Effects of high-dose versus standard-dose quadrivalent influenza vaccine among patients with diabetes: A post-hoc analysis of the DANFLU-1 trial.

AIM: High-dose quadrivalent influenza vaccine (QIV-HD) has been shown to be more effective than standard-dose (QIV-SD) in reducing influenza infection, but whether diabetes status affects relative vaccine effectiveness (rVE) is unknown. We aimed to assess rVE on change in glycated haemoglobin [HbA1c (∆HbA1c)], incident diabetes, total all-cause hospitalizations (first + recurrent), and a composite of all-cause mortality and hospitalization for pneumonia or influenza. METHODS: DANFLU-1 was a pragmatic, open-label trial randomizing adults (65-79 years) 1:1 to QIV-HD or QIV-SD during the 2021/22 influenza season. Cox proportional hazards regression was used to estimate rVE against incident diabetes and the composite endpoint, negative binomial regression to estimate rVE against all-cause hospitalizations, and ANCOVA when assessing rVE against ∆HbA1c. RESULTS: Of the 12 477 participants, 1162 (9.3%) had diabetes at baseline. QIV-HD, compared with QIV-SD, was associated with a reduction in the rate of all-cause hospitalizations irrespective of diabetes [overall: 647 vs. 742 events, incidence rate ratio (IRR): 0.87, 95% CI (0.76-0.99); diabetes: 93 vs. 118 events, IRR: 0.80, 95% CI (0.55-1.15); without diabetes: 554 vs. 624 events, IRR: 0.88, 95% CI (0.76-1.01), pinteraction = 0.62]. Among those with diabetes, QIV-HD was associated with a lower risk of the composite outcome [2 vs. 11 events, HR: 0.18, 95% CI (0.04-0.83)] but had no effect on ∆HbA1c; QIV-HD adjusted mean difference: ∆ + 0.2 mmol/mol, 95% CI (-0.9 to 1.2). QIV-HD did not affect the risk of incident diabetes [HR 1.18, 95% CI (0.94-1.47)]. CONCLUSIONS: In this post-hoc analysis, QIV-HD versus QIV-SD was associated with an increased rVE against the composite of all-cause death and hospitalization for pneumonia/influenza, and the all-cause hospitalization rate irrespective of diabetes status.

Association of COVID-19 vaccination with duration of hospitalization in older adults in Hong Kong.

INTRODUCTION: The association between COVID-19 vaccination and length of hospital stay may provide further insight into vaccination benefits, but few studies have investigated such associations in detail. We aimed to investigate the association between COVID-19 vaccination and length of hospital stay in COVID-19 patients during Omicron waves in Hong Kong, and explore potential predictors. METHODS: This retrospective cohort study was conducted on local patients aged ≥60 years who were admitted due to COVID-19 infection in Hong Kong in 2022, from 1 February to 22 November, and with 28 days of follow-up since admission. The exposure was either not vaccinated; or having received 2/3/4 doses of CoronaVac (Sinovac); or 2/3/4 doses of BNT162b2 (BioNTech/Fosun Pharma/Pfizer). Length of stay in hospital was the main outcome. Accelerated failure time models were used to quantify variation in hospital stay for vaccinated compared with unvaccinated patients, accounting for age, sex, comorbidity, type of vaccine and number of doses received, care home residence and admission timing; stratified by age groups and epidemic waves. RESULTS: This study included 32,398 patients aged 60 years and above for main analysis, their median (IQR) age was 79 (71-87) years, 53% were men, and 40% were unvaccinated. The patients were stratified by confirmation prior to or since 23 May 2022, resulting in a sample size of 15,803 and 16,595 in those two waves respectively. Vaccinated patients were found to have 13-39% shorter hospital stay compared to unvaccinated patients. More vaccine doses received were associated with shorter hospital stay, and BNT162b2 recipients had slightly shorter hospital stays than CoronaVac recipients. CONCLUSION: Vaccination was associated with reduced hospital stay in breakthrough infections. Increased vaccination uptake in older adults may improve hospital bed turnover and public health outcomes especially during large community epidemics.

Reported effectiveness of COVID-19 monovalent booster vaccines and hybrid immunity against mild and severe Omicron disease in adults: A systematic review and meta-regression analysis.

