Durability for 12 months of antibody response to a booster dose of monovalent BNT162b2 in adults who had initially received 2 doses of inactivated vaccine.

This study examined the strength and durability of antibody responses in 277 adults who received a heterologous third dose of the BNT162b2 vaccine, following two doses of an inactivated vaccine. Neutralizing antibody levels against both the ancestral virus and Omicron BA.2 subvariant decreased from one month to 6 months after the third dose, and were then maintained at 12 months. Participants who received both a fourth dose and reported a SARS-CoV-2 infection had the highest antibody titers at 365 days after the third dose. Individuals with chronic medical conditions had lower antibody levels against the Omicron BA.2 subvariant at 12 months after the third dose. The results suggest that the heterologous third dose provides durable neutralizing antibody responses, which may be influenced by subsequent infection or vaccination and pre-existing medical conditions. These findings may help explain the differences in immune protection between vaccination and natural infection.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

BACKGROUND: Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. METHODS: We quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022, based on calendar-time proportional hazards models and matching approaches. RESULTS: We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR 1.66; 95% CI 1.07, 2.59; p = 0.02) after the first dose. CONCLUSIONS: Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

Antibody Fc receptor binding and T cell responses to homologous and heterologous immunization with inactivated or mRNA vaccines against SARS-CoV-2.

Whole virion inactivated vaccine CoronaVac (C) and Spike (S) mRNA BNT162b2 (B) vaccines differ greatly in their ability to elicit neutralizing antibodies but have somewhat comparable effectiveness in protecting from severe COVID-19. We conducted further analyses for a randomized trial (Cobovax study, NCT05057169) of third dose homologous and heterologous booster vaccination, i.e. four interventions CC-C, CC-B, BB-C and BB-B. Here, we assess vaccine immunogenicity beyond neutralizing function, including S and non-S antibodies with Fc receptor (FcR) binding, antibody avidity and T cell specificity to 6 months post-vaccination. Ancestral and Omicron S-specific IgG and FcR binding are significantly higher by BNT162b2 booster than CoronaVac, regardless of first doses. Nucleocapsid (N) antibodies are only increased in homologous boosted CoronaVac participants (CC-C). CoronaVac primed participants have lower baseline S-specific CD4+ IFNγ+ cells, but are significantly increased by either CoronaVac or BNT162b2 boosters. Priming vaccine content defined T cell peptide specificity preference, with S-specific T cells dominating B primed groups and non-S structural peptides contributing more in C primed groups, regardless of booster type. S-specific CD4+ T cell responses, N-specific antibodies, and antibody effector functions via Fc receptor binding may contribute to protection and compensate for less potent neutralizing responses in CoronaVac recipients.

Evaluation of an influenza-like illness sentinel surveillance system in South Korea, 2017-2023.

BACKGROUND: Guided by the data from the surveillance system, public health efforts have contributed to reducing the burden of influenza in many countries. During the COVID-19 pandemic, many surveillance resources were directed at tracking the severe acute respiratory syndrome-Coronavirus 2. However, most countries have not reported surveillance evaluations during the COVID-19 pandemic. METHODS: Using the U.S. CDC surveillance evaluation method, we evaluated the influenza-like illness (ILI) sentinel surveillance performance in South Korea between January 2017 and September 2023. For the timeliness, we measured the mean time lag between the reports from the sentinel sites to the Korea Disease Control and Prevention Agency (KDCA) and surveillance result dissemination from KDCA. For the completeness, we measured the submission rate of complete reports per overall number of reports from each sentinel site to the KDCA. For the sensitivity, we calculated the correlation coefficient between the monthly number of ILI reports and the patients with ILI from the Korea national reimbursement data by either Pearson's or Spearman's test. For the representativeness, we compared the age-specific distribution of ILI between the surveillance data and the national reimbursement data using a chi-squared test. RESULTS: We found that the surveillance performance of timeliness (less than 2 weeks) and completeness (97 %-98 %) was stable during the study period. However, we found a reduced surveillance sensitivity (correlation coefficient: 0.73 in 2020, and 0.84 in 2021) compared to that of 2017-2019 (0.96-0.99), and it recovered in 2022-2023 (0.93-0.97). We found no statistical difference across the proportion of age groups between the surveillance and reimbursement data during the study period (all P-values > 0.05). CONCLUSIONS: Ongoing surveillance performance monitoring is necessary to maintain efficient policy decision-making for the control of the influenza epidemic. Additional research is needed to assess the overall influenza surveillance system including laboratory and hospital-based surveillance in the country.

