François Haguinet

Estimates of mortality attributable to influenza and RSV in the United States during 1997–2009 by influenza type or subtype, age, cause of death, and risk status

Influenza and respiratory syncytial virus (RSV) cause substantial mortality from respiratory and other causes in the USA, especially among people aged 65 and older.

Interim estimates of 2014/15 influenza vaccine effectiveness in preventing laboratory-confirmed influenza-related hospitalisation from the Serious Outcomes Surveillance Network of the Canadian Immunization Research Network, January 2015.

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). .

Interim estimates of 2013/14 influenza clinical severity and vaccine effectiveness in the prevention of laboratory-confirmed influenza-related hospitalisation, Canada, February 2014

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).

Modelling estimates of the burden of respiratory syncytial virus infection in children in the UK

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.

Influenza-attributable burden in United Kingdom primary care

SUMMARY Influenza 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 <5 years and 1·3%/0·1% of seniors aged ⩾75 years had a GP episode for respiratory illness attributed to influenza A/B. Two-thirds of influenza-attributable GP episodes were estimated to result in prescription of antibiotics. These estimates are substantially greater than those derived from clinically reported influenza-like illness in surveillance programmes. Because health service costs of influenza are largely borne in general practice, these are important findings for cost-benefit assessment of influenza vaccination programmes.

Effect of the adjuvanted (AS03) A/H1N1 2009 pandemic influenza vaccine on the risk of rejection in solid organ transplant recipients in England: a self-controlled case series

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.

The Importance of Frailty in the Assessment of Influenza Vaccine Effectiveness Against Influenza-Related Hospitalization in Elderly People

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.

Safety of AS03-adjuvanted split-virion H1N1 (2009) pandemic influenza vaccine: a prospective cohort study

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.

Risk of solid organ transplant rejection following vaccination with seasonal trivalent inactivated influenza vaccines in England: A self-controlled case-series.

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.

Post-authorisation passive enhanced safety surveillance of seasonal influenza vaccines: protocol of a pilot study in England

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.