Seasonal influenza vaccine effectiveness in asthma

Introduction Influenza is a seasonal viral respiratory infection that causes considerable morbidity and mortality, particularly in individuals with chronic medical conditions such as asthma. Vaccination is one of the most effective available preventive measures against influenza and is recommended for children and adults with asthma. Despite the longstanding recommendation in developed countries that people with asthma be vaccinated against influenza, less than half of the asthma population eligible for the vaccine are immunised every year. Some of the reasons for this suboptimal coverage include doubts about the benefits of the vaccines and safety concerns amongst both healthcare providers and asthma patients. In 2012, a Cochrane systematic review concluded that evidence from randomised controlled trials (RCTs) on the effect of influenza vaccines on asthma-related clinical outcomes from influenza infection is unclear. However, the review confirmed that influenza vaccination was safe. Therefore, this doctoral research program had the following main aims: 1. To conduct rigorous secondary research in the form of a systematic review to identify, appraise and integrate evidence, not limited by study design, for vaccine protection in asthma against influenza infection and influenza-related clinical outcomes. This review also included and appraised evidence on vaccination safety in people with asthma. 2. To conduct primary research work to fill evidence gaps identified in the systematic review by providing more accurate estimates of the protective effects of influenza vaccines against influenza infection in people with asthma over multiple influenza seasons using routinely collected data from Scotland. 3. To estimate the effectiveness of influenza vaccination in preventing laboratory-confirmed influenza in people with asthma, and variation in vaccine effectiveness (VE) between influenza seasons, influenza types/subtypes, influenza vaccine types and other asthma individuals’ characteristics. To measure the vaccine uptake and explore the main characteristics of people with asthma related to influenza vaccination uptake using routinely collected data from community and secondary healthcare level settings. Methods A programme of work was undertaken which included three complementary phases. In the Phase One, I conducted a systematic review of the literature and searched for published and unpublished studies assessing the efficacy, effectiveness and safety of influenza vaccines over a 46-year period (1970 to 2016). Study selection, data extraction and quality appraisal of studies was carried out independently by two reviewers who followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) reporting checklist. Meta-analysis of clinical and epidemiological similar studies was also performed. In Phase Two, I conducted a test-negative design (TND) case-control study to assess the VE against real-time polymerase chain reaction (RT-PCR) laboratory confirmed influenza in people with asthma. For this study, I used Scottish health administrative data from the Seasonal Influenza Vaccine Effectiveness II (SIVE II) project over 14 influenza seasons (2000/01 to 2015/16). The SIVE II project used healthcare data collected from routinely available datasets and created a large national primary care and laboratory-linked dataset. The main aim of the SIVE II project was to assess the effectiveness of the live attenuated and trivalent inactivated influenza vaccines of all at-risk groups for influenza (e.g. asthma) in Scotland. Some of the SIVE project’s objectives were the evaluation of VE against RT-PCR laboratory-confirmed influenza and influenza-related clinical outcomes (e.g. influenza and asthma-related general practice consultations, hospitalisations and death). Therefore, my work in this phase was part of the SIVE II project as it focused on people with asthma. Additional stratified VE estimates related to various viral strains, vaccines types and asthma individuals’ characteristics were also provided, but from seasons 2010/11 onwards. A generalised additive logistic regression model was used for the calculation of all the VE estimates. Finally, in the Phase Three, I undertook a vaccine uptake analysis exploring factors related to vaccine uptake in the asthma population using data from primary care centres and hospitalisation over 16 influenza seasons (2000/01 to 2016/17) in Scotland. A multivariate logistic regression model was performed to identity any relation between characteristics of the asthma population and vaccine uptake levels in the community. Results The Systematic review identified 20,396 papers, and 35 studies met the inclusion criteria. It was possible to carry out meta-analyses of data from four of these studies. The review found that the influenza vaccination protects children and adults with asthma against influenza infection and influenza-related complications such as asthma exacerbations. However, the overall quality of evidence was rated as very low for all outcomes. The meta-analysis of two TND