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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

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.

Rotavirus (RV) is the most common cause of acute gastroenteritis in children5 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.The aim of this study was to discuss spontaneous data from the GSK worldwide safety database on IS post-Rotarix administration.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.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.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.Rotavirus (RV) is the most common cause of acute gastroenteritis and a major cause of death in young children worldwide. Vaccination has been instrumental in reducing the impact of RV disease. Real-world evidence suggests an increased risk of intussusception (an infrequent type of bowel obstruction) in infants following RV vaccination. We reviewed IS cases reported spontaneously worldwide in children following a two-dose vaccination with the human RV vaccine (Rotarix, GlaxoSmithKline [GSK]) since its launch in 2004. We observed that (1) IS occurred more frequently 7 days after the first dose and, to a lesser extent, after the second dose; (2) boys were more frequently affected than girls (56.3%); (3) of 862 confirmed reported cases, 557 required hospitalisation; and (4) surgical intervention was required for 294 of 557 hospitalised cases. We used statistical analysis to assess whether the number of cases observed would be higher or lower than the natural occurrence of IS (irrespective of vaccination). These results were in line with the known RV vaccine safety profile. It is important to constantly monitor the real-world safety profile of RV vaccines in the postmarketing setting. Since the outcomes of early management of IS are favourable compared with delayed management, healthcare professionals should inform parents to seek immediate medical advice if they observe unusual behaviour in their vaccinated child. In conclusion, our analyses on data of a large patient pool for this rare event reinforce the favourable safety profile of human RV vaccine and the benefits of vaccination in young children.

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.

The effectiveness of influenza vaccination in reducing influenza-related hospitalizations among patients with COPD is not well described, and influenza vaccination uptake remains suboptimal.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.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 age75 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]).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.ClinicalTrials.govNo.:NCT01517191; URL www.clinicaltrials.gov.

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 ( 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.

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

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.

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., Graphical Abstract

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.

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 RR2-10.1136/bmjopen-2016-015469

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

SUMMARYInfluenza is rarely laboratory-confirmed and the outpatient influenza burden is rarely studied due to a lack of suitable data. We used the Clinical Practice Research Datalink (CPRD) and surveillance data from Public Health England in a linear regression model to assess the number of persons consulting UK general practitioners (GP episodes) for respiratory illness, otitis media and antibiotic prescriptions attributable to influenza during 14 seasons, 1995–2009. In CPRD we ascertained influenza vaccination status in each season and risk status (conditions associated with severe influenza outcomes). Seasonal mean estimates of influenza-attributable GP episodes in the UK were 857 996 for respiratory disease including 68 777 for otitis media, with wide inter-seasonal variability. In an average season, 2·4%/0·5% of children aged

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.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 or65 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.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 adults65 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%).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.

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.

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.

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.

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

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.

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.

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. Electronic supplementary material The online version of this article (doi:10.1186/s12879-015-1218-z) contains supplementary material, which is available to authorized users.

