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Deals with a study which explored the influence of annual risk for Mycobacterium tuberculosis infection on the age-specific proportion of clustered cases. Methods; Results; Discussion.

Presents a study which assessed the interferon-gamma responsiveness to purified protein derivative and tuberculin antigens from mycobacteria species among adults in Malawi, where vaccination provides no protection against pulmonary tuberculosis. Information on mycobacteria vaccines; Materials and methods used; Results and discussion.

Both the absolute levels and the seasonal pattern of pertussis have changed over the past four decades in England and Wales. Three-to-four-year period epidemics tended to peak in the early or middle part of the year prior to 1957, during the last quarter between 1958 and 1975, and have been bimodal, with peaks in February and September, in both epidemics since 1976. Analysis of reported incidence data reveals similarities in the underlying seasonal pattern of transmission throughout this period. Seasonal effects include an increase in transmesion coincident with the opening of schools in September. Other features of the pattern, such as a sharp fall in transmission in late November and a protracted low during February and March, are more difficult to explain, but may indicate important factors in the natural hiatory of pertussis. The bimodality of recent epidemics appears to be a consequence of a seasonal low in transmission during February and March followed by a high level of transmission during the summer months. These seasonal trends may in turn reflect the increasing proportion of cases among pre-school children as a consequence of the fall in vaccine uptake during the mid 1970's. [ABSTRACT FROM PUBLISHER]

Clarkson J A (Ross Institute, London School of Hygiene and Tropical Medicine, Keppel St, London WC1E 7HT, UK) and Fine P E M. The efficiency of measles and pertussis notification in England and Wales. 1985, 14: 153–168. This paper examines methods for estimating the efficiency of measles and pertussis notification with particular reference to England and Wales. Crude estimates are obtained from a comparison of annual numbers of births and notifications, and this approach is modified to include detailed age-specific data. Other sources of data, notably the Hospital In-Patient Enquiry, are used to give detailed estimates over time. These analyses provide evidence for a strong positive correlation between notification efficiency and incidence for both diseases and for a dramatic fall in the notification efficiency for pertussis between 1957 and 1976. This decrease is of particular interest insofar as it could explain in part the apparent fall in size of successive pertussis epidemics during that period. It is estimated that since 1976 the spotter practices of the Royal College of General Practitioners General Practice Research Unit have been approximately 1.5 times more efficient at reporting measles and 2.5 times more efficient at reporting pertussis than the national average for reporting to the Office of Population Censuses and Surveys. Finally it is noted that estimates of notification efficiency are positively correlated with the assumed level of vaccine efficacy, and that all these methods require assumptions concerning the proportion of vaccinations which are recorded, the proportion of vaccinations which are successful in immunizing the recipient, and the proportion of the population which ultimately contracts the infection. In general, measles notification in England and Wales is considerably better than that for pertussis, being of the order of 40–60% for the former and only 5–25% for the latter. [ABSTRACT FROM PUBLISHER]

Published predictions of the impact which different levels of vaccination should have on measles incidence are discussed in the context of observed data on vaccine uptake and measles incidence in England and Wales. Discrepancies are noted between prediction and observation with regard to the effect of vaccination on epidemic periodicity. epidemic size, age distribution of cases, and the disappearance of measles from communities. These errors are attributable to failures to recognize the implications of seasonal trends in incidence, age dependence of risk, and the non-homogeneity of human populations. Predictive models are useful hypotheses, but should be assessed critically against observation. [ABSTRACT FROM PUBLISHER]

Fine P E M [Ross Institute, London School of Hygiene and Tropical Medicine, Keppel Street, London WC 1E 7HT, United Kingdom] and Clarkson J A. Measles in England and Wales—I: An analysis of factors underlying seasonal patterns. International Journal of Epidemiology 1982, 11: 5–14. Examination of weekly measles notifications for England and Wales, 1950–1979, reveals a regular biennial pattern of major and minor epidemics before the national immunization programme began in 1968, followed by an annual cycle of minor epidemics. Each year the reported incidence reaches its annual low between weeks 36 to 39, very close to the opening of primary schools. Analysis of these data with a simple mass action model reveals that the underlying transmission parameter has had a similar annual pattern in years of major and minor epidemics. The transmission parameter rises three times each year, coinciding with opening of school terms, and falls with school term and mid–term holidays. This pattern of the transmission parameter has been maintained in the decaded since national vaccination began, indicating that the importance of schools in the annual dynamics of measles has not changed. The analysis further suggests that the national measles vaccination programme has not lowered the total number of individuals susceptible to measles in England and Wales. [ABSTRACT FROM PUBLISHER]

