Early signal detection of adverse events following influenza vaccination using proportional reporting ratio, Victoria, Australia.

INTRODUCTION: Timely adverse event following immunisation (AEFI) signal event detection is essential to minimise further vaccinees receiving unsafe vaccines. We explored the proportional reporting ratio (PRR) ability to detect two known signal events with influenza vaccines with the aim of providing a model for prospective routine signal detection and improving vaccine safety surveillance in Australia. METHODS: Passive AEFI surveillance reports from 2008-2017 relating to influenza vaccines were accessed from the Australian SAEFVIC (Victoria) database. Proportional reporting ratios were calculated for two vaccine-event categories; fever and allergic AEFI. Signal detection sensitivity for two known signal events were determined using weekly data; cumulative data by individual year and; cumulative for all previous years. Signal event thresholds of PRR ≥2 and Chi-square ≥4 were applied. RESULTS: PRR provided sensitive signal detection when calculated cumulatively by individual year or by all previous years. Known signal events were detected 15 and 11 days earlier than traditional methods used at the time of the actual events. CONCLUSION: Utilising a single jurisdiction's data, PRR improved vaccine pharmacovigilance and showed the potential to detect important safety signals much earlier than previously. It has potential to maximise immunisation safety in Australia. This study progresses the necessary work to establish national cohesion for passive surveillance signal detection and strengthen routine Australian vaccine pharmacovigilance.

Estimating Influenza Vaccine Effectiveness With the Test-Negative Design Using Alternative Control Groups: A Systematic Review and Meta-Analysis.

One important assumption in case-control studies is that control selection should be independent of exposure. Nevertheless, it has been hypothesized that virus interference might lead to a correlation between receipt of influenza vaccination and increased risk of infection with other respiratory viruses. We investigated whether such a phenomenon might affect a study design commonly used to estimate influenza vaccine effectiveness (VE). We searched publications in MEDLINE, PubMed, and Web of Science. We identified 12 studies using the test-negative design (2011-2017) that reported VE estimates separately derived by 3 alternative control groups: 1) all patients testing negative for influenza (FLU), VEFLU-; 2) patients who tested positive for other/another respiratory virus (ORV), VEORV+; and 3) patients who tested negative for all viruses in the panel (PAN), VEPAN-. These included VE estimates from 7 countries for all age groups from 2003/2004 to 2013/2014. We observed no difference in vaccination coverage between the ORV-positive and PAN-negative control groups. A total of 63 VEFLU- estimates, 62 VEORV+ estimates, and 33 VEPAN- estimates were extracted. Pooled estimates of the difference in VE (ΔVE) were very similar between groups. In meta-regression, no association was found between the selection of control group and VE estimates. In conclusion, we did not find any differences in VE estimates based on the choice of control group.

Evaluation of 'SAEFVIC', A Pharmacovigilance Surveillance Scheme for the Spontaneous Reporting of Adverse Events Following Immunisation in Victoria, Australia.

INTRODUCTION: Australia is traditionally an early adopter of vaccines, therefore comprehensive and effective post-licensure vaccine pharmacovigilance is critical to maintain confidence in immunisation, both nationally and internationally. With adverse event following immunisation (AEFI) surveillance the responsibility of Australian jurisdictions, Victoria operates an enhanced passive AEFI surveillance system integrated with clinical services, called 'SAEFVIC' (Surveillance of Adverse Events Following Vaccination In the Community). OBJECTIVE: The aim of this study was to evaluate Victoria's current AEFI surveillance system 'SAEFVIC' and inform ongoing quality improvement of vaccine pharmacovigilance in Victoria and Australia. METHODS: We conducted a retrospective structured desktop evaluation of AEFI reporting received by SAEFVIC from 2007 to 2014, to evaluate the system according to its stated objectives, i.e. to improve AEFI reporting; provide AEFI signal detection; and to maintain consumer confidence in vaccination. RESULTS: AEFI reporting has tripled since SAEFVIC commenced (incidence risk ratio [IRR] 3.04, 95% confidence interval [CI] 2.35-3.93), raising Victoria to be the lead jurisdiction by AEFI reporting volume and to rank third by population reporting rate nationally. The largest increase was observed in children. Data were utilised to investigate potential signal events and inform vaccine policy. Signal detection required clinical suspicion by surveillance nurses, or prior vaccine-specific concerns. Subsequent vaccination post-AEFI was documented for 56.2% (95% CI 54.1-58.4) of reports, and the proportion of children due or overdue for vaccination was 2.3% higher for those reporting AEFI compared with the general population. CONCLUSION: SAEFVIC has improved AEFI surveillance, facilitates signal investigation and validation, and supports consumer confidence in immunisation. Expansion of the system nationally has the potential to improve capacity and capability of vaccine pharmacovigilance, particularly through data consistency and jurisdictional comparability in Australia.

