Seasonal Vaccine Effectiveness Research Articles

Patient subtyping analysis of baseline multi-omic data reveals distinct pre-immune states associated with antibody response to seasonal influenza vaccination

Understanding the molecular mechanisms underpinning diverse vaccination responses is critical for developing efficient vaccines. Molecular subtyping can offer insights into heterogeneous nature of responses and aid in vaccine design. We analyzed multi-omic data from 62 haemagglutinin seasonal influenza vaccine recipients (2019–2020), including transcriptomics, proteomics, glycomics, and metabolomics data collected pre-vaccination. We performed a subtyping analysis on the integrated data revealing five subtypes with distinct molecular signatures. These subtypes differed in the expression of pre-existing adaptive or innate immunity signatures, which were linked to significant variation in baseline immunoglobulin A (IgA) and hemagglutination inhibition (HAI) titer levels. It is worth noting that these differences persisted through day 28 post-vaccination, indicating the effect of initial immune state on vaccination response. These findings highlight the significance of interpersonal variation in baseline immune status as a crucial factor in determining the effectiveness of seasonal vaccines. Ultimately, incorporating molecular profiling could enable personalized vaccine optimization.

Epidemiological effectiveness of domestic influenza vaccines in cases with vaccination against a new coronavirus infection in 2022–2023

The study presents the results of an epidemiological prospective field cohort study on a comparative assessment of the epidemiological effectiveness of domestic inactivated influenza vaccines and vaccines against new coronavirus infection during immunization of adults aged 18 years. Statistically significant differences were found in the incidence of influenza, acute upper respiratory infections, and new coronavirus infection between the vaccinated and unvaccinated groups. The etiologies of cases of acute upper respiratory infections registered in the study participants during the epidemic season of influenza in 2022–2023 were verified. The clinical symptoms of influenza in the vaccinated group were significantly less severe than those in the unvaccinated group. No significant differences were found in the clinical picture of acute upper respiratory infections between the compared groups. Influenza immunoprophylaxis is an urgent problem, which consists of the ability of viruses to change their antigenic structure and avoid immunity, remaining in constant circulation. Thus, the antigenic composition of influenza vaccines must be systematically updated to ensure the formation of effective population immunity. More studies on the etiological spectrum of respiratory pathogens and assessment of the epidemiological effectiveness of vaccination against vaccine-controlled infections in the analyzed groups are needed. Therefore, to assess immunological protection, including the assessment of the epidemiological effectiveness of seasonal vaccines used against influenza and new coronavirus infection, the priority age group includes individuals aged 18–25 years (especially those belonging to organized collectives) and adults with an unfavorable premorbid background. The use of domestic vaccines against influenza and the new coronavirus infection for specific immunoprophylaxis is generally recognized as the most effective sanitary and anti-epidemic (preventive) measure in the morbidity management of several infectious diseases.

The race toward a universal influenza vaccine: Front runners and the future directions

Influenza virus is the pathogen of influenza (flu) and millions of people suffer from the infection worldwide, posing a significant health risk. The current influenza vaccines induce neutralizing antibodies against hemagglutinin (HA) to achieve strain-specific neutralization. The effectiveness of seasonal vaccines is usually low and unpredictable because of the antigenic variation and genetic plasticity of viruses, as well as the interference of preexisting immunity. A universal influenza vaccine is urgently needed to prevent a wide variety of influenza viruses. Nevertheless, reaching this difficult optimal goal requires a step-by-step approach. Innovative strategies and vaccine platforms are being developed in order to generate robust cross-protective immunity. In this review, we summarize candidate influenza vaccines that meet two criteria: first, they are designed to provide protection against multiple influenza viruses; second, they had passed regulatory evaluations and have entered various stages of clinical trials. We discuss these vaccine candidates based on the different vaccine-production platforms, with the focus on antigen selection, design, adjuvants, immunomodulators, and routes of vaccine delivery in the development of universal influenza vaccines.

Estimands and Estimation of COVID-19 Vaccine Effectiveness Under the Test-Negative Design: Connections to Causal Inference.

