Punam Mangtani

Protection by BCG Vaccine Against Tuberculosis: A Systematic Review of Randomized Controlled Trials

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.

Influenza vaccination in pregnancy: current evidence and selected national policies

In several countries, pregnant women are recommended seasonal influenza vaccination and identified as a priority group for vaccination in the event of a pandemic. We review the evidence for the risks of influenza and the risks and benefits of seasonal influenza vaccination in pregnancy. Data on influenza vaccine safety in pregnancy are inadequate, but the few published studies report no serious side-effects in women or their infants, including no indication of harm from vaccination in the first trimester. National policies differ widely, mainly because of the limited data available, particularly on vaccination in the first trimester. The evidence of excess morbidity during seasonal influenza supports vaccinating healthy pregnant women in the second or third trimester and those with comorbidities in any trimester. The evidence of excess mortality in two previous influenza pandemics supports vaccinating in any trimester during a pandemic.

Vulnerability to winter mortality in elderly people in Britain: population based study

Abstract Objective To examine the determinants of vulnerability to winter mortality in elderly British people. Design Population based cohort study (119 389 person years of follow up). Setting 106 general practices from the Medical Research Council trial of assessment and management of older people in Britain. Participants People aged ≥ 75 years. Main outcome measures Mortality (10 123 deaths) determined by follow up through the Office for National Statistics. Results Month to month variation accounted for 17% of annual all cause mortality, but only 7.8% after adjustment for temperature. The overall winter:non-winter rate ratio was 1.31 (95% confidence interval 1.26 to 1.36). There was little evidence that this ratio varied by geographical region, age, or any of the personal, socioeconomic, or clinical factors examined, with two exceptions: after adjustment for all major covariates the winter:non-winter ratio in women compared with men was 1.11 (1.00 to 1.23), and those with a self reported history of respiratory illness had a winter:non-winter ratio of 1.20 (1.08 to 1.34) times that of people without a history of respiratory illness. There was no evidence that socioeconomic deprivation or self reported financial worries were predictive of winter death. Conclusion Except for female sex and pre-existing respiratory illness, there was little evidence for vulnerability to winter death associated with factors thought to lead to vulnerability. The lack of socioeconomic gradient suggests that policies aimed at relief of fuel poverty may need to be supplemented by additional measures to tackle the burden of excess winter deaths in elderly people.

Effect of BCG vaccination against Mycobacterium tuberculosis infection in children: systematic review and meta-analysis

Objectives To determine whether BCG vaccination protects against Mycobacterium tuberculosis infection as assessed by interferon γ release assays (IGRA) in children. Design Systematic review and meta-analysis. Searches of electronic databases 1950 to November 2013, checking of reference lists, hand searching of journals, and contact with experts. Setting Community congregate settings and households. Inclusion criteria Vaccinated and unvaccinated children aged under 16 with known recent exposure to patients with pulmonary tuberculosis. Children were screened for infection with M tuberculosis with interferon γ release assays. Data extraction Study results relating to diagnostic accuracy were extracted and risk estimates were combined with random effects meta-analysis. Results The primary analysis included 14 studies and 3855 participants. The estimated overall risk ratio was 0.81 (95% confidence interval 0.71 to 0.92), indicating a protective efficacy of 19% against infection among vaccinated children after exposure compared with unvaccinated children. The observed protection was similar when estimated with the two types of interferon γ release assays (ELISpot or QuantiFERON). Restriction of the analysis to the six studies (n=1745) with information on progression to active tuberculosis at the time of screening showed protection against infection of 27% (risk ratio 0.73, 0.61 to 0.87) compared with 71% (0.29, 0.15 to 0.58) against active tuberculosis. Among those infected, protection against progression to disease was 58% (0.42, 0.23 to 0.77). Conclusions BCG protects against M tuberculosis infection as well as progression from infection to disease. Trial registration PROSPERO registration No CRD42011001698 (www.crd.york.ac.uk/prospero/).

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.

A Cohort Study of the Effectiveness of Influenza Vaccine in Older People, Performed Using the United Kingdom General Practice Research Database

BACKGROUND The effectiveness of influenza vaccination against hospitalization and death can only ethically be assessed in observational studies. A concern is that individuals who are vaccinated are healthier than individuals who are not vaccinated, potentially biasing estimates of effectiveness upward. METHODS We conducted a historical cohort study of individuals >64 years of age, for whom there were data available in the General Practice Research Database for 1989 to 1999 in England and Wales. Rates of admissions for acute respiratory diseases and rates of death due to respiratory disease were compared over 692,819 person-years in vaccine recipients and 1,534,280 person-years in vaccine nonrecipients. RESULTS The pooled effectiveness of vaccine against hospitalizations for acute respiratory disease was 21% (95% confidence interval [CI], 17%-26%). The rate reduction attributable to vaccination was 4.15 hospitalizations/100,000 person-weeks in the influenza season. Among vaccine recipients, no important reduction in the number of admissions to the hospital was seen outside influenza seasons. The pooled effectiveness of vaccine against deaths due to respiratory disease was 12% (95% CI, 8%-16%). A greater proportionate reduction was seen among people without medical disorders, but absolute rate reduction was higher in individuals with medical disorders, compared with individuals without such disorders (6.14 deaths due to respiratory disease/100,000 person-weeks vs. 3.12 deaths due to respiratory disease/100,000 person-weeks). Clear protection against death due to all causes was not seen. CONCLUSIONS Influenza vaccination reduces the number of hospitalizations and deaths due to respiratory disease, after correction for confounding in individuals >64 years of age who had a high risk or a low risk for influenza. For elderly people, untargeted influenza vaccination is of confirmed benefit against serious outcomes.