Background: Waning of COVID-19 vaccine efficacy/effectiveness (VE) has been observed across settings and epidemiological contexts. We conducted a systematic review of COVID-19 VE studies and performed a meta-regression analysis to improve understanding of determinants of waning. Methods: Systematic review of PubMed, medRxiv and the WHO-International Vaccine Access Center database summarizing VE studies on 31 December 2022. Studies were those presenting primary adult VE data from hybrid immunity or third/fourth mRNA COVID-19 monovalent vaccine doses [due to limited data with other vaccines] against Omicron, compared with unvaccinated individuals or individuals eligible for corresponding booster doses but who did not receive them. We used meta-regression models, adjusting for confounders, with weeks since vaccination as a restricted cubic spline, to estimate VE over time since vaccination. Results: We identified 55 eligible studies reporting 269 VE estimates. Most estimates (180/269; 67 %) described effectiveness of third dose vaccination; with 48 (18 %) and 41 (15 %) describing hybrid immunity and fourth dose effectiveness, respectively, mostly (200; 74 %) derived from test-negative design studies. Most estimates (176/269; 65 %) reported VE compared with unvaccinated comparison groups. Estimated VE against mild outcomes declined following third dose vaccination from 62 % (95 % CI: 58 % - 66 %) after 4 weeks to 48 % (41 % - 55 %) after 20 weeks. Fourth dose VE against mild COVID-19 declined from 48 % (41 % - 56 %) after 4 weeks to 47 % (19 % - 65 %) after 20 weeks. VE for severe outcomes was higher and declined in the three-dose group from 90 % (87 % - 92 %) after 4 weeks to 70 % (65 - 74 %) after 20 weeks. Conclusions: Time-since vaccination is an important determinant of booster dose VE, a finding which may support seasonal COVID-19 booster doses. Integration of VE and immunological parameters - and longer-term data including from other vaccine types - are needed to better-understand determinants of clinical protection.

Effectiveness of high-dose versus standard-dose quadrivalent influenza vaccine against recurrent hospitalizations and mortality in relation to influenza circulation: A post-hoc analysis of the DANFLU-1 randomized clinical trial.

OBJECTIVES: To evaluate the relative effectiveness of high-dose quadrivalent influenza vaccine (QIV-HD) versus standard-dose quadrivalent influenza vaccine (QIV-SD) against recurrent hospitalizations and its potential variation in relation to influenza circulation. METHODS: We did a post-hoc analysis of a pragmatic, open-label, randomized trial of QIV-HD versus QIV-SD performed during the 2021-2022 influenza season among adults aged 65-79 years. Participants were enrolled in October 2021-November, 2021 and followed for outcomes from 14 days postvaccination until 31 May, 2022. We investigated the following outcomes: Hospitalizations for pneumonia or influenza, respiratory hospitalizations, cardio-respiratory hospitalizations, cardiovascular hospitalizations, all-cause hospitalizations, and all-cause death. Outcomes were analysed as recurrent events. Cumulative numbers of events were assessed weekly. Cumulative relative effectiveness estimates were calculated and descriptively compared with influenza circulation. The trial is registered at Clinicaltrials.gov: NCT05048589. RESULTS: Among 12,477 randomly assigned participants, receiving QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza (10 vs. 33 events, incidence rate ratio [IRR] 0.30 [95% CI, 0.14-0.64]; p 0.002) and all-cause hospitalizations (647 vs. 742 events, IRR 0.87 [95% CI, 0.76-0.99]; p 0.032) compared with QIV-SD. Trends favouring QIV-HD were consistently observed over time including in the period before active influenza transmission; i.e. while the first week with a ≥10% influenza test positivity rate was calendar week 10, 2022, the first statistically significant reduction in hospitalizations for pneumonia or influenza was already observed by calendar week 3, 2022 (5 vs. 15 events, IRR 0.33 [95% CI, 0.11-0.94]; p 0.037). DISCUSSION: In a post-hoc analysis, QIV-HD was associated with lower incidence rates of hospitalizations for pneumonia or influenza and all-cause hospitalizations compared with QIV-SD, with trends evident independent of influenza circulation levels. Our exploratory results correspond to a number needed to treat of 65 (95% CI 35-840) persons vaccinated with QIV-HD compared with QIV-SD to prevent one additional all-cause hospitalization per season. Further research is needed to confirm these hypothesis-generating findings.

The need for a clinical case definition in test-negative design studies estimating vaccine effectiveness.