Fine P E M [Ross Institute, London School of Hygiene and Tropical Medicine, Keppel Street, London WC1E 7HT, United Kingdom] and Clarkson J A. Measles in England and Wales—II: The impact of the Measles Vaccination Programme on the distribution of immunity in the population. 1982, : 15–25. Measles notification and vaccination data for England and Wales are analysed to reveal trends in age-specific incidence and immunity levels in successive cohorts born since 1950. A method for cumulating infection and vaccination experience is described in detail. The analysis reveals that there was a trend towards lower incidence rates of measles, and towards younger average age of cases, for the 10 years prior to commencement of the national immunization programme in 1968. Since the immunization programme began, there has been a dramatic and complicated shift in the age pattern of measles immunity in the population, such that some young age groups are now better protected, but some older age groups less well protected, than they were before the programme. These trends are discussed with critical attention to the possibility that they may reflect biases in the available data. It is concluded that the number of susceptibles over 10 years of age is increasing, and that this could have appreciable public health implications in the years to come. It appears that the total number of individuals susceptible to measles has remained relatively constant, between 4 and 4.5 million, before and after the immunization programme. Though consistent with basic theory, this maintenance of constant overall number of susceptibles has not been demonstrated before. Because the implications of these analyses are important for the strategy of measles control, it is important that appropriate serological surveys be carried out in order to assess the validity of the findings. [ABSTRACT FROM PUBLISHER]

It has been reported that the efficacy of pertussis vaccines appears to be lower when assessed in household contact studies than when assessed in cohort analyses of general populations. This observation may be attributable in part to methodological factors in home contact studies, in particular to the Inclusion of retrospectively ascertained cases and of households In which the primary case constituted a vaccine failure. These biases are Illustrated using data from a study of the efficacy of pertussis vacdnes carried out by the Public Health Laboratory Service Epidemiological Research Laboratory PHLS/ERL in England during 1978–1980. This analysis reveals several factors which should be considered in the design, analysis and interpretation of household contact studies for evaluation of vaccine efficacy. [ABSTRACT FROM PUBLISHER]

The authors discuss a study led by Michele Tameris and colleagues and published by "Lancet" online on February 4, 2013 and in the March 23, 2013 issue regarding a phase 2b trial of a tuberculosis vaccine in infants in South Africa. The vaccine, a modified Vaccinia virus Ankara expressing antigen 85A, is described. The lack of evidence of the vaccine's efficacy in terms of preventing tuberculosis or infection with Mycobacterium tuberculosis is also mentioned.

The article discusses steps taken by the World Health Organization (WHO) to prevent leprosy. Important contributions have been made by the WHO in leprosy research and control through including it in leprosy in the multi-agency Special Programme for Research and Training in Tropical Diseases (TDR) and by leading a global leprosy elimination initiative.

A letter to the editor is presented in response to the article "Randomizedtrial of BCG vaccination at birth to low-birth weight children: beneficial nonspecific effects in the neonatal period?" by P. Aaby and colleagues in a previous 2011 issue is presented.