Debate Regarding Oseltamivir Use for Seasonal and Pandemic Influenza.

A debate about the market-leading influenza antiviral medication, oseltamivir, which initially focused on treatment for generally mild illness, has been expanded to question the wisdom of stockpiling for use in future influenza pandemics. Although randomized controlled trial evidence confirms that oseltamivir will reduce symptom duration by 17-25 hours among otherwise healthy adolescents and adults with community-managed disease, no randomized controlled trials have examined the effectiveness of oseltamivir against more serious outcomes. Observational studies, although criticized on methodologic grounds, suggest that oseltamivir given early can reduce the risk for death by half among persons hospitalized with confirmed infection caused by influenza A(H1N1)pdm09 and influenza A(H5N1) viruses. However, available randomized controlled trial data may not be able to capture the effect of oseltamivir use among hospitalized patients with severe disease. We assert that data on outpatients with relatively mild disease should not form the basis for policies on the management of more severe disease.

Influenza vaccine effectiveness in general practice and in hospital patients in Victoria, 2011-2013.

OBJECTIVE: To compare influenza vaccine effectiveness in the general practice and hospital settings. DESIGN: Analysis of annual case test-negative studies. SETTING: Victorian sentinel hospitals and general practices, 2011-2013. PARTICIPANTS: Patients presenting to general practitioners, or those admitted to hospital with an influenza-like illness who were tested for influenza using a polymerase chain reaction assay. Cases were patients with a positive test result for influenza; non-cases (controls) had a negative test result. MAIN OUTCOME MEASURES: Vaccine effectiveness against laboratory-confirmed influenza. RESULTS: Hospitalised patients were on average older and reported a higher proportion of comorbidities than general practice patients. The pooled estimate of influenza vaccine effectiveness against laboratory-confirmed infection for the 3 years was 50% (95% CI, 26%-66%) for general practice patients and 39% (95% CI, 28%-47%) for patients admitted to hospital. CONCLUSIONS: Influenza vaccines appeared to be similarly modestly effective in the general practice and hospital settings. Influenza vaccination appears to prevent hospital admission by preventing symptomatic infection rather than by attenuating the severity of illness.

Flutracking weekly online community survey of influenza-like illness annual report, 2015.

Flutracking is a national online community influenza-like illness (ILI) surveillance system that monitors weekly ILI activity and impact in the Australian community. This article reports on the 2015 findings from Flutracking. From 2014 to 2015 there was a 38.5% increase in participants to 27,824 completing at least 1 survey with a peak weekly response of 25,071 participants. The 2015 Flutracking national ILI weekly fever and cough percentages peaked in late August at 5.0% in the unvaccinated group, in the same week as the national counts of laboratory confirmed influenza peaked. A similar percentage of Flutracking participants took two or more days off from work or normal duties in 2015 (peak level 2.3%) compared with 2014 (peak level 2.5%) and the peak weekly percentage of participants seeking health advice was 1.6% in both 2014 and 2015. Flutracking fever and cough peaked in the same week as Influenza Complications Alert Network surveillance system influenza hospital admissions. The percentage of Flutracking participants aged 5 to 19 years with cough and fever in 2015 was the highest since 2011. The 2015 season was marked by a transition to predominantly influenza B strain circulation, which particularly affected younger age groups. However, for those aged 20 years and over, the 2015 national Flutracking influenza season was similar to 2014 in community ILI levels and impact.

Influenza Vaccine Effectiveness and Uptake in Children at Risk of Severe Disease.

