The prospective evaluation of the TB strain typing service in England: a mixed methods study.

BACKGROUND: In response to rising TB notification rates in England, universal strain typing was introduced in 2010. We evaluated the acceptability, effectiveness and cost-effectiveness of the TB strain typing service (TB-STS). METHODS: We conducted a mixed-methods evaluation using routine laboratory, clinic and public health data. We estimated the effect of the TB-STS on detection of false positive Mycobacterium tuberculosis diagnoses (2010-2012); contact tracing yield (number of infections or active disease per pulmonary TB case); and diagnostic delay. We developed a deterministic age-structured compartmental model to explore the effectiveness of the TB-STS, which informed a cost-effectiveness analysis. RESULTS: Semi-structured interviews explored user experience. Strain typing identified 17 additional false positive diagnoses. The TB-STS had no significant effect on contact tracing yield or diagnostic delay. Mathematical modelling suggested increasing the proportion of infections detected would have little value in reducing TB incidence in the white UK-born population. However, in the non-white UK-born and non-UK-born populations, over 20 years, if detection of latent infection increases from 3% to 13% per year, then TB incidence would decrease by 11%; reducing diagnostic delay by one week could lead to 25% reduction in incidence. The current TB-STS was not predicted to be cost-effective over 20 years (£95 628/quality-adjusted life-years). Interviews found people had mixed experiences, but identified broader benefits, of the TB-STS. CONCLUSIONS: To reduce costs, improve efficiency and increase effectiveness, we recommend changes to the TB-STS, including discontinuing routine cluster investigations and focusing on reducing diagnostic delay across the TB programme. This evaluation of a complex intervention informs the future of strain typing in the era of rapidly advancing technologies.

Immunity to polio, measles and rubella in women of child-bearing age and estimated congenital rubella syndrome incidence, Cambodia, 2012.

Significant gaps in immunity to polio, measles, and rubella may exist in adults in Cambodia and threaten vaccine-preventable disease (VPD) elimination and control goals, despite high childhood vaccination coverage. We conducted a nationwide serological survey during November-December 2012 of 2154 women aged 15-39 years to assess immunity to polio, measles, and rubella and to estimate congenital rubella syndrome (CRS) incidence. Measles and rubella antibodies were detected by IgG ELISA and polio antibodies by microneutralization testing. Age-structured catalytic models were fitted to rubella serological data to predict CRS cases. Overall, 29.8% of women lacked immunity to at least one poliovirus (PV); seroprevalence to PV1, PV2 and PV3 was 85.9%, 93.4% and 83.3%, respectively. Rubella and measles antibody seroprevalence was 73.3% and 95.9%, respectively. In the 15-19 years age group, 48.2% [95% confidence interval (CI) 42.4-54.1] were susceptible to either PV1 or PV3, and 40.3% (95% CI 33.0-47.5) to rubella virus. Based on rubella antibody seroprevalence, we estimate that >600 infants are born with CRS in Cambodia annually. Significant numbers of Cambodian women are still susceptible to polio and rubella, especially those aged 15-19 years, emphasizing the need to include adults in VPD surveillance and a potential role for vaccination strategies targeted at adults.

Accelerating progress towards tuberculosis elimination: the need for combination treatment and prevention.

Although estimated tuberculosis (TB) incidence is now falling globally, we are unlikely to achieve the Millennium Development Goal (MDG) TB targets without changing the emphasis of the global TB response in high human immunodeficiency virus prevalence settings. Two independent modelling exercises using South African data with different structures and assumptions conclude that, until new drugs, diagnostics and vaccines are available, a fully funded and accessible combination approach to anti-tuberculosis treatment and prevention, based on knowledge of local TB epidemiology and evidence-informed policy, is essential to accelerate progress towards zero new tuberculous infections, zero TB deaths and zero suffering from TB.

Systematic review and meta-analysis of the current evidence on the duration of protection by bacillus Calmette-Guérin vaccination against tuberculosis.

