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Background Recent studies have demonstrated the possibility of negative associations between prior influenza vaccines and subsequent influenza vaccine effectiveness (VE), depending on season and strain. We investigated this association over 4 consecutive influenza seasons (2011–2012 through 2014–2015) in Canada. Methods Using a matched test-negative design, laboratory-confirmed influenza cases and matched test-negative controls admitted to hospitals were enrolled. Patients were stratified into 4 groups according to influenza vaccine history (not vaccinated current and prior season [referent], vaccinated prior season only, vaccinated current season only, and vaccinated both current and prior season). Conditional logistic regression was used to estimate VE; prior vaccine impact was assessed each season for overall effect and effect stratified by age (<65 years, ≥65 years) and type/subtype (A/H1N1, A/H3N2, influenza B). Results Overall, mainly nonsignificant associations were observed. Trends of nonsignificant decreased VE among patients repeatedly vaccinated in both prior and current season relative to the current season only were observed in the A/H3N2-dominant seasons of 2012–2013 and 2014–2015. Conversely, in 2011–2012, during which B viruses circulated, and in 2013–2014, when A/H1N1 circulated, being vaccinated in both seasons tended to result in a high VE in the current season against the dominant circulating subtype. Conclusions Prior vaccine impact on subsequent VE among Canadian inpatients was mainly nonsignificant. Even in circumstances where we observed a trend of negative impact, being repeatedly vaccinated was still more effective than not receiving the current season's vaccine. These findings favor continuation of annual influenza vaccination recommendations, particularly in older adults. Clinical Trials Registration NCT01517191. [ABSTRACT FROM AUTHOR]

The evaluation of safety is critical in all clinical trials. However, the quantitative analysis of safety data in clinical trials poses statistical difficulties because of multiple potentially overlapping endpoints. Tree-temporal scan statistic approaches address this issue and have been widely employed in other data sources, but not to date in clinical trials. We evaluated the performance of three complementary scan statistical methods for routine quantitative safety signal detection: the self-controlled tree-temporal scan (SCTTS), a tree-temporal scan based on group comparison (BGTTS), and a log-rank based tree-temporal scan (LgRTTS). Each method was evaluated using data from two phase III clinical trials, and simulated data (simulation study). In the case study, the reference set was adverse events (AEs) in the Reference Safety Information of the evaluated vaccine. The SCTTS method had higher sensitivity than other methods, and after dose 1 detected 80 true positives (TP) with a positive predictive value (PPV) of 60%. The LgRTTS detected 49 TPs with 69% PPV. The BGTTS had 90% of PPV with 38 TPs. In the simulation study, with simulated reference sets of AEs, the SCTTS method had good sensitivity to detect transient effects. The LgRTTS method showed the best performance for the detection of persistent effects, with high sensitivity and expected probability of type I error. These three methods provide complementary approaches to safety signal detection in clinical trials or across clinical development programmes. All three methods formally adjust for multiple testing of large numbers of overlapping endpoints without being excessively conservative., (© 2024 GlaxoSmithKline. Pharmaceutical Statistics published by John Wiley & Sons Ltd.)

Introduction: The Vaccine Adverse Event Reporting System (VAERS) has already been challenged by an extreme increase in the number of individual case safety reports (ICSRs) after the market introduction of coronavirus disease 2019 (COVID-19) vaccines. Evidence from scientific literature suggests that when there is an extreme increase in the number of ICSRs recorded in spontaneous reporting databases (such as the VAERS), an accompanying increase in the number of disproportionality signals (sometimes referred to as 'statistical alerts') generated is expected., Objectives: The objective of this study was to develop a natural language processing (NLP)-based approach to optimize signal management by excluding disproportionality signals related to listed adverse events following immunization (AEFIs). COVID-19 vaccines were used as a proof-of-concept., Methods: The VAERS was used as a data source, and the Finding Associated Concepts with Text Analysis (FACTA+) was used to extract signs and symptoms of listed AEFIs from MEDLINE for COVID-19 vaccines. Disproportionality analyses were conducted according to guidelines and recommendations provided by the US Centers for Disease Control and Prevention. By using signs and symptoms of listed AEFIs, we computed the proportion of disproportionality signals dismissed for COVID-19 vaccines using this approach. Nine NLP techniques, including Generative Pre-Trained Transformer 3.5 (GPT-3.5), were used to automatically retrieve Medical Dictionary for Regulatory Activities Preferred Terms (MedDRA PTs) from signs and symptoms extracted from FACTA+., Results: Overall, 17% of disproportionality signals for COVID-19 vaccines were dismissed as they reported signs and symptoms of listed AEFIs. Eight of nine NLP techniques used to automatically retrieve MedDRA PTs from signs and symptoms extracted from FACTA+ showed suboptimal performance. GPT-3.5 achieved an accuracy of 78% in correctly assigning MedDRA PTs., Conclusion: Our approach reduced the need for manual exclusion of disproportionality signals related to listed AEFIs and may lead to better optimization of time and resources in signal management., (© 2023. The Author(s).)

Introduction: Time- and resource-demanding activities related to processing individual case safety reports (ICSRs) include manual procedures to evaluate individual causality with the final goal of dismissing false-positive safety signals. Eminent experts and a representative from pharmaceutical industries and regulatory agencies have highlighted the need to automatize time- and resource-demanding procedures in signal detection and validation. However, to date there is a sparse availability of automatized tools for such purposes., Objectives: ICSRs recorded in spontaneous reporting databases have been and continue to be the cornerstone and the most important data source in signal detection. Despite the richness of this data source, the incessantly increased amount of ICSRs recorded in spontaneous reporting databases has generated problems in signal detection and validation due to the increase in resources and time needed to process cases. This study aimed to develop a new artificial intelligence (AI)-based framework to automate resource- and time-consuming steps of signal detection and signal validation, such as (1) the selection of control groups in disproportionality analyses and (2) the identification of co-reported drugs serving as alternative causes, to look to dismiss false-positive disproportionality signals and therefore reduce the burden of case-by-case validation., Methods: The Summary of Product Characteristics (SmPC) and the Anatomical Therapeutic Chemical (ATC) classification system were used to automatically identify control groups within and outside the chemical subgroup of the proof-of-concept drug under investigation, galcanezumab. Machine learning, specifically conditional inference trees, has been used to identify alternative causes in disproportionality signals., Results: By using conditional inference trees, the framework was able to dismiss 20.00% of erenumab, 14.29% of topiramate, and 13.33% of amitriptyline disproportionality signals on the basis of purely alternative causes identified in cases. Furthermore, of the disproportionality signals that could not be dismissed purely on the basis of the alternative causes identified, we estimated a 15.32%, 25.39%, and 26.41% reduction in the number of galcanezumab cases to undergo manual validation in comparison with erenumab, topiramate, and amitriptyline, respectively., Conclusion: AI could significantly ease some of the most time-consuming and labor-intensive steps of signal detection and validation. The AI-based approach showed promising results, however, future work is needed to validate the framework., (© 2023. The Author(s).)