Background Antiviral treatment of influenza in outpatient settings is associated with modest improvement in outcomes but benefit in inpatient settings remains unclear. We assessed the impact of antiviral treatment on the severe outcomes death and intensive care unit (ICU) admission and/or need for mechanical ventilation (MV) in hospitalized influenza patients. Methods Patients admitted to hospitals of the CIRN SOS Network with an acute respiratory illness from 2011/12–2013/14 who tested polymerase chain reaction (PCR) positive for influenza were included. Demographic and medical information were obtained from patient interview or the medical chart. Main outcomes of interest were ICU admission and/or need for MV, and death. Logistic regression with backwards stepwise selection was used to estimate odds ratios (ORs) and 95% confidence limits (CIs) for the association between antiviral use and severe outcomes overall, and stratified by time from symptom onset to antiviral start ( Results Over 3 influenza seasons, 4,679 patients were enrolled; 59% were aged ≥65 years, 52% were female, and 89% had a comorbidity. Influenza vaccination status was available for 4,019 (86%) patients, of whom 1,796 (45%) had received current season vaccine. Of 4,679 patients, 16% of patients were admitted to ICU and/or required MV and 9% died. Overall, 54% of hospitalized influenza patients received an antiviral; mean time from the onset of symptoms to antiviral start was 4.28 days (range: 0–21 days). Treatment with antivirals was associated with a significant reduction in admission to ICU and/or need for MV (OR = 0.10; 95% CI: 0.08–0.13; P Conclusion In this study, treatment with antivirals in hospitalized patients with influenza was associated with a significant reduction in ICU admission and MV, even when initiated a mean of 4.28 days from symptom onset. Reduction in death was not demonstrated. These findings support current recommendations for antiviral use in hospitalized adults and suggest increased compliance with these guidelines may reduce morbidity and cost. Disclosures M. K. Andrew, GSK: Grant Investigator, Research grant; Pfizer: Grant Investigator, Research grant; Sanofi-Pasteur: Grant Investigator, Research grant; A. Chit, Sanofi pasteur: Employee, Salary; G. Dos Santos, GSK: Employee, Salary; Business and Decision Life Sciences (Contractor for GSK Vaccines): Independent Contractor, Salary; M. Elsherif, Canadian Institutes of Health Research: Investigator, Research grant; Public Health Agency of Canada: Investigator, Research grant; GSK: Investigator, Research grant; F. Haguinet, GSK: Employee, Salary; S. A. Halperin, GSK: Scientific Advisor, Consulting fee; GSK: Grant Investigator, Research grant; T. Hatchette, GSK: Grant Investigator, Grant recipient; Pfizer: Grant Investigator, Grant recipient; Abbvie: Speaker for a talk on biologics and risk of TB reactivation, Speaker honorarium; B. Ibarguchi, GSK: Employee, Salary; J. M. Langley, GSK: Investigator, Research grant; Canadian Institutes of Health Research: Investigator, Research grant; J. Mcelhaney, GSK: Scientific Advisor, Honorarium to institution; Sanofi pasteur: Scientific Advisor, Honorarium to institution; A. Mcgeer, Hoffman La Roche: Investigator, Research grant; GSK: Investigator, Research grant; Sanofi pasteur: Investigator, Research grant; J. Powis, Merck: Grant Investigator, Research grant; GSK: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant; Synthetic Biologicals: Investigator, Research grant; M. Semret, GSK: Investigator, Research grant; Pfizer: Investigator, Research grant; V. Shinde, Novavax: Employee, Salary; GSK: Shareholder, Stocks; GSK: Employee, Salary; S. Trottier, Canadian Institutes of Health Research: Investigator, Research grant; L. Valiquette, GSK: Investigator, Research grant; S. McNeil, GSK: Contract Clinical Trials and Grant Investigator, Research grant; Merck: Contract Clinical Trials and Speaker’s Bureau, Speaker honorarium; Novartis: Contract Clinical Trials, No personal renumeration; Sanofi pasteur: Contract Clinical Trials, No personal renumeration