Test negative studies have been used extensively for the estimation of COVID-19 vaccine effectiveness (VE). Such studies are able to estimate VE against medically-attended illness under certain assumptions. Selection bias may be present if the probability of participation is associated with vaccination or COVID-19, but this can be mitigated through use of a clinical case definition to screen patients for eligibility, which increases the likelihood that cases and non-cases come from the same source population. We examined the extent to which this type of bias could harm COVID-19 VE through systematic review and simulation. A systematic review of test-negative studies was re-analysed to identify studies ignoring the need for clinical criteria. Studies using a clinical case definition had a lower pooled VE estimate compared with studies that did not. Simulations varied the probability of selection by case and vaccination status. Positive bias away from the null (i.e., inflated VE consistent with the systematic review) was observed when there was a higher proportion of healthy, vaccinated non-cases, which may occur if a dataset contains many results from asymptomatic screening in settings where vaccination coverage is high. We provide an html tool for researchers to explore site-specific sources of selection bias in their own studies. We recommend all groups consider the potential for selection bias in their vaccine effectiveness studies, particularly when using administrative data.

Influenza vaccination and cardiovascular events in patients with ischaemic heart disease and heart failure: A meta-analysis.

AIM: Randomized controlled trials (RCTs) enrolling patients at high cardiovascular risk have found that influenza vaccination may reduce the incidence of cardiovascular events. We performed an updated meta-analysis assessing the effect of influenza vaccination on the incidence of cardiovascular events in patients with ischaemic heart disease or heart failure. METHODS AND RESULTS: We searched PubMed, EMBASE and other sources to identify RCTs examining the effect of influenza vaccination on the incidence of cardiovascular events assessed as efficacy outcomes in patients with ischaemic heart disease or heart failure. Eligible studies followed patients for at least one influenza season, defined as a minimum duration of 6 months. The primary endpoint was a composite of cardiovascular death, acute coronary syndrome, stent thrombosis or coronary revascularization, stroke or heart failure hospitalization. The secondary endpoints were cardiovascular death and all-cause death. Two investigators independently identified and extracted data from studies. Results were compared using hazard ratios (HRs) in both random effects and fixed effects models. We included five peer-reviewed and one non peer-reviewed RCTs for a total of 9340 patients. Five trials included patients with ischaemic heart disease (n = 4211) and one trial included patients with heart failure (n = 5129). Influenza vaccination was associated with a reduced incidence of the primary composite endpoint (random effects HR [rHR] 0.74, 95% confidence interval [CI] 0.63-0.88, p < 0.001, I2 = 52%), cardiovascular death (rHR 0.63, 95% CI 0.42-0.95, p = 0.028, I2 = 58%) and all-cause death (rHR 0.72, 95% CI 0.54-0.95, p = 0.0227, I2 = 52%). Results were similar when non peer-reviewed data were excluded. CONCLUSION: In this meta-analysis of available RCTs in patients at high cardiovascular risk, influenza vaccination was associated with a reduced incidence of cardiovascular events, cardiovascular death and all-cause death as compared to placebo or no treatment.

Revisiting assumptions in test-negative studies for estimating vaccine effectiveness: the need for a clinical case definition.

Test negative studies have been used extensively for the estimation of COVID-19 vaccine effectiveness (VE). Such studies are able to estimate VE against medically-attended illness under certain assumptions. Selection bias may be present if the probability of participation is associated with vaccination or COVID-19, but this can be mitigated through use of a clinical case definition to screen patients for eligibility, which increases the likelihood that cases and non-cases come from the same source population. We examined the extent to which this type of bias could harm COVID-19 VE through systematic review and simulation. A systematic review of test-negative studies was re-analysed to identify studies ignoring the need for clinical criteria. Studies using a clinical case definition had a lower pooled VE estimate compared with studies that did not. Simulations varied the probability of selection by case and vaccination status. Positive bias away from the null (i.e., inflated VE consistent with the systematic review) was observed when there was a higher proportion of healthy, vaccinated non-cases, which may occur if a dataset contains many results from asymptomatic screening in settings where vaccination coverage is high. We provide an html tool for researchers to explore site-specific sources of selection bias in their own studies. We recommend all group consider the potential for selection bias in their vaccine effectiveness studies, particularly when using administrative data.

High-Dose Influenza Vaccine Is Associated With Reduced Mortality Among Older Adults With Breakthrough Influenza Even When There Is Poor Vaccine-Strain Match.