Introduction: Identifying individual characteristics or underlying conditions linked to adverse drug reactions (ADRs) can help optimise the benefit-risk ratio for individuals. A systematic evaluation of statistical methods to identify subgroups potentially at risk using spontaneous ADR report datasets is lacking., Objectives: In this study, we aimed to assess concordance between subgroup disproportionality scores and European Medicines Agency Pharmacovigilance Risk Assessment Committee (PRAC) discussions of potential subgroup risk., Methods: The subgroup disproportionality method described by Sandberg et al., and variants, were applied to statistically screen for subgroups at potential increased risk of ADRs, using data from the US FDA Adverse Event Reporting System (FAERS) cumulative from 2004 to quarter 2 2021. The reference set used to assess concordance was manually extracted from PRAC minutes from 2015 to 2019. Mentions of subgroups presenting potential differentiated risk and overlapping with the Sandberg method were included., Results: Twenty-seven PRAC subgroup examples representing 1719 subgroup drug-event combinations (DECs) in FAERS were included. Using the Sandberg methodology, 2 of the 27 could be detected (one for age and one for sex). No subgroup examples for pregnancy and underlying condition were detected. With a methodological variant, 14 of 27 examples could be detected., Conclusions: We observed low concordance between subgroup disproportionality scores and PRAC discussions of potential subgroup risk. Subgroup analyses performed better for age and sex, while for covariates not well-captured in FAERS, such as underlying condition and pregnancy, additional data sources should be considered., (© 2023. The Author(s).)

Introduction: Rotavirus (RV) is the most common cause of acute gastroenteritis in children <5 years of age worldwide, and vaccination reduces the disease burden. Evidence from postmarketing surveillance studies suggested an increased risk of intussusception (IS) in infants post-RV vaccination. An overall positive benefit-risk balance for the human RV vaccine (HRV) Rotarix (GlaxoSmithKline [GSK], Belgium) has been established and recent findings indicate an indirect effect of reduced IS over the long term., Objective: The aim of this study was to discuss spontaneous data from the GSK worldwide safety database on IS post-Rotarix administration., Methods: The database was reviewed for all spontaneous IS cases from 2004 to 2020. Additionally, an observed versus expected (O/E) analysis was done for adverse events attributed to IS. Data were reviewed as overall worldwide and stratified by region (Europe/USA/Japan) and dose., Results: A male predominance of IS patients was observed, consistent with earlier reports. The most frequently reported events in confirmed IS cases (Brighton Collaboration Working Group [BCWG] level 1) with time to onset ≤ 30 days post-vaccination were vomiting (55.8%), haematochezia (47.2%), and crying (21.1%). The observations from the IS spontaneous cases review and results of the O/E analysis are consistent with the known IS safety profile of RV vaccines: a transient increased incidence of IS post-vaccination (primarily in Europe/Japan/worldwide), mostly within 7 days postdose 1., Conclusion: Since the outcomes of early IS management are favourable over delayed management, healthcare professionals should inform parents about the importance of seeking immediate medical advice in case of unusual behaviour of the vaccinated infant. GSK continues to monitor the IS risk post-Rotarix administration through routine pharmacovigilance activities., (© 2022. The Author(s), under exclusive licence to Springer Nature Switzerland AG.)

Introduction: The Accelerated Development of Vaccine benefit-risk Collaboration in Europe (ADVANCE) public-private collaboration, aimed to develop and test a system for rapid benefit-risk monitoring of vaccines using healthcare databases in Europe. The objective of this proof-of-concept (POC) study was to test the feasibility of the ADVANCE system to generate incidence rates (IRs) per 1000 person-years and incidence rate ratios (IRRs) for risks associated with whole cell- (wP) and acellular- (aP) pertussis vaccines, occurring in event-specific risk windows in children prior to their pre-school-entry booster., Methods: The study population comprised almost 5.1 million children aged 1 month to <6 years vaccinated with wP or aP vaccines during the study period from 1 January 1990 to 31 December 2015. Data from two Danish hospital (H) databases (AUH and SSI) and five primary care (PC) databases from, UK (THIN and RCGP RSC), Spain (SIDIAP and BIFAP) and Italy (Pedianet) were analysed. Database-specific IRRs between risk vs. non-risk periods were estimated in a self-controlled case series study and pooled using random-effects meta-analyses., Results: The overall IRs were: fever, 58.2 (95% CI: 58.1; 58.3), 96.9 (96.7; 97.1) for PC DBs and 8.56 (8.5; 8.6) for H DBs; convulsions, 7.6 (95% CI: 7.6; 7.7), 3.55 (3.5; 3.6) for PC and 12.87 (12.8; 13) for H; persistent crying, 3.9 (95% CI: 3.8; 3.9) for PC, injection-site reactions, 2.2 (95% CI 2.1; 2.2) for PC, hypotonic hypo-responsive episode (HHE), 0.4 (95% CI: 0.4; 0.4), 0.6 (0.6; 0.6) for PC and 0.2 (0.2; 0.3) for H; and somnolence: 0.3 (95% CI: 0.3; 0.3) for PC. The pooled IRRs for persistent crying, fever, and ISR, adjusted for age and healthy vaccinee period were higher after wP vs. aP vaccination, and lower for convulsions, for all doses. The IRR for HHE was slightly lower for wP than aP, while wP was associated with somnolence only for dose 1 and dose 3 compared with aP., Conclusions: The estimated IRs and IRRs were comparable with published data, therefore demonstrating that the ADVANCE system was able to combine several European healthcare databases to assess vaccine safety data for wP and aP vaccination., Competing Interests: Declaration of Competing Interest Caitlin Dodd, Talita Duarte-Salles, Gino Picelli, Lara Tramontan, Giorgia Danieli, Ana Correa, Chris McGee, Elisa Martín-Merino, Consuelo Huerta, Hanne-Dorthe Emborg, Kaatje Bollaerts, Klara Berencsi declared no conflicts of interest. Daniel Weibel declared personal fees from GSK outside the submitted work. Olivia Mahaux, Francois Haguinet and Vincent Bauchau declared that they are employed by GSK and hold shares from GSK. Lina Titievsky declared that she is employed Pfizer and holds stocks from Pfizer. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and the Bill & Melinda Gates Foundation outside the submitted work., (Copyright © 2019 The Authors. Published by Elsevier Ltd.. All rights reserved.)