Interplay between viral shedding, age, and symptoms on individual infectiousness of influenza cases in households.

BACKGROUND: Understanding factors affecting the infectiousness of influenza cases is crucial for disease prevention and control. Viral shedding is expected to correlate with infectiousness of cases, but it is strongly associated with age and the presence of symptoms. METHODS: To elucidate this complex interplay, we analyze with an individual-based household transmission model a detailed household transmission study of influenza with 442 households and 1710 individuals from 2008 to 2017 in Hong Kong, to characterize the household transmission dynamics and identify factors affecting transmissions. RESULTS: We estimate that age, fever symptoms and viral load were all associated with higher infectiousness. However, by model comparison, the best model includes age and fever as factors affecting individual infectiousness, and estimates that pre-school and school-age children were 317% (95% credible interval (CrI): 103%, 1042%) and 161% (95% CrI: 33%, 601%) more infectious than adults respectively, and patients having fever had 146% (95% CrI: 37%, 420%) higher infectiousness. Adding heterogeneity on individual infectiousness of cases does not improve the model fit, suggesting these factors could explain the difference in individual infectiousness. CONCLUSIONS: Our study clarifies the contribution of age, symptoms and viral shedding to individual infectiousness of influenza cases in households.

Influenza Vaccine Effectiveness and Progress Towards a Universal Influenza Vaccine.

At various times in recent decades, surges have occurred in optimism about the potential for universal influenza vaccines that provide strong, broad, and long-lasting protection and could substantially reduce the disease burden associated with seasonal influenza epidemics as well as the threat posed by pandemic influenza. Each year more than 500 million doses of seasonal influenza vaccine are administered around the world, with most doses being egg-grown inactivated subunit or split-virion vaccines. These vaccines tend to have moderate effectiveness against medically attended influenza for influenza A(H1N1) and influenza B, and somewhat lower for influenza A(H3N2) where differences between vaccine strains and circulating strains can occur more frequently due to antigenic drift and egg adaptations in the vaccine strains. Several enhanced influenza vaccine platforms have been developed including cell-grown antigen, the inclusion of adjuvants, or higher antigen doses, to improve immunogenicity and protection. During the COVID-19 pandemic there was unprecedented speed in development and roll-out of relatively new vaccine platforms, including mRNA vaccines and viral vector vaccines. These new platforms present opportunities to improve protection for influenza beyond existing products. Other approaches continue to be explored. Incremental improvements in influenza vaccine performance should be achievable in the short to medium term.

Evaluating the impact of extended dosing intervals on mRNA COVID-19 vaccine effectiveness in adolescents.

Extending the dosing interval of a primary series of mRNA COVID-19 vaccination has been employed to reduce myocarditis risk in adolescents, but previous evaluation of impact on vaccine effectiveness (VE) is limited to risk after second dose. Here, we quantified the impact of the dosing interval based on case notifications and vaccination uptake in Hong Kong from January to April 2022. We estimated that the hazard ratio (HR) and odds ratio (OR) of infections after the second dose for extended (28 days or more) versus regular (21-27 days) dosing intervals ranged from 0.86 to 0.99 from calendar-time proportional hazards models, and from 0.85 to 0.87 from matching approaches, respectively. Adolescents in the extended dosing groups (including those who did not receive a second dose in the study period) had a higher hazard of infection than those with a regular dosing interval during the intra-dose period (HR: 1.66; 95% CI: 1.07, 2.59; p = 0.02) after the first dose. Implementing an extended dosing interval should consider multiple factors including the degree of myocarditis risk, the degree of protection afforded by each dose, and the extra protection achievable using an extended dosing interval.

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

The serial interval distribution is used to approximate the generation time distribution, an essential parameter to infer the transmissibility (${R}_t$) of an epidemic. However, serial interval distributions may change as an epidemic progresses. We examined detailed contact tracing data on laboratory-confirmed cases of COVID-19 in Hong Kong during the five waves from January 2020 to July 2022. We reconstructed the transmission pairs and estimated time-varying effective serial interval distributions and factors associated with longer or shorter intervals. Finally, we assessed the biases in estimating transmissibility using constant serial interval distributions. We found clear temporal changes in mean serial interval estimates within each epidemic wave studied and across waves, with mean serial intervals ranged from 5.5 days (95% CrI: 4.4, 6.6) to 2.7 (95% CrI: 2.2, 3.2) days. The mean serial intervals shortened or lengthened over time, which were found to be closely associated with the temporal variation in COVID-19 case profiles and public health and social measures and could lead to the biases in predicting ${R}_t$. Accounting for the impact of these factors, the time-varying quantification of serial interval distributions could lead to improved estimation of ${R}_t$, and provide additional insights into the impact of public health measures on transmission.