Background: The importance of remote infection with M.tuberculosis as a cause of tuberculosis disease (TB) is unclear, with limited evidence of impact on TB rates beyond 10 years. Our objective was to assess rates of tuberculosis over 30 years by M.tuberculosis infection status at baseline in Karonga District, Northern Malawi. Materials and methods: Population-based surveys of tuberculin skin testing (TST) from the 1980s were linked with follow-up and TB surveillance in Karonga district. We compared rates of microbiologically-confirmed TB by baseline TST induration <5mm (no evidence of M.tuberculosis infection) and those with baseline TST >17mm (evidence of M.tuberculosis infection), using hazard ratios by time since baseline and attributable risk percent. The attributable risk percent was calculated to estimate the proportion of TB in those infected that can be attributed to that prior infection. We analysed whole genome sequences of M.tuberculosis strains to identify recent transmission. Results: Over 412,959 person-years, 208 incident TB episodes were recorded. Compared to the small induration group, rates of TB were much higher in the first two years in the large induration group, and remained higher to 20 years: age, sex and area-adjusted hazard ratios (HR) 2–9 years post-TST 4.27 (95%CI 2.56–7.11); 10–19 years after TST 2.15 (1.10–4.21); ≥20 years post-TST 1.88 (0.76–4.65). The attributable risk percent of remote infection was 76.6% (60.9–85.9) 2–9 years post-TST, and 53.5% (9.1–76.2) 10–19 years post-TST. Individuals with large TST indurations had higher rates of unique-strain TB (HR adjusted for age, sex and area = HR 6.56 (95% CI 1.96–22.99)), suggesting disease following remote infection, but not of linked-strain TB (recent transmission). Conclusions: M.tuberculosis infection can increase the risk of TB far beyond 10 years, accounting for a substantial proportion of TB occurring among those remotely infected. [ABSTRACT FROM AUTHOR]

A response from the authors of a research paper on disease outbreaks in highly vaccinated populations, that was published in a previous issue is presented.

Leprosy is a chronic infection of the skin and peripheral nerves caused by Mycobacterium leprae. Despite recent improvements in disease control, leprosy remains an important cause of infectious disability globally. Large-scale genetic association studies in Chinese, Vietnamese and Indian populations have identified over 30 susceptibility loci for leprosy. There is a significant burden of leprosy in Africa, however it is uncertain whether the findings of published genetic association studies are generalizable to African populations. To address this, we conducted a genome-wide association study (GWAS) of leprosy in Malawian (327 cases, 436 controls) and Malian (247 cases, 368 controls) individuals. In that analysis, we replicated four risk loci previously reported in China, Vietnam and India; MHC Class I and II, LACC1 and SLC29A3. We further identified a novel leprosy susceptibility locus at 10q24 (rs2015583; combined p = 8.81 × 10−9; OR = 0.51 [95% CI 0.40 − 0.64]). Using publicly-available data we characterise regulatory activity at this locus, identifying ACTR1A as a candidate mediator of leprosy risk. This locus shows evidence of recent positive selection and demonstrates pleiotropy with established risk loci for inflammatory bowel disease and childhood-onset asthma. A shared genetic architecture for leprosy and inflammatory bowel disease has been previously described. We expand on this, strengthening the hypothesis that selection pressure driven by leprosy has shaped the evolution of autoimmune and atopic disease in modern populations. More broadly, our data highlights the importance of defining the genetic architecture of disease across genetically diverse populations, and that disease insights derived from GWAS in one population may not translate to all affected populations. Author summary: Leprosy remains a leading cause of infectious disability globally. Human genetic variation is a major determinant of susceptibility to infection, including leprosy. Large-scale genetic association studies have been pivotal in advancing our understanding of leprosy biology. These studies have been performed in Chinese, Vietnamese and Indian populations, and it remains unclear whether these insights are informative of leprosy susceptibility in African populations. To address this, we performed a genome-wide association study of leprosy susceptibility in Malawi and Mali. In doing so we replicate known leprosy susceptibility loci at MHC class I and II, LACC1 and SLC29A3. Furthermore, we identify a novel leprosy susceptibility locus, which has been under recent selection pressure, which demonstrates pleiotropy with inflammatory bowel disease and atopic disease. We identify expression of ACTR1A in CD4+ T cells as candidate effector of leprosy risk at this locus. These data deepen our understanding of leprosy biology and further implicate this ancient pathogen in the evolution of immune-mediated diseases in modern populations. [ABSTRACT FROM AUTHOR]