The test-negative design is routinely used for the monitoring of seasonal flu vaccine effectiveness. More recently, it has become integral to the estimation of COVID-19 vaccine effectiveness, in particular for more severe disease outcomes. Because the design has many important advantages and is becoming a mainstay for monitoring postlicensure vaccine effectiveness, epidemiologists and biostatisticians may be interested in further understanding the effect measures being estimated in these studies and connections to causal effects. Logistic regression is typically applied to estimate the conditional risk ratio but relies on correct outcome model specification and may be biased in the presence of effect modification by a confounder. We give and justify an inverse probability of treatment weighting (IPTW) estimator for the marginal risk ratio, which is valid under effect modification. We use causal directed acyclic graphs, and counterfactual arguments under assumptions about no interference and partial interference to illustrate the connection between these statistical estimands and causal quantities. We conduct a simulation study to illustrate and confirm our derivations and to evaluate the performance of the estimators. We find that if the effectiveness of the vaccine varies across patient subgroups, the logistic regression can lead to misleading estimates, but the IPTW estimator can produce unbiased estimates. We also find that in the presence of partial interference both estimators can produce misleading estimates.

The Clinical Effect of Seasonal Flu Vaccination on Health-Related Quality of Life.

PurposeThis study aimed to determine the clinical effect of seasonal flu vaccination in adult outpatients based on the effect on health-related quality of life (HRQOL).Patients and MethodsWe reviewed the clinical data of adult flu outpatients with mild symptoms who presented to the outpatient clinic of Teikyo University Hospital, Tokyo, Japan, from 2018 to 2020 winter season and were enrolled in the prospective observational study of the clinical efficacy of anti-flu agents (UMIN000034896). We evaluated influenza vaccination status, clinical symptoms, and the status of HRQOL as measured by Short Form-8® (SF-8®) at first visit. The SF-8® survey generated two-component summaries; a physical component summary and a mental component summary.ResultsThe data of 79 patients were evaluated in this study. Of the 79 patients, 37 were vaccinated for influenza at least three weeks before contracting seasonal influenza. Not every patient needed to be hospitalized for treatment. There were no significant differences in clinical backgrounds between vaccinated patients and non-vaccinated patients. Univariate analysis showed influenza vaccination was significantly associated with higher scores on the physical component summary of HRQOL (p=0.0011).ConclusionInfluenza vaccinations would be clinically valuable for adult outpatients with seasonal flu and mild symptoms, because they can significantly inhibit the decrease of HRQOL due to influenza infection.

Decline in Seasonal Influenza Vaccine Effectiveness With Vaccination Program Maturation: A Systematic Review and Meta-analysis.

BackgroundEvidence suggests that repeated influenza vaccination may reduce vaccine effectiveness (VE). Using influenza vaccination program maturation (PM; number of years since program inception) as a proxy for population-level repeated vaccination, we assessed the impact on pooled adjusted end-season VE estimates from outpatient test-negative design studies.MethodsWe systematically searched and selected full-text publications from January 2011 to February 2020 (PROSPERO: CRD42017064595). We obtained influenza vaccination program inception year for each country and calculated PM as the difference between the year of deployment and year of program inception. We categorized PM into halves (cut at the median), tertiles, and quartiles and calculated pooled VE using an inverse-variance random-effects model. The primary outcome was pooled VE against all influenza.ResultsWe included 72 articles from 11 931 citations. Across the 3 categorizations of PM, a lower pooled VE against all influenza for all patients was observed with PM. Substantially higher reductions were observed in older adults (≥65 years). We observed similar results for A(H1N1)pdm09, A(H3N2), and influenza B.ConclusionsThe evidence suggests that influenza VE declines with vaccination PM. This study forms the basis for further discussions and examinations of the potential impact of vaccination PM on seasonal VE.

Vaccine effectiveness of live attenuated and trivalent inactivated influenza vaccination in 2010/11 to 2015/16: the SIVE II record linkage study.

