Seasonal Influenza Vaccine Effectiveness (SIVE): an observational retrospective cohort study – exploitation of a unique community-based national-linked database to determine the effectiveness of the seasonal trivalent influenza vaccine

Background Globally, seasonal influenza is responsible for an estimated 3 to 5 million cases of severe illness and 250,000 to 500,000 deaths per year. It is uncertain to what extent national vaccination programmes can prevent this morbidity and mortality. Objective To determine the effectiveness of the seasonal trivalent inactivated influenza vaccine. Design We undertook a retrospective observational cohort study. A propensity score model was constructed and adjusted odds ratios (ORs) were calculated to assess differences in vaccine uptake according to a number of patient characteristics. Adjusted illness and mortality hazard ratios (HRs) were estimated from a Cox proportional hazards model adjusted for sex, age, socioeconomic status, smoking status, urban/rural location, clinical at-risk groups (i.e. patients with chronic respiratory, heart, kidney, liver or neurological disease, immunosuppression and diabetes), Charlson comorbidity index, previous pneumococcal and influenza vaccination, and number of previous primary care consultations, prescribed drugs and hospital admissions. We also included nursing home residence and social care support. Vaccine effectiveness (VE) was expressed as a percentage, and represents a reduction in risk provided by the vaccine for a given outcome (e.g. laboratory-confirmed influenza). This was calculated as 1 − HR, where HR is that of the measured clinical outcome in vaccinated compared with unvaccinated individuals. For estimates of VE derived from linked virological swab data, we carried out a nested case–control study design. Setting A national linkage of patient-level primary care, hospital, death certification and virological swab-linked data across nine influenza seasons (2000–9). Participants A nationally representative sample of the Scottish population during 1,767,919 person-seasons of observation. Cases of influenza were confirmed using reverse transcription-polymerase chain reaction (RT-PCR) in a subset of the population ( n = 3323). Interventions Trivalent inactivated seasonal influenza vaccination ( n = 274,071). Main outcome measures VE, pooled across seasons and adjusting for confounders, was estimated by determining laboratory-confirmed influenza, influenza-related morbidity and mortality including primary care influenza-like illnesses, hospitalisation and death from influenza and pneumonia. Results Most vaccines (93.6%; n = 256,474 vaccines) were administered to at-risk patients targeted for vaccination, with a 69.3% uptake among those aged ≥ 65 years (178,754 vaccinations during 258,100 person-seasons). For at-risk patients aged < 65 years there was a 26.2% uptake (77,264 vaccinations during 295,116 person-seasons). VE in preventing RT-PCR laboratory-confirmed influenza was 57.1% [95% confidence interval (CI) 31.3% to 73.3%]. VE was 18.8% (95% CI –103.7% to 67.6%) in patients aged ≥ 65 years and 59.6% (95% CI 21.9% to 79.1%) in those aged < 65 years at risk of serious complications from influenza. In the matched analysis (156,096 person-seasons), adjusted VE for reducing primary care consultations for influenza-like illnesses was 16.3% (95% CI 5.7% to 26.0%). VE in reducing hospitalisations was 19.3% for influenza and pneumonia (95% CI 8.3% to 29.1%) and 26.7% for pneumonia and chronic obstructive pulmonary disease (95% CI 19.8% to 32.9%). VE in reducing death due to influenza and pneumonia was 37.9% (95% CI 29.5% to 45.4%). Conclusions Few countries' health systems allow for the integrated and accessible data recording that made this study possible and made it feasible to collate centrally almost all hospitalisations and deaths attributed to influenza, thereby allowing completeness of reporting. Using these data, we found most influenza vaccines were administered to those at risk of serious complications from influenza. In a nationally representative cohort we found that the vaccine was associated with a significant decrease in the risk of RT-PCR-confirmed influenza (the decrease was substantial particularly for at-risk patients aged < 65 years) and complications arising from influenza (where more modest decreases were found). Although the modest size of our cohort made it possible to collate centrally almost all cases of influenza-related disease, analysis of subgroups (in particular older age groups) or by individual season resulted in poorer precision and wide CIs. Any future work should therefore aim to address this issue by ensuring adequate power to test VE in these subgroups of patients, while minimising the effect of bias, such as health-seeking behaviour. Funding The National Institute for Health Research Health Services and Delivery Research programme.