The Accelerated Development of VAccine beNefit-risk Collaboration in Europe (ADVANCE) is a public-private collaboration aiming to develop and test a system for rapid vaccine benefit-risk monitoring using existing European healthcare databases. Incidence rate (IR) estimates of vaccination-associated adverse events that are needed to model vaccination risks can be calculated from existing healthcare databases when vaccination (exposure) data are available. We assessed different methods to derive IRs in risk periods following vaccination when exposure data are missing in one database, using estimated IRs and IRRs from other databases for febrile seizures, fever and persistent crying. IRs were estimated for children aged 0-5 years in outcome-specific risk and non-risk periods following the first dose of acellular pertussis (aP) vaccination in four primary care databases and one hospital database. We compared derived and observed IRs in each database using three methods: 1) multiplication of non-risk period IR for database i by IR ratio (IRR) obtained from meta-analysis of IRRs estimated using the self-controlled case-series method, from databases other than i; 2) same method as 1, but multiplying with background IR; and 3) meta-analyses of observed IRs from databases other than i. IRs for febrile seizures were lower in primary care databases than the hospital database. The derived IR for febrile seizures using data from primary care databases was lower than that observed in the hospital database, and using data from the hospital database gave a higher derived IR than that observed in the primary care database. For fever and persistent crying the opposite was observed. We demonstrated that missing IRs for a post-vaccination period can be derived but that the type of database and the method of event data capture can have an impact on potential bias. We recommend IRs are derived using data from similar database types (hospital or primary care) with caution as even this can give heterogeneous results., Competing Interests: Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: [Caitlin Dodd, Maria de Ridder, Tom de Smedt, Chris McGee, Talita Duarte-Salles, Hanne-Dorthe Emborg, Consuelo Huerta, Elisa Martín-Merino, Gino Picelli, Klara Berencsi, Giorgia Danieli declared that they have no potential conflicts of interest. Daniel Weibel declared that he has received personal fees from GSK for work unrelated to the submitted work. Olivia Mahaux and Francois Haguinet declared that they are employed by GSK and hold company shares. Simon de Lusignan declared that he has received grants from GSK, Takeda, and Seqirus / JSS, and also personal fees from Sequirus and Sanofi, for work unrelated to the submitted work. Miriam Sturkenboom declared that she has received grants from Novartis, CDC and Bill & Melinda Gates Foundation, for work unrelated to the submitted work]., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

A diligent, systematic, regular review of aggregate safety data is essential, particularly early after vaccine introduction, as this is when safety signals not identified during clinical development may emerge. In October 2017, the US Centers for Disease Control and Prevention Advisory Committee on Immunization Practices recommended the adjuvanted recombinant zoster vaccine (RZV; Shingrix, GSK) as the preferred vaccine for preventing herpes zoster (HZ) and related complications in immunocompetent adults aged ≥ 50 years. Subsequently, GSK experienced an unprecedented high demand for RZV. In this methodology paper, we summarize the enhanced measures undertaken to assess RZV safety during its early post-marketing experience in the USA, Canada and Germany. In addition to the routine signal-detection methods already in place for all vaccines, GSK established tailored and enhanced safety monitoring for RZV based on aggregate data of spontaneous reports and manufacturing data. Proactive, near real-time detection and evaluation of signals was a key objective. A dedicated in-house signal-detection tool customized for RZV was employed on a weekly (rather than the routine monthly) basis, allowing for a centralized, more frequent review of data on a single web-based platform. We also identified the background incidence rates of preselected medical events of interest in the first countries to introduce RZV (USA, Canada and Germany) to perform observed-to-expected analyses. This approach may offer a solution to the challenges associated with the assessment and monitoring of vaccine safety in an efficient and timely manner in the context of high vaccine uptake.

Dengue is endemic in Brazil. The dengue surveillance system's reliance on passive reporting may underestimate disease incidence and cannot detect asymptomatic/pauci-symptomatic cases. In this 3-year prospective cohort study (NCT01391819) in 5- to 13-year-old children from nine schools in Fortaleza ( N = 2,117), we assessed dengue virus (DENV) infection seroprevalence by IgG indirect ELISA at yearly visits and disease incidence through active and enhanced passive surveillance. Real-time quantitative polymerase chain reaction (RT-qPCR) and DENV IgM/IgG capture ELISA were used for diagnosis. We further characterized confirmed and probable cases with a plaque reduction neutralization test. At enrollment, 54.1% (95% CI: 46.6, 61.4) of children were DENV IgG positive. The annual incidence of laboratory-confirmed symptomatic dengue cases was 11.0 (95% CI: 7.3, 14.7), 18.1 (10.4, 25.7), and 10.2 (0.7, 19.7), and of laboratory-confirmed or probable dengue cases with neutralizing antibody profile evocative of dengue exposure was 13.2 (6.6, 19.9), 18.7 (5.3, 32.2), and 8.4 (2.4, 19.2) per 1,000 child-years in 2012, 2013, and 2014, respectively. By RT-qPCR, we identified 14 DENV-4 cases in 2012-2013 and seven DENV-1 cases in 2014. During the course of the study, 32.8% of dengue-naive children experienced a primary infection. Primary inapparent dengue infection was detected in 20.3% (95% CI: 13.6, 29.1) of dengue-naive children in 2012, 8.7% (6.9, 10.9) in 2013, and 5.1% (4.4, 6.0) in 2014. Our results confirmed the high dengue endemicity in Fortaleza, with active and enhanced passive surveillance detecting three to five times more cases than the National System of Disease Notification.

Background: The European Medicines Agency (EMA) requires vaccine manufacturers to conduct enhanced real-time surveillance of seasonal influenza vaccination. The EMA has specified a list of adverse events of interest to be monitored. The EMA sets out 3 different ways to conduct such surveillance: (1) active surveillance, (2) enhanced passive surveillance, or (3) electronic health record data mining (EHR-DM). English general practice (GP) is a suitable setting to implement enhanced passive surveillance and EHR-DM., Objective: This study aimed to test the feasibility of conducting enhanced passive surveillance in GP using the yellow card scheme (adverse events of interest reporting cards) to determine if it has any advantages over EHR-DM alone., Methods: A total of 9 GPs in England participated, of which 3 tested the feasibility of enhanced passive surveillance and the other 6 EHR-DM alone. The 3 that tested EPS provided patients with yellow (adverse events) cards for patients to report any adverse events. Data were extracted from all 9 GPs' EHRs between weeks 35 and 49 (08/24/2015 to 12/06/2015), the main period of influenza vaccination. We conducted weekly analysis and end-of-study analyses., Results: Our GPs were largely distributed across England with a registered population of 81,040. In the week 49 report, 15,863/81,040 people (19.57% of the registered practice population) were vaccinated. In the EPS practices, staff managed to hand out the cards to 61.25% (4150/6776) of the vaccinees, and of these cards, 1.98% (82/4150) were returned to the GP offices. Adverse events of interests were reported by 113 /7223 people (1.56%) in the enhanced passive surveillance practices, compared with 322/8640 people (3.73%) in the EHR-DM practices., Conclusions: Overall, we demonstrated that GPs EHR-DM was an appropriate method of enhanced surveillance. However, the use of yellow cards, in enhanced passive surveillance practices, did not enhance the collection of adverse events of interests as demonstrated in this study. Their return rate was poor, data entry from them was not straightforward, and there were issues with data reconciliation. We concluded that customized cards prespecifying the EMA's adverse events of interests, combined with EHR-DM, were needed to maximize data collection., International Registered Report Identifier (irrid): RR2-10.1136/bmjopen-2016-015469., (©Simon de Lusignan, Ana Correa, Gaël Dos Santos, Nadia Meyer, François Haguinet, Rebecca Webb, Christopher McGee, Rachel Byford, Ivelina Yonova, Sameera Pathirannehelage, Filipa Matos Ferreira, Simon Jones. Originally published in JMIR Public Health and Surveillance (http://publichealth.jmir.org), 14.11.2019.)