Background: Trials of BCG vaccination to prevent or reduce severity of COVID-19 are taking place in adults, some of whom have been previously vaccinated, but evidence of the beneficial, non-specific effects of BCG come largely from data on mortality in infants and young children, and from in-vitro and animal studies, after a first BCG vaccination. We assess all-cause mortality following a large BCG revaccination trial in Malawi.Methods: The Karonga Prevention trial was a population-based, double-blind, randomised controlled in Karonga District, northern Malawi, that enrolled participants between January, 1986, and November, 1989. The trial compared BCG (Glaxo-strain) revaccination versus placebo to prevent tuberculosis and leprosy. 46 889 individuals aged 3 months to 75 years were randomly assigned to receive BCG revaccination (n=23 528) or placebo (n=23 361). Here we report mortality since vaccination as recorded during active follow-up in northern areas of the district in 1991-94, and in a demographic surveillance follow-up in the southern area in 2002-18. 7389 individuals who received BCG (n=3746) or placebo (n=3643) lived in the northern follow-up areas, and 5616 individuals who received BCG (n=2798) or placebo (n=2818) lived in the southern area. Year of death or leaving the area were recorded for those not found. We used survival analysis to estimate all-cause mortality.Findings: Follow-up information was available for 3709 (99·0%) BCG recipients and 3612 (99·1%) placebo recipients in the northern areas, and 2449 (87·5%) BCG recipients and 2413 (85·6%) placebo recipients in the southern area. There was no difference in mortality between the BCG and placebo groups in either area, overall or by age group or sex. In the northern area, there were 129 deaths per 19 694 person-years at risk in the BCG group (6·6 deaths per 1000 person-years at risk [95% CI 5·5-7·8]) versus 133 deaths per 19 111 person-years at risk in the placebo group (7·0 deaths per 1000 person-years at risk [95% CI 5·9-8·2]; HR 0·94 [95% CI 0·74-1·20]; p=0·62). In the southern area, there were 241 deaths per 38 399 person-years at risk in the BCG group (6·3 deaths per 1000 person-years at risk [95% CI 5·5-7·1]) versus 230 deaths per 38 676 person-years at risk in the placebo group (5·9 deaths per 1000 person-years at risk [95% CI 5·2-6·8]; HR 1·06 [95% CI 0·88-1·27]; p=0·54).Interpretation: We found little evidence of any beneficial effect of BCG revaccination on all-cause mortality. The high proportion of deaths attributable to non-infectious causes beyond infancy, and the long time interval since BCG for most deaths, might obscure any benefits.Funding: British Leprosy Relief Association (LEPRA); Wellcome Trust. [ABSTRACT FROM AUTHOR]

This systematic review and analysis suggests that BCG vaccination in infancy, or BCG vaccination when stringent tuberculin testing excludes those with a small degree of prior infection or sensitization to environmental mycobacteria, protects against pulmonary diseases even in the tropics.Background. Randomized trials assessing BCG vaccine protection against tuberculosis have widely varying results, for reasons that are not well understood.Methods. We examined associations of trial setting and design with BCG efficacy against pulmonary and miliary or meningeal tuberculosis by conducting a systematic review, meta-analyses, and meta-regression.Results. We identified 18 trials reporting pulmonary tuberculosis and 6 reporting miliary or meningeal tuberculosis. Univariable meta-regression indicated efficacy against pulmonary tuberculosis varied according to 3 characteristics. Protection appeared greatest in children stringently tuberculin tested, to try to exclude prior infection with Mycobacterium tuberculosis or sensitization to environmental mycobacteria (rate ratio [RR], 0.26; 95% confidence interval [CI], .18–.37), or infants (RR, 0.41; 95% CI, .29–.58). Protection was weaker in children not stringently tested (RR, 0.59; 95% CI, .35–1.01) and older individuals stringently or not stringently tested (RR, 0.88; 95% CI, .59–1.31 and RR, 0.81; 95% CI, .55–1.22, respectively). Protection was higher in trials further from the equator where environmental mycobacteria are less and with lower risk of diagnostic detection bias. These associations were attenuated in a multivariable model, but each had an independent effect. There was no evidence that efficacy was associated with BCG strain. Protection against meningeal and miliary tuberculosis was also high in infants (RR, 0.1; 95% CI, .01–.77) and children stringently tuberculin tested (RR, 0.08; 95% CI, .03–.25).Conclusions. Absence of prior M. tuberculosis infection or sensitization with environmental mycobacteria is associated with higher efficacy of BCG against pulmonary tuberculosis and possibly against miliary and meningeal tuberculosis. Evaluations of new tuberculosis vaccines should account for the possibility that prior infection may mask or block their effects. [ABSTRACT FROM PUBLISHER]