BACKGROUND: High-dose (HD) influenza vaccine offers improved protection from influenza virus infection among older adults compared with standard-dose (SD) vaccine. Here, we explored whether HD vaccine attenuates disease severity among older adults with breakthrough influenza. METHODS: This was a retrospective cohort study of US claims data for influenza seasons 2016-2017, 2017-2018, and 2018-2019, defined as 1 October through 30 April, among adults aged ≥65 years. After adjusting the different cohorts for the probability of vaccination conditional on patients' characteristics, we compared 30-day mortality rate post-influenza among older adults who experienced breakthrough infection after receipt of HD or SD influenza vaccines and among those not vaccinated (NV). RESULTS: We evaluated 44 456 influenza cases: 23 109 (52%) were unvaccinated, 15 037 (33.8%) received HD vaccine, and 6310 (14.2%) received SD vaccine. Significant reductions in mortality rates among breakthrough cases were observed across all 3 seasons for HD vs NV, ranging from 17% to 29% reductions. A significant mortality reduction of 25% was associated with SD vaccination vs NV in the 2016-2017 season when there was a good match between circulating influenza viruses and selected vaccine strains. When comparing HD vs SD cohorts, mortality reductions were higher among those who received HD in the last 2 seasons when mismatch between vaccine strains and circulating H3N2 viruses was documented, albeit not significant. CONCLUSIONS: HD vaccination was associated with lower post-influenza mortality among older adults with breakthrough influenza, even during seasons when antigenically drifted H3N2 circulated. Improved understanding of the impact of different vaccines on attenuating disease severity is warranted when assessing vaccine policy recommendations.

Age distribution of dengue cases in southern Vietnam from 2000 to 2015.

BACKGROUND: Dengue is the most common vector-borne viral infection. In recent times, an increase in the age of cases with clinical dengue has been reported in the national surveillance system and published literature of Vietnam. This change not only alter the risk of transmission and disease burden in different populations but also will impact for prevention and control strategies. A retrospective study was conducted from 2000 to 2015 in 19 provinces of southern Vietnam to describe the changes in age distribution of dengue cases and circulating serotypes. METHODOLOGY/PRINCIPAL FINDINGS: The study is a time trend analysis of the data aggregated from the database of dengue surveillance system. The database consisted of clinically diagnosed and laboratory-confirmed cases of dengue in southern Vietnam from 2000 to 2015. In the study period, the mean age of dengue cases increased from 12.2 ± 8.8 years old (y/o) to 16.8 ± 13.3 y/o between 2000 and 2015. Majority of severe cases were observed in the age group of 5-9 y/o and 10-14 y/o. Overall, the mortality and case fatality rates (CFR) were lowest during 2010 to 2015, and all four serotypes of dengue were observed. CONCLUSIONS/SIGNIFICANCE: With the exception of severe form, the age distribution of clinical cases of dengue appears to be shifting towards older age groups. An increase in the mean age of clinical cases of dengue has been observed in southern Vietnam over the past decade, and the highest incidence was observed in age group of 5-14 y/o. All serotypes of dengue were in circulation.

Hospitalizations and mortality during the first year of the COVID-19 pandemic in Hong Kong, China: An observational study.

Background: Hong Kong followed a strict COVID-19 elimination strategy in 2020. We estimated the impact of the COVID-19 pandemic responses on all-cause and cause-specific hospitalizations and deaths in 2020. Methods: Interrupted time-series analysis using negative binomial regression accounting for seasonality and long-term trend was used on weekly 2010-2020 data to estimate the change in hospitalization risk and excess mortality occurring both within and out of hospitals. Findings: In 2020, as compared to a 2010-2019 baseline, we observed an overall reduction in all-cause hospitalizations, and a concurrent increase in deaths. The overall hospitalization reduction (per 100,000 population) was 4809 (95% CI: 4692, 4926) in 2020, with respiratory diseases (632, 95% CI: 607, 658) and cardiovascular diseases (275, 95% CI: 264, 286) contributing most. The overall excess mortality (per 100,000 population) was 25 (95% CI: 23, 27) in 2020, mostly among individuals with pre-existing cardiovascular diseases (12, 95% CI: 11, 13). A reduction in excess in-hospital mortality (-10 per 100,000, 95% CI: -12, -8) was accompanied by an increase in excess out-of-hospital mortality (32, 95% CI: 29, 34). Interpretation: The COVID-19 pandemic might have caused indirect impact on population morbidity and mortality likely through changed healthcare seeking particularly in youngest and oldest individuals and those with cardiovascular diseases. Better healthcare planning is needed during public health emergencies with disruptions in healthcare services. Funding: Health and Medical Research Fund, Collaborative Research Fund, AIR@InnoHK and RGC Senior Research Fellow Scheme, Hong Kong.