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

Background: Hong Kong enforced stringent travel restrictions during the COVID-19 pandemic. Understanding the characteristics of imported COVID-19 cases is important for establishing evidence-based control measures. Methods: Retrospective cohort study summarising the characteristics of imported cases detected in Hong Kong between 13 November 2020 and 31 January 2022, when compulsory quarantine was implemented. Findings: A total of 2269 imported COVID-19 cases aged 0-85 years were identified, of which 48.6 % detected on arrival. A shorter median delay from arrival to isolation was observed in Delta and Omicron cases (3 days) than in ancestral strain and other variants cases (12 days; p < 0.001). Lower Ct values at isolation were observed in Omicron cases than in ancestral strain or other variants cases. No Omicron cases were detected beyond 14 days after arrival. Cases detected after 14 days of quarantine (n=58, 2.6 %) were more likely asymptomatic at isolation and had higher Ct value during isolation, some of them indicating re-positivity or post-arrival infections. Conclusions: Testing inbound travellers at arrival and during quarantine can detect imported cases early, but may not prevent all COVID-19 introductions into the community. Public health measures should be adapted in response to the emergence of SARS-CoV-2 variants based on evidence from ongoing surveillance.

A(H2N2) and A(H3N2) influenza pandemics elicited durable cross-reactive and protective antibodies against avian N2 neuraminidases.

Human cases of avian influenza virus (AIV) infections are associated with an age-specific disease burden. As the influenza virus N2 neuraminidase (NA) gene was introduced from avian sources during the 1957 pandemic, we investigate the reactivity of N2 antibodies against A(H9N2) AIVs. Serosurvey of healthy individuals reveal the highest rates of AIV N2 antibodies in individuals aged ≥65 years. Exposure to the 1968 pandemic N2, but not recent N2, protected against A(H9N2) AIV challenge in female mice. In some older adults, infection with contemporary A(H3N2) virus could recall cross-reactive AIV NA antibodies, showing discernable human- or avian-NA type reactivity. Individuals born before 1957 have higher anti-AIV N2 titers compared to those born between 1957 and 1968. The anti-AIV N2 antibodies titers correlate with antibody titers to the 1957 N2, suggesting that exposure to the A(H2N2) virus contribute to this reactivity. These findings underscore the critical role of neuraminidase immunity in zoonotic and pandemic influenza risk assessment.

Diagnostic performance of multiplex lateral flow tests in ambulatory patients with acute respiratory illness.

We assessed the performance of three different multiplex lateral flow assays manufactured by SureScreen, Microprofit and Goldsite which provide results for influenza, respiratory syncytial virus (RSV) and SARS-CoV-2. Between 4 April and 20 October 2023, 1646 patients 6 months and older presenting to an outpatient department of a hospital in Hong Kong with ≥2 symptoms or signs of an acute respiratory illness were enrolled. The point estimates for all three multiplex tests had sensitivity >80% for influenza A and SARS-CoV-2 compared to PCR, and the tests manufactured by Microprofit and Goldsite had sensitivity >84% to detect RSV. Specificity was >97% for all three tests except for the SureScreen test which had specificity 86.2% (95% CI: 83.9% to 88.3%) for influenza A. Sensitivity was lower than reported by the manufacturers, resulting in a higher risk of false negatives. The three multiplex tests performed better in patients with high viral loads.

Forecasting of influenza activity and associated hospital admission burden and estimating the impact of COVID-19 pandemic on 2019/20 winter season in Hong Kong.

