Tuberculosis in England, a high-income Western European setting with low incidence: Recent trends, Social determinants and Prevention through BCG vaccination.

While the tuberculosis (TB) burden in England is low compared to some parts of the word, annual incidence rates have not declined in over two decades, and remain among the highest in developed countries. In the first part of my thesis, I examined trends in TB notifications rates in England with emphasis on the UK-born population, which because of its relatively lower incidence, has received less attention than foreign-born groups. This analysis showed that for nearly two decades, rates have remained mostly stagnant in White UK-born populations, except in the elderly in which rates continue to decline, whereas TB rates have been declining in foreign-born subjects and UK-born ethnic minority groups in the past decade. Given the strong link between poverty and TB, I also investigated the association between socioeconomic deprivation and the risk of TB in England. An ecological analysis suggested that the association between small-area level deprivation and TB rates in a recent 5-year period was much stronger in the UK-born population than in the foreign-born population. To investigate the role of deprivation in the UK-born White population further, I used data from a case-control study of UK-born White young adults in which information was collected on individual-level socio-economic determinants of health. The analysis showed a four times higher risk of TB in subjects with an education level below O-levels compared to those with a degree, as well as an association between increased TB risk and area-level deprivation, tobacco smoking, drug use, and homelessness. In the second part of the thesis, I focused on BCG vaccination, a longstanding part of the TB prevention toolkit, and which has been somewhat overlooked compared to case finding and treatment. I reported a survey of the implementation at the local level of the 2005 change to England’s BCG policy replacing the universal vaccination of schoolchildren by targeted vaccination of higher-risk infants. Heterogeneity in the healthcare service pathways for BCG vaccination was noted, as well as challenges to the identification of, and service delivery to, the targeted groups. I also conducted an ecological study estimating the vaccine uptake in a 3-year period (2006-2008) following the policy change and its association to some area-level factors, with results suggesting that about one third of eligible infants may have missed vaccination. Finally, I conducted a historical cohort study measuring the long-term duration of BCG-derived protection against tuberculosis using data from Norway, a low-incidence setting comparable to England. I found that BCG effectiveness lasts for at least 20 years, longer than previously estimated. Overall, my thesis highlights the existence of stagnant TB rates in UK-born White young adults, and particular social determinants such as tobacco smoking, drug use and homelessness, that are amenable to specific interventions to reduce the risk of TB in a currently neglected population group. It also presents evidence to improve BCG policies targeted at high-risk groups in low-incidence settings and vaccination uptake. The new information on the duration of BCG protection can also help inform any review of the costeffectiveness of BCG vaccination in the general population

Correlates of vaccine-induced protection: methods and implications

The document presents an overview of definitions and methods in the area of immune correlates of vaccine-induced protection. This subject has far-reaching implications for the evaluation of vaccine efficacy, for passive protection, e.g. maternal immunity and risk screening, e.g. tuberculin testing or rubella antibody testing of pregnant women, as well as for basic understanding of pathogenesis and immunity

Drug misuse, tobacco smoking, alcohol and other social determinants of tuberculosis in UK-born adults in England: a community-based case-control study

Addressing social determinants of tuberculosis (TB) is essential to achieve elimination, including in low-incidence settings. We measured the association between socio-economic status and intermediate social determinants of health (SDHs, including drug misuse, tobacco smoking and alcohol), and TB, taking into account their clustering in individuals. We conducted a case-control study in 23–38 years old UK-born White adults with frst tuberculosis episode, and randomly selected age and sex frequencymatched community controls. Data was collected on education, household overcrowding, tobacco smoking, alcohol and drugs use, and history of homelessness and prison. Analyses were done using logistic regression models, informed by a formal theoretical causal framework (Directed Acyclic Graph). 681 TB cases and 1183 controls were recruited. Tuberculosis odds were four times higher in subjects with education below GCSE O-levels, compared to higher education (OR=3.94; 95%CI: 2.74, 5.67), after adjusting for other TB risk factors (age, sex, BCG-vaccination and stays ≥3 months in Africa/Asia). When simultaneously accounting for respective SDHs, higher tuberculosis risk was independently associated with tobacco smoking, drugs use (especially injectable drugs OR=5.67; 95%CI: 2.68, 11.98), homelessness and area-level deprivation. Population Attributable Fraction estimates suggested that tobacco and class-A drug use were, respectively, responsible for 18% and 15% of TB cases in this group. Our fndings suggest that socio-economic deprivation remains a driver of tuberculosis in England, including through drugs misuse, tobacco smoking, and homelessness. These fndings further support the integration of health and social services in high-risk young adults to improve TB control eforts

Observational study to estimate the changes in the effectiveness of bacillus Calmette-Guérin (BCG) vaccination with time since vaccination for preventing tuberculosis in the UK.

