BCG Immunization Research Articles

The influence of BCG immunisation on tuberculin reactivity and booster effect in adults in a country with a high prevalence of tuberculosis

The relationship of age and previous BCG vaccination with tuberculin skin test (TST) reactivity was investigated to assess the interpretation of TST results in the adult population of Turkey, where there is a high prevalence of tuberculosis and a routine BCG vaccination programme. The influences of age and BCG vaccine status on booster reaction were also evaluated. TST was applied (5 tuberculin units of purified protein derivative intradermally) to two healthy adult groups, namely 98 medical students and 187 elderly people in a retirement home. The TST was considered positive if an induration > or = 10 mm in diameter was produced. Subjects (41 elderly people and 39 students) with a reaction < 10 mm in diameter were retested 1 week later. There was no significant difference between the students (59.1%) and elderly subjects (58.8%) with respect to positive TST response. No influence of BCG scars on TST reactivity was observed in either group. The booster effect was seen more commonly in the elderly, but the presence of a BCG scar did not influence the booster effect in either group. It was concluded that a positive TST response and booster reaction in adults in high-prevalence countries may be caused by latent tuberculosis rather than previous vaccination.

EPI vaccines-induced antibody prevalence in 8-9 year-olds in The Gambia.

We evaluated antibody prevalence to measles, polio 1 and 3, and tetanus toxoid antibodies in 8-9 year-old children in The Gambia within the framework of the Gambia Hepatitis Intervention Study (GHIS), a large vaccine trial aimed at evaluating vaccine efficacy against hepatitis B virus (HBV) infection, chronic carriage and primary liver cancer in a high risk population. The results of the present survey were compared with a previous survey performed with the same objectives and same methodology but in different children at 3-4 years of age. Four clusters of 200 children each were sampled as representative of the whole country. Children would have received BCG, diphtheria-pertussis-tetanus vaccine (DPT), poliovirus vaccine (OPV), measles and yellow fever immunization. The measles haemoagglutination inhibition test (HAI) was used to detect measles antibody. Antibodies to polioviruses 1 and 3 were tested using the standard polio neutralization assay described in the EPI manual (WHO 1990). An enzyme-linked immuno-sorbent assay (ELISA) was used to measure tetanus toxoid antibodies. A high proportion of children were fully vaccinated in both age groups. Measles antibody concentrations were < or =1 : 8 in 8.2% of 8-9 year-old vaccinated children. In the previous survey of 3-4 year-old children this was 11.3%. In the present survey, GMC was lower than in the 3-4 year-old children; 88% of 3-4 year-olds and 89% of 8-9 year-olds had detectable antibody levels against poliovirus type 1. Fewer children at 8-9 years of age had antibodies against poliovirus type 3 than 3-4 year-olds (78%vs. 89% P < 0.001). A significant overall lower proportion of 8-9 year-old children had detectable tetanus toxoid antibodies compared to 3-4 year-old children (87%vs. 95% P < 0.001), as well as those who received four doses of DPT (90%vs. 97% P < 0.001). Conclusions High vaccine coverage is achieved in The Gambia with EPI. With time the number of vaccinated children who are not protected against measles, poliovirus 3 and tetanus increases. Besides the maintenance of high vaccine coverage in infants and young children, booster doses of some of the EPI vaccines in adolescents should be considered.

A polyvalent DNA vaccine expressing an ESAT6–Ag85B fusion protein protects mice against a primary infection with Mycobacterium tuberculosis and boosts BCG-induced protective immunity

In this study, we evaluated the protective efficacy of a DNA vaccine (pE6/85) expressing an ESAT6–Ag85B fusion protein against a primary Mycobacterium tuberculosis infection in mice. In short-term studies, vaccination with pE6/85 protected as well as Mycobacterium bovis BCG immunization with similar lung pathology and bacterial burdens detected 28 days after a low dose aerogenic challenge (>1.0 log 10 reduction relative to naïves). In a survival experiment, the protection induced by pE6/85 immunization was also not significantly different than that elicited by BCG vaccination with the mean-times-to-death (±standard error of the mean) being 102 ± 20, 271 ± 32 and 299 ± 14 days for naïve, pE6/85 and BCG-vaccinated mice, respectively. Furthermore, boosting with pE6/85 but not BCG or a DNA vaccine cocktail at 1 year after an initial BCG immunization (when BCG-induced protection was declining), augmented protection in the lung at 15 and 18 months to levels detected at 3 months post-BCG vaccination.

Selective neonatal BCG vaccination

Aims: To assess the implementation of the “Selective Neonatal BCG Immunisation Policy”, and to study the causes of non‐compliance, or failure of uptake of BCG immunization. Methods: The Birth Register data were used to generate a list of babies born in the catchment area of Basildon and Thurrock NHS Trust between 1 January 2001 and 31 December 2001 who were eligible for BCG immunization. The Community Child Health computer was used to generate information about their BCG immunization status. Results: 201 children were included in the study. One hundred and seventy‐one children had received BCG immunization in the neonatal period, out of which 169 had received it before discharge from the hospital. Two children were immunized in the community in the neonatal period. Thus, 85% of the newborns eligible for BCG immunization received their vaccination in the neonatal period. Conclusions: The current “Neonatal BCG Immunisation Policy” is effective, and there is a high uptake of the vaccine in the neonatal period within the hospital itself. Newborn infants who do not receive BCG immunization in hospital rarely get immunized in the community.

