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

Estimating time-varying exposure-outcome associations using case-control data: logistic and case-cohort analyses.

BACKGROUND: Traditional analyses of standard case-control studies using logistic regression do not allow estimation of time-varying associations between exposures and the outcome. We present two approaches which allow this. The motivation is a study of vaccine efficacy as a function of time since vaccination. METHODS: Our first approach is to estimate time-varying exposure-outcome associations by fitting a series of logistic regressions within successive time periods, reusing controls across periods. Our second approach treats the case-control sample as a case-cohort study, with the controls forming the subcohort. In the case-cohort analysis, controls contribute information at all times they are at risk. Extensions allow left truncation, frequency matching and, using the case-cohort analysis, time-varying exposures. Simulations are used to investigate the methods. RESULTS: The simulation results show that both methods give correct estimates of time-varying effects of exposures using standard case-control data. Using the logistic approach there are efficiency gains by reusing controls over time and care should be taken over the definition of controls within time periods. However, using the case-cohort analysis there is no ambiguity over the definition of controls. The performance of the two analyses is very similar when controls are used most efficiently under the logistic approach. CONCLUSIONS: Using our methods, case-control studies can be used to estimate time-varying exposure-outcome associations where they may not previously have been considered. The case-cohort analysis has several advantages, including that it allows estimation of time-varying associations as a continuous function of time, while the logistic regression approach is restricted to assuming a step function form for the time-varying association

Small-area level socio-economic deprivation and tuberculosis rates in England: An ecological analysis of tuberculosis notifications between 2008 and 2012.

BACKGROUND: Tuberculosis (TB) rates in England are among the highest in high-income countries. Poverty and historic and current immigration from high TB incidence parts of the world are two major drivers of tuberculosis in England. However, little has been done in recent years to examine socio-economic trends in TB rates in England, and to disentangle the role of deprivation from that of place of birth in the current TB epidemiology. OBJECTIVES: To assess the association between England's 2008-2012 TB notification rates and small area-level deprivation, together and separately in the UK-born and foreign-born populations. METHODS: Ecological analysis of the association between quintiles of England's 2010 Index of Multiple Deprivation (IMD) and TB rates at the Lower-layer Super Output Area (LSOA; average population ~1500) level, using negative binomial and zero-inflated negative binomial regression models, adjusting for age, sex, urban/rural area classification, and area-level percentage of non-White residents. RESULTS: There was a log-linear gradient between area-deprivation levels and TB rates, with overall TB rates in the most deprived quintile areas three times higher than the least deprived quintile after adjustment for age and sex (IRR = 3.35; 95%CI: 3.16 to 3.55). The association and gradient were stronger in the UK-born than the foreign-born population, with UK-born TB rates in the most deprived quintiles about two-and-a-half times higher than the least deprived quintile (IRR = 2.39; 95%CI: 2.19 to 2.61) after controlling for age, sex, urban/rural classification and percentage of non-White residents; whereas the comparable figure for foreign-born persons was 80% higher (IRR = 1.78; 95%CI: 1.66 to 1.91). CONCLUSIONS: Socio-economic deprivation continues to play a substantial role in sustaining the TB epidemic in England, especially in the UK-born population. This supports the case for further investigations of the underlying social- determinants of TB

Duration of BCG protection against tuberculosis and change in effectiveness with time since vaccination in Norway: a retrospective population-based cohort study.

BACKGROUND: Little is known about how long the BCG vaccine protects against tuberculosis. We assessed the long-term vaccine effectiveness (VE) in Norwegian-born individuals. METHODS: In this retrospective population-based cohort study, we studied Norwegian-born individuals aged 12-50 years who were tuberculin skin test (TST) negative and eligible for BCG vaccination as part of the last round of Norway's mandatory mass tuberculosis screening and BCG vaccination programme between 1962 and 1975. We excluded individuals who had tuberculosis before or in the year of screening and those with unknown TST and BCG status. We obtained TST and BCG information and linked it to the National Tuberculosis Register, population and housing censuses, and the population register for emigrations and deaths. We followed individuals up to their first tuberculosis episode, emigration, death, or Dec 31, 2011. We used Cox regressions to estimate VE against all tuberculosis and just pulmonary tuberculosis by time since vaccination, adjusted for age, time, county-level tuberculosis rates, and demographic and socioeconomic indicators. FINDINGS: Median follow-up was 41 years (IQR 32-49) for 83 421 BCG-unvaccinated and 44 years (41-46) for 297 905 vaccinated individuals, with 260 tuberculosis episodes. Tuberculosis rates were 3·3 per 100 000 person-years in unvaccinated and 1·3 per 100 000 person-years in vaccinated individuals. The adjusted average VE during 40 year follow-up was 49% (95% CI 26-65), although after 20 years, the VE was not significant (up to 9 years VE [excluding tuberculosis episodes in the first 2 years] 61% [95% CI 24-80]; 10-19 years 58% [27-76]; 20-29 years 38% [-32 to 71]; 30-40 years 42% [-24 to 73]). VE against pulmonary tuberculosis up to 9 years (excluding tuberculosis episodes in the first 2 years) was 67% (95% CI 27-85), 10-19 years was 63% (32-80), 20-29 years was 50% (-19 to 79), and 30-40 years was 40% (-46 to 76). INTERPRETATION: Findings are consistent with long-lasting BCG protection, but waning of VE with time. The vaccine could be more cost effective than has been previously estimated FUNDING: Norwegian Institute of Public Health and London School of Hygiene & Tropical Medicine