BACKGROUND: Data demonstrating the effectiveness of inactivated trivalent influenza vaccine (TIV) for children at increased risk of severe disease are limited. Our objective was to determine the effectiveness of TIV in children with risk factors for severe disease and to compare vaccine uptake, parental attitudes and prescriber recommendations in children with and without risk factors for severe disease. METHODS: Children aged 6-59 months presenting for emergency care (2008 to 2014) with an influenza-like illness were eligible. Influenza polymerase chain reaction/culture was performed on nasopharyngeal samples. Vaccination status was confirmed via the national register and/or vaccine providers. The test-negative design was used to estimate vaccine effectiveness (VE). Risk factors, parental attitudes and prescriber recommendations were assessed by parental questionnaire. RESULTS: Two thousand seven hundred twenty-three children were recruited. Risk factors for severe disease included comorbid medical conditions (11.6%), preterm birth (13.0%) and indigeneity (5.0%). Influenza was identified in 546 (20.1%) participants. Overall VE (2008 and 2010 to 2014) was 70.0% (95% confidence interval: 47.7 to 82.9); VE for children with medical comorbidities, children born preterm and children <2 years were 82.5% (14.6 to 96.4), 79.2% (10.9 to 95.1) and 84.7% (49.6 to 95.3), respectively. After adverse events in 2010, the number of children fully vaccinated with TIV declined significantly. This included children with and without risk factors for severe disease. Attitudes were similar in parents of children with and without risk factors for severe disease. CONCLUSIONS: VE for TIV in young children with and without risk factors for severe disease was ≥70%. Despite this, participation in the preschool influenza vaccination program remains low with parents and prescribers unconvinced of the benefits and safety of TIV.

Influenza vaccine effectiveness for hospital and community patients using control groups with and without non-influenza respiratory viruses detected, Auckland, New Zealand 2014.

BACKGROUND: We aimed to estimate the protection afforded by inactivated influenza vaccine, in both community and hospital settings, in a well characterised urban population in Auckland during 2014. METHODS: We used two different comparison groups, all patients who tested negative for influenza and only those patients who tested negative for influenza and had a non-influenza respiratory virus detected, to calculate the vaccine effectiveness in a test negative study design. Estimates were made separately for general practice outpatient consultations and hospitalised patients, stratified by age group and by influenza type and subtype. Vaccine status was confirmed by electronic record for general practice patients and all respiratory viruses were detected by real time polymerase chain reaction. RESULTS: 1039 hospitalised and 1154 general practice outpatient consultations met all the study inclusion criteria and had a respiratory sample tested for influenza and other respiratory viruses. Compared to general practice patients, hospitalised patients were more likely to be very young or very old, to be Maori or Pacific Islander, to have a low income and to suffer from chronic disease. Vaccine effectiveness (VE) adjusted for age and other participant characteristics using all influenza negative controls was 42% (95% CI: 16 to 60%) for hospitalised and 56% (95% CI: 35 to 70%) for general practice patients. The vaccine appeared to be most effective against the influenza A(H1N1)pdm09 strain with an adjusted VE of 62% (95% CI:38 to 77%) for hospitalised and 59% (95% CI:36 to 74%) for general practice patients, using influenza virus negative controls. Similar results found when patients testing positive for a non-influenza respiratory virus were used as the control group. CONCLUSION: This study contributes to validation of the test negative design and confirms that inactivated influenza vaccines continue to provide modest but significant protection against laboratory-confirmed influenza.

Transmission of the First Influenza A(H1N1)pdm09 Pandemic Wave in Australia Was Driven by Undetected Infections: Pandemic Response Implications.

BACKGROUND: During the first wave of influenza A(H1N1)pdm09 in Victoria, Australia the rapid increase in notified cases and the high proportion with relatively mild symptoms suggested that community transmission was established before cases were identified. This lead to the hypothesis that those with low-level infections were the main drivers of the pandemic. METHODS: A deterministic susceptible-infected-recovered model was constructed to describe the first pandemic wave in a population structured by disease severity levels of asymptomatic, low-level symptoms, moderate symptoms and severe symptoms requiring hospitalisation. The model incorporated mixing, infectivity and duration of infectiousness parameters to calculate subgroup-specific reproduction numbers for each severity level. RESULTS: With stratum-specific effective reproduction numbers of 1.82 and 1.32 respectively, those with low-level symptoms, and those with asymptomatic infections were responsible for most of the transmission. The effective reproduction numbers for infections resulting in moderate symptoms and hospitalisation were less than one. Sensitivity analyses confirmed the importance of parameters relating to asymptomatic individuals and those with low-level symptoms. CONCLUSIONS: Transmission of influenza A(H1N1)pdm09 was largely driven by those invisible to the health system. This has implications for control measures--such as distribution of antivirals to cases and contacts and quarantine/isolation--that rely on detection of infected cases. Pandemic plans need to incorporate milder scenarios, with a graded approach to implementation of control measures.

