Hemagglutination inhibition antibody titers mediate influenza vaccine efficacy against symptomatic influenza A(H1N1), A(H3N2), and B/Victoria infections.

BACKGROUND: The hemagglutination inhibition antibody (HAI) titer mediates only a part of vaccine-induced protection against influenza virus infections. Using causal mediation analysis, we quantified the proportion of vaccine efficacy mediated by post-vaccination HAI titers. METHODS: Causal mediation analyses were conducted using data collected for a randomized, active-comparator controlled, phase 3 trial of a candidate inactivated, split-virion seasonal quadrivalent influenza vaccine (QIV) in children aged 3 to 8 years conducted from October 2010 to December 2011 in eight countries. Vaccine efficacy was estimated with a weighted Cox proportional hazards regression model. Estimates were decomposed into the direct and indirect effects mediated by post-vaccination HAI titers. RESULTS: The proportions of vaccine efficacy mediated by post-vaccination HAI titers were estimated to be 22% (95% CI: 18%, 47%) for influenza A(H1N1), 20% (95% CI: 16%, 39%) for influenza A(H3N2), and 37% (95% CI: 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 previous studies, possibly reflecting expected heterogeneity in antigenic similarity between vaccine and circulating viruses across seasons. Data from more influenza seasons are needed to understand better the mediating effects of HAI titers on vaccine efficacy.

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.

Effectiveness of social distancing measures and lockdowns for reducing transmission of COVID-19 in non-healthcare, community-based settings.

Social distancing measures (SDMs) are community-level interventions that aim to reduce person-to-person contacts in the community. SDMs were a major part of the responses first to contain, then to mitigate, the spread of SARS-CoV-2 in the community. Common SDMs included limiting the size of gatherings, closing schools and/or workplaces, implementing work-from-home arrangements, or more stringent restrictions such as lockdowns. This systematic review summarized the evidence for the effectiveness of nine SDMs. Almost all of the studies included were observational in nature, which meant that there were intrinsic risks of bias that could have been avoided were conditions randomly assigned to study participants. There were no instances where only one form of SDM had been in place in a particular setting during the study period, making it challenging to estimate the separate effect of each intervention. The more stringent SDMs such as stay-at-home orders, restrictions on mass gatherings and closures were estimated to be most effective at reducing SARS-CoV-2 transmission. Most studies included in this review suggested that combinations of SDMs successfully slowed or even stopped SARS-CoV-2 transmission in the community. However, individual effects and optimal combinations of interventions, as well as the optimal timing for particular measures, require further investigation. This article is part of the theme issue 'The effectiveness of non-pharmaceutical interventions on the COVID-19 pandemic: the evidence'.

The impact of repeated vaccination on relative influenza vaccine effectiveness among vaccinated adults in the United Kingdom.

Annual seasonal influenza vaccination is recommended for individuals at high risk of developing post-infection complications in many locations. However, reduced vaccine immunogenicity and effectiveness have been observed among repeat vaccinees in some influenza seasons. We investigated the impact of repeated influenza vaccination on relative vaccine effectiveness (VE) among individuals who were recommended for influenza vaccination in the United Kingdom with a retrospective cohort study using primary healthcare data from the Clinical Practice Research Datalink, a primary care database in the United Kingdom. Relative VE was estimated against general practitioner-diagnosed influenza-like illnesses (GP-ILI) and medically attended acute respiratory illnesses (MAARI) among participants who have been repeatedly vaccinated compared with first-time vaccinees using proportional hazards models. Relative VE against MAARI may be reduced for individuals above 65 years old who were vaccinated in the current and previous influenza seasons for some influenza seasons. However, these findings were not conclusive as we could not exclude the possibility of residual confounding in our dataset. The use of routinely collected data from electronic health records to examine the effects of repeated vaccination needs to be complemented with sufficient efforts to include negative control outcomes to rule out residual confounding.

Distinguishing Causation From Correlation in the Use of Correlates of Protection to Evaluate and Develop Influenza Vaccines.

There is increasing attention to the need to identify new immune markers for the evaluation of existing and new influenza vaccines. Immune markers that could predict individual protection against infection and disease, commonly called correlates of protection (CoPs), play an important role in vaccine development and licensing. Here, we discuss the epidemiologic considerations when evaluating immune markers as potential CoPs for influenza vaccines and emphasize the distinction between correlation and causation. While an immune marker that correlates well with protection from infection can be used as a predictor of vaccine efficacy, it should be distinguished from an immune marker that plays a mechanistic role in conferring protection against a clinical endpoint-the latter might be a more reliable predictor of vaccine efficacy and a more appropriate target for rational vaccine design. To clearly distinguish mechanistic and nonmechanistic CoPs, we suggest using the term "correlates of protection" for nonmechanistic CoPs, and ''mediators of protection'' for mechanistic CoPs. Furthermore, because the interactions among and relative importance of correlates or mediators of protection can vary according to age or prior vaccine experience, the effect sizes and thresholds for protective effects for CoPs could also vary in different segments of the population.