Understanding maternal dengue virus (DENV) neutralizing antibody kinetics in infants remains timely to develop a safe and effective childhood immunization. This retrospective study evaluated the prevalence and persistence of maternal antibody titers against DENV serotypes 1 to 4 in 139 Thai infants at 2, 6, and 7 months of age, using serum samples collected in a vaccination trial ( http://clinicaltrials.gov ; NCT00197275). Neutralizing antibodies against all 4 DENV serotypes were detected in 87.8% and 22.9% of infants at 2 and 7 months, respectively. At 2 months, DENV-4 neutralizing antibody geometric mean titers were notably lower (80) compared with DENV-1 to DENV-3 (277-471). Our results corroborate previous findings that DENV-1 to DENV-4 maternal antibodies persist at 7 months despite titers decrease from 2 months onwards. As persisting maternal antibodies may inhibit immune responses in DENV-vaccinated infants, a comprehensive understanding of DENV antibody kinetics is required in the perspective of vaccine development for infants.

Background: The effectiveness of influenza vaccination in reducing influenza-related hospitalizations among patients with COPD is not well described, and influenza vaccination uptake remains suboptimal., Methods: Data were analyzed from a national, prospective, multicenter cohort study including patients with COPD, hospitalized with any acute respiratory illness or exacerbation between 2011 and 2015. All patients underwent nasopharyngeal swab screening with polymerase chain reaction (PCR) testing for influenza. The primary outcome was an influenza-related hospitalization. We identified influenza-positive cases and negative control subjects and used multivariable logistic regression with a standard test-negative design to estimate the vaccine effectiveness for preventing influenza-related hospitalizations., Results: Among 4,755 hospitalized patients with COPD, 4,198 (88.3%) patients with known vaccination status were analyzed. The adjusted analysis showed a 38% reduction in influenza-related hospitalizations in vaccinated vs unvaccinated individuals. Influenza-positive patients (n = 1,833 [38.5%]) experienced higher crude mortality (9.7% vs 7.9%; P = .047) and critical illness (17.2% vs 12.1%; P < .001) compared with influenza-negative patients. Risk factors for mortality in influenza-positive patients included age > 75 years (OR, 3.7 [95% CI, 0.4-30.3]), cardiac comorbidity (OR, 2.0 [95% CI, 1.3-3.2]), residence in long-term care (OR, 2.6 [95% CI, 1.5-4.5]), and home oxygen use (OR, 2.9 [95% CI, 1.6-5.1])., Conclusions: Influenza vaccination significantly reduced influenza-related hospitalization among patients with COPD. Initiatives to increase vaccination uptake and early use of antiviral agents among patients with COPD could reduce influenza-related hospitalization and critical illness and improve health-care costs in this vulnerable population., Trial Registry: ClinicalTrials.govNo.:NCT01517191; URL www.clinicaltrials.gov., (Copyright © 2018 American College of Chest Physicians. Published by Elsevier Inc. All rights reserved.)

Objectives: Herpes zoster (HZ) is caused by reactivation of varicella-zoster virus which remains latent in individuals after a varicella infection. It is expected that HZ will be more frequent in immunocompromised (IC) individuals than in immunocompetent (IC-free). This study assessed the incidence rate (IR) of HZ in individuals with a wide set of IC conditions and in IC-free individuals., Setting: A retrospective cohort study was conducted in England using data (January 2000 to March 2012) from the Clinical Practice Research Datalink with linkage to the Hospital Episodes Statistics., Participants: A cohort of 621 588 individuals with 16 selected IC conditions and a gender/age-matched cohort of IC-free individuals were identified. The IC conditions included haematopoietic stem cell transplant (HSCT), solid organ transplant, malignancies, autoimmune diseases and users of immunosuppressive medications., Outcomes: IR of HZ per 1000 person-years (PY) was estimated. Proportions of postherpetic neuralgia (PHN) and other HZ complications within 90 days of HZ onset were also estimated among patients with HZ. Risk factors for PHN in IC individuals with HZ were assessed by a multivariate regression model., Results: The overall IR of HZ in the IC cohort was 7.8/1000 PY (95% CI 7.7 to 7.9), increasing with age from 3.5/1000 PY (3.4-3.7) in individuals aged 18-49 years to 12.6/1000 PY (12.2-13.0) in individuals aged ≥80 years. This IR in the IC-free cohort was 6.2/1000 PY (6.1-6.3). The overall IR of HZ varied across IC conditions, ranging from 5.3 (5.1-5.5) in psoriasis to 41.7/1000 PY (35.7-48.4) in HSCT. The proportions of PHN and other HZ complications were 10.7% (10.2-11.1) and 2.9% (2.7-3.2) in the IC cohort, but 9.1% (8.7-9.5) and 2.3% (2.1-2.6) in the IC-free cohort, respectively., Conclusion: IC population contributes to the public health burden of HZ in England. Vaccination might be the most preferable HZ preventive measure for the IC population., Competing Interests: Competing interests: VB, FH, EE and EAY are employees of the GSK group of companies. AEG, YEH and MG have nothing to disclose. GF was employed by the GSK group of companies between 2012 and February 2015, during which the study was designed and implemented. Later, as an employee of P-95 Epidemiology and Pharmacovigilance, GF provided contracted consultancy services to the GSK group of companies for this and other GSK-sponsored studies. P-95 provides contracted services to the GSK group of companies beyond the scope of this study., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2018. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Ongoing assessment of influenza vaccine effectiveness (VE) is critical to inform public health policy. This study aimed to determine the VE of trivalent influenza vaccine (TIV) for preventing influenza-related hospitalizations and other serious outcomes over three consecutive influenza seasons., Methods: The Serious Outcomes Surveillance (SOS) Network of the Canadian Immunization Research Network (CIRN) conducted active surveillance for influenza in adults ≥16 years (y) of age during the 2011/2012, 2012/2013 and 2013/2014 seasons in hospitals across Canada. A test-negative design was employed: cases were polymerase chain reaction (PCR)-positive for influenza; controls were PCR-negative for influenza and were matched to cases by date, admission site, and age (≥65 y or <65 y). All cases and controls had demographic and clinical characteristics (including influenza immunization status) obtained from the medical record. VE was estimated as 1-OR (odds ratio) in vaccinated vs. unvaccinated patients × 100%. The primary outcome was VE of TIV for preventing laboratory-confirmed influenza-related hospitalization; secondary outcomes included VE of TIV for preventing influenza-related intensive care unit (ICU) admission/mechanical ventilation, and influenza-related death., Results: Overall, 3394 cases and 4560 controls were enrolled; 2078 (61.2%) cases and 2939 (64.5%) controls were ≥65 y. Overall matched, adjusted VE was 41.7% (95% Confidence Interval (CI): 34.4-48.3%); corresponding VE in adults ≥65 y was 39.3% (95% CI: 29.4-47.8%) and 48.0% (95% CI: 37.5-56.7%) in adults <65 y, respectively. VE for preventing influenza-related ICU admission/mechanical ventilation in all ages was 54.1% (95% CI: 39.8-65.0%); in adults ≥65 y, VE for preventing influenza-related death was 74.5% (95% CI: 44.0-88.4%)., Conclusions: While effectiveness of TIV to prevent serious outcomes varies year to year, we demonstrate a statistically significant and clinically important TIV VE for preventing hospitalization and other serious outcomes over three seasons. Public health messaging should highlight the overall benefit of influenza vaccines over time while acknowledging year to year variability. ClinicalTrials.gov Identifier: NCT01517191., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