Global, regional and national estimates of influenza-attributable ischemic heart disease mortality.

Background: Influenza virus infection is associated with incident ischemic heart disease (IHD) events. Here, we estimate the global, regional, and national IHD mortality burden attributable to influenza. Methods: We used vital registration data from deaths in adults ≥50 years (13.2 million IHD deaths as underlying cause) to assess the relationship between influenza activity and IHD mortality in a non-linear meta-regression framework from 2010 to 2019. This derived relationship was then used to estimate the global influenza attributable IHD mortality. We estimated the population attributable fraction (PAF) of influenza for IHD deaths based on the relative risk associated with a given level of weekly influenza test positivity rate and multiplied PAFs by IHD mortality from the Global Burden of Disease study. Findings: Influenza activity was associated with increased risk of IHD mortality across all countries analyzed. The mean PAF of influenza for IHD mortality was 3.9% (95% uncertainty interval [UI] 2.5-5.3%), ranging from <1% to 10%, depending on country and year. Globally, 299,858 IHD deaths (95% UI 191,216-406,809) in adults ≥50 years could be attributed to influenza, with the highest rates per 100,000 population in the Central Europe, Eastern Europe and Central Asia Region (32.3; 95% UI 20.6-43.8), and in the North Africa and Middle East Region (26.7; 95% UI 17-36.2). Interpretation: Influenza may contribute substantially to the burden of IHD. Our results suggest that if there were no influenza, an average of 4% of IHD deaths globally would not occur. Funding: Collaborative study funded by Sanofi Vaccines.

A Pragmatic Randomized Feasibility Trial of Influenza Vaccines.

Randomized Feasibility Trial of Influenza VaccinesThis pragmatic, open-label, active-controlled, randomized feasibility trial of QIV-HD versus QIV-SD was conducted in Danish citizens aged 65 to 79 years during the 2021-2022 influenza season. Randomization was integrated into routine vaccination practice. Only nationwide administrative health registries were used for data collection.

Seasonal influenza, its complications and related healthcare resource utilization among people 60 years and older: A descriptive retrospective study in Japan.

Evidence suggests that older people aged ≥65 years and those aged 60-64 years with chronic medical conditions are at higher risk of developing severe complications due to influenza virus infection when compared with young, healthy adults. Although seasonal influenza is monitored through a nationwide passive surveillance in Japan, influenza related outcomes and medical resource consumption have not been fully documented. This retrospective database study aimed to describe the epidemiological and clinical characteristics of medically attended influenza cases aged ≥60 years and the associated medical resource consumption in Japan. We used clinically diagnosed influenza (CDI) based on the international classification of disease codes, and laboratory-confirmed influenza (LCI) based on influenza test results, to identify the patient population during a total of nine seasons (2010/2011 to 2018/2019). A total of 372,356 CDI and 31,122 LCI cases were identified from 77 medical institutions. The highest numbers of medically-attended influenza episodes were in patients aged 65-74 years and 75-84 years. On average, across seasons, 5.9% of all-cause hospitalizations were attributable to CDI and 0.4% were LCI. Influenza viruses type A and B co-circulated annually in varying degree of intensity and were associated with similar level of complications, including cardiovascular-related. Oxygen therapy increased with age; by contrast, mechanical ventilation, dialysis, blood transfusion, and intensive care unit admission were higher in the younger groups. In-hospital mortality for inpatients aged ≥ 85 years with CDI and LCI were 18.6% and 15.5%, respectively. Considering the burden associated with medically-attended influenza in this population, influenza prevention, laboratory confirmation and clinical management should be emphasized by general practicians and specialists like cardiologists to protect this aging population.

Looking Back on 50 Years of Literature to Understand the Potential Impact of Influenza on Extrapulmonary Medical Outcomes.