BACKGROUND: Recent evidence suggests that the duration of protection by bacillus Calmette-Guérin (BCG) may exceed previous estimates with potential implications for estimating clinical and cost-efficacy. OBJECTIVES: To estimate the protection and duration of protection provided by BCG vaccination against tuberculosis, explore how this protection changes with time since vaccination, and examine the reasons behind the variation in protection and the rate of waning of protection. DATA SOURCES: Electronic databases including MEDLINE, Excerpta Medica Database (EMBASE), Cochrane Databases, NHS Economic Evaluation Database (NHS EED), Database of Abstracts of Reviews of Effects (DARE), Web of Knowledge, Biosciences Information Service (BIOSIS), Latin American and Caribbean Health Sciences Literature (LILACs), MEDCARIB Database, Cumulative Index to Nursing and Allied Health Literature (CINAHL) were searched from inception to May 2009. Index to Theses, System for Information on Grey Literature in Europe (SIGLE), Centre for Agricultural Bioscience International (CABI) Abstracts, Scopus, Article First, Academic Complete, Africa-Wide Information, Google Scholar, Global Health, British National Bibliography for Report Literature, and clinical trial registration websites were searched from inception to October 2009. REVIEW METHODS: Electronic databases searches, screening of identified studies, data extraction and analysis were undertaken. Meta-analysis was used to present numerical and graphical summaries of clinical efficacy and efficacy by time since vaccination. Evidence of heterogeneity was assessed using the tau-squared statistic. Meta-regression allowed the investigation of observed heterogeneity. Factors investigated included BCG strain, latitude, stringency of pre-BCG vaccination tuberculin testing, age at vaccination, site of disease, study design and vulnerability to biases. Rate of waning of protection was estimated using the ratio of the measure of efficacy after 10 years compared with the efficacy in the first 10 years of a study. RESULTS: Study selection. A total of 21,030 references were identified, providing data on 132 studies after abstract and full-text review. Efficacy. Protection against pulmonary tuberculosis in adults is variable, ranging from substantial protection in the UK MRC trial {rate ratio 0.22 [95% confidence interval (CI) 0.16 to 0.31]}, to absence of clinically important benefit, as in the large Chingleput trial [rate ratio 1.05 (95% CI 0.88 to 1.25)] and greater in latitudes further away from the equator. BCG vaccination efficacy was usually high, and varied little by form of disease (with higher protection against meningeal and miliary tuberculosis) or study design when BCG vaccination was given only to infants or to children after strict screening for tuberculin sensitivity. High levels of protection against death were observed from both trials and observational studies. The observed protective effect of BCG vaccination did not differ by the strain of BCG vaccine used in trials. DURATION: Reviewed studies showed that BCG vaccination protects against pulmonary and extrapulmonary tuberculosis for up to 10 years. Most studies either did not follow up participants for long enough or had very few cases after 15 years. This should not be taken to indicate an absence of effect: five studies (one trial and four observational studies) provided evidence of measurable protection at least 15 years after vaccination. Efficacy declined with time. The rate of decline was variable, with faster decline in latitudes further from the equator and in situations where BCG vaccination was given to tuberculin-sensitive participants after stringent tuberculin testing. LIMITATIONS: The main limitation of this review relates to quality of included trials, most of which were conducted before current standards for reporting were formulated. In addition, data were lacking in some areas and the review had to rely on evidence from observational studies. CONCLUSIONS: BCG vaccination protection against tuberculosis varies between populations, to an extent that cannot be attributed to chance alone. Failure to exclude those already sensitised to mycobacteria and study latitude closer to the equator were associated with lower efficacy. These factors explained most of the observed variation. There is good evidence that BCG vaccination protection declines with time and that protection can last for up to 10 years. Data on protection beyond 15 years are limited; however, a small number of trials and observational studies suggest that BCG vaccination may protect for longer. Further studies are required to investigate the duration of protection by BCG vaccination. FUNDING: The National Institute for Health Research Health Technology Assessment programme.

Limited impact of tuberculosis control in Hong Kong: attributable to high risks of reactivation disease.

Over 50% of the global burden of tuberculosis occurs in South East Asia and the Western Pacific. Since 1950, notification rates in high-income countries in these settings have declined slowly and have remained over ten-fold greater than those in Western populations. The reasons for the slow decline are poorly understood. Using an age-structured model describing the incidence of Mycobacterium tuberculosis infection and disease applied to notification data from Hong Kong, we illustrate that in Hong Kong, a high prevalence of M. tuberculosis infection among older individuals and a high risk of disease through reactivation (e.g. up to 17-fold greater than that estimated for infected males in the United Kingdom) may explain this slow decline. If this feature of the epidemiology of tuberculosis is widespread, the WHO directly observed treatment short-course (DOTS) strategy may have a smaller impact in Asia in the short term than has been implied by recent predictions, all of which have been based on disease risk estimates derived from Western Europe. As a result, it may be difficult to meet the targets for tuberculosis control, which have been prescribed by the UN Millennium Development Goals.