Like other tropical and subtropical regions, influenza viruses can circulate year-round in Hong Kong. However, during the COVID-19 pandemic, there was a significant decrease in influenza activity. The objective of this study was to retrospectively forecast influenza activity during the year 2020 and assess the impact of COVID-19 public health social measures (PHSMs) on influenza activity and hospital admissions in Hong Kong. Using weekly surveillance data on influenza virus activity in Hong Kong from 2010 to 2019, we developed a statistical modeling framework to forecast influenza virus activity and associated hospital admissions. We conducted short-term forecasts (1-4 weeks ahead) and medium-term forecasts (1-13 weeks ahead) for the year 2020, assuming no PHSMs were implemented against COVID-19. We estimated the reduction in transmissibility, peak magnitude, attack rates, and influenza-associated hospitalization rate resulting from these PHSMs. For short-term forecasts, mean ambient ozone concentration and school holidays were found to contribute to better prediction performance, while absolute humidity and ozone concentration improved the accuracy of medium-term forecasts. We observed a maximum reduction of 44.6% (95% CI: 38.6% - 51.9%) in transmissibility, 75.5% (95% CI: 73.0% - 77.6%) in attack rate, 41.5% (95% CI: 13.9% - 55.7%) in peak magnitude, and 63.1% (95% CI: 59.3% - 66.3%) in cumulative influenza-associated hospitalizations during the winter-spring period of the 2019/2020 season in Hong Kong. The implementation of PHSMs to control COVID-19 had a substantial impact on influenza transmission and associated burden in Hong Kong. Incorporating information on factors influencing influenza transmission improved the accuracy of our predictions.

Preliminary findings from the Dynamics of the Immune Responses to Repeat Influenza Vaccination Exposures (DRIVE I) Study: a Randomized Controlled Trial.

BACKGROUND: Studies have reported that repeated annual vaccination may influence influenza vaccination effectiveness in the current season. METHODS: We established a 5-year randomized placebo-controlled trial of repeated influenza vaccination (Flublok, Sanofi Pasteur) in adults 18-45 years of age. In the first two years, participants received vaccination (V) or saline placebo (P) as follows: P-P, P-V, or V-V. Serum samples were collected each year just before vaccination and after 30 and 182 days. A subset of sera collected at 5 timepoints from 95 participants were tested for antibodies against vaccine strains. RESULTS: From 23 October 2020 through 11 March 2021 we enrolled and randomized 447 adults. Among vaccinated individuals, antibody titers increased between days 0 and 30 against each of the vaccine strains, with smaller increases for repeat vaccinees who on average had higher pre-vaccination titers in year 2. There were statistically significant differences in the proportion of participants achieving >=four-fold rises in antibody titer for the repeat vaccinees for influenza A(H1N1), B/Victoria and B/Yamagata, but not for A(H3N2). Among participants who received vaccination in year 2, there were no statistically significant differences between the P-V and V-V groups in geometric mean titers at day 30 or the proportions of participants with antibody titers ≥40 at day 30 for any of the vaccine strains. CONCLUSIONS: In the first two years, during which influenza did not circulate, repeat vaccinees and first-time vaccinees had similar post-vaccination geometric mean titers to all four vaccine strains, indicative of similar levels of clinical protection.

Hemagglutination Inhibition Antibody Titers as Mediators of Influenza Vaccine Efficacy Against Symptomatic Influenza A(H1N1), A(H3N2), and B/Victoria Virus Infections.

BACKGROUND: The hemagglutination inhibition antibody (HAI) titer contributes only a part of vaccine-induced protection against influenza virus infections. Using causal mediation analysis, we quantified the proportion of vaccine efficacy mediated by postvaccination HAI titers. METHODS: We conducted causal mediation analyses using data from a randomized, active-comparator controlled, phase III, trial of an inactivated, split-virion seasonal quadrivalent influenza vaccine in children conducted from October 2010 to December 2011 in 8 countries. Vaccine efficacy was estimated using a weighted Cox proportional hazards model. Estimates were decomposed into the direct and indirect effects mediated by postvaccination HAI titers. RESULTS: The proportions of vaccine efficacy mediated by postvaccination HAI titers were estimated to be 22% (95% confidence interval, 18%--47%) for influenza A(H1N1), 20% (16%-39%) for influenza A(H3N2), and 37% (26%-85%) for influenza B/Victoria. CONCLUSIONS: HAI titers partially mediate influenza vaccine efficacy against influenza A(H1N1), A(H3N2), and B/Victoria. Our estimates were lower than in previous studies, possibly reflecting expected heterogeneity in antigenic similarity between vaccine and circulating viruses across seasons.

Predicting Efficacies of Fractional Doses of Vaccines by Using Neutralizing Antibody Levels: Systematic Review and Meta-Analysis.

