transmission. Quantification of the variation over time in serial intervals led to improved estimation of Rt, and provided additional insights into the impact of public health measures on transmission of infections. One-Sentence SummaryReal-time estimates of serial interval distributions can improve assessment of COVID-19 transmission dynamics and control.