Analyses of the 1957 (Asian) influenza pandemic in the United Kingdom and the impact of school closures.

Many countries plan to close schools during a future influenza pandemic, although the potential impact is poorly understood. We apply a model of the transmission dynamics of pandemic influenza to consultation, serological and clinical data from the United Kingdom from the 1957 (Asian) influenza pandemic, to estimate the basic reproduction number (R0), the proportion of infected individuals who experience clinical symptoms and the impact of school/nursery closures. The R0 for Asian influenza was about 1.8 and 60-65% of infected individuals were estimated to have experienced clinical symptoms. During a future pandemic, closure of schools/nurseries could reduce the epidemic size only by a very small amount (<10%) if R0 is high (e.g. 2.5 or 3.5), and modest reductions, e.g. 22% might be possible if it is low (1.8) and schools are closed early, depending on assumptions about contact patterns. Further data on contact patterns and their dependence on school closures are needed.

HIV epidemic trend and antiretroviral treatment need in Karonga District, Malawi.

We describe the development of the HIV epidemic in Karonga District, Malawi over 22 years using data from population surveys and community samples. These data are used to estimate the trend in HIV prevalence, incidence and need for antiretroviral treatment (ART) using a simple mathematical model. HIV prevalence rose quickly in the late 1980s and early 1990s, stabilizing at around 12% in the mid-1990s. Estimated annual HIV incidence rose quickly, peaking in the early 1990s at 2.2% among males and 3.1% among females, and then levelled off at 1.3% among males and 1.1% among females by the late 1990s. Assuming a 2-year eligibility period, both our model and the UNAIDS models predicted 2.1% of adults were in need of ART in 2005. This prediction was sensitive to the assumed eligibility period, ranging from 1.6% to 2.6% if the eligibility period was instead assumed to be 1.5 or 2.5 years, respectively.

Mixture analysis of tuberculin survey data from northern Malawi and critique of the method.

SETTING: Various methods have been used to estimate the prevalence of Mycobacterium tuberculosis infection from tuberculin survey data. All are complicated by prior sensitisation to environmental mycobacteria and bacille Calmette-Guérin (BCG) vaccination. Mixture analysis has recently been proposed as a means of overcoming misclassification and improving infection prevalence estimates. OBJECTIVE: To compare conventional and mixture model estimates of M. tuberculosis infection prevalence. DESIGN: Mixture models with two or three univariate normal components were fitted to the results of 53 909 tuberculin tests conducted in northern Malawi during 1980-1984. Data were stratified by BCG status, sex and age and corrected for digit preference. Prevalence estimates derived from mixture models were compared with those of conventional methods. RESULTS: The optimal model was age-dependent, with three- and one-component solutions preferred in younger and older age groups, respectively. In contrast with findings from elsewhere, a component corresponding to BCG vaccination was indistinguishable from that attributable to environmental mycobacterial exposure, and infection prevalence estimates in younger individuals with a BCG scar were inflated, irrespective of the method used. CONCLUSION: The validity of infection prevalence and incidence estimates based on mixture modelling is probably locale-dependent, and the assumptions underlying mixture models may not realistically reflect underlying immunological processes.

The predicted impact of private sector MMR vaccination on the burden of Congenital Rubella Syndrome.

In many developing countries, Measles-Mumps-Rubella (MMR) vaccine is available through the private but not the public sectors, and there is no systematic rubella vaccination among adult women. In this paper, we extend previous modeling studies to demonstrate that in developing countries with a medium-high force of infection (200-400/1000 per year), current levels of private sector MMR coverage (<60%) would lead to increases in the incidence of Congenital Rubella Syndrome (CRS) both among unvaccinated individuals and the general population even when mixing between vaccinated and unvaccinated individuals is fairly minimal. Our findings highlight the need for countries to establish surveillance of trends in susceptibility to rubella and CRS incidence and perhaps introduce rubella vaccination among women of child-bearing age.

Exogenous re-infection as a cause of recurrent tuberculosis in a low-incidence area.