There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged ≥ 65 years and for those aged < 65 years who are at an increased risk of complications from influenza infection (e.g. people with asthma). To examine the vaccine effectiveness of LAIV and TIV. Cohort study and test-negative designs to estimate vaccine effectiveness. A self-case series study to ascertain adverse events associated with vaccination. A national linkage of patient-level general practice (GP) data from 230 Scottish GPs to the Scottish Immunisation & Recall Service, Health Protection Scotland virology database, admissions to Scottish hospitals and the Scottish death register. A total of 1,250,000 people. LAIV for 2- to 11-year-olds and TIV for older people (aged ≥ 65 years) and those aged < 65 years who are at risk of diseases, from 2010/11 to 2015/16. The main outcome measures include vaccine effectiveness against laboratory-confirmed influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR), influenza-related morbidity and mortality, and adverse events associated with vaccination. Two-fifths (40%) of preschool-aged children and three-fifths (60%) of primary school-aged children registered in study practices were vaccinated. Uptake varied among groups [e.g. most affluent vs. most deprived in 2- to 4-year-olds, odds ratio 1.76, 95% confidence interval (CI) 1.70 to 1.82]. LAIV-adjusted vaccine effectiveness among children (aged 2-11 years) for preventing RT-PCR laboratory-confirmed influenza was 21% (95% CI -19% to 47%) in 2014/15 and 58% (95% CI 39% to 71%) in 2015/16. No significant adverse events were associated with LAIV. Among at-risk 18- to 64-year-olds, significant trivalent influenza vaccine effectiveness was found for four of the six seasons, with the highest vaccine effectiveness in 2010/11 (53%, 95% CI 21% to 72%). The seasons with non-significant vaccine effectiveness had low levels of circulating influenza virus (2011/12, 5%; 2013/14, 9%). Among those people aged ≥ 65 years, TIV effectiveness was positive in all six seasons, but in only one of the six seasons (2013/14) was significance achieved (57%, 95% CI 20% to 76%). The study found that LAIV was safe and effective in decreasing RT-PCR-confirmed influenza in children. TIV was safe and significantly effective in most seasons for 18- to 64-year-olds, with positive vaccine effectiveness in most seasons for those people aged ≥ 65 years (although this was significant in only one season). The UK Joint Committee on Vaccination and Immunisation has recommended the use of adjuvanted injectable vaccine for those people aged ≥ 65 years from season 2018/19 onwards. A future study will be required to evaluate this vaccine. Current Controlled Trials ISRCTN88072400. This project was funded by the National Institute for Health Research (NIHR) Health Technology Assessment programme and will be published in full in Health Technology Assessment; Vol. 24, No. 67. See the NIHR Journals Library website for further project information.

Effects of Prior Season Vaccination on Current Season Vaccine Effectiveness in the United States Flu Vaccine Effectiveness Network, 2012-2013 Through 2017-2018.

We compared effects of prior vaccination and added or lost protection from current season vaccination among those previously vaccinated. Our analysis included data from the US Flu Vaccine Effectiveness Network among participants ≥9 years old with acute respiratory illness from 2012-2013 through 2017-2018. Vaccine protection was estimated using multivariate logistic regression with an interaction term for effect of prior season vaccination on current season vaccine effectiveness. Models were adjusted for age, calendar time, high-risk status, site, and season for combined estimates. We estimated protection by combinations of current and prior vaccination compared to unvaccinated in both seasons or current vaccination among prior vaccinated. A total of 31 819 participants were included. Vaccine protection against any influenza averaged 42% (95% confidence interval [CI], 38%-47%) among those vaccinated only the current season, 37% (95% CI, 33-40) among those vaccinated both seasons, and 26% (95% CI, 18%-32%) among those vaccinated only the prior season, compared with participants vaccinated neither season. Current season vaccination reduced the odds of any influenza among patients unvaccinated the prior season by 42% (95% CI, 37%-46%), including 57%, 27%, and 55% against A(H1N1), A(H3N2), and influenza B, respectively. Among participants vaccinated the prior season, current season vaccination further reduced the odds of any influenza by 15% (95% CI, 7%-23%), including 29% against A(H1N1) and 26% against B viruses, but not against A(H3N2). Our findings support Advisory Committee on Immunization Practices recommendations for annual influenza vaccination. Benefits of current season vaccination varied among participants with and without prior season vaccination, by virus type/subtype and season.