The Karonga Health and Demographic Surveillance System (Karonga HDSS) in northern Malawi currently has a population of more than 35 000 individuals under continuous demographic surveillance since completion of a baseline census (2002–2004). The surveillance system collects data on vital events and migration for individuals and for households. It also provides data on cause-specific mortality obtained by verbal autopsy for all age groups, and estimates rates of disease for specific presentations via linkage to clinical facility data. The Karonga HDSS provides a structure for surveys of socio-economic status, HIV sero-prevalence and incidence, sexual behaviour, fertility intentions and a sampling frame for other studies, as well as evaluating the impact of interventions, such as antiretroviral therapy and vaccination programmes. Uniquely, it relies on a network of village informants to report vital events and household moves, and furthermore is linked to an archive of biological samples and data from population surveys and other studies dating back three decades. [ABSTRACT FROM AUTHOR]

Background. BCG vaccination of infants is thought to provide good protection in all settings. This study investigated whether Malawian infants made weaker responses across a cytokine panel after BCG vaccination, compared with UK infants. Methods. Diluted whole-blood samples were cultured with Mycobacterium tuberculosis purified protein derivative for 6 days from BCG-vaccinated infants 3 months (n = 40 Malawi, 28 UK) and 12 months (n = 34 Malawi, 26 UK) after vaccination, and also from UK unvaccinated infants (n = 9 at 3 months, n = 10 at 12 months). Forty-two cytokines were measured in supernatants using a multiplex bead array assay. Principal component analysis was used to summarize the overall patterns in cytokine responses. Results. We found differences in median responses in 27 of the 42 cytokines: 7 higher in the UK and 20 higher in Malawi. The cytokines with higher responses in the UK were all T helper 1 related. The cytokines with higher responses in Malawi included innate proinflammatory cytokines, regulatory cytokines, interleukin 17, T helper 2 cytokines, chemokines, and growth factors. Principal component analysis separated the BCG-vaccinated infants from Malawi from the UK vaccinated infants and from the unvaccinated infants. Conclusions. Malawian infants make cytokine responses following BCG vaccination, but the cytokine profile is different from that in the UK. The different biosignatures following BCG vaccination in the 2 settings may indicate variability in the protective efficacy of infant BCG vaccination. [ABSTRACT FROM AUTHOR]

Routine vaccination programmes have led to substantial declines in the incidence of most of the target diseases. In these circumstances, vaccine effects beyond those on the target diseases may become evident. Several studies have suggested that certain vaccines may influence mortality in low income settings in ways that cannot be attributed to effects on target diseases. Trials of such 'non-specific' effects are difficult if not impossible to organise; and observational studies of them are prone to serious confounding, because those who do or do not receive vaccines are likely to differ in many ways, some of which relate to their subsequent risk of early death, independent of vaccination. They are also prone to other biases, including the selective loss of vaccination records for children who die. We review these potential sources of bias and suggest what and how data may be collected to optimise the validity of such studies. [ABSTRACT FROM AUTHOR]

Bacille Calmette-Guérin (BCG) vaccination induces a marked increase in the interferon (IFN)-γ response to Mycobacterium tuberculosis purified protein derivative (Mtb PPD) in UK adolescents, but not in Malawian adolescents. We hypothesized that Mtb PPD-induced IFN-γ after BCG vaccination would be similar in infants from these 2 countries. Infants were vaccinated with BCG during the first 3-13 weeks of life. Three months after BCG vaccination, 51 (100%) of 51 UK infants had an IFN-γ response to Mtb PPD, compared to 41 (53%) of 78 of Malawian infants, in whom responses varied according to their season of birth. We conclude that population differences in immune responses after BCG vaccination are observed among infants, as well as among young adults. [ABSTRACT FROM AUTHOR]