Efficacy of polysaccharide pneumococcal vaccine in adults in more developed countries: the state of the evidence

We review studies on the efficacy against disease caused by Streptococcus pneumoniae of the 23-valent polysaccharide pneumococcal vaccine in adult populations in the more developed countries. Meta-analyses of primary vaccine trials have attempted to reduce uncertainty from lack of power. Vaccine efficacy calculated from studies in South African gold-miners and in Papua New Guinea, with high attack rates and differing serotype patterns, cannot automatically be applied to more developed countries. Meta-analyses will overestimate a protective effect if this clinical heterogeneity is ignored. Meta-analyses limited to trials in the more developed setting show no protective effect against pneumococcal pneumonia and a non-significant protective effect against bacteraemia. Lack of a specific diagnosis limits the ability to detect a protective effect against pneumococcal pneumonia. Most, but not all, observational studies confirm a protective effect against bacteraemia. An effect on mortality in more developed countries has yet to be documented.

Validation of influenza and pneumococcal vaccine status in adults based on self-report

Self-report of polysaccharide pneumococcal vaccination is not thought reliable because of the increased risk of adverse events from inadvertent re-vaccination in elderly people. Some studies suggest a high sensitivity of self-report and hence a low risk of adverse events if vaccination is administered when medical records are unavailable. Self-report of pneumococcal and influenza vaccination in a sample of >64-year-olds in the United Kingdom was compared with information in their medical records. Self-report of pneumococcal vaccination, in contrast to some of the other studies had a low sensitivity. The findings here support the need for accurate knowledge of prior vaccine status before offering the polysaccharide pneumococcal vaccine. The study also confirms that self-report of influenza vaccination could be relied upon if rapid knowledge of uptake is required.

Socioeconomic deprivation and notification rates for tuberculosis in London during 1982-91.

Abstract Objectives: To investigate the association between four sociodemographic measures (unemployment, overcrowding, low social class, and the proportion of migrants from areas of high prevalence of tuberculosis) and average level and rate of change of notification rates for tuberculosis. Design: Ecological analysis of both the average and the rate of change of standardised annual notification rates for tuberculosis from 1982-91 and sociodemographic measures from the 1981 and 1991 censuses. Setting: 32 London boroughs. Subjects and data: Sociodemographic measures from the 1981 and 1991 censuses and tuberculosis notification rates for 1982-91. Main outcome measures: A measure of the association between average levels and rate of change in tuberculosis notification rates and four sociodemographic measures in 1981 and between the rate of change in tuberculosis notification rates between 1981 and 1991 and changes in sociodemographic measures between 1981 and 1991. Results: The average level of notifications was correlated with overcrowding and the proportion of migrants but not with unemployment or social class. No significant association was found between the rate of change in notification rates and sociodemographic measures in 1981. An association was found between increases in unemployment and the rate of change in notification rates, but the effect was small. Changes in the levels of unemployment explained 23% of the variation between boroughs in the rate of change in their notification rates. Conclusion: The average tuberculosis notification rates were related to overcrowding and the proportion of migrants in 1981. Only increases in unemployment from 1981 to 1991, however, were significantly associated with the rate of change in notifications over the same period. Key messages Key messages Sociodemographic variables such as poverty, overcrowding, and migration (from parts of the world with relatively high rates of tuberculosis) are known to be associated with higher rates of tuberculosis The recent rates of change in notification rates in London boroughs in the past decade do not seem to be associated with the absolute levels of overcrowding, unemployment, social class distribution, or proportion of migrants as measured in the 1981 census An association, however, was found between changes in unemployment levels between 1981 and 1991 and the rates of change in tuberculosis notification rates in the same period, but the effect was small Further research is necessary to determine the reasons for the association found and to investigate the other factors contributing to the changing rates of tuberculosis in the developed world

Safety of immunization during pregnancy: A review of the evidence of selected inactivated and live attenuated vaccines

Vaccine-preventable infectious diseases are responsible for significant maternal, neonatal, and young infant morbidity and mortality. While there is emerging scientific evidence, as well as theoretical considerations, indicating that certain vaccines are safe for pregnant women and fetuses, policy formulation is challenging because of perceived potential risks to the fetus. This report presents an overview of available evidence on pregnant women vaccination safety monitoring in pregnant women, from both published literature and ongoing surveillance programs. Safety data were reviewed for vaccines against diseases which increase morbidity in pregnant women, their fetus or infant as well as vaccines which are used in mass vaccination campaigns against diseases. They include inactivated seasonal and pandemic influenza, mono- and combined meningococcal polysaccharide and conjugated vaccines, tetanus toxoid and acellular pertussis combination vaccines, as well as monovalent or combined rubella, oral poliomyelitis virus and yellow fever vaccines. No evidence of adverse pregnancy outcomes has been identified from immunization of pregnant women with these vaccines.