Effectiveness of influenza vaccine in reducing influenza-associated hospitalizations and deaths among the elderly population; Lazio region, Italy, season 2016-2017

ABSTRACT Background This study aimed to estimate influenza vaccine effectiveness (VE) in preventing influenza-related deaths and hospitalizations in the elderly population. Methods We retrospectively analyzed the cohort of 1,251,218 elderly aged ≥65 years who were residing in the Lazio region in 2016–2017. We estimated influenza VE using the Cox proportional hazards model, adjusting for demographic characteristics, preexisting health-risk conditions, and prior vaccinations. Results Estimated VE was 14% (95% confidence interval (CI): 11 to 17); 26% (95%CI: 19 to 33) in preventing influenza-related deaths and 13% (95%CI: 10 to 16) in preventing influenza-related hospitalizations. Seasonal VE was higher in the elderly vaccinated in prior seasons (VE = 20%, 95%CI: 17 to 23). We found no significant differences in effectiveness by vaccine type, although the MF59-adjuvanted vaccine appeared more effective than other vaccines in individuals aged ≥75 years, particularly in those aged ≥90 years (VE = 18%, 95%CI: 9 to 26). Conclusions Although VE was low, vaccination still provided benefits in preventing influenza-related hospitalizations and deaths in the elderly, particularly among those vaccinated in prior seasons. Efforts should therefore be made to improve vaccine uptake and the utilization of vaccines with greater effectiveness in the oldest elderly (e.g. high-dose and adjuvanted cell-based vaccines).

Predominance of a Drifted Influenza A (H3N2) Clade and its Association with Age-specific Influenza Vaccine Effectiveness Variations, Influenza Season 2018-2019.

Background: Influenza A (H3N2) clade 3C.3a was the predominant influenza virus in Israel throughout the 2018-2019 season, constituting a drift from the influenza A (H3N2) vaccine. We estimated the end-of season vaccine effectiveness (VE) by age, among community patients with influenza-like illness (ILI), considering the hemagglutinin (HA) gene mutations and amino acid substitutions of influenza A (H3N2) viruses detected. Methods: Nose-throat samples were analyzed for the presence of influenza virus, type/subtype, and HA gene sequence. HA gene sequences and amino acid substitutions were compared to the influenza A/Singapore/INFIMH-16-0019/2016 (H3N2)-like 2018-2019 vaccine virus, and a phylogenetic tree was generated. Influenza VE against influenza A (H3N2) was estimated using the test-negative design. VE was estimated by age group and by 15 year moving age intervals. Results: In total, 90% of the influenza A (H3N2) viruses belonged to the 3C.3a clade, constituting a unique situation in the northern hemisphere. Adjusted all-age influenza A (H3N2) VE was −3.5% (95% CI: −51.2 to 29.1). Although adjusted VEs were very low among infants, children, and young adults, a VE of 45% (95% CI: −19.2 to 74.6) was estimated among adults aged ≥45 years old. Conclusions: The higher VE point estimates among older adults may be related to previous exposure to similar influenza viruses.

Patient and practice level factors associated with seasonal influenza vaccine uptake among at-risk adults in England, 2011 to 2016: An age-stratified retrospective cohort study

We sought to gain insights into the determinants of seasonal influenza vaccine (SIV) uptake by conducting an age-stratified analysis (18–64 and 65+) of factors associated with SIV uptake among at-risk adults registered to English practices. Records for at-risk English adults between 2011 and 2016 were identified using the Clinical Practice Research Datalink database. SIV uptake was assessed annually. The associations of patient, practice, and seasonal characteristics with SIV uptake were assessed via cross-sectional and longitudinal analyses, using mixed-effects and general estimating equation logistic regression models. Overall SIV uptake was 35.3% and 74.0% for adults 18–64 and 65+, respectively. Relative to white patients, black patients were least likely to be vaccinated (OR18-64: 0.82 (95% CI: 0.80, 0.85); OR65+: 0.59 (95% CI: 0.56, 0.62)), while Asian patients among 18–64 year olds were most likely to be vaccinated (OR18-64: 1.10 (95% CI: 1.07, 1.13)). Females were more likely than males to be vaccinated among 18–64 year olds (OR18-64: 1.19 (95% CI: 1.18, 1.20)). Greater socioeconomic deprivation was associated with decreased odds of uptake among older patients (OR65+: 0.74 (95% CI: 0.71, 0.77)). For each additional at-risk condition, odds of uptake increased (OR18-64: 2.33 (95% CI: 2.31, 2.36); OR65+: 1.39 (95% CI: 1.38, 1.39)). Odds of uptake were highest among younger patients with diabetes (OR18-64: 4.25 (95% CI: 4.18, 4.32)) and older patients with chronic respiratory disease (OR65+: 1.60 (95% CI: 1.58, 1.63)), whereas they were lowest among morbidly obese patients of all ages (OR18-64: 0.68 (95% CI: 0.67, 0.70); OR65+: 0.97 (95% CI: 0.94, 0.99)). Prior influenza season severity and vaccine effectiveness were marginally predictive of uptake. Our age-stratified analysis uncovered SIV uptake disparities by ethnicity, sex, age, socioeconomic deprivation, and co-morbidities, warranting further attention by GPs and policymakers alike.