Background: The Serious Outcomes Surveillance (SOS) Network was established to monitor seasonal influenza complications among hospitalized Canadian adults and to assess the effectiveness of influenza vaccination against severe outcomes. Here we report age- and strain-specific vaccine effectiveness (VE) in preventing severe outcomes during a season characterized by mixed outbreaks of four different influenza strains., Methods: This prospective, multicentre, test-negative case-control study evaluated the VE of trivalent influenza vaccine (TIV) in the prevention of laboratory-confirmed influenza-hospitalization in adults aged ≥16 years (all adults) and adults aged 16-64 years (younger adults). The SOS Network identified hospitalized patients with diagnoses potentially attributable to influenza during the 2011/12 influenza season. Swabs collected at admission were tested by reverse transcriptase polymerase chain reaction (RT PCR) or viral culture to discriminate influenza cases (positive) from controls (negative). VE was calculated as 1-odds ratio (OR) of vaccination in cases versus controls × 100., Results: Overall, in all adults, the unadjusted and adjusted VEs of TIV against influenza-hospitalization were 41.8% (95% Confidence Interval [CI]: 26.0, 54.3), and 42.8% (95% CI: 23.8, 57.0), respectively. In younger adults (16-64 years), the unadjusted and adjusted VEs of TIV against influenza-hospitalization were 35.8% (95% CI: 4.5, 56.8) and 33.2% (95% CI: -6.7, 58.2), respectively. In the all adults group, adjusted VE against influenza A/H1N1 was 72.5% (95% CI: 30.5, 89.1), against A/H3N2 was 86.1% (95% CI: 40.1, 96.8), against B/Victoria was 40.5% (95% CI: -28.9, 72.6), and against B/Yamagata was 32.3% (95% CI: -8.3, 57.7). The adjusted estimate of early season VE (from November 1 to March 11) was 54.4% (95% CI: 29.7-70.4), which was higher than late season (from March 11 to May 25) VE estimate (VE: 29.7%, 95% CI: -5.3, 53.1)., Conclusions: These results suggest that TIV was highly effective against A viruses and moderately effective against B viruses during a mild season characterised by co-circulation of four influenza strains in Canada. Findings underscore the need to provide VE assessment by subtype/lineage as well as the timing of vaccination (early season vs late season) to accurately evaluate vaccine performance and thus guide public health decision-making., Trial Registration: ClinicalTrials.gov Identifier: NCT01517191. Registration was retrospective and the date of registration was January 17, 2012.

Background: Influenza is an important cause of morbidity and mortality among older adults. Even so, effectiveness of influenza vaccine for older adults has been reported to be lower than for younger adults, and the impact of frailty on vaccine effectiveness (VE) and outcomes is uncertain. We aimed to study VE against influenza hospitalization in older adults, focusing on the impact of frailty., Methods: We report VE of trivalent influenza vaccine (TIV) in people ≥65 years of age hospitalized during the 2011-2012 influenza season using a multicenter, prospective, test-negative case-control design. A validated frailty index (FI) was used to measure frailty., Results: Three hundred twenty cases and 564 controls (mean age, 80.6 and 78.7 years, respectively) were enrolled. Cases had higher baseline frailty than controls (P = .006). In the fully adjusted model, VE against influenza hospitalization was 58.0% (95% confidence interval [CI], 34.2%-73.2%). The contribution of frailty was important; adjusting for frailty alone yielded a VE estimate of 58.7% (95% CI, 36.2%-73.2%). VE was 77.6% among nonfrail older adults and declined as frailty increased., Conclusions: Despite commonly held views that VE is poor in older adults, we found that TIV provided good protection against influenza hospitalization in older adults who were not frail, though VE diminished as frailty increased., Clinical Trials Registration: NCT01517191., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Post-authorisation safety studies (PASS) of vaccines assess or quantify the risk of adverse events following immunisation that were not identified or could not be estimated pre-licensure. The aim of this perspective paper is to describe the authors' experience in the design and conduct of twelve PASS that contributed to the evaluation of the benefit-risk of vaccines in real-world settings. We describe challenges and learnings from selected PASS of rotavirus, malaria, influenza, human papillomavirus and measles-mumps-rubella-varicella vaccines that assessed or identified potential or theoretical risks, which may lead to changes to risk management plans and/or to label updates. Study settings include the use of large healthcare databases and de novo data collection. PASS methodology is influenced by the background incidence of the outcome of interest, vaccine uptake, availability and quality of data sources, identification of the at-risk population and of suitable comparators, availability of validated case definitions, and the frequent need for case ascertainment in large databases. Challenges include the requirement for valid exposure and outcome data, identification of, and access to, adequate data sources, and mitigating limitations including bias and confounding. Assessing feasibility is becoming a key step to confirm that study objectives can be met in a timely manner. PASS provide critical information for regulators, public health agencies, vaccine manufacturers and ultimately, individuals. Collaborative approaches and synergistic efforts between vaccine manufacturers and key stakeholders, such as regulatory and public health agencies, are needed to facilitate access to data, and to drive optimal study design and implementation, with the aim of generating robust evidence., (Copyright © 2017 GSK Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Aim: To pilot enhanced safety surveillance of seasonal influenza vaccine meeting the European Medicines Agency (EMA) requirement to rapidly detect a significant increase in the frequency or severity of adverse events of interest (AEIs), which may indicate risk from the new season's vaccine., Study Design: A prospective passive enhanced safety surveillance combining data collection from adverse drug reaction (ADR) cards with automated collection of pseudonymised routinely collected electronic health record (EHR) data. This study builds on a feasibility study carried out at the start of the 2015/2016 influenza season. We will report influenza vaccine exposure and any AEIs reported via ADR card or recorded directly into the EHR, from the commencement of influenza vaccination and ends as specified by EMA (30 November 2016)., Setting: Ten volunteer English general practices, primarily using the GSK influenza vaccines. They had selected this vaccine in advance of the study., Participants: People who receive a seasonal influenza vaccine, in each age group defined in EMA interim guidance: 6 months to 5 years, 6-12 years, 13-17 years, 18-65 years and >65 years., Outcome Measures: The primary outcome measure is the rate of AEIs occurring within 7 days postvaccination, using passive surveillance of general practitioner (GP) EHR systems enhanced by a card-based ADR reporting system. Extracted data will be presented overall by brand (Fluarix Tetra vs others), by age strata and risk groups. The secondary outcome measure is the vaccine uptake among the subjects registered in the enrolled general practices., Ethics and Dissemination: Ethical approval was granted by the Proportionate Review Sub-committee of the North East-Newcastle & North Tyneside 2 on 5 August 2016. The study received approval from the Health Research Authority on 1 September 2016. We will produce an interim analysis within 8 weeks, and an end-of-study report, which will be submitted to peer-reviewed journals., Competing Interests: Competing interests: SdeL and AC participate in a European consortium called IMOVE+ funded by Horizon 2020 to monitor seasonal influenza vaccine effectiveness across Europe. GDS reports he was employed by Business & Decision Life Sciences on behalf of GSK Vaccines at the time of the study and is now employed by the GSK group of companies. FH are employees of the GSK group of companies. GDS holds shares in the GSK group of companies as part of their employee remuneration., (© Article author(s) (or their employer(s) unless otherwise stated in the text of the article) 2017. All rights reserved. No commercial use is permitted unless otherwise expressly granted.)