Background Recent controversy has arisen from observational studies suggesting a potential negative association between prior influenza vaccination and subsequent influenza vaccine effectiveness (VE). As immunologic theories suggest this impact could vary by season/strain, we investigated this association over 4 influenza seasons in Canada. Methods The CIRN SOS Network prospectively enrolled laboratory-confirmed influenza cases and influenza-negative controls admitted to participating hospitals. Using a test-negative control design, matched conditional logistic regression modeling stratifying participants into 4 groups (not vaccinated current or prior season [referent], vaccinated prior season only, vaccinated current season only, and vaccinated both current and prior season) was used to calculate odds ratios (OR) to estimate the effect of vaccination status on influenza-related hospitalization (VE= 1-OR x100). We assessed VE overall and stratified by strain (A/H3N2, A/H1N1, and influenza B) for 4 influenza seasons in Canada: 2011/2012–2014/2015. Results Although impact of prior vaccination varied, the largest strain-specific impacts were observed in the H3N2 dominant seasons 2012/2013 and 2014/2015, seasons where the H3N2 vaccine component was matched, and mismatched, respectively, to the circulating strain. In 12/13, adjusted VE against influenza H3N2 hospitalization was 58.6% (95% Confidence Interval [CI]: 32.5–74.7%) for patients vaccinated in current season only, relative to 30.9% (10.8–46.5%) among those vaccinated in both prior and current season; VE against influenza B hospitalization in 12/13 was 83.2% (18.9–96.5%) in current season only vaccinees and 54.1% (-6.0–80.2%) in both seasons vaccinees. In 14/15, H3N2 VE was 35.3% (-32.6–68.5%) in current season only vaccinees and -8.3% (-56.7–25.1%) in both seasons vaccinees. Conclusion While our findings support a possible negative association between prior influenza vaccination and subsequent season VE against some strains in certain seasons, non-statistically significant reductions in VE were observed. Future prospective studies, using varying methodology to examine this association and to explore contributing biological/immunological mechanisms, are critical to inform immunization policy. Disclosures M. K. Andrew, GSK: Grant Investigator, Research grant; Pfizer: Grant Investigator, Research grant; Sanofi-Pasteur: Grant Investigator, Research grant; T. Hatchette, GSK: Grant Investigator, Grant recipient; Pfizer: Grant Investigator, Grant recipient; Abbvie: Speaker for a talk on biologics and risk of TB reactivation, Speaker honorarium; G. Dos Santos, GSK: Employee, Salary; Business and Decision Life Sciences (Contractor for GSK Vaccines): Independent Contractor, Salary; M. Elsherif, Canadian Institutes of Health Research: Investigator, Research grant; Public Health Agency of Canada: Investigator, Research grant; GSK: Investigator, Research grant; F. Haguinet, GSK: Employee, Salary; J. Mcelhaney, GSK: Scientific Advisor, Honorarium to institution; sanofi pasteur: Scientific Advisor, Honorarium to institution; A. Mcgeer, Hoffman La Roche: Investigator, Research grant; GSK: Investigator, Research grant; sanofi pasteur: Investigator, Research grant; J. Powis, Merck: Grant Investigator, Research grant; GSK: Grant Investigator, Research grant; Roche: Grant Investigator, Research grant; Synthetic Biologicals: Investigator, Research grant; M. Semret, GSK: Investigator, Research grant; Pfizer: Investigator, Research grant; R. Sharma, GSK: Employee and Shareholder, Salary; V. Shinde, Novavax: Employee, Salary; GSK: Shareholder, Stocks; GSK: Employee, Salary; S. Trottier, Canadian Institutes of Health Research: Investigator, Research grant; S. McNeil, GSK: Contract Clinical Trials and Grant Investigator, Research grant; Merck: Contract Clinical Trials and Speaker’s Bureau, Speaker honorarium; Novartis: Contract Clinical Trials, No personal renumeration; sanofi pasteur: Contract Clinical Trials, No personal renumeration

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

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.Prospective, cohort, observational, postauthorisation safety study.87 general practices forming part of the Medical Research Council General Practice Research Framework and widely distributed throughout England.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.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.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 aged5 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.Results indicate that the AS03-adjuvanted H1N1 pandemic vaccine showed a clinically acceptable reactogenicity and safety profile in all age and risk groups studied.ClinicalTrials.gov, NCT00996853.

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

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 Electronic supplementary material The online version of this article (doi:10.1186/s12889-016-3128-4) contains supplementary material, which is available to authorized users.

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). .

The 2014/15 influenza season in Canada has been characterised to date by early and intense activity dominated by influenza A(H3N2). A total of 99.0% (593/599) hospitalisations for laboratory-confirmed influenza with a known influenza virus type enrolled in sentinel hospitals of the Serious Outcomes Surveillance Network of the Canadian Immunization Research Network were due to influenza A. Of the 216 with a known subtype, influenza A(H3N2) accounted for 99.1% (n=214). Interim unmatched vaccine effectiveness (VE) estimates adjusted for age and presence of one or more medical comorbidities were determined by test-negative case-control design to be ?16.8% (90% confidence interval (CI): ?48.9 to 8.3) overall and ?22.0% (90% CI: ?66.5 to 10.7) for laboratory-confirmed influenza A(H3N2). Among adults?aged under?65 years, the overall VE was 10.8% (90% CI: ?50.2 to 47.0) while in adults?aged 65 years or older, the overall VE was ?25.4% (90% CI: ?65.0 to 4.6). .