The impact of repeated vaccination using 10-year vaccination history on protection against influenza in older adults: a test-negative design study across the 2010/11 to 2015/16 influenza seasons in Ontario, Canada.

IntroductionAnnual influenza vaccination is recommended for older adults, but evidence regarding the impact of repeated vaccination has been inconclusive.AimWe investigated vaccine effectiveness (VE) against laboratory-confirmed influenza and the impact of repeated vaccination over 10 previous seasons on current season VE among older adults.MethodsWe conducted an observational test-negative study in community-dwelling adults aged > 65 years in Ontario, Canada for the 2010/11 to 2015/16 seasons by linking laboratory and health administrative data. We estimated VE using multivariable logistic regression. We assessed the impact of repeated vaccination by stratifying by previous vaccination history.ResultsWe included 58,304 testing episodes for respiratory viruses, with 11,496 (20%) testing positive for influenza and 31,004 (53%) vaccinated. Adjusted VE against laboratory-confirmed influenza for the six seasons combined was 21% (95% confidence interval (CI): 18 to 24%). Patients who were vaccinated in the current season, but had received no vaccinations in the previous 10 seasons, had higher current season VE (34%; 95%CI: 9 to 52%) than patients who had received 1–3 (26%; 95%CI: 13 to 37%), 4–6 (24%; 95%CI: 15 to 33%), 7–8 (13%; 95%CI: 2 to 22%), or 9–10 (7%; 95%CI: −4 to 16%) vaccinations (trend test p = 0.001). All estimates were higher after correcting for misclassification of current season vaccination status. For patients who were not vaccinated in the current season, residual protection rose significantly with increasing numbers of vaccinations received previously.ConclusionsAlthough VE appeared to decrease with increasing numbers of previous vaccinations, current season vaccination likely provides some protection against influenza regardless of the number of vaccinations received over the previous 10 influenza seasons.

Association of Seasonal Severity and Vaccine Effectiveness With Influenza Vaccination Rates in Children

This study examines the associations of seasonal influenza severity as well as current and prior year’s vaccine effectiveness with yearly influenza vaccination rates stratified by age groups.

900. Effect of Influenza Vaccine Priming on Current Season Vaccine Effectiveness among Children and Adolescents, US Flu VE Network 2014–2015 Through 2017–2018

BackgroundStudies have demonstrated that optimal protection against childhood influenza requires two “priming” doses of influenza vaccine in the first season of vaccination. Two doses of influenza vaccine are recommended for US children aged 6 months-8 years who received ≤1 dose in prior seasons. We examined risk of influenza among children fully or partially vaccinated during study seasons and vaccine effectiveness (VE) by the number of priming doses.MethodsAnalyses included children aged 6 months-17 years enrolled during outpatient visits for acute illness for ≤7 days with cough in the US Influenza Vaccine Effectiveness Network during 2014–2015 through 2017–2018. Participants’ respiratory specimens were tested for influenza by rRT-PCR. Vaccination histories back to birth year were obtained from electronic immunization records. VE was calculated by comparing vaccination odds among influenza-positive cases to test-negative controls, as 100 × (1 − odds ratio) adjusted for season, site, age, high-risk status, and calendar time.ResultsOf 7,583 children, 6,362 (84%) had received ≥1 dose in their lifetime. Among vaccinated children, 90% were primed prior to the enrollment season, and 80% were primed prior to age 2 years. Most (55%) received two priming doses in their first season. Among children recommended to receive two priming doses in the enrollment season, receipt of two doses vs. one was associated with a lower risk of influenza illness (aOR: 0.60; 95% CL: 0.36, 1.00). VE of ≥1 dose in the enrollment season against any influenza among unprimed children was 53% (95% CL: 36, 66). VE of ≥1 dose in the enrollment season was similar among children primed with one dose in their first season (46%; 95% CL: 34, 55) and among those primed with two doses (46%; 95% CL: 35, 55). Overall results were similar when stratified by age and for A/H3N2 viruses, which predominated during study years.ConclusionAmong the US children recommended to receive two priming doses of vaccine in the enrollment season, receipt of two doses provided optimal protection. VE in seasons after the priming did not differ by the number of priming doses. Results were driven by predominance of A/H3N2 viruses and may not be similar for A/H1N1pdm09 or B viruses. Current US influenza vaccine recommendations for children are effective and appropriate.Disclosures All Authors: No reported Disclosures.