studies found a moderate VE of 45.0% (95% confidence interval (CI): 31.0 to 56.0) against influenza infection over two seasons in the United States (US) population. The protective effects of the vaccine against asthma exacerbations was also identified based on another US based study over a 3-year period in children with asthma. Specifically, the incidence rate ratio of the vaccine against asthma hospitalizations and emergency department visits ranged from 0.6 (95% CI: 0.4 to 0.8) to 0.8 (95% CI: 0.6 to 1.1). The safety of the inactivated vaccines was also shown. Specifically, a large RCT study in US found an absolute difference of 1.1 percent (95% CI: -1.4 to 3.6) for asthma exacerbations between 2,032 inactivated vaccine and placebo recipients. However, more evidence is needed to assess the safety of the live attenuated vaccines against asthma-related adverse events in preschool children. The TND case-control study included 6,921 swab samples tested for influenza and identified an overall VE of 49.4% (95% CI: 39.7 to 57.5) in 5,824 asthma patients over a 14-year period in Scotland. Higher and significant VE estimates were observed in seasons with good antigenic match between the viral and vaccine strains. The highest VE (76.1%; 95% CI: 55.6 to 87.1) was found in 2010/11 season where the A(H1N1) strain dominated and a good antigenic match with the vaccine was found. Significant protection was observed against the A(H1N1) and B strains, with non-significant protection for the A(H3N2) strain. Significant VE estimates were found in younger adults aged 18-54 years old (VE: 54.0%; 95% CI: 39.2 to 65.2) where protection was found against all circulating influenza strains. The live vaccines offered protection against the influenza B type in children < 17 years old (VE: 96.4%; 95% CI: 46.0 to 100.0). The vaccine uptake analysis revealed characteristics in the asthma population that are related to higher uptake of the vaccine. The overall uptake was 33.6% among 194,319 individuals with asthma identified from 223 general practices and 65.9% among 6,232 patients with asthma with an emergency hospital admission due to influenza or pneumonia over a 16-year period. In the community and at hospital settings higher uptake levels were observed for females (38.7% and 37.0%), younger children aged 5-11 years old (24.5% and 0.8%), older adults aged >75 years old (82.8% and 31.0%) and influenza vaccination history (80.5% and 56.8%). History of primary and secondary care visits (70.4% and 52.8%) and the presence of multiple medical conditions (83.2%) were also related with higher uptake in the community. Higher vaccination rates (65.2%) were observed in individuals using medications, particularly inhaled and oral corticosteroids. Females, adults aged >65 years old, individuals living in remote rural areas, with comorbidities, with history of influenza or pneumococcal vaccination, ex-smokers and with history of five primary care visits and two emergency hospital admissions were more likely to have been vaccinated in the current season. Conclusions This program of work has identified evidence supporting the protective effects of influenza vaccination asthma from previous studies and has contributed new evidence supporting the use of influenza vaccination in the asthma population. In addition, factors related to vaccine uptake in people with asthma were explored. Thus, the current suboptimal uptake levels seen in the UK and globally might be improved by more effective targeting interventions to subgroups of people with asthma defined by specific demographic, clinical and other characteristics that are associated with a lower propensity for vaccination. The systematic review and the TND case-control study confirm that a moderate protection against laboratory diagnosed influenza infection can be achieved with current vaccines in people with asthma. Evidence from the systematic review also showed beneficial effects of the vaccination against clinical outcomes such as influenza-related asthma exacerbations and healthcare visits or hospital admissions. In addition, the primary research work provided stratified VE estimates across multiple influenza seasons and confirmed that vaccination prevents influenza incidence and complication in children and adults with asthma. This thesis has therefore contributed to filling important gaps in the evidence base regarding the benefits of the influenza vaccination in people with asthma. It has also identified the need for additional evidence: specifically, studies should now focus on providing VE estimates for older adults (e.g. 55 years old), for children with LAIV administration and for asthma-related clinical outcomes. Vaccination policymakers can now use my research findings (for example, providing better estimates of safety and effectiveness to inform shared decision making and how to better target interventions to promote uptake) to enhance evidence-based recommendations for clinical practice that could result in improved health of people with asthma by preventing or reducing the burden of influenza virus during each influenza season

COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infection and severe COVID-19 outcomes from Delta AY.4.2:Cohort and test-negative study of 5.4 million individuals in Scotland

Background: In July 2021, a new variant of SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2) in the Delta lineage was detected in the United Kingdom (UK), named AY.4.2 or "Delta plus". By October 2021, the AY.4.2 variant accounted for approximately 10-11% of cases in the UK. AY.4.2 was designated as a variant under investigation by the UK Health and Security Agency on 20 October 2021. This study aimed to investigate vaccine effectiveness (VE) against symptomatic COVID-19 (Coronavirus disease 2019) infection and COVID-19 hospitalisation/death for the AY.4.2 variant. Methods: We used the Scotland-wide Early Pandemic Evaluation and Enhanced Surveillance (EAVE-II) platform to estimate the VE of the ChAdOx1, BNT162b2, and mRNA-1273 vaccines against symptomatic infection and severe COVID-19 outcomes in adults. The study was conducted from June 8 to October 25, 2021. We used a test-negative design (TND) to estimate VE against reverse transcriptase polymerase chain reaction (RT-PCR) confirmed symptomatic SARS-CoV-2 infection while adjusting for sex, socioeconomic status, number of coexisting conditions, and splines in time and age. We also performed a cohort study using a Cox proportional hazards model to estimate VE against a composite outcome of COVID-19 hospital admission or death, with the same adjustments. Results: We found an overall VE against symptomatic SARS-CoV-2 infection due to AY.4.2 of 73% (95% confidence interval (CI) = 62-81) for >14 days post-second vaccine dose. Good protection against AY.4.2 symptomatic infection was observed for BNT162b2, ChAdOx1, and mRNA-1273. In unvaccinated individuals, the hazard ratio (HR) for COVID-19 hospital admission or death from AY.4.2 among community detected cases was 1.77 (95% CI = 1.02-3.07) relative to unvaccinated individuals who were infected with Delta, after adjusting for multiple potential confounders. VE against AY.4.2 COVID-19 admissions or deaths was 87% (95% CI = 74-93) >28 days post-second vaccination relative to unvaccinated. Conclusions: We found that AY.4.2 was associated with an increased risk of COVID-19 hospitalisations or deaths in unvaccinated individuals compared with Delta and that vaccination provided substantial protection against symptomatic SARS-CoV-2 and severe COVID-19 outcomes following Delta AY.4.2 infection. High levels of vaccine uptake and protection offered by existing vaccines, as well as the rapid emergence of the Omicron variant may have contributed to the AY.4.2 variant never progressing to a variant of concern

Risk of serious COVID-19 outcomes among adults with asthma in Scotland:a national incident cohort study