SETTING: Surveillance data from the National Tuberculosis Register for the period 1993-1997 complemented with DNA fingerprinting results of Mycobacterium tuberculosis isolates. OBJECTIVE: To estimate the proportion of disease attributable to recent re-infection among Dutch tuberculosis patients with reported tuberculosis infection or disease before 1981. DESIGN: Data from 1,547 Dutch patients diagnosed between 1994 and 1997 in the Netherlands were studied. Cases with reported tuberculosis infection or disease before 1981 were attributed to reactivation if their M. tuberculosis isolate was unclustered based on DNA fingerprinting or if they were the first case in a cluster, and to re-infection if they were clustered, but not as the first case. RESULTS: In total, 183 Dutch tuberculosis patients (12%) had reported tuberculosis infection or disease before 1981. Tuberculosis in 29 of these patients (16%) was attributed to recent re-infection. CONCLUSION: In this setting with a low tuberculosis incidence, approximately one in six new disease episodes among patients with previous tuberculosis infection or disease may be attributable to recent re-infection.

The effect of age and study duration on the relationship between 'clustering' of DNA fingerprint patterns and the proportion of tuberculosis disease attributable to recent transmission.

Though it is recognized that the extent of 'clustering' of isolates from tuberculosis cases in a given population is related to the amount of disease attributable to recent transmission, the relationship between the two statistics is poorly understood. Given age-dependent risks of disease and the fact that a long study (e.g. spanning several years) is more likely to identify transmission-linked cases than a shorter study, both measures, and thus the relationship between them, probably depend strongly on the ages of the cases ascertained and study duration. The contribution of these factors is explored in this paper using an age-structured model which describes the introduction and transmission of M. tuberculosis strains with different DNA fingerprint patterns in The Netherlands during this century, assuming that the number of individuals contacted by each case varies between cases and that DNA fingerprint patterns change over time through random mutations, as observed in several studies. Model predictions of clustering in different age groups and over different time periods between 1993 and 1997 compare well against those observed. According to the model, the proportion of young cases with onset in a given time period who were 'clustered' underestimated the proportion of disease attributable to recent transmission in this age group (by up to 25% in males); for older individuals, clustering overestimated this proportion. These under- and overestimates decreased and increased respectively as the time period over which the cases were ascertained increased. These results have important implications for the interpretation of estimates of the proportion of disease attributable to recent transmission, based on 'clustering' statistics, as are being derived from studies of the molecular epidemiology of tuberculosis in many populations.

Lifetime risks, incubation period, and serial interval of tuberculosis.

The lifetime risk of developing disease, the incubation period, and the time period between infection and transmission (the serial interval) are three important measures for interpreting trends in tuberculous infection and disease but are complicated by strong age dependencies regarding disease risk and by the potential for reinfection to occur. By using a model of the epidemiology of tuberculosis in England and Wales, the authors demonstrated that all three measures changed dramatically during the 20th century largely as a result of declines in the risk of infection. The estimated lifetime risk was highest following infection in early adulthood and declined with year of infection; the age-weighted average was approximately 12% during the last 50 years. Incubation period distributions depend on whether they are viewed prospectively (from infection to disease onset) or retrospectively (since infection for cases with disease onset at a particular time). As children rarely develop infectious forms of tuberculosis, infections acquired in childhood are associated with considerably longer serial intervals than those acquired in adulthood. These unusual properties are probably shared by other infections with long intervals between infection and disease. The results are important for interpreting data on transmission patterns, as are now being derived from molecular epidemiologic studies.

Interpreting DNA fingerprint clusters of Mycobacterium tuberculosis. European Concerted Action on Molecular Epidemiology and Control of Tuberculosis.

Many studies of tuberculosis have defined clusters of patients on the basis of shared DNA fingerprint patterns of their Mycobacterium tuberculosis isolates. Clustering has been equated with recent transmission, and factors associated with clustering have been sought as a guide to population subgroups with high rates of ongoing transmission of M. tuberculosis. Considerable caution should be exercised in conducting and interpreting these studies. Groups of strains may be identical for reasons other than recent transmission, depending, for example, on the stability of the marker and the number of strains in the population over time. Cases actually due to recent transmission may not be seen as clustered if they are new immigrants to the population or if not all cases in the population are included in the study. The amount of clustering seen will depend on the duration of the study. Studies should give precise information on the study setting, the proportion of cases included, the recruitment period and the definition of clustering used. The data on clustering should be disaggregated at least by age, sex and immigration status. To be maximally informative, studies should involve a high proportion of all cases in a population, be conducted in conjunction with conventional epidemiological investigations of contacts (if possible), and should provide information on tuberculosis incidence in the population and on patients' age, sex, human immunodeficiency virus status, drug resistance and social and ethnic group.

Tuberculin sensitivity: conversions and reversions in a rural African population.

