Reconstructing household transmission dynamics to estimate the infectiousness of asymptomatic influenza virus infections.

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.

Pandemic fatigue impedes mitigation of COVID-19 in Hong Kong.

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.

Estimation of the Time-Varying Effective Reproductive Number of COVID-19 Based on Multivariate Time Series of Severe Health Outcomes.

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.

Prior infections and effectiveness of SARS-CoV-2 vaccine in test-negative studies: A systematic review and meta-analysis.

Prior infection with SARS-CoV-2 can provide protection against infection and severe COVID-19. We aimed to determine the impact of pre-existing immunity on the vaccine effectiveness (VE) estimates. We systematically reviewed and meta-analysed 66 test-negative design (TND) studies that examined VE against infection or severe disease (hospitalization, ICU admission, or death) for primary vaccination series. 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 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 pre-existing 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 stratified by infection history, respectively.

Comparative epidemiology of outbreaks caused by SARS-CoV-2 Delta and Omicron variants in China.

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 (Rt) 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.

Decreased risk of non-influenza respiratory infection after influenza B virus infection in children.

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.

Investigation of the Impact of Childhood Immune Imprinting on Birth Year-Specific Risk of Clinical Infection During Influenza A Virus Epidemics in Hong Kong.

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.

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

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.

Epidemiology of SARS-CoV-2 Omicron BA.5 Infections, Macau, June-July 2022.

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.

Effects of School-Based Preventive Measures on COVID-19 Incidence, Hong Kong, 2022.

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.

Accounting for the Potential of Overdispersion in Estimation of the Time-varying Reproduction Number.

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.

Effectiveness of CoronaVac and BNT162b2 Vaccines Against Severe Acute Respiratory Syndrome Coronavirus 2 Omicron BA.2 Infections in Hong Kong.

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.

Biphasic Waning of Hemagglutination Inhibition Antibody Titers After Influenza Vaccination in Children.

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.

Estimating the Latent Period of Coronavirus Disease 2019 (COVID-19).

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.

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.

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.

Effectiveness of International Travel Controls for Delaying Local Outbreaks of COVID-19.

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.

Restaurant-Based Measures to Control Community Transmission of COVID-19, Hong Kong.

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.

Determining Existing Human Population Immunity as Part of Assessing Influenza Pandemic Risk.

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 (R0) 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 R0 by only 18%-20%. The smallest R0 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 R0 by 47%, thus reducing pandemic risk.

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

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.

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

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-γ 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.