There is considerable uncertainty over whether adults with asthma should be offered booster vaccines against SARS-CoV-2 and, if so, who should be prioritised for booster vaccination. We were asked by the UK's Joint Commission on Vaccination and Immunisation to undertake an urgent analysis to identify which adults with asthma were at an increased risk of serious COVID-19 outcomes to inform deliberations on booster COVID-19 vaccines. This national incident cohort study was done in all adults in Scotland aged 18 years and older who were included in the linked dataset of Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II). We used data from EAVE II to investigate the risk of COVID-19 hospitalisation and the composite outcome of intensive care unit (ICU) admission or death from COVID-19 among adults with asthma. A Cox proportional hazard model was used to derive adjusted hazard ratios (HRs) and 95% CIs for the association between asthma and COVID-19 hospital admission and ICU admission or death, stratified by markers of history of an asthma attack defined by either oral corticosteroid prescription (prednisolone, prednisone, and dexamethasone) in the 2 years before March 1, 2020, or hospitalisation for asthma before March 1, 2020. Analyses were adjusted for age, sex, socioeconomic status, comorbidity, previous hospitalisation, and vaccine status. Between March 1, 2020, and July 27, 2021, 561 279 (12·7%) of 4 421 663 adults in Scotland had clinician-diagnosed-and-recorded-asthma. Among adults with asthma, 39 253 (7·0%) had confirmed SARS-CoV-2 infections, of whom 4828 (12·3%) were admitted to hospital for COVID-19 (among them, an estimated 600 [12·4%] might have been due to nosocomial infections). Adults with asthma were found to be at an increased risk of COVID-19 hospital admission (adjusted HR 1·27, 95% CI 1·23-1·32) compared with those without asthma. When using oral corticosteroid prescribing in the preceding 2 years as a marker for history of an asthma attack, the adjusted HR was 1·54 (95% CI 1·46-1·61) for those with three or more prescribed courses of oral corticosteroids, 1·37 (1·26-1·48) for those with two prescribed courses, 1·30 (1·23-1·37) for those with one prescribed course, and 1·15 (1·11-1·21) for those without any courses, compared with those aged 18 years or older without asthma. Adults with asthma were found to be at an increased risk of COVID-19 ICU admission or death compared with those without asthma (adjusted HR 1·13, 95 % CI 1·05-1·22). The adjusted HR was 1·44 (95% CI 1·31-1·58) for those with three or more prescribed courses of oral corticosteroids, 1·27 (1·09-1·48) for those with two prescribed courses, 1·04 (0·93-1·16) for those with one prescribed course, and 1·06 (0·97-1·17) for those without any course, compared with adults without asthma. Adults with asthma who have required two or more courses of oral corticosteroids in the previous 2 years or a hospital admission for asthma before March 1, 2020, are at increased risk of both COVID-19 hospitalisation and ICU admission or death. Patients with a recent asthma attack should be considered a priority group for booster COVID-19 vaccines. UK Research and Innovation (Medical Research Council), Research and Innovation Industrial Strategy Challenge Fund, Health Data Research UK, and Scottish Government

Defining asthma and assessing asthma outcomes using electronic health record data: a systematic scoping review

There is currently no consensus on approaches to defining asthma or assessing asthma outcomes using electronic health record-derived data. We explored these approaches in the recent literature and examined the clarity of reporting.We systematically searched for asthma-related articles published between January 1, 2014 and December 31, 2015, extracted the algorithms used to identify asthma patients and assess severity, control and exacerbations, and examined how the validity of these outcomes was justified.From 113 eligible articles, we found significant heterogeneity in the algorithms used to define asthma (n=66 different algorithms), severity (n=18), control (n=9) and exacerbations (n=24). For the majority of algorithms (n=106), validity was not justified. In the remaining cases, approaches ranged from using algorithms validated in the same databases to using nonvalidated algorithms that were based on clinical judgement or clinical guidelines. The implementation of these algorithms was suboptimally described overall.Although electronic health record-derived data are now widely used to study asthma, the approaches being used are significantly varied and are often underdescribed, rendering it difficult to assess the validity of studies and compare their findings. Given the substantial growth in this body of literature, it is crucial that scientific consensus is reached on the underlying definitions and algorithms.</jats:p

Vaccine effectiveness of live attenuated and trivalent inactivated influenza vaccination in 2010/11 to 2015/16:the SIVE II record linkage study