2760. Accounting for Vaccination History in Estimates of Current Season Vaccine Effectiveness in the US Flu VE Network, 2012–2013 Through 2017–2018

BackgroundCurrent season vaccine effectiveness (VE) and influenza risk may vary in persons based on vaccination history. United States Influenza Vaccine Effectiveness (US Flu VE) Network studies have explored prior vaccination effects using a single referent group of patients unvaccinated in both the prior and current seasons. We investigated vaccine benefit among those with and without prior season vaccination.MethodsOur analysis included data from the US Flu VE Network among patients aged ≥9 years old with acute respiratory illness during 6 influenza seasons, 2012–2013 through 2017–2018. We determined current and prior season vaccination status from documented immunizations. Current season VE against laboratory confirmed influenza was estimated using multivariate logistic regression with an interaction term for prior and current season vaccination. Models were adjusted for age, calendar time, high-risk status, and site.ResultsOf 31,819 patients included in the analysis over 6 seasons, 9188 were influenza positive by RT–PCR. Percent flu positivity was greatest among those unvaccinated (34%), followed by those vaccinated in the prior season only (29%), those vaccinated in both seasons (25%), and those vaccinated in the current season only (23%). Among patients with prior season vaccination, current season VE against any influenza was 14% (95% CL: 5, 22) and against A(H3N2), A(H1N1)pdm09, and B was 10% (95% CL: 3, 17), 36% (95%CL: 25, 46), and 40% (95% CL: 33, 46), respectively. Among patients unvaccinated in the prior season, VE was 42% (95% CL: 37, 46) against any influenza in the current season and was 31% (95%CL: 22, 39), 57% (95% CL: 47, 65), and 55% (95% CL: 48, 61) against A(H3N2), A(H1N1)pdm09, and B, respectively. We observed significant interaction of prior season vaccination on current season VE in 4 of 6 seasons (P < 0.20).ConclusionCurrent season vaccination was overall protective regardless of vaccination history. Among those vaccinated in the prior season, current season vaccination may provide some benefit in addition to residual protection from previous vaccination.Disclosures All authors: No reported disclosures.

Exploring the potential public health benefits of universal influenza vaccine

ABSTRACT Background: Broadly protective, long-lasting universal influenza vaccines are under development in response to low-moderate seasonal vaccine effectiveness, frequent genetic changes in circulating viruses and extended turnaround for vaccine manufacture. Because a long-lasting vaccine might be less effective than a seasonal vaccine that has been matched to current circulating strains, the public health impact of its introduction should be evaluated. Methods: A modified agent-based model (ABM) examined multi-year effects of a universal vaccine among 18 to 49-year-olds, given in Year 1 only. The proportion of vaccinated 18 to 49-year-olds who received universal vaccine was varied from 0% to 100%. Model parameters were drawn from US databases and the medical literature. Outcomes were 4-year cumulative and annual influenza cases as well as annual cases averted/100,000 population for 3 age groups, 0–17 years, 18–49 years and 50+ years. Results: In Year 1 when universal vaccine was given to 50% or 100% of all vaccinated 18 to 49-year-olds, more influenza cases occurred, compared to no universal vaccine, but fewer cases occurred in Years 2–4 as overall protection increased. Cumulative averted cases over 4 years in 18 to 49-year-olds were 892/100,000 and 1,687/100,000 population for the 50% and 100% universal vaccine for 18 to 49-year-olds scenarios, respectively, with additional benefits to children and older adults through indirect effects. Conclusions: In ABM, the universal vaccine with a conservative VE estimate given once to 18 to 49-year-olds reduced influenza cases among all age groups in Years 2–4 following its introduction. Reduced influenza burden may occur sooner if VE of universal vaccines exceeds that assumed in these models.