SETTING: Karonga District, northern Malawi, 1980-1989. OBJECTIVE: To measure and interpret incidence and prevalence of tuberculin sensitivity. DESIGN: Tuberculin testing carried out within two total population surveys. Tuberculin 'positivity' and 'conversion' were defined using criteria recommended by the Tuberculosis Surveillance Research Unit and the American Thoracic Society, respectively. RESULTS: Data on 64,225 tests were available for analysis, including paired results on 6991 individuals tested in both surveys. Frequency distributions of induration varied by age, sex, BCG scar status and zone within the district. The prevalence of 'positivity' was similar in males and females until age 15, then higher among males, and was consistently higher among individuals with than among those without a BCG scar. Tuberculin 'conversion' rates estimated from cross-sectional data ranged from 0.34 to 1.15 per cent per annum. Conversion rates derived from longitudinal data were found to increase linearly with age, and the reversion rates declined rapidly with age among younger individuals. Such trends, which have been reported in other populations, are shown here to arise as an artefact of test instability. Prospective follow-up of observed converters showed greatly increased risks of tuberculosis, in particular during the two years following the second ('converted') test (relative risk > 10). CONCLUSION: Estimation of a convincing 'true' annual risk of infection from tuberculin survey data is not possible from either cross-sectional or longitudinal data, due to misclassifications and the instability of delayed type hypersensitivity over time. An apparent increase in infection risk with age can arise as an artefact of test instability. BCG-induced tuberculin sensitivity declines rapidly in this population in most individuals. It is necessary to consider tuberculin reversions, whether real or apparent, when interpreting tuberculin data on individuals or populations.

Interpreting the decline in tuberculosis: the role of secular trends in effective contact.

BACKGROUND: The dramatic decline in tuberculosis (TB) in developed countries during the past century has been attributed to many factors, including improvements in living and social conditions and, more recently, effective treatment. Each of these changes should have reduced the average number of individuals 'effectively contacted' (i.e. sufficiently to transmit infection) by each infectious TB case. METHOD: Estimates of the average number of individuals effectively contacted by each infectious TB case, for each year since 1900 in England and Wales, are derived as the ratio between published estimates of the annual risk of infection and estimates of the prevalence of infectious cases, as derived using a published model of the epidemiology of TB. RESULTS: The results suggest that each infectious case contacted, on average, about 22 individuals in 1900 sufficiently to transmit Mycobacterium tuberculosis infection, and that this number declined to about 10 by 1950 and to approximately one by 1990. CONCLUSIONS: Although several factors contributed to the decline in TB in developed countries during this century, a major contributor has been the decline in the number of effective contacts by each case over time. Similar declines have doubtless occurred over the past century for many infections in developed countries.

Influence of sampling on estimates of clustering and recent transmission of Mycobacterium tuberculosis derived from DNA fingerprinting techniques.

The availability of DNA fingerprinting techniques for Mycobacterium tuberculosis has led to attempts to estimate the extent of recent transmission in populations, using the assumption that groups of tuberculosis patients with identical isolates ("clusters") are likely to reflect recently acquired infections. It is never possible to include all cases of tuberculosis in a given population in a study, and the proportion of isolates found to be clustered will depend on the completeness of the sampling. Using stochastic simulation models based on real and hypothetical populations, the authors demonstrate the influence of incomplete sampling on the estimates of clustering obtained. The results show that as the sampling fraction increases, the proportion of isolates identified as clustered also increases and the variance of the estimated proportion clustered decreases. Cluster size is also important: the underestimation of clustering for any given sampling fraction is greater, and the variability in the results obtained is larger, for populations with small clusters than for those with the same number of individuals arranged in large clusters. A considerable amount of caution should be used in interpreting the results of studies on clustering of M. tuberculosis isolates, particularly when sampling fractions are small.

Modelling the incidence of congenital rubella syndrome in developing countries.