Background: There is good evidence of vaccine effectiveness in healthy individuals but less robust evidence for vaccine effectiveness in the populations targeted for influenza vaccination. The live attenuated influenza vaccine (LAIV) has recently been recommended for children in the UK. The trivalent influenza vaccine (TIV) is recommended for all people aged≥65 years and for those aged<65 years who are at an increased risk of complications from influenza infection (e.g. people with asthma). Objective: To examine the vaccine effectiveness of LAIV and TIV. Design: Cohort study and test-negative designs to estimate vaccine effectiveness. A self-case series study to ascertain adverse events associated with vaccination. Setting: A national linkage of patient-level general practice (GP) data from 230 Scottish GPs to the Scottish Immunisation & Recall Service, Health Protection Scotland virology database, admissions to Scottish hospitals and the Scottish death register. Participants: A total of 1,250,000 people. Interventions: LAIV for 2- to 11-year-olds and TIV for older people (aged≥65 years) and those aged<65 years who are at risk of diseases, from 2010/11 to 2015/16. Main outcome measures: The main outcome measures include vaccine effectiveness against laboratory-confirmed influenza using real-time reverse-transcription polymerase chain reaction (RT-PCR), influenza-related morbidity and mortality, and adverse events associated with vaccination. Results: Two-fifths (40%) of preschool-aged children and three-fifths (60%) of primary school-aged children registered in study practices were vaccinated. Uptake varied among groups [e.g. most affluent vs. most deprived in 2- to 4-year-olds, odds ratio 1.76, 95% confidence interval (CI) 1.70 to 1.82]. LAIV-adjusted vaccine effectiveness among children (aged 2-11 years) for preventing RT-PCR laboratoryconfirmed influenza was 21% (95% CI -19% to 47%) in 2014/15 and 58% (95% CI 39% to 71%) in 2015/16. No significant adverse events were associated with LAIV. Among at-risk 18- to 64-year-olds, significant trivalent influenza vaccine effectiveness was found for four of the six seasons, with the highest vaccine effectiveness in 2010/11 (53%, 95% CI 21% to 72%). The seasons with non-significant vaccine effectiveness had low levels of circulating influenza virus (2011/12, 5%; 2013/14, 9%). Among those people aged≥65 years, TIV effectiveness was positive in all six seasons, but in only one of the six seasons (2013/14) was significance achieved (57%, 95% CI 20% to 76%). Conclusions: The study found that LAIV was safe and effective in decreasing RT-PCR-confirmed influenza in children. TIV was safe and significantly effective in most seasons for 18- to 64-year-olds, with positive vaccine effectiveness in most seasons for those people aged≥65 years (although this was significant in only one season). Future work: The UK Joint Committee on Vaccination and Immunisation has recommended the use of adjuvanted injectable vaccine for those people aged≥65 years from season 2018/19 onwards. A future study will be required to evaluate this vaccine. Trial registration: Current Controlled Trials ISRCTN88072400

Early pandemic evaluation and enhanced surveillance of COVID-19 (EAVE II) : protocol for an observational study using linked Scottish national data

Introduction Following the emergence of the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in December 2019 and the ensuing COVID-19 pandemic, population-level surveillance and rapid assessment of the effectiveness of existing or new therapeutic or preventive interventions are required to ensure that interventions are targeted to those at highest risk of serious illness or death from COVID-19. We aim to repurpose and expand an existing pandemic reporting platform to determine the attack rate of SARS-CoV-2, the uptake and effectiveness of any new pandemic vaccine (once available) and any protective effect conferred by existing or new antimicrobial drugs and other therapies. Methods and analysis A prospective observational cohort will be used to monitor daily/weekly the progress of the COVID-19 epidemic and to evaluate the effectiveness of therapeutic interventions in approximately 5.4 million individuals registered in general practices across Scotland. A national linked dataset of patient-level primary care data, out-of-hours, hospitalisation, mortality and laboratory data will be assembled. The primary outcomes will measure association between: (A) laboratory confirmed SARS-CoV-2 infection, morbidity and mortality, and demographic, socioeconomic and clinical population characteristics; and (B) healthcare burden of COVID-19 and demographic, socioeconomic and clinical population characteristics. The secondary outcomes will estimate: (A) the uptake (for vaccines only); (B) effectiveness; and (C) safety of new or existing therapies, vaccines and antimicrobials against SARS-CoV-2 infection. The association between population characteristics and primary outcomes will be assessed via multivariate logistic regression models. The effectiveness of therapies, vaccines and antimicrobials will be assessed from time-dependent Cox models or Poisson regression models. Self-controlled study designs will be explored to estimate the risk of therapeutic and prophylactic-related adverse events. Ethics and dissemination We obtained approval from the National Research Ethics Service Committee, Southeast Scotland 02. The study findings will be presented at international conferences and published in peer-reviewed journals