Forecasting hospital pneumonia admissions using influenza surveillance, climate and community data

ObjectiveUsing the information that we have available, our primary objective is to explore if there was any cross-correlation between pneumonia admissions and hospital influenza positivity. We then aim to develop a data driven approach to forecast pneumonia admissions using data from our hospital’s weekly surveillance. We also attempted using external sources of information such as national infectious diseases notifications and climate data to see if they were useful for our model.IntroductionInfluenza peaks around June and December in Singapore every year. Facing an ageing population, hospitals in Singapore have been constantly reaching maximum bed occupancy. The ability to be able to make early decisions during peak periods is important. Tan Tock Seng Hospital is the second largest adult acute care general hospital in Singapore. Pneumonia-related emergency department (ED) admissions are a huge burden to the hospital's resources. The number of cases vary year on year as it depends on seasonal vaccine effectiveness and the population’s immunity to the circulating strain. While many pneumonia cases are of unknown origin, they tend to mirror the influenza seasons very closely.MethodsWe used data from epidemiological week (e-week) 1 of 2013 to e-week 34 of August 2017 to train our model, with the next 52 weeks (e-week of 35 of 2017 to e-week 34 of 2018 ) being used as validation cohort. Pneumonia and influenza data were obtained from our hospital’s weekly surveillance. National level acute upper respiratory illness (AURI) was obtained from Ministry of Health’s (MOH) weekly infectious diseases bulletin. Climate data were obtained from the National Environment Agency’s website. Daily rainfall, temperature and wind data from the S20 satellite station were used. Automatic autoregressive (A-ARIMA), non-seasonal and seasonal vector autoregressive models (VAR) were used to either analyse the univariate pneumonia trends or simultaneously model pneumonia, influenza, AURI notification and climatic data. Granger-causality tests were performed to check if these variables were causal of pneumonia admissions. As most of the seasonal variation are seen in older patients, stratified analysis were performed on those that were below and above 65 years old. Forecasts were calculated up to 3 weeks in advance. Mean absolute error (MAE), mean absolute percentage error (MAPE), and root mean squared error (RMSE) were used to validate the model performance. These performance metrics were applied on 3-week ahead forecasts comparing A-ARIMA, VAR, and seasonal-adjusted VAR.ResultsFigure 1 shows that both influenza and pneumonia admissions follow similar trends. We see that the number of influenza cases have reduced as compared to the previous years. The number hospital influenza cases and the number of AURI cases nationwide are strongly cross-correlated with pneumonia admissions. Granger-causality tests confirmed the directionality of the relationships (p &lt;0.01). Climate factors do not strongly affect the number of pneumonia admissions. (Fig 2) Unsurprisingly, the A-ARIMA model showed that the 1-day forecasts were most accurate (MAE: 7.0; MAPE: 12.7; RMSE: 8.7 for elderly subgroup). However, the 3-day ahead forecasts were only slightly less precise (MAE: 7.2 ; MAPE: 13.2; RMSE: 9 for elderly subgroup). Testing for significant lags using the various information criteria suggested that a lag3 model should be used. The non-seasonal and seasonal VAR models showed that historical pneumonia admissions and influenza positivity was the best model. The MAPE for all 3 models hovered between 12-13%, with the A-ARIMA model performing slightly better. This is not surprising as the A-ARIMA takes the latest information at hand to derive the best model. Accounting for seasonality allowed better precision as compared to the non-seasonal VAR but was not better as compared to the A-ARIMA model.ConclusionsHospital surveillance data are the most useful for developing forecast models for hospital pneumonia admissions. Climate data were likely not to be useful as Singapore does not experience much variaton in weather throughout the year. Pneumonia peaks do not follow necessarily fall on the same week every season. Therefore, both the autoregressive and seasonal-adjusted vector autoregressive models can be useful complements to each other for forecasting pneumonia admissions.