The effectiveness of influenza vaccination in preventing hospitalisation in children in Western Australia.

BACKGROUND: There is increasing evidence demonstrating influenza vaccine effectiveness (VE) in the prevention of influenza in children, including the very young. Data demonstrating the effectiveness against severe disease, including hospitalisation, are limited. We aimed to determine the VE of the southern hemisphere trivalent inactivated influenza vaccine (TIV) in preventing laboratory-confirmed influenza-associated hospitalisation in children. PATIENTS AND METHODS: Laboratory records were used to identify children with confirmed influenza hospitalised (i.e., cases) during a 5 year period (2008, 2010-2013) at the only tertiary paediatric facility in Western Australia. Cases and time, age and ward matched controls were retrospectively reviewed to determine risk factors, vaccination status and outcome. Adjusted odds ratios and VE estimates were derived using conditional logistic regression models. RESULTS: Three hundred and eighty five cases were identified (Influenza A, 64.9%; Influenza B, 35.1%). Influenza-like illness and pneumonia were the most frequent presentation (74.5% and 23.9%, respectively). The median length of stay was 2 days (Interquartile range 1-4 days). Twenty children (5.2%) required admission to the intensive care unit. Vaccine uptake in cases and controls was low (4.9% and 8.5%, respectively). Three hundred and six case-control pairs were included in the VE analysis, of which 19 pairs were informative with discrepant vaccination status. VE (fully vaccinated vs. unvaccinated) was estimated to be 62.3% (95% CI: -6.6%, 86.7%). CONCLUSION: In this study, the point estimate for the effectiveness of TIV in preventing influenza-associated hospitalisation in children was similar to that reported for emergency or outpatient attended, laboratory-confirmed influenza, yet confidence intervals were wide. Vaccine uptake remains low. Studies, enroling larger numbers of children, ideally with higher vaccine uptake, are needed to provide additional evidence on TIV protection against influenza hospitalisation in children.

Hospitalization Fatality Risk of Influenza A(H1N1)pdm09: A Systematic Review and Meta-Analysis.

During the 2009 influenza pandemic, uncertainty surrounding the severity of human infections with the influenza A(H1N1)pdm09 virus hindered the calibration of the early public health response. The case fatality risk was widely used to assess severity, but another underexplored and potentially more immediate measure is the hospitalization fatality risk (HFR), defined as the probability of death among H1N1pdm09 cases who required hospitalization for medical reasons. In this review, we searched for relevant studies published in MEDLINE (PubMed) and EMBASE between April 1, 2009, and January 9, 2014. Crude estimates of the HFR ranged from 0% to 52%, with higher estimates from tertiary-care referral hospitals in countries with a lower gross domestic product, but in wealthy countries the estimate was 1%-3% in all settings. Point estimates increased substantially with age and with lower gross domestic product. Early in the next pandemic, estimation of a standardized HFR may provide a picture of the severity of infection, particularly if it is presented in comparison with a similarly standardized HFR for seasonal influenza in the same setting.

Inter-Seasonal Influenza is Characterized by Extended Virus Transmission and Persistence.

The factors that determine the characteristic seasonality of influenza remain enigmatic. Current models predict that occurrences of influenza outside the normal surveillance season within a temperate region largely reflect the importation of viruses from the alternate hemisphere or from equatorial regions in Asia. To help reveal the drivers of seasonality we investigated the origins and evolution of influenza viruses sampled during inter-seasonal periods in Australia. To this end we conducted an expansive phylogenetic analysis of 9912, 3804, and 3941 hemagglutinnin (HA) sequences from influenza A/H1N1pdm, A/H3N2, and B, respectively, collected globally during the period 2009-2014. Of the 1475 viruses sampled from Australia, 396 (26.8% of Australian, or 2.2% of global set) were sampled outside the monitored temperate influenza surveillance season (1 May - 31 October). Notably, rather than simply reflecting short-lived importations of virus from global localities with higher influenza prevalence, we documented a variety of more complex inter-seasonal transmission patterns including "stragglers" from the preceding season and "heralds" of the forthcoming season, and which included viruses sampled from clearly temperate regions within Australia. We also provide evidence for the persistence of influenza B virus between epidemic seasons, in which transmission of a viral lineage begins in one season and continues throughout the inter-seasonal period into the following season. Strikingly, a disproportionately high number of inter-seasonal influenza transmission events occurred in tropical and subtropical regions of Australia, providing further evidence that climate plays an important role in shaping patterns of influenza seasonality.