Background: Estimates of influenza and respiratory syncytial virus (RSV) burden must be periodically updated to inform public health strategies. We estimated seasonal influenza- and RSV-attributable hospitalizations in the US from 1997 to 2009 according to age and risk status (NCT01599390)., Methods: Multiple linear regression modelling was used to attribute hospitalizations to influenza or RSV using virological surveillance and hospitalization data. Hospitalization data were obtained from the US Nationwide Inpatient Sample and virology data were obtained from FluView (Centers for Disease Control and Prevention). Outcomes included any mention of ICD-coded respiratory disease and cardiorespiratory disease diagnoses. We also explored a broader definition of respiratory disease that included mention of relevant respiratory sign/symptoms and viral infection ("respiratory broad")., Results: Applying the respiratory broad outcome, our model attributed ~300,000 and ~200,000 hospitalizations to influenza and RSV, respectively. Influenza A/H3N2 was the predominant cause of influenza-related hospitalizations in most seasons, except in three seasons when influenza B was dominant; likewise, A/H3N2 caused most influenza-related hospitalizations in all age segments, except in children <18 years where the relative contribution of A/H3N2 and B was similar. Most influenza A- and B-related hospitalizations occurred in seniors while approximately one half and one third of all RSV-related events occurred in children 0-4 years and seniors 65+ years, respectively. High-risk status was associated with higher risk of both influenza- and RSV-attributable hospitalizations in adults, but not in children., Conclusions: Our study assessed the burden of influenza and RSV, information that is important for both cost effectiveness studies and for prioritization of the development of antivirals and vaccines. For seniors, we found that the burdens of influenza and RSV were both substantial. Among children <18 years, about half of all influenza hospitalizations were due to influenza B, most occurring in children without noted risk conditions. RSV hospitalizations among children were confined to those 0-4 years. Our study also demonstrated the importance of the outcome used to estimate hospitalization burden. Our findings highlight the burden of influenza among children regardless of risk status and underscore the prevalence of RSV infections among both young children and older adults.

Two prospective, multi-centre, observational studies (GlaxoSmithKline [GSK] identifier No. 110938 and 112519) were performed over 2 influenza seasons (2007-2008 and 2008-2009) in the Republic of Korea (ROK) with the aim to evaluate the burden of laboratory-confirmed influenza (LCI) in patients ≥ 50 years of age seeking medical attention for acute respiratory illness (ARI). The median participant age was 58 years in the 2007-2008 season and 60 years in the 2008-2009 season. LCI was observed in 101/346 (29.2%) of ARI patients in the 2007-2008 season and in 166/443 (37.5%) of ARI patients in the 2008-2009 season. Compared to patients with non-influenza ARI, those with LCI had higher rates of decreased daily activities (60.4% vs. 32.9% in 2007-2008 and 46.4% vs. 25.8% in 2008-2009), work absenteeism (51.1% vs. 25.6% and 14.4% vs. 7.7%), and longer duration of illness. These results indicated that influenza is an important cause of ARI in adults aged 50 and older causing more severe illness than non-influenza related ARI., Competing Interests: All authors completed the disclosure declaration. Matias G, Ray R, Carneiro R, and Haguinet F are employed by the GlaxoSmithKline (GSK) Group of Companies. Ray R reports ownership of stock options and/or restricted shares. Kyaw M and Monegal JS report having been employed by the GSK Group of Companies at the time of the study. Kim WJ, Lee CK, Cheong HJ, Lee JS, and Kim M report no competing interests. Involvement of GSK employees did not compromise the scientific integrity of this work.

Background: Although many studies have modelled the national burdens of hospitalizations and deaths due to influenza, few studies have considered the outpatient burden. To fill this gap for the United States (US), we applied traditional statistical modelling approaches to time series derived from large medical claims databases held in the private sector., Methods: We accessed ICD-9-coded office visit data extracted from Truven Health Analytics' MarketScan Commercial database covering about one third of the US population <65 years during 2001-2009, and Medicare Supplemental data covering about one fifth of US seniors 65+ during 2006-2009. We extracted weekly time series of visits due to respiratory diagnoses, otitis media (OM), and urinary tract infections (UTI), a "negative control". We used multiple linear regression modelling to estimate age-specific influenza-related excess in office visits., Results: In the <65 year age group, in the 8 pre-pandemic seasons studied and for the broadest defined respiratory outcome, the model attributed an average of ~14.5 M (Standard deviation [SD] across seasons 3.9 million) office visits to influenza (rate of 5,581/100,000 population). Of these, ~80 % of visits occurred in the 5-17 and 18-49 age group. In school children aged 5-17 year olds and adult 18-64 year age groups the majority of visits were due to influenza B, while A/H3N2 explained most visits in children <5 year olds. The model further attributed ~2.2 M OM visits (SD across seasons 790,000) annually to influenza, of which 86 % of these occurred in children <18 years; this indicates that 6.4 % of all infants <2 years and 4.9 % of all toddlers aged 2-4 years in the US have an influenza-attributable outpatient visit with an OM diagnosis. In seniors 65 years and older, our model attributed ~0.7 M (SD across seasons 351,000) respiratory visits to influenza (rate of 1,887/100,000 population). The model identified no significant excess UTI (negative control) visits in most seasons., Conclusions: This is to our knowledge a first study of the outpatient burden of influenza in the US in a large database. The model estimated that 10 % of all children <18 years and 4 % of the entire population <65 years seek outpatient care for respiratory illness attributable to influenza annually., Trial Registration: ClinicalTrial.gov, NCT02019732 .

Background: Annual seasonal influenza vaccination is recommended for transplant recipients. No formal pharmacoepidemiology study has been published on the association between solid organ transplant (SOT) rejection and vaccination with seasonal trivalent inactivated influenza vaccines (TIIVs)., Methods: The risk of SOT (liver, kidney, lung, heart or pancreas) rejection after TIIV vaccination was assessed using a self-controlled case-series method (NCT01715792). SOT recipients in England with transplant rejection were selected from the Clinical Practice Research Datalink and linked Hospital Episode Statistics inpatient data. The study period (September 2006 to August 2009) encompassed three consecutive influenza seasons. We calculated the relative incidence (RI) of SOT rejection between the 30- and 60-day post-vaccination risk periods and the control periods (any follow-up period excluding risk periods), using a Poisson regression model., Results: In seasons 2006/07, 2007/08, 2008/09 and pooled seasons, 132, 136, 168 and 375 subjects, respectively, experienced at least one transplant rejection; approximately half (45%-51%) of these subjects had received a TIIV. For season 2006/07, the RI of rejection of any organ, adjusted for time since transplantation, was 0.74 (95% CI: 0.24-2.28) and 0.58 (95% CI: 0.24-1.38) during the 30-day and 60-day risk periods, respectively. Corresponding RIs for season 2007/08 were 1.21 (95% CI: 0.55-2.64) and 1.31 (95% CI: 0.69-2.48); for season 2008/09, 0.99 (95% CI: 0.43-2.28) and 0.64 (95% CI: 0.31-1.33); and for pooled seasons 1.01 (95% CI: 0.58-1.76) and 0.88 (95% CI: 0.56-1.38). The results of a separate analysis of kidney rejections and analyses that took into account additional potential confounders were consistent with those of the main analyses, with 95% CIs including 1 and upper limits below 3., Conclusion: This study provides reassuring evidence of the safety profile of TIIVs in SOT recipients, thus supporting current recommendations to vaccinate this risk group annually., (Copyright © 2016 GSK Biologicals SA. Published by Elsevier Ltd.. All rights reserved.)