Until recently, evidence that protection from the bacillus Calmette-Guérin (BCG) vaccination lasted beyond 10 years was limited. In the past few years, studies in Brazil and the USA (in Native Americans) have suggested that protection from BCG vaccination against tuberculosis (TB) in childhood can last for several decades. The UK's universal school-age BCG vaccination programme was stopped in 2005 and the programme of selective vaccination of high-risk (usually ethnic minority) infants was enhanced. To assess the duration of protection of infant and school-age BCG vaccination against TB in the UK. Two case-control studies of the duration of protection of BCG vaccination were conducted, the first on minority ethnic groups who were eligible for infant BCG vaccination 0-19 years earlier and the second on white subjects eligible for school-age BCG vaccination 10-29 years earlier. TB cases were selected from notifications to the UK national Enhanced Tuberculosis Surveillance system from 2003 to 2012. Population-based control subjects, frequency matched for age, were recruited. BCG vaccination status was established from BCG records, scar reading and BCG history. Information on potential confounders was collected using computer-assisted interviews. Vaccine effectiveness was estimated as a function of time since vaccination, using a case-cohort analysis based on Cox regression. In the infant BCG study, vaccination status was determined using vaccination records as recall was poor and concordance between records and scar reading was limited. A protective effect was seen up to 10 years following infant vaccination [< 5 years since vaccination: vaccine effectiveness (VE) 66%, 95% confidence interval (CI) 17% to 86%; 5-10 years since vaccination: VE 75%, 95% CI 43% to 89%], but there was weak evidence of an effect 10-15 years after vaccination (VE 36%, 95% CI negative to 77%; p = 0.396). The analyses of the protective effect of infant BCG vaccination were adjusted for confounders, including birth cohort and ethnicity. For school-aged BCG vaccination, VE was 51% (95% CI 21% to 69%) 10-15 years after vaccination and 57% (95% CI 33% to 72%) 15-20 years after vaccination, beyond which time protection appeared to wane. Ascertainment of vaccination status was based on self-reported history and scar reading. The difficulty in examining vaccination sites in older women in the high-risk minority ethnic study population and the sparsity of vaccine record data in the later time periods precluded robust assessment of protection from infant BCG vaccination > 10 years after vaccination. Infant BCG vaccination in a population at high risk for TB was shown to provide protection for at least 10 years, whereas in the white population school-age vaccination was shown to provide protection for at least 20 years. This evidence may inform TB vaccination programmes (e.g. the timing of administration of improved TB vaccines, if they become available) and cost-effectiveness studies. Methods to deal with missing record data in the infant study could be explored, including the use of scar reading. The National Institute for Health Research Health Technology Assessment programme. During the conduct of the study, Jonathan Sterne, Ibrahim Abubakar and Laura C Rodrigues received other funding from NIHR; Ibrahim Abubakar and Laura C Rodrigues have also received funding from the Medical Research Council. Punam Mangtani received funding from the Biotechnology and Biological Sciences Research Council

Post-COVID-19 condition and persisting symptoms in English schoolchildren: repeated surveys to March 2022

BACKGROUND: Both post-COVID-19 condition (long COVID) and the presence of persisting symptoms that do not meet formal definitions of post-COVID-19-condition may adversely affect quality of life and function. However, their prevalence among children and young people in England is unclear. METHODS: We used data from repeated surveys in a large cohort of English schoolchildren from the COVID-19 Schools Infection Survey (SIS) for the school year 2021/22 to describe the weighted prevalence of post-COVID-19-condition and compare persisting symptoms between individuals with a positive SARS-CoV-2 test and those with neither a positive test history nor suspected infection. RESULTS: Among 7797 children from 173 schools, 1.8% of primary school pupils (aged 4 to 11 years), 4.5% of secondary school pupils in years 7-11 (aged 11 to 16 years) and 6.9% of those in years 12-13 (aged 16 to 18 years) met a definition of post-COVID-19 condition in March 2022. Specific persisting symptoms such as anxiety or difficulty concentrating were frequently reported regardless of prior infection status and increased with age: 48.0% of primary school pupils, 52.9% of secondary school pupils in years 7-11 and 79.5% in years 12-13 reporting at least one symptom lasting more than 12 weeks. Persisting loss of smell and taste, cardiovascular and some systemic symptoms were more frequently reported by those with a previous positive test. CONCLUSIONS: We showed that ongoing symptoms were frequently reported by English schoolchildren regardless of SARS-CoV-2 test results and some specific symptoms such as loss of smell and taste were more prevalent in those with a positive test history. Our study emphasises the wide-ranging impacts of the COVID-19 pandemic on the health and wellbeing of children and young people