Background: With the emergence of SARS-CoV-2 variants that have eluded immunity from vaccines and prior infections, vaccine shortages and vaccine effectiveness pose unprecedented challenges for governments in expanding booster vaccination programs. The fractionation of vaccine doses might be an effective strategy for helping society to face these challenges, as fractional doses may have efficacies comparable with those of the standard doses. Objective: This study aims to investigate the relationship between vaccine immunogenicity and protection and to project efficacies of fractional doses of vaccines for COVID-19 by using neutralizing antibody levels. Methods: In this study, we analyzed the relationship between in vitro neutralization levels and the observed efficacies against both asymptomatic infection and symptomatic infection, using data from 13 studies of 10 COVID-19 vaccines and from convalescent cohorts. We further projected efficacies for fractional doses, using neutralization as an intermediate variable, based on immunogenicity data from 51 studies included in our systematic review. Results: In comparisons with the convalescent level, vaccine efficacy against asymptomatic infection and symptomatic infection increased from 8.8% (95% CI 1.4%-16.1%) to 71.8% (95% CI 63%-80.7%) and from 33.6% (95% CI 23.6%-43.6%) to 98.6% (95% CI 97.6%-99.7%), respectively, as the mean neutralization level increased from 0.1 to 10 folds of the convalescent level. Additionally, mRNA vaccines provided the strongest protection, which decreased slowly for fractional dosing with dosages between 50% and 100% of the standard dose. We also observed that although vaccine efficacy increased with the mean neutralization level, the rate of this increase was slower for vaccine efficacy against asymptomatic infection than for vaccine efficacy against symptomatic infection. Conclusions: Our results are consistent with studies on immune protection from SARS-CoV-2 infection. Based on our study, we expect that fractional-dose vaccination could provide partial immunity against SARS-CoV-2 and its variants. Our findings provide a theoretical basis for the efficacy of fractional-dose vaccines, serving as reference evidence for implementing fractional dosing vaccine policies in areas facing vaccine shortages and thereby mitigating disease burden. Fractional-dose vaccination could be a viable vaccination strategy comparable to full-dose vaccination and deserves further exploration.

Limited impact of lifting universal masks on SARS-CoV-2 transmission in schools: The crucial role of outcome measurements.

Amid the COVID-19 pandemic, education systems globally implemented protective measures, notably mandatory mask wearing. As the pandemic's dynamics changed, many municipalities lifted these mandates, warranting a critical examination of these policy changes' implications. This study examines the effects of lifting mask mandates on COVID-19 transmission within Massachusetts school districts. We first replicated previous research that utilized a difference-in-difference (DID) model for COVID-19 incidence. We then repeated the DID analysis by replacing the outcome measurement with the reproductive number (Rt ), reflecting the transmissibility. Due to the data availability, the Rt we estimated only measures the within school transmission. We found a similar result in the replication using incidence with an average treatment effect on treated (ATT) of 39.1 (95% CI: 20.4 to 57.4) COVID-19 cases per 1,000 students associated with lifting masking mandates. However, when replacing the outcome measurement to Rt , our findings suggest that no significant association between lifting mask mandates and reduced Rt (ATT: 0.04, 95% CI: -0.09 to 0.18), except for the first 2 weeks postintervention. Moreover, we estimated Rt below 1 at 4 weeks before lifting mask mandates across all school types, suggesting nonsustainable transmission before the implementation. Our reanalysis suggested no evidence of lifting mask mandates in schools impacted the COVID-19 transmission in the long term. Our study highlights the importance of examining the transmissibility outcome when evaluating interventions against transmission.

Addressing current limitations of household transmission studies by collecting contact data.

Modeling studies of household transmission data have helped characterize the role of children in influenza and COVID-19 epidemics. However, estimates from these studies may be biased since they do not account for the heterogeneous nature of household contacts. Here, we quantified the impact of contact heterogeneity between household members on the estimation of child relative susceptibility and infectivity. We simulated epidemics of SARS-CoV-2-like and influenza-like infections in a synthetic population of 1,000 households assuming heterogeneous contact levels. Relative contact frequencies were derived from a household contact study according to which contacts are more frequent in the father-mother pair, followed by the child-mother, child-child, and finally child-father pairs. Child susceptibility and infectivity were then estimated while accounting for heterogeneous contacts or not. When ignoring contact heterogeneity, child relative susceptibility was underestimated by approximately 20% in the two disease scenarios. Child relative infectivity was underestimated by 20% when children and adults had different infectivity levels. These results are sensitive to our assumptions of European-style household contact patterns; but they highlight that household studies collecting both disease and contact data are needed to assess the role of complex household contact behavior on disease transmission and improve estimation of key biological parameters.

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.