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.

Homologous and heterologous boosting with CoronaVac and BNT162b2: a randomized trial (the Cobovax study) (preprint)

Background: There are few trials comparing homologous and heterologous third doses of COVID-19 vaccination with inactivated vaccines and mRNA vaccines. Methods: We conducted an open-label randomized trial in adults >=18 years of age who received two doses of inactivated vaccine (CoronaVac) or mRNA vaccine (BNT162b2) >=6 months earlier, randomised in 1:1 ratio to receive a third dose of either vaccine. We compared the reactogenicity, immunogenicity and cell-mediated immune responses, and assessed vaccine efficacy against infections during follow-up. Results: We enrolled 219 adults who previously received two doses of CoronaVac and randomised to CoronaVac ("CC-C", n=101) or BNT162b2 ("CC-B", n=118) third dose; and 232 adults who previously received BNT162b2 and randomised to CoronaVac ("BB-C", n=118) or BNT162b2 ("BB-B", n=114). There were more frequent reports of mild reactions in recipients of third-dose BNT162b2, which generally subsided within 7 days. Third doses significantly increased neutralising PRNT50 antibody titers against ancestral virus and Omicron BA.1 variant in all four study arms, and against Omicron BA.2 in all arms except CC-C, with statistically significant improvements for recipients of a third dose of BNT162b2 over CoronaVac irrespective of prior vaccine type. Boosting of CD4+ T cells only occurred in CoronaVac-primed arms, but we did not identify overall differences between vaccine groups in CD4+ and CD8+ T cell responses. When Omicron BA.2 was circulating, we identified 58 infections with cumulative incidence of 15.3% and 15.4% in the CC-C and CC-B (p=0.93), and 16.7% and 14.0% in the BB-C and BB-B arms, respectively (p=0.56). Conclusions: Similar levels of incidence of infection in each arm suggest all third dose combinations may provide similar degrees of protection against prevalent Omicron BA.2 infection, despite very weak antibody responses to BA.2 in the recipients of a CoronaVac third dose. Further research is warranted to identify appropriate correlates of protection for inactivated COVID-19 vaccines.

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.

Slow waning of antibodies following a third dose of BNT162b2 in adults who had previously received two doses of inactivated vaccine (preprint)

IntroductionThird doses of COVID-19 vaccination provide an important boost to immunity, reducing the risk of symptomatic infection and the risk of severe disease. Third doses have been particularly important for improving protection against variants. However, waning of clinical protection particularly against Omicron has been noted after receipt of third doses. MethodsWe administered BNT162b2 as a third dose to adults aged [≥]30 years who had previously received two doses of inactivated vaccination. We collected blood before the third dose and again after one month and six months, and tested sera using a spike receptor binding domain IgG enzyme-linked immunosorbent assay, a surrogate virus neutralization test, and live virus plaque reduction neutralization assay against ancestral virus and Omicron BA.2. ResultsWe administered BNT162b2 as a third dose to 314 adults. We found robust antibody responses to the ancestral strain at six months after receipt of BNT162b2. Antibody responses to Omicron BA.2 were weaker after the third dose and had declined to a low level by six months. From a small number of participants we observed that natural infection or a fourth dose of vaccination generated similar antibody levels against ancestral virus, but infection generated higher antibody level against Omicron BA.2 than vaccination, suggesting a potential advantage in the breadth of antibody response from hybrid immunity. ConclusionsWhile antibody levels against the ancestral strain remained robust at six months after the third dose, antibody levels against Omicron BA.2 had fallen to low levels suggesting the potential benefits of a fourth dose.

Within-hotel transmission of SARS-CoV-2 during on-arrival quarantine in Hong Kong (preprint)

Background: On-arrival quarantine has been one of the primary measures used to prevent the introduction of COVID-19 into Hong Kong since the start of the pandemic. Most on-arrival quarantines have been done in hotels, with the duration of quarantine and testing frequency during quarantine varying throughout the pandemic for various reasons. However, hotels are not necessarily designed with infection control in mind. We aimed to study the potential risk of transmission between persons in on-arrival quarantine. Methods: We examined data on each laboratory-confirmed COVID-19 case identified in on-arrival quarantine in a hotel in Hong Kong between 1 May 2020 and 31 January 2022. We sequenced the full genomes of viruses from cases that overlapped with other confirmed cases in terms of the hotel of stay, date of arrival and date of testing positive. A combination of epidemiological information and sequence information was then used to identify probable transmission events. Findings: Among 221 imported cases that overlapped with other quarantined cases, phylogenetic analysis identified eight suspected clusters comprising 20 cases in total. Only three of these clusters had been recognised as hotel transmission events. Interpretation: We have identified potential occurrences of COVID-19 transmission within hotel quarantine in Hong Kong demonstrating the underlying low but non-zero risk associated with sequestering arrivals within hotels. In future pandemics, on-arrival quarantine in hotels could be used to delay the introduction of infection, but the construction of purpose-built facilities for on-arrival quarantine might be necessary to minimize importation risk.

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.

Strength and durability of antibody responses to BNT162b2 and CoronaVac (preprint)

We studied 2864 adults in Hong Kong who received CoronaVac inactivated virus vaccine (Sinovac) and BNT162b2 mRNA vaccine (Comirnaty, BioNTech/Fosun Pharma). We found stronger and more durable antibody responses to two doses of the mRNA vaccine, and slightly stronger initial antibody responses to each vaccine in younger adults and women.

BNT162b2 vaccine boosts neutralizing antibodies to ancestral SARS-CoV-2 & Omicron variant in adults who previously received two doses of inactivated vaccine (preprint)

BackgroundLimited data exist on antibody responses to mixed vaccination strategies involving inactivated COVID-19 vaccines, particularly in the context of emerging variants. MethodsWe conducted an open label trial of a third vaccine dose of an mRNA vaccine (BNT162b2, Fosun Pharma/BioNTech) in adults aged [≥]30 years who had previously received two doses of inactivated COVID-19 vaccine. We collected blood samples before administering the third dose and 28 days later, and tested for antibodies to the ancestral virus using a binding assay (ELISA), a surrogate virus neutralization test (sVNT) and a live virus plaque reduction neutralization test (PRNT). We also tested for antibodies against the Omicron variant using live-virus PRNT. ResultsIn 315 participants, a third dose of BNT162b2 substantially increased antibody titers on each assay. Mean ELISA levels increased from an optical density (OD) of 0.3 to 2.2 (p<0. 001), and mean sVNT levels increased from an inhibition of 17% to 96% (p<0.001). In a random subset of 20 participants, the geometric mean PRNT50 titers rose very substantially by at least 24 fold from Day 0 to Day 28 against the ancestral virus (p<0.001) and rose by at least 11 fold against the Omicron variant (p<0.001). In daily monitoring, post-vaccination reactions subsided within 7 days for over 99% of participants. ConclusionsA third dose of COVID-19 vaccination with an mRNA vaccine substantially improved antibody levels against the ancestral virus and the Omicron variant with well-tolerated safety profile, in adults who had received two doses of inactivated vaccine 6 months earlier. SummaryIn this open label trial of Chinese adults aged [≥]30 years who received two doses of inactivated COVID-19 vaccine 6 months earlier, third-dose mRNA vaccine substantially improved antibody levels against the ancestral virus and Omicron variant with well-tolerated safety profile.