The prevalence and risk factors for human Brucella species infection in a cross-sectional survey of a rural population in Punjab, India

Brucellosis is an important neglected zoonosis. Effective cattle vaccines are available but are infrequently used in India, where rural households commonly own one or two cattle as sources of protein and income. We assessed the prevalence of infection and risk factors in humans

Implementation of COVID-19 Preventive Measures and Staff Well-Being in a Sample of English Schools 2020-2021.

BACKGROUND: We examined fidelity and feasibility of implementation of COVID-19 preventive measures in schools, and explored associations between adherence to these measures and staff well-being, to inform policy on sustainable implementation and staff wellbeing. METHODS: Surveys were conducted across 128 schools in England with 107 headteachers and 2698 staff-members with reference to autumn term 2020, examining school-level implementation of preventive measures, adherence, and teacher burnout (response rates for headteacher and staff surveys were 84% and 59%, respectively). RESULTS: The median number of measures implemented in primary and secondary schools was 33 (range 23-41), and 32 (range 22-40), respectively; most measures presented challenges. No differences were found regarding number of measures implemented by school-level socio-economic disadvantage. High adherence was reported for staff wearing face-coverings, staff regularly washing their hands, (secondary only) desks facing forwards, and (primary only) increased cleaning of surfaces and student hand-washing. Adherence to most measures was reported as higher in primary than secondary schools. Over half of school leaders and 42% (517/1234) of other teaching staff suffered from high emotional exhaustion. Higher teacher-reported school-wide adherence with measures was consistently associated with lower burnout for leaders and other teaching staff. CONCLUSIONS: Findings indicate a tremendous effort in implementing preventive measures and an urgent need to support investments in improving teacher wellbeing

National and regional prevalence of SARS-CoV-2 antibodies in primary and secondary school children in England: the School Infection Survey, a national open cohort study, November 2021SARS-CoV-2 antibody prevalence in school children.

BACKGROUND: SARS-CoV-2 infection rates are likely to be underestimated in children because of asymptomatic or mild infections. We aim to estimate national and regional prevalence of SARS-CoV-2 antibodies in primary (4-11 years old) and secondary (11-18 years old) school children between 10 November and 10 December 2021. METHODS: Cross-sectional surveillance in England using two-stage sampling, firstly stratifying into regions and selecting local authorities, then selecting schools according to a stratified sample within selected local authorities. Participants were sampled using a novel oral fluid-validated assay for SARS-CoV-2 spike and nucleocapsid IgG antibodies. RESULTS: 4980 students from 117 state-funded schools (2706 from 83 primary schools, 2274 from 34 secondary schools) provided a valid sample. After weighting for age, sex, and ethnicity, and adjusting for assay accuracy, the national prevalence of SARS-CoV-2 antibodies in primary school students, who were all unvaccinated, was 40.1% (95% CI 37.3-43.0). Antibody prevalence increased with age (p < 0.001) and was higher in urban than rural schools (p = 0.01). In secondary school students, the adjusted, weighted national prevalence of SARS-CoV-2 antibodies was 82.4% (95% CI 79.5-85.1); including 71.5% (95% CI 65.7-76.8) in unvaccinated and 97.5% (95% CI 96.1-98.5) in vaccinated students. Antibody prevalence increased with age (p < 0.001), and was not significantly different in urban versus rural students (p = 0.1). CONCLUSIONS: In November 2021, using a validated oral fluid assay, national SARS-CoV-2 seroprevalence was estimated to be 40.1% in primary school students and 82.4% in secondary school students. In unvaccinated children, this was approximately threefold higher than confirmed infections highlighting the importance of seroprevalence studies to estimate prior exposure. DATA AVAILABILITY: Deidentified study data are available for access by accredited researchers in the ONS Secure Research Service (SRS) for accredited research purposes under part 5, chapter 5 of the Digital Economy Act 2017. For further information about accreditation, contact [email protected] or visit the SRS website