Influenza Hemagglutination-inhibition Antibody Titer as a Mediator of Vaccine-induced Protection for Influenza B.

BACKGROUND: The hemagglutination inhibition (HAI) assay is an established correlate of protection for the inactivated influenza vaccine. However, the proportion of vaccine-induced protection that is mediated by the post-vaccination HAI titer has not been assessed. METHODS: We used data from a randomized, placebo-controlled trial of a split-virion inactivated influenza vaccine in children aged 6-17 years. Sera were collected before and 30 days after receipt of vaccination or placebo and tested by the HAI assay against B/Brisbane/60/2008-like (B/Victoria lineage). We fitted Cox proportional hazards models to the time to laboratory-confirmed influenza B. We used causal mediation analysis to estimate the proportion of the total effect of vaccination that was mediated by higher HAI titers. RESULTS: We estimated that vaccine efficacy against confirmed B/Victoria infection was 68% (95% confidence interval, 33%, 88%), and post-vaccination HAI titers explained 57% of the effect of vaccination on protection. CONCLUSIONS: The majority of the effect of inactivated influenza vaccination in children is mediated by the increased HAI titer after vaccination; however, other components of the immune response to vaccination may also play a role in protection and should be further explored. Causal mediation analysis provides a framework to quantify the role of various mediators of protection.

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.

Cost effectiveness of fractional doses of COVID-19 vaccine boosters in India.

BACKGROUND: Coronavirus disease 2019 (COVID-19) continues to be a major global public health crisis that exacts significant human and economic costs. Booster vaccination of individuals can improve waning immunity and reduce the impact of community epidemics. METHODS: Using an epidemiological model that incorporates population-level severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) transmission and waning of vaccine-derived immunity, we identify the hypothetical potential of mass vaccination with fractionated vaccine doses specific to ChAdOx1 nCoV-19 (AZD1222 [Covishield]; AstraZeneca) as an optimal and cost-effective strategy in India's Omicron outbreak. FINDINGS: We find that the optimal strategy is 1/8 fractional dosing under mild (Re ∼ 1.2) and rapid (Re ∼ 5) transmission scenarios, leading to an estimated $6 (95% confidence interval [CI]: -13, 26) billion and $2 (95% CI: -26, 30) billion in health-related net monetary benefit over 200 days, respectively. Rapid and broad use of fractional dosing for boosters, together with delivery costs divided by fractionation, could substantially gain more net monetary benefit by $11 (95% CI: -10, 33) and $2 (95% CI: -23, 28) billion, respectively, under the mild and rapid transmission scenarios. CONCLUSIONS: Mass vaccination with fractional doses of COVID-19 vaccines to boost immunity in a vaccinated population could be a cost-effective strategy for mitigating the public health costs of resurgences caused by vaccine-evasive variants, and fractional dosing deserves further clinical and regulatory evaluation. FUNDING: Financial support was provided by the AIR@InnoHK Program from Innovation and Technology Commission of the Government of the Hong Kong Special Administrative Region.

Modeling comparative cost-effectiveness of SARS-CoV-2 vaccine dose fractionation in India.

Given global Coronavirus Disease 2019 (COVID-19) vaccine shortages and inequity of vaccine distributions, fractionation of vaccine doses might be an effective strategy for reducing public health and economic burden, notwithstanding the emergence of new variants of concern. In this study, we developed a multi-scale model incorporating population-level transmission and individual-level vaccination to estimate the costs of hospitalization and vaccination and the economic benefits of reducing COVID-19 deaths due to dose-fractionation strategies in India. We used large-scale survey data of the willingness to pay together with data of vaccine and hospital admission costs to build the model. We found that fractional doses of vaccines could be an economically viable vaccination strategy compared to alternatives of either full-dose vaccination or no vaccination. Dose-sparing strategies could save a large number of lives, even with the emergence of new variants with higher transmissibility.

COVID-19 transmission in Hong Kong despite universal masking.

OBJECTIVES: mask-wearing outside the home has been almost universal in Hong Kong since late January 2020 with very high compliance. Nevertheless, community spread of COVID-19 has still occurred. We aimed to assess the settings where COVID-19 transmission occurred and determine the fraction of transmission events that occurred in settings where masks are not usually worn. METHODS: we reviewed detailed information provided by the Hong Kong Department of Health on local COVID-19 cases diagnosed up to 30 September 2020 to determine the most likely settings in which transmission occurred. We classified them in probably mask-on or mask-of and compared the prevalence of asymptomatic infections in these settings. RESULTS: among the 2425 cases (65.3%, 2425/3711) with information on transmission setting, 77.6% of the transmission occurred in household and social settings where face masks are not usually worn. Infections that occurred in mask-on settings were more likely to be asymptomatic (adjusted odds ratio 1.33; 95% confidence interval: 1.04, 1.68). CONCLUSIONS: we conclude that universal mask-wearing can reduce transmission, but transmission can continue to occur in settings where face masks are not usually worn. The higher proportion of asymptomatic cases in mask-on settings could be related to a milder disease presentation or earlier case detection.