Understanding influenza vaccine protection in the community: an assessment of the 2013 influenza season in Victoria, Australia.

BACKGROUND: The influenza virus undergoes frequent antigenic drift, necessitating annual review of the composition of the influenza vaccine. Vaccination is an important strategy for reducing the impact and burden of influenza, and estimating vaccine effectiveness (VE) each year informs surveillance and preventative measures. We aimed to describe the influenza season and to estimate the effectiveness of the influenza vaccine in Victoria, Australia, in 2013. METHODS: Routine laboratory notifications, general practitioner sentinel surveillance (including a medical deputising service) data, and sentinel hospital admission surveillance data for the influenza season (29 April to 27 October 2013) were collated in Victoria, Australia, to describe influenza-like illness or confirmed influenza during the season. General practitioner sentinel surveillance data were used to estimate VE against medically-attended laboratory confirmed influenza. VE was estimated using the case test negative design as 1-adjusted odds ratio (odds of vaccination in cases compared with controls) × 100%. Cases tested positive for influenza while non-cases (controls) tested negative. Estimates were adjusted for age group, week of onset, time to swabbing and co-morbidities. RESULTS: The 2013 influenza season was characterised by relatively low activity with a late peak. Influenza B circulation preceded that of influenza A(H1)pdm09, with very little influenza A(H3) circulation. Adjusted VE for all influenza was 55% (95%CI: -11, 82), for influenza A(H1)pdm09 was 43% (95%CI: -132, 86), and for influenza B was 56% (95%CI: -51, 87) Imputation of missing data raised the influenza VE point estimate to 64% (95%CI: 13, 85). CONCLUSIONS: Clinicians can continue to promote a positive approach to influenza vaccination, understanding that inactivated influenza vaccines prevent at least 50% of laboratory-confirmed outcomes in hospitals and the community.

The impact of pandemic A(H1N1)pdm09 influenza and vaccine-associated adverse events on parental attitudes and influenza vaccine uptake in young children.

INTRODUCTION: Parental attitudes towards vaccination significantly influence vaccine uptake. The A(H1N1)pdm09 influenza pandemic was followed in 2010 by an unprecedented increase in febrile reactions in children receiving trivalent inactivated influenza vaccine manufactured by bioCSL. Uptake of TIV in children <5 years in Western Australia (WA) decreased in 2010 and has remained low. The impact of pandemic A(H1N1)pdm09 and adverse-events on parental attitudes towards vaccination is uncertain. MATERIALS AND METHODS: A parental attitudes survey towards influenza illness and vaccination was conducted as part of the West Australian Influenza Vaccine Effectiveness study. Vaccination status was assessed by parental interview and confirmed by the national register and/or vaccine providers. Parental attitudes from vaccinated and unvaccinated children and attitudes in 2008-2009 and 2010-2012 were compared. Principal Component Analysis was conducted to determine core attitudes that influenced vaccine uptake. RESULTS: Vaccination history and parental attitude surveys were available from 2576 children. Parents of fully vaccinated children less frequently stated that influenza was a mild disease, more frequently stated that influenza vaccine was safe and were less frequently worried about vaccine side effects. Uptake of influenza vaccine decreased significantly from 2010 onwards. From 2010, parents were less concerned about severe influenza, but more concerned about vaccine side effects and safety. Despite this significant shift in attitudes towards influenza vaccine, parental acceptance of vaccines on the national immunisation program did not change. Principal Component Analysis revealed that attitudes around vaccine safety and efficacy were the most important attitudes impacting on vaccine uptake. CONCLUSIONS: Parental attitudes to influenza vaccine changed from 2010. Confidence in the WA preschool influenza vaccination program remains low yet appeared unchanged for other vaccines. Restoring public confidence in childhood influenza vaccination is needed before uptake can be improved.