BACKGROUND: As of 1997, less than one-third of developing countries included rubella vaccine in their national immunization programme. In countries that have achieved high coverage of measles vaccine, an ideal opportunity exists to include control of rubella and congenital rubella syndrome (CRS) in enhanced measles control activities. Data on the burden of congenital rubella syndrome are important to guide rubella vaccination policies. METHODS: We reviewed the literature to identify studies of rubella antibody prevalence in developing countries that were conducted on populations with no major selection bias, prior to wide-scale rubella vaccination in the country. We used a simple catalytic model to describe the age-specific prevalence of susceptibility to rubella virus infection in given populations. Estimates of the incidence of infection among pregnant women were calculated using expressions for the average prevalence of susceptibility to infection and the incidence of infection during gestation. To estimate the number of cases of CRS, we assumed an overall risk of 65% after infection in the first 16 weeks of pregnancy and zero risk thereafter. These estimates were derived for each country for which data were available, then for each World Health Organization region, excluding Europe. RESULTS: The estimated mean incidence of CRS per 100,000 live births was lowest in the Eastern Mediterranean region (77.4, range 0-212) and highest in the Americas (175, range 0-598). The mean of the estimates of the total number of cases of CRS in developing countries in 1996 was approximately 110,000. The range was, however, very wide, from as few as 14,000 to as many as 308,000 cases. CONCLUSIONS: Congenital rubella syndrome is an under-recognized public health problem in many developing countries. There is an urgent need for collection of appropriate data to estimate the cost-effectiveness of a potential global rubella control programme.

PIP: Inclusion of rubella vaccine in the national immunization program was found to be implemented in less than one-third of the developing countries in a review conducted by WHO. This paper examines the incidence of congenital rubella syndrome (CRS) cases in developing countries using published rubella infection prevalence. Documented literature of previous studies and medical data on women attending antenatal clinics were gathered and rubella antibody prevalence was identified before the wide-scale rubella vaccination. A catalytic model was used in describing age-specific prevalence of rubella virus infection in given populations, while expressions for the average prevalence of susceptibility to infection and incidence of infection during gestation was used to estimate the incidence of infection among pregnant women. Using the data gathered from each country and WHO regions, an overall risk of 65% after infection in the first 16 weeks and zero risk of defect later in pregnancy was assumed to estimate the incidence of CRS. Results revealed that the estimated mean incidence of CRS per 100,000 live births was significantly lower in the eastern Mediterranean region (77.4, range 0-212) and higher in the Americas (175, range 0-598). On the other hand, the 1996 CRS mean estimate for developing countries was approximately 110,000, ranging from 14,000 to 308,000 cases. This study concludes with the stated need for an improved CRS program in developing countries as well as adequate data collection necessary for cost-effectiveness evaluation of potential global rubella control programs.

The long-term dynamics of tuberculosis and other diseases with long serial intervals: implications of and for changing reproduction numbers.

The net and basic reproduction numbers are among the most widely-applied concepts in infectious disease epidemiology. A net reproduction number (the average number of secondary infectious cases resulting from each case in a given population) of above 1 is conventionally associated with an increase in incidence; the basic reproduction number (defined analogously for a 'totally susceptible' population) provides a standard measure of the 'transmission potential' of an infection. Using a model of the epidemiology of tuberculosis in England and Wales since 1900, we demonstrate that these measures are difficult to apply if disease can follow reinfection, and that they lose their conventional interpretations if important epidemiological parameters, such as the rate of contact between individuals, change over the time interval between successive cases in a chain of transmission (the serial interval). The net reproduction number for tuberculosis in England and Wales appears to have been approximately 1 from 1900 until 1950, despite concurrent declines in morbidity and mortality rates, and it declined rapidly in the second half of this century. The basic reproduction number declined from about 3 in 1900, reached 2 by 1950, and first fell below 1 in about 1960. Reductions in effective contact between individuals over this period, measured in terms of the average number of individuals to whom each case could transmit the infection, meant that the conventional basic reproduction number measure (which does not consider subsequent changes in epidemiological parameters) for a given year failed to reflect the 'actual transmission potential' of the infection. This latter property is better described by a variant of the conventional measure which takes secular trends in contact into account. These results are relevant for the interpretation of trends in any infectious disease for which epidemiological parameters change over time periods comparable to the infectious period, incubation period or serial interval.

The effect of heterologous immunity upon the apparent efficacy of (e.g. BCG) vaccines.

Exposure of populations to microbes which share antigens with pathogens can influence the apparent efficacy of vaccines. This may explain the great variation (from below 0 to 80%) observed in protection by Bacillus Calmette Guérin (BCG) against tuberculosis. This paper explores three models for the effect of such heterologous immunity, and demonstrates that: (a) if the immune responses to the microbial antigens in nature and in the vaccines differ qualitatively, there will be no effect on observed efficacy; (b) if the immune responses differ only quantitatively, the observed vaccine efficacy will be reduced, and it will be minimal when vaccine-induced and heterologous protection are of similar magnitude; and (c) if the heterologous exposure can block the vaccine action, then observed efficacy will be reduced and may even appear negative. These results provide important guidance for the interpretation of BCG's utility and for the development and evaluation of new vaccines, in particular against tuberculosis.