Patterns of Inpatient Antibiotic Use Among Public Hospitals in Hong Kong from 2000 to 2015.

BACKGROUND: Studies have demonstrated that higher rates of antibiotic resistance are found in countries with higher antibiotic consumption. The global increase in antibiotic consumption is a major public health concern. OBJECTIVES: The objective of this study was to describe the antibiotic dispensing patterns in public hospitals in Hong Kong from 2000 to 2015. METHODS: We acquired data on all hospital admissions with any antibiotics dispensed from 2000 to 2015 from the Hong Kong public hospitals. The annual proportion of hospital admissions with antibiotics dispensed was estimated and stratified by age group. An interrupted time series analysis was conducted to examine any potential change in tetracycline dispensing after the release of the new clinical practice guideline. RESULTS: A total of 35,535,506 antibiotic prescriptions were dispensed among 2,161,360 unique hospitalized patients from 2000 to 2015. Antibiotics were dispensed in 29.2% of all hospital admissions in the public hospitals, the annual proportions of hospital admissions with antibiotics dispensed increased over the study period from 27.87% in 2000 to 31.39% in 2015, ranging from 27.17 to 31.39%. However, a significant increase was only observed in age groups of 5-19, 20-44, and 85 years or above when stratifying by age. In the interrupted time series analysis, a change in trend was detected for tetracycline dispensing that coincided with the time of publication of the new clinical practice guideline. CONCLUSIONS: We found that the overall volume of antibiotic use increased between 2000 and 2015. The rise in the dispensing of carbapenems in our study is concerning. The significant change in tetracycline use after being recommended as one of the preferred regimens demonstrated that the change in the clinical practice guideline had an immediate effect on the antibiotic prescribing practice in Hong Kong public hospitals.

Determinants of methicillin-resistant Staphylococcus aureus (MRSA) prevalence in the Asia-Pacific region: A systematic review and meta-analysis.

OBJECTIVES: Published literature on methicillin-resistant Staphylococcus aureus (MRSA) in the Asia-Pacific region was reviewed to document the prevalence of MRSA in the region and to examine the impact of variability in study design on the reported MRSA prevalence data. METHODS: This review included studies reporting MRSA prevalence between 2000 and 2016. Studies were excluded if they did not contain complete information on antimicrobial susceptibility testing (AST) methods. Primary outcomes were the proportion of MRSA among S. aureus isolates (resistance proportion) or among individual samples (prevalence). RESULTS: A total of 229 studies in 19 countries/territories were included in the study. There was substantial heterogeneity in both outcomes (resistance proportion, I2=99.59%; prevalence, I2=99.83%), precluding pooled averages, and meta-regression analyses revealed that these variations were explained by country income status and participant characteristics but not by methodological differences in AST. Also, no significant secular changes in MRSA prevalence or resistance proportions in Asia-Pacific were found. CONCLUSION: The resistance proportions and prevalence of MRSA infections in Asia-Pacific are comparable with those reported in other regions with no significant secular changes in the past decade. Country income status and characteristics of the sample population explained more variation in the reported resistance proportions and prevalence of MRSA than methodological differences in AST across locations in the region.

Use of influenza antivirals in patients hospitalized in Hong Kong, 2000-2015.

OBJECTIVES: We aimed to describe patterns in the usage of antivirals to treat influenza virus infection in hospitals in Hong Kong from 2000 through 2015. METHODS: We analyzed centralized electronic health records that included dispensation information and diagnosis codes. Information collected on admissions included patient age, sex, admission year and month, and medications dispensed, and were matched with the first 15 discharge diagnosis codes. We divided monthly admission episodes by relevant population denominators to obtain admission rates, and stratified analyses by drug type, age group, and diagnosis codes. RESULTS: Amantadine was used for influenza treatment in the early 2000s but changed with recommendations to avoid its use in 2006, and is now mainly used to treat Parkinson's disease. Oseltamivir usage increased substantially in 2009 and is now commonly used, with almost 40,000 hospitalizations treated with oseltamivir in the years 2012 through 2015, 66% of which was in persons ≥65 years of age. During the entire study period, of the 98,253 admission episodes in which oseltamivir was dispensed, 40,698 (41%) included a diagnosis code for influenza, and 80,283 (82%) included any diagnosis code for respiratory illness. CONCLUSIONS: The amount of oseltamivir used from 2012-15 was comparable to a separate ecological estimate of around 13,000 influenza-associated hospitalizations per year on average. We did not have access to individual patient laboratory testing data.