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

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 first tuberculosis episode, and randomly selected age and sex frequency-matched 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 findings suggest that socio-economic deprivation remains a driver of tuberculosis in England, including through drugs misuse, tobacco smoking, and homelessness. These findings further support the integration of health and social services in high-risk young adults to improve TB control efforts

Loa loa Alben Trial data

Loiasis is a parasitic infection endemic in the African rain forest caused by the filarial nematode Loa loa. Loiasis can be co-endemic with onchocerciasis and/or lymphatic filariasis. Ivermectin, the drug used in the control of these diseases, can induce serious adverse reactions in patients with high L loa microfilaraemia (LLM). A drug is needed which can lower LLM below the level that represents a risk so that ivermectin mass treatment to support onchocerciasis and lymphatic filariasis elimination can be implemented safely. Sixty men and women from a loiasis endemic area in Cameroon were randomized after stratification by screening LLM (≤30000, 30001-50000, >50000) to three treatment arms: two doses albendazole followed by 4 doses matching placebo (n = 20), six doses albendazole (n = 20) albendazole or 6 doses matching placebo (n = 20) administered every two months. LLM was measured before each treatment and 14, 18, 21 and 24 months after the first treatment. Monitoring for adverse events occurred three and seven days as well as 2 months after each treatment. None of the adverse events recorded were considered treatment related. The percentages of participants with ≥ 50% decrease in LLM from pre-treatment for ≥ 4 months were 53%, 17% and 11% in the 6-dose, 2-dose and placebo treatment arms, respectively. The difference between the 6-dose and the placebo arm was significant (p = 0.01). The percentages of participants with LLM < 8100 mf/ml for ≥4 months were 21%, 11% and 0% in the 6-dose, 2-dose and placebo treatment arms, respectively. The 6-dose regimen reduced LLM significantly, but the reduction was insufficient to eliminate the risk of severe and/or serious adverse reactions during ivermectin mass drug administration in loiasis co-endemic areas

Effect of Two or Six Doses 800 mg of Albendazole Every Two Months on Loa loa Microfilaraemia: A Double Blind, Randomized, Placebo-Controlled Trial.

BACKGROUND: Loiasis is a parasitic infection endemic in the African rain forest caused by the filarial nematode Loa loa. Loiasis can be co-endemic with onchocerciasis and/or lymphatic filariasis. Ivermectin, the drug used in the control of these diseases, can induce serious adverse reactions in patients with high L loa microfilaraemia (LLM). A drug is needed which can lower LLM below the level that represents a risk so that ivermectin mass treatment to support onchocerciasis and lymphatic filariasis elimination can be implemented safely. METHODOLOGY: Sixty men and women from a loiasis endemic area in Cameroon were randomized after stratification by screening LLM (≤ 30000, 30001-50000, >50000) to three treatment arms: two doses albendazole followed by 4 doses matching placebo (n = 20), six doses albendazole (n = 20) albendazole or 6 doses matching placebo (n = 20) administered every two months. LLM was measured before each treatment and 14, 18, 21 and 24 months after the first treatment. Monitoring for adverse events occurred three and seven days as well as 2 months after each treatment. PRINCIPAL FINDINGS: None of the adverse events recorded were considered treatment related. The percentages of participants with ≥ 50% decrease in LLM from pre-treatment for ≥ 4 months were 53%, 17% and 11% in the 6-dose, 2-dose and placebo treatment arms, respectively. The difference between the 6-dose and the placebo arm was significant (p = 0.01). The percentages of participants with LLM < 8100 mf/ml for ≥ 4 months were 21%, 11% and 0% in the 6-dose, 2-dose and placebo treatment arms, respectively. CONCLUSIONS/ SIGNIFICANCE: The 6-dose regimen reduced LLM significantly, but the reduction was insufficient to eliminate the risk of severe and/or serious adverse reactions during ivermectin mass drug administration in loiasis co-endemic areas

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 [&lt; 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 &gt; 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