Background: Influenza is rarely confirmed with laboratory testing and accurate assessment of the overall burden of influenza is difficult. We used statistical modelling methods to generate updated, granular estimates of the number/rate of influenza-attributable hospitalisations and deaths in the United Kingdom. Such data are needed on a continuing basis to inform on cost-benefit analyses of treatment interventions, including vaccination., Methods: Weekly age specific data on hospital admissions (1997-2009) and on deaths (1997-2009) were obtained from national databases. Virology reports (1996-2009) of influenza and respiratory syncytial virus detections were provided by Public Health England. We used an expanded set of ICD-codes to estimate the burden of illness attributable to influenza which we refer to as 'respiratory disease broadly defined'. These codes were chosen to optimise the balance between sensitivity and specificity. A multiple linear regression model controlled for respiratory syncytial virus circulation, with stratification by age and the presence of comorbid risk status (conditions associated with severe influenza outcomes)., Results: In the United Kingdom there were 28,516 hospitalisations and 7163 deaths estimated to be attributable to influenza respiratory disease in a mean season, with marked variability between seasons. The highest incidence rates of influenza-attributable hospitalisations and deaths were observed in adults aged 75+ years (252/100,000 and 131/100,000 population, respectively). Influenza B hospitalisations were highest among 5-17 year olds (12/100,000 population). Of all estimated influenza respiratory deaths in 75+ year olds, 50 % occurred out of hospital, and 25 % in 50-64 year olds. Rates of hospitalisations and death due to influenza-attributable respiratory disease were increased in adults identified as at-risk., Conclusions: Our study points to a substantial but highly variable seasonal influenza burden in all age groups, particularly affecting 75+ year olds. Effective influenza prevention or early intervention with anti-viral treatment in this age group may substantially impact the disease burden and associated healthcare costs. The high burden of influenza B hospitalisation among 5-17 year olds supports current United Kingdom vaccine policy to extend quadrivalent seasonal influenza vaccination to this age group., Trial Registration: ClinicalTrial.gov, NCT01520935.

Objective: The burden of respiratory syncytial virus (RSV) illness is not well characterised in primary care. We estimated the burden of disease attributable to RSV in children in the UK between 1995 and 2009., Design: Time-series regression modelling., Setting: A multiple linear regression model based on weekly viral surveillance (RSV and influenza, Public Health England), and controlled for non-specific seasonal drivers of disease, estimated the proportion of general practitioner (GP) episodes of care (counted as first visit in a series within 28 days; Clinical Practice Research Datalink, CPRD), hospitalisations (Hospital Episode Statistics, HES) and deaths (Office of National Statistics, ONS) attributable to RSV each season., Participants: Children 0-17 years registered with a GP in CPRD, or with a respiratory disease outcome in the HES or ONS databases., Primary Outcome Measures: RSV-attributable burden of GP episodes, hospitalisations and deaths due to respiratory disease by age. RSV-attributable burden associated with selected antibiotic prescriptions., Results: RSV-attributable respiratory disease in the UK resulted in an estimated 450 158 GP episodes, 29 160 hospitalisations and 83 deaths per average season in children and adolescents, with the highest proportions in children <6 months of age (14 441/100 000 population, 4184/100 000 and 6/100 000, respectively). In an average season, there were an estimated 125 478 GP episodes for otitis media and 416 133 prescriptions for antibiotics attributable to RSV. More GP episodes, hospitalisations and deaths from respiratory disease were attributable to RSV than to influenza in children under 5 years., Conclusions: The burden of RSV in children in the UK exceeds that of influenza. RSV in children and adolescents contributes substantially to GP office visits for a diverse range of illnesses, and was associated with an average 416 133 prescribed antibiotic courses per season. Effective antiviral treatments and preventive vaccines are urgently needed for the management of RSV infection in children., Trial Registration Number: NCT01706302., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Objective: To assess the risk of solid organ transplant (SOT) rejection after vaccination with the adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine Pandemrix., Design: Self-controlled case series (SCCS) in the UK Clinical Practice Research Datalink (CPRD) and its linked component of the Hospital Episodes Statistics (HES) inpatient database. Analyses were conducted using the SCCS method for censored, perturbed or curtailed post-event exposure., Participants: Of the 184 transplant recipients having experienced at least one SOT rejection (liver, kidney, lung, heart or pancreas) during the study period from 1 October 2009 to 31 October 2010, 91 participants were included in the main analysis, of which 71 had been exposed to Pandemrix., Main Outcome Measures: Occurrence of SOT rejection during risk (30 and 60 days after any Pandemrix dose) and control periods. Covariates in the CPRD included time since transplantation, seasonal influenza vaccination, bacterial and viral infections, previous SOT rejections and malignancies., Results: The relative incidence (RI) of rejection of any one of the five transplanted organs, adjusted for time since transplantation, was 1.05 (95% CI 0.52 to 2.14) and 0.80 (95% CI 0.42 to 1.50) within 30 and 60 days after vaccination, respectively. Similar estimates were observed for rejection of a kidney only, the most commonly transplanted organ (RI within 30 days after vaccination: 0.85 (95% CI 0.38 to 1.90)). Across various models and sensitivity analyses, RI estimates remained stable and within a consistent range around 1.0., Conclusions: These results suggest a reassuring safety profile for Pandemrix with regard to the risk of rejection in SOT recipients in England and contribute to inform the benefit-risk of AS03-adjuvanted pandemic influenza vaccines in transplanted patients in the event of future pandemics., Trial Registration Number: NCT01715792., (Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to http://www.bmj.com/company/products-services/rights-and-licensing/)