Seasonal influenza vaccine effectiveness in people with asthma: a national test-negative design case-control study

Financial support. The work was funded by the Chief Scientist Office of the Scottish Government under the grant (AUKCAR/14/03) and the NIHR–Health Technology Assessment (HTA) Programme (13/34/14) for the Seasonal Influenza Vaccination Effectiveness II (SIVE II) study. As principal investigator, C. R. S. received a grant for the SIVE-II project from the NIHR HTA. This work was carried out with the support of the Asthma UK Centre for Applied Research (AUK-AC-2012-01), the Farr Institute (MR/M501633/2), Health Data Research UK (an initiative funded by UK Research and Innovation, Department of Health and Social Care England and the devolved administrations and leading medical research charities), the European Union’s Horizon 2020 research and innovation programme (under grant agreement No 634446) and European Centre for Disease Prevention and Control (Influenza-Monitoring Vaccine Effectiveness). Acknowledgments. The authors thank and acknowledge all colleagues at the Asthma UK Centre for Applied Research for their support in this study. Disclaimer. The funding bodies had no role in the design of the study, review process, analysis, interpretation, or reporting of data. The views and opinions expressed herein are those of the authors and do not necessarily reflect those of the Health Technology Assessment Programme, National Institute for Health Research (NIHR), National Health Service, or the Department of Health. Potential conflicts of interest. The authors: No reported conflicts of interest. All authors have submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Conflicts that the editors consider relevant to the content of the manuscript have been disclosed.Peer reviewedPublisher PDFPublisher PD

COVID-19 in Pregnancy in Scotland (COPS):protocol for an observational study using linked Scottish national data

Funding: EAVE II funded by the Medical Research Council (MR/R008345/1) with the support of BREATHE - The Health Data Research Hub for Respiratory Health [MC_PC_19004], which is funded through the UK Research and Innovation Industrial Strategy Challenge Fund and delivered through Health Data Research UK. Additional support has been provided through the Scottish Government DG Health and Social Care. COPS receive additional funding from Tommy’s charity (1060508; SC039280). SJS is supported by Wellcome Trust (209560/Z/17/Z).Introduction The effects of SARS-CoV-2 in pregnancy are not fully delineated. We will describe the incidence of COVID-19 in pregnancy at population level in Scotland, in a prospective cohort study using linked data. We will determine associations between COVID-19 and adverse pregnancy, neonatal and maternal outcomes and the proportion of confirmed cases of SARS-CoV-2 infection in neonates associated with maternal COVID-19. Methods and analysis Prospective cohort study using national linked data sets. We will include all women in Scotland, UK, who were pregnant on or became pregnant after, 1 March 2020 (the date of the first confirmed case of SARS-CoV-2 infection in Scotland) and all births in Scotland from 1 March 2020 onwards. Individual-level data will be extracted from data sets containing details of all livebirths, stillbirth, terminations of pregnancy and miscarriages and ectopic pregnancies treated in hospital or attending general practice. Records will be linked within the Early Pandemic Evaluation and Enhanced Surveillance of COVID-19 (EAVE II) platform, which includes primary care records, virology and serology results and details of COVID-19 Community Hubs and Assessment Centre contacts and deaths. We will perform analyses using definitions for confirmed, probable and possible COVID-19 and report serology results (where available). Outcomes will include congenital anomaly, miscarriage, stillbirth, termination of pregnancy, preterm birth, neonatal infection, severe maternal disease and maternal deaths. We will perform descriptive analyses and appropriate modelling, adjusting for demographic and pregnancy characteristics and the presence of comorbidities. The cohort will provide a platform for future studies of the effectiveness and safety of therapeutic interventions and immunisations for COVID-19 and their effects on childhood and developmental outcomes. Ethics and dissemination COVID-19 in Pregnancy in Scotland is a substudy of EAVE II(, which has approval from the National Research Ethics Service Committee. Findings will be reported to Scottish Government, Public Health Scotland and published in peer-reviewed journals.Publisher PDFPeer reviewe