We conducted a scoping review of the epidemiological literature from the past 50 years to document the contribution of influenza virus infection to extrapulmonary clinical outcomes. We identified 99 publications reporting 243 associations using many study designs, exposure and outcome definitions, and methods. Laboratory confirmation of influenza was used in only 28 (12%) estimates, mostly in case-control and self-controlled case series study designs. We identified 50 individual clinical conditions associated with influenza. The most numerous estimates were of cardiocirculatory diseases, neurological/neuromuscular diseases, and fetal/newborn disorders, with myocardial infarction the most common individual outcome. Due to heterogeneity, we could not generate summary estimates of effect size, but of 130 relative effect estimates, 105 (81%) indicated an elevated risk of extrapulmonary outcome with influenza exposure. The literature is indicative of systemic complications of influenza virus infection, the requirement for more effective influenza control, and a need for robust confirmatory studies.

Seroepidemiological study of Japanese encephalitis virus in Chiang Mai: Immunity and susceptibility 28 years after introduction of a vaccination programme.

BACKGROUND: Thailand has introduced a nationwide vaccination against Japanese encephalitis virus (JEV) into National Immunization Programme since the 1990's. To improve the understanding of immunity and susceptibility of the population after 28 years of a vaccination programme, we conducted a JEV seroepidemiological study in a JEV-endemic area of Thailand. METHODS: An age-stratified, population-based, seroepidemiological study was conducted in Chiang Mai, Thailand-a northern Thai province where is an endemic area of Japanese encephalitis. Nine districts were chosen based on administrative definition: rural (n = 3); urban (n = 3); and peri-urban (n = 3). Within each district, eligible participants were randomly selected from 3 age groups: adolescents (10-20 years); adults (21-50 years); and older adults/elderly (≥51 years) by computer randomization. Plaque reduction neutralization tests (PRNT50 and PRNT90) were performed to measure neutralizing antibodies to JEV. To account for the cross-reactivity of JEV and other flaviviruses, JEV seroprotection was defined according to age, previous history of JEV vaccination, and PRNT50/PRNT90 levels of study participants. RESULTS: Overall, 279 adolescents, 297 adults, and 297 older adults/elderly were enrolled from nine districts. Age-stratified, protocol-defined, cluster-adjusted JEV seroprotection rates were 61% (95% CI: 48-73%), 43% (95% CI: 31-57%), and 52% (95% CI: 37-67%) for adolescents, adults, and older adults/elderly, respectively. Living in peri-urban districts, having a history of prior dengue virus infection, and previously receiving mouse brain-derived JEV vaccine were significantly associated with seroprotection to JEV in adolescents. Older age and male sex were associated with seroprotection for adults; and only male sex was the associated factor for older adults/elderly (P <0.05). CONCLUSIONS: Approximately half of population living in a JEV-endemic area demonstrated seroprotection to JEV. Ongoing nationwide surveillance on JEV seropepidemiology is an important strategy to understand the evolving population-level immunity to JEV, and to help formulating the appropriate recommendations on JE immunization.

Vaccine effectiveness of one, two, and three doses of BNT162b2 and CoronaVac against COVID-19 in Hong Kong: a population-based observational study.

BACKGROUND: Hong Kong maintained low circulation of SARS-CoV-2 until a major community epidemic of the omicron (B.1.1.529) sublineage BA.2 began in January, 2022. Both mRNA (BNT162b2 [Fosun Pharma-BioNTech]) and inactivated CoronaVac (Sinovac, Beijing, China) vaccines are widely available; however, vaccination coverage has been low, particularly in older adults aged 70 years or older. We aimed to assess vaccine effectiveness in this predominantly infection-naive population. METHODS: In this observational study, we used individual-level case data on mild or moderate, severe or fatal, and fatal disease in patients hospitalised with COVID-19 along with census information and coverage data of BNT162b2 and CoronaVac. We used a negative binomial model, adjusting for age, sex, and calendar day to estimate vaccine effectiveness of one, two, and three doses of both BNT162b2 and CoronaVac vaccines, and relative effectiveness by number of doses and vaccine type. FINDINGS: Between Dec 31, 2020, and March 16, 2022, 13·2 million vaccine doses were administered in Hong Kong's 7·4-million population. We analysed data from confirmed cases with mild or moderate (n=5566), severe or fatal (n=8875), and fatal (n=6866) COVID-19. Two doses of either vaccine protected against severe disease and death within 28 days of a positive test, with higher effectiveness among adults aged 60 years or older with BNT162b2 (vaccine effectiveness 89·3% [95% CI 86·6-91·6]) compared with CoronaVac (69·9% [64·4-74·6]). Three doses of either vaccine offered very high levels of protection against severe or fatal outcomes (97·9% [97·3-98·4]). INTERPRETATION: Third doses of either BNT162b2 or CoronaVac provide substantial additional protection against severe COVID-19 and should be prioritised, particularly in older adults older than 60 years and others in high-risk populations who received CoronaVac primary schedules. Longer follow-up is needed to assess duration of protection across different vaccine platforms and schedules. FUNDING: COVID-19 Vaccines Evaluation Program, Chinese Center for Disease Control and Prevention.