Background: Growing evidence suggests respiratory syncytial virus (RSV) is an important cause of respiratory disease in adults. However, the adult burden remains largely uncharacterized as most RSV studies focus on children, and population-based studies with laboratory-confirmation of infection are difficult to implement. Indirect modelling methods, long used for influenza, can further our understanding of RSV burden by circumventing some limitations of traditional surveillance studies that rely on direct linkage of individual-level exposure and outcome data., Methods: Multiple linear time-series regression was used to estimate RSV burden in the United Kingdom (UK) between 1995 and 2009 among the total population and adults in terms of general practice (GP) episodes (counted as first consultation ≥28 days following any previous consultation for same diagnosis/diagnostic group), hospitalisations, and deaths for respiratory disease, using data from Public Health England weekly influenza/RSV surveillance, Clinical Practice Research Datalink, Hospital Episode Statistics, and Office of National Statistics. The main outcome considered all ICD-listed respiratory diseases and, for GP episodes, related symptoms. Estimates were adjusted for non-specific seasonal drivers of disease using secular cyclical terms and stratified by age and risk group (according to chronic conditions indicating severe influenza risk as per UK recommendations for influenza vaccination). Trial registration NCT01706302 . Registered 11 October 2012., Results: Among adults aged 18+ years an estimated 487,247 GP episodes, 17,799 hospitalisations, and 8,482 deaths were attributable to RSV per average season. Of these, 175,070 GP episodes (36 %), 14,039 hospitalisations (79 %) and 7,915 deaths (93 %) were in persons aged 65+ years. High- versus low-risk elderly were two-fold more likely to have a RSV-related GP episode or death and four-fold more likely be hospitalised for RSV. In most seasons since 2001, more GP episodes, hospitalisations and deaths were attributable to RSV in adults than to influenza., Conclusion: RSV is associated with a substantial disease burden in adults comparable to influenza, with most of the hospitalisation and mortality burden in the elderly. Treatment options and measures to prevent RSV could have a major impact on the burden of RSV respiratory disease in adults, especially the elderly.

Background: Literature on the epidemiology of herpes zoster (HZ) in cancer patients is sparse and does not include the elderly. The objectives of this study were to determine the incidence of HZ and related complications in elderly cancer patients and assess risk factors associated with HZ., Methods: Patients ≥65 years diagnosed with cancer in 1991-2007 were identified from the Surveillance, Epidemiology, and End Results (SEER) cancer registry-Medicare linked database in this retrospective, longitudinal, open cohort study. The observation period spanned from first cancer diagnosis until the end of data availability. A random group of non-cancer Medicare patients served as the comparison group. Cases of HZ and related complications were ascertained from medical claims. Incidence rates (IR) and adjusted IR ratios were reported., Results: The study population consisted of 82,832 hematologic (HEM) and 944,777 solid cancer patients (SOLID). During follow-up, 9.2% of HEM and 6.3% of SOLID were diagnosed with HZ. The IR of HZ was significantly higher in HEM than SOLID (31.0 vs. 14.9 per 1,000 patient-years, p <0.01). The adjusted IR ratio vs. non-cancer elderly patients was 2.4 in HEM and 1.2 in SOLID. The proportion of patients with complications was higher in HEM than SOLID (17.8% vs. 15.8%, p <0.01). Age, gender, race, certain cancer therapies, and immunosuppression were HZ risk factors., Conclusions: Elderly cancer patients run a 1.2-2.4 times higher risk of developing HZ than those without cancer. The rates of HZ and HZ-related complications are significantly higher for hematologic than solid cancer patients.

Background: Influenza and respiratory syncytial virus (RSV) cause substantial mortality from respiratory and other causes in the USA, especially among people aged 65 and older., Objectives: We estimated the influenza-attributable mortality and RSV-attributable mortality in the USA, stratified by age and risk status, using outcome definitions with different sensitivity and specificity., Methods: Influenza- and RSV-associated mortality was assessed from October 1997-March 2009 using multiple linear regression modeling on data obtained from designated government repositories., Results: The main outcomes and measures included mortality outcome definitions-pneumonia and influenza, respiratory broad, and cardiorespiratory disease. A seasonal average of 10,682 (2287-16,363), 19,100 (4862-29,245), and 28,169 (6797-42,316) deaths was attributed to influenza for pneumonia and influenza, respiratory broad, and cardiorespiratory outcome definitions, respectively. Corresponding values for RSV were 6211 (4584-8169), 11,300 (8546-14,244), and 17,199 (13,384-21,891), respectively. A/H3N2 accounted for seasonal average of 71% influenza-attributable deaths; influenza B accounted for most (51-95%) deaths during four seasons. Approximately 70% influenza-attributable deaths occurred in individuals ≥75 years, with increasing mortality for influenza A/H3N2 and B, but not A/H1N1. In children aged 0-4 years, an average of 97 deaths was attributed to influenza (A/H3N2 = 49, B = 33, A/H1N1 = 15) and 165 to respiratory broad outcome definition (RSV). Influenza-attributable mortality was 2.94-fold higher in high-risk individuals., Conclusions: Influenza-attributable mortality was highest in older and high-risk individuals and mortality in children was higher than reported in passive Centers for Disease Control and Prevention surveillance. Influenza B-attributable mortality was higher than A in four of 12 seasons. Our estimates represent an updated assessment of influenza-attributable mortality in the USA., (© 2014 The Authors. Influenza and Other Respiratory Viruses Published by John Wiley & Sons Ltd.)

During the 2013/14 influenza season in Canada, 631 of 654 hospitalisations for laboratory-confirmed influenza enrolled in sentinel hospitals were due to Influenza A. Of the 375 with known subtype, influenza A(H1N1) accounted for 357. Interim unmatched vaccine effectiveness adjusted for age and presence of one or more medical comorbidities was determined by test-negative case-control design to be 58.5% (90% confidence interval (CI): 43.9-69.3%) overall and 57.9% (90% CI: 37.7-71.5) for confirmed influenza A(H1N1).

Objectives: To assess the safety of an AS03-adjuvanted split virion H1N1 (2009) vaccine (Pandemrix) in persons vaccinated during the national pandemic influenza vaccination campaign in the UK., Design: Prospective, cohort, observational, postauthorisation safety study., Setting: 87 general practices forming part of the Medical Research Council General Practice Research Framework and widely distributed throughout England., Participants: A cohort of 9143 individuals aged 7 months to 97 years who received at least one dose of the AS03-adjuvanted H1N1 pandemic vaccine during the national pandemic influenza vaccination campaign in the UK was enrolled. 94% completed the 6-month follow-up. Exclusion criteria were previous vaccination with other H1N1 pandemic vaccine and any child in care., Primary and Secondary Outcome Measures: Medically attended adverse events (MAEs) occurring within 31 days after any dose, serious adverse events (SAEs) and adverse events of special interest (AESIs) following vaccination were collected for all participants. Solicited adverse events (AEs) were assessed in a subset of participants., Results: MAEs were reported in 1219 participants and SAEs in 113 participants during the 31-day postvaccination period. The most frequently reported MAEs and SAEs were consistent with events expected to be reported during the winter season in this population: lower respiratory tract infections, asthma and pneumonia. The most commonly reported solicited AEs were irritability in young children aged <5 years (61.8%), muscle aches in children aged 5-17 years (61.9%) and adults (46.9%). 18 AESIs, experienced by 14 patients, met the criteria to be considered for the observed-to-expected analyses. AESIs above the expected number were neuritis (1 case within 31 days) and convulsions (8 cases within 181 days). There were 41 deaths during the 181-day period after vaccination, fewer than expected., Conclusions: Results indicate that the AS03-adjuvanted H1N1 pandemic vaccine showed a clinically acceptable reactogenicity and safety profile in all age and risk groups studied., Trial Registration: ClinicalTrials.gov, NCT00996853.