Impact of repeated influenza vaccinations in persons over 65 years of age: A large population-based cohort study of severe influenza over six consecutive seasons, 2011/12–2016/17

BackgroundA forty-year debate on the potential negative effects of repeated seasonal influenza vaccination has been inconclusive, with multiple observational studies of various design providing heterogeneous results too inadequate to inform vaccination policy. MethodsA large population-based cohort study including over one-million observations in individuals over age 65 from six consecutive seasons (2011/12–2016/17) in Stockholm County, Sweden. Current season vaccine effectiveness (VE) against severe, mostly hospital-attended, influenza was assessed using Cox multivariate regression analyses adjusting for demographic variables, comorbidities and previous seasonal influenza vaccination status. ResultsIn none of the six seasons was VE significantly different in persons vaccinated in the current season only, compared to those who had been vaccinated in both the current and the previous season. Neither were there any differences in VE during the seasons 2014/15–2016/17 when comparing persons vaccinated during the current season only vs. those vaccinated during one-three or four-five previous influenza seasons. In contrast, persons only vaccinated during one or more previous years had no protection during the current season. ConclusionsPersons above 65 years are the largest group at risk for severe or complicated influenza and policy should support their yearly seasonal influenza vaccination, which is to-date the best preventive measure available for all risk groups. No negative effects of repeated seasonal vaccination were seen in this large population-based cohort of older persons with severe influenza, which strengthens the recommendation that persons belonging to this age group should be vaccinated yearly.

A Simple and Robust Approach for Evaluation of Antivirals Using a Recombinant Influenza Virus Expressing Gaussia Luciferase.

Influenza A virus (IAV) causes seasonal epidemics and occasional but devastating pandemics, which are major public health concerns. Because the effectiveness of seasonal vaccines is highly variable and the currently available drugs are limited in their efficacy because of the emergence of drug resistance, there is an urgent need to develop novel antivirals. In this study, we characterized a recombinant IAV-carrying Gaussia luciferase (Gluc) gene and determined its potential as a tool for evaluating therapeutics. We demonstrated that this recombinant IAV is replication-competent in tissue culture and pathogenic in mice, although it is slightly attenuated compared to the parental virus. Luciferase expression correlated well with virus propagation both in vitro and in vivo, providing a simple measure for viral replication in tissue culture and in mouse lungs. To demonstrate the utility of this virus, ribavirin and oseltamivir phosphate were used to treat the IAV-infected cells and mice, and we observed the dose-dependent inhibition of viral replication by a luciferase assay. Moreover, the decreased luciferase expression in the infected lungs could predict the protective efficacy of antiviral interventions as early as day 2 post virus challenge. In summary, this study provides a new and quantitative approach to evaluate antivirals against IAV.

Exploring the effect of previous inactivated influenza vaccination on seasonal influenza vaccine effectiveness against medically attended influenza: Results of the European I-MOVE multicentre test-negative case-control study, 2011/2012-2016/2017.

BackgroundResults of previous influenza vaccination effects on current season influenza vaccine effectiveness (VE) are inconsistent.ObjectivesTo explore previous influenza vaccination effects on current season VE among population targeted for vaccination.MethodsWe used 2011/2012 to 2016/2017 I‐MOVE primary care multicentre test‐negative data. For each season, we compared current season adjusted VE (aVE) between individuals vaccinated and unvaccinated in previous season. Using unvaccinated in both seasons as a reference, we then compared aVE between vaccinated in both seasons, current only, and previous only.ResultsWe included 941, 2645 and 959 influenza‐like illness patients positive for influenza A(H1N1)pdm09, A(H3N2) and B, respectively, and 5532 controls. In 2011/2012, 2014/2015 and 2016/2017, A(H3N2) aVE point estimates among those vaccinated in previous season were −68%, −21% and −19%, respectively; among unvaccinated in previous season, these were 33%, 48% and 46%, respectively (aVE not computable for influenza A(H1N1)pdm09 and B). Compared to current season vaccination only, VE for both seasons' vaccination was (i) similar in two of four seasons for A(H3N2) (absolute difference [ad] 6% and 8%); (ii) lower in three of four seasons for influenza A(H1N1)pdm09 (ad 18%, 26% and 29%), in two seasons for influenza A(H3N2) (ad 27% and 39%) and in two of three seasons for influenza B (ad 26% and 37%); (iii) higher in one season for influenza A(H1N1)pdm09 (ad 20%) and influenza B (ad 24%).ConclusionsWe did not identify any pattern of previous influenza vaccination effect. Prospective cohort studies documenting influenza infections, vaccinations and vaccine types are needed to understand previous influenza vaccinations' effects.