Methods to account for measured and unmeasured confounders in influenza relative vaccine effectiveness studies: A brief review of the literature.

Observational seasonal influenza relative vaccine effectiveness (rVE) studies employ a variety of statistical methods to account for confounding and biases. To better understand the range of methods employed and implications for policy, we conducted a brief literature review. Across 37 included rVE studies, 10 different types of statistical methods were identified, and only eight studies reported methods to detect residual confounding, highlighting the heterogeneous state of the literature. To improve the comparability and credibility of future rVE research, researchers should clearly explain methods and design choices and implement methods to detect and quantify residual confounding.

The impact of clinical risk conditions on influenza and pneumonia diagnoses in England: a nationally representative retrospective cohort study, 2010-2019.

The impact of influenza and pneumonia on individuals in clinical risk groups in England has not previously been well characterized. Using nationally representative linked databases (Clinical Practice Research Database (CPRD), Hospital Episode Statistics (HES) and Office for National Statistics (ONS)), we conducted a retrospective cohort study among adults (≥ 18 years) during the 2010/2011-2019/2020 influenza seasons to estimate the incidence of influenza- and pneumonia-diagnosed medical events (general practitioner (GP) diagnoses, hospitalisations and deaths), stratified by age and risk conditions. The study population included a seasonal average of 7.2 million individuals; approximately 32% had ≥1 risk condition, 42% of whom received seasonal influenza vaccines. Medical event incidence rates increased with age, with ~1% of adults aged ≥75 years hospitalized for influenza/pneumonia annually. Among individuals with vs. without risk conditions, GP diagnoses occurred 2-5-fold more frequently and hospitalisations were 7-10-fold more common. Among those with obesity, respiratory, kidney or cardiovascular disorders, hospitalisation were 5-40-fold more common than in individuals with no risk conditions. Though these findings likely underestimate the full burden of influenza, they emphasize the concentration of disease burden in specific age and risk groups and support existing recommendations for influenza vaccination.

Feasibility of randomizing Danish citizens aged 65-79 years to high-dose quadrivalent influenza vaccine vs. standard-dose quadrivalent influenza vaccine in a pragmatic registry-based setting: rationale and design of the DANFLU-1 Trial.

BACKGROUND: High-dose influenza vaccines provide better protection against influenza infection than standard-dose in persons aged 65 years and above; however, in most countries, high-dose vaccines are not widely implemented. Assessing the relative effectiveness of high-dose compared to standard-dose vaccines on hospitalizations and mortality would enable more robust public health and cost-effectiveness estimates. This study aims to investigate the feasibility of conducting a pragmatic randomized clinical trial in Denmark comparing high-dose to standard-dose vaccines utilizing existing vaccination infrastructure and the Danish nationwide health registries for data collection. METHODS: The DANFLU-1 trial (NCT05048589) is a pragmatic, open-label, active-controlled randomized trial randomizing Danish citizens aged 65-79 years to either high-dose quadrivalent influenza vaccine or standard-dose quadrivalent influenza vaccine. The study utilizes the infrastructure of a private vaccination provider (Danske Lægers Vaccinations Service) for recruitment, inclusion, randomization, and vaccination. All collection of baseline and follow-up data including safety monitoring is performed centrally by the Department of Cardiology at Herlev and Gentofte Hospital, Copenhagen, Denmark using the Danish nationwide health registries. The study aims to include 40,000 participants during the 2021/2022 influenza season. The primary endpoints address feasibility and include the number of participants enrolled, randomization balance, and representativeness compared to the Danish general population. Relative vaccine effectiveness will also be assessed, however, this feasibility study is not powered for clinical outcomes and may be affected by the COVID-19 pandemic. DISCUSSION: The DANFLU-1 study is investigating the feasibility of conducting a large-scale pragmatic clinical trial in Denmark utilizing existing infrastructure and the Danish nationwide registries. This will provide valuable insight, especially for potential future fully powered vaccine trials, but also for trials wishing to investigate other interventions. TRIAL REGISTRATION: Clinicaltrials.gov : NCT05048589 , registered September 17, 2021.