Objective To assess the social and economic impact of HIV-related illness and death on the spouses of HIV-infected individuals. Methods From population-based surveys in the 1980s in Karonga district, northern Malawi, 197 ‘index individuals’ were identified as HIV-positive. A total of 396 HIV-negative ‘index individuals’ were selected as a comparison group. These individuals, and their spouses and children, were followed up in 1998–2000, in a retrospective cohort study. All analyses compared spouses of HIV-positive indexes with those of HIV-negative indexes. Results By 1998–2000, most marriages involving an HIV-positive index individual had ended in widowhood. Twenty-Six percent of the wives of HIV-positive index men experienced household dissolution precipitated by widowhood, compared with 5% of the wives of HIV-negative index men. Corresponding percentages for husbands of index women were 14% and 1%. Widow inheritance was uncommon. The remarriage rate among separated or widowed wives of HIV-positive index men was half that of such wives of HIV-negative index men. About 30% of surviving wives of HIV-positive index men were household heads at the time of follow-up, compared with 5% of such wives of HIV-negative index men. Almost all these women were widows who lost their husband when >35 years old, and they had relatively few household assets. Conclusions The social and economic impact of HIV on the spouses of HIV-infected individuals in rural northern Malawi is substantial. Interventions that strengthen society’s ability to absorb and support widows and widowers, and their dependents, without necessarily involving the traditional coping mechanism of remarriage, are essential. [ABSTRACT FROM AUTHOR]

Background. The proportion of cases of tuberculosis due to recent infection can be estimated in long-term population-based studies using molecular techniques. Here, we present what is, to our knowledge, the first such study in an area with high human immunodeficiency virus (HIV) prevalence. Methods. All patients with tuberculosis in Karonga District, Malawi, were interviewed. Isolates were genotyped using restriction-fragment-length polymorphism (RFLP) patterns. Strains were considered to be ‘clustered’ if at least 1 other patient had an isolate with an identical pattern. Results. RFLP results were available from 83% of culture-positive patients from late 1995 to early 2003. When strains with <5 bands were excluded, 72% (682/948) were clustered. Maximum clustering was reached using a 4-year window, with an estimated two-thirds of cases due to recent transmission. The proportion clustered decreased with age and varied by area of residence. In older adults, clustering was less common in men and more common in patients who were HIV positive (adjusted odds ratio, 5.1 [95% confidence interval, 2.1–12.6]). Conclusions. The proportion clustered found in the present study was among the highest in the world, suggesting high rates of recent transmission. The association with HIV infection in older adults may suggest that HIV has a greater impact on disease caused by recent transmission than on that caused by reactivation. [ABSTRACT FROM AUTHOR]

Background. DNA fingerprint patterns of Mycobacterium tuberculosis strains vary within individuals and between epidemiologically linked individuals because of pattern evolution, new infections, and laboratory error. We explored the importance of these factors. Methods. Cultures from individuals in northern Malawi who had been diagnosed with tuberculosis (TB) during 1996–2001 were fingerprinted with restriction fragment-length polymorphism (RFLP). Probable laboratory error was inferred by use of dates or isolated positive cultures. Pattern evolution was explored within and between individuals, and the relative importance of relapse and reinfection was estimated in individuals with recurrent TB. Results. RFLP results were available for 930 isolates from 806 individuals. The maximum laboratory-error rate was 3.9%. Pattern evolution was more common in linked individuals (17%) than on relapse (11%) or during treatment (3%). Twenty individuals had recurrent TB after completing treatment: in human immunodeficiency virus (HIV)- positive individuals, 7 of 12 recurrences were due to reinfection, compared with 0 of 8 in HIV-negative individuals (P = .01). Conclusions. The rate of DNA fingerprint-pattern evolution is not linear, and rates of change calculated from repeat cultures within individuals may not be applicable to transmission between individuals. The high proportion of recurrence due to reinfection found in HIV-positive individuals suggests that secondary prophylaxis and/or antiretroviral treatments are needed for such individuals. [ABSTRACT FROM AUTHOR]