Turberculosis: Current issues on diagnosis and management

In 1993, the World Health Organisation (WHO) declared tuberculosis (TB) a global emergency and in 1996, South Africa declared TB as a priority disease. The most effective means of controlling TB is through rapid diagnosis by direct sputum microscopy for acid fast bacilli (AFB), or culture for Mycobacteium tuberculosis (MTB) and prompt initiation of the correct therapy by means of the Directly Observed Treatment, Short course (DOTS) strategy. ln 1997, it was estimated that 10 million of the 30 million people infected with the human immuno-deficiency virus (HM worldwide were co-infected with TB. This review article focuses on TB diagnosis, including newer laboratory tests, treatment, and chemoprophylaxis. Special issues such as extra pulmonary TB, childhood TB, BCG immunisation, and the deadly alliance between TB and HIV/AIDS are also considered. Tuberculosis is a treatable disease and the aim of any family practitioner should be to treat smear positive patients as soon as possible, and cure them at the first attempt.

Controversies in BCG immunization.

Despite controversies BCG vaccination has stood the test of time. World Health Organization continues to recommend its use in infant immunization programme in countries with heavy endemicity and where threatening HIV epidemic in an emerging problem > 85% efficacy have been established in recent years against hematogenous spread of the disease and > or = 50% efficacy even against pulmonary tuberculosis. Host related factors, agent related factors, vaccine related factors and inadequacy of evaluation tests determine the BCG vaccine efficacy. Identification of complete BCG genome in 1998 has opened new vistas in newer BCG vaccine development. Adoption of a '5C' concept viz. Case detection, Chemotherapy short course, Contact elimination, Chemoprophylaxis and lastly control in BCG vaccine will be a desirable national approach in combating adult and childhood TB.

Effect of BCG vaccination on cytokine mRNA expression in atopic children with asthma

Background: To investigate whether a preexisting T H2-type immune response could be suppressed by BCG immunization in atopic children with asthma. Methods and results: We have used PCR to amplify reverse transcribed (RT) IFN-γ and IL-5 mRNA expressed by peripheral blood mononuclear cells (PBMCs) in response to in vitro phytohemagglutinin A, purified protein derivative and Dermatophagoides pteronyssinus II stimulation from nine atopic children, both before and 8 weeks after BCG vaccination. We have demonstrated that IFN-γ expression was induced in response to all stimulants (IFN-γ/β-actin) after the vaccination, whereas there was no expression before ( P<0.001). Although there was a tendency to diminish in the expression of IL-5 mRNA in response to the stimulants, only PHA rendered a statistically significant decrease after the vaccination. Conclusions: These results provide some evidence of TH1 dominance after BCG administration in atopic children.

Thames water boosts output

In the United Kingdom, BCG immunization of neonates provides good protection against military and meningeal disease, and probably against other forms of tuberculosis, in all ethnic groups. Serious adverse reactions to BCG immunization are rare. Cost-effectiveness studies of BCG immunization in neonates have not been reported, and ‘universal’ BCG immunization is not recommended in the United Kingdom. The Department of Health does recommend immunization for children and infants of immigrants from countries with a high prevalence of tuberculosis. There are problems associated with such a ‘selective’ policy, as determining what is ‘high’ prevalence and thus defining ‘at risk’ groups is difficult, and there may be political and practical difficulties in its implementation. This may result in low coverage in eligible groups. A ‘universal’ policy of BCG immunization for all neonates may be politically more acceptable and easier to implement in districts with high tuberculosis notification rates. Although there is no cost-effectiveness data to determine at what tuberculosis notification rate a universal policy should be adopted, an universal policy has been suggested for districts with overall notification rate of greater than 40 per 100,000.Within districts there may be large variations in tuberculosis notification rates between different areas. Thisis becoming more common with the amalgamation and merger of smaller districts into new larger purchasing organizations. New River Health Authority is such a district formed by the amalgamation of the former districts of Haringey with a high tuberculosis notification rate, and Enfield with a lower TB notification rate. In order to maximize coverage in the ‘at risk’ neonates, a different neonatal BCG policy has been adopted in the two areas. This has been possible because of the flexibility of the mechanisms for contracting with different provider units. Although the overall notification rate was not thought to be sufficiently high to justify a ‘universal’ neonatal policy throughout the district, a ‘universal’ policy has been instituted in the main provider unit in the former district Haringey. A ‘selective’ policy, subject to ongoing evaluation to ensure high coverage, continues to be operated by the main provider unit in the former district of Enfield.

4P-1071 BCG immunization is atherogenic in the chronically hypercholesterolaemic rabbit: Immune and vascular endothelial effects

4P-1071 BCG immunization is atherogenic in the chronically hypercholesterolaemic rabbit: Immune and vascular endothelial effects

Enhanced immunogenicity of BCG vaccine by using a viral-based GM-CSF transgene adjuvant formulation

The failure of current BCG vaccine in controlling the global tuberculosis (TB) epidemic highlights an urgent need for improved TB vaccine formulations. In this study, we have investigated the effect of a novel adenoviral granulocyte macrophage-colony stimulating factor (GM-CSF) transgene-based adjuvant formulation (AdGM-CSF) on BCG vaccination in a mouse strain that is genetically weak responders to BCG vaccine. BALB/c mice were immunized subcutaneously (s.c.) with PBS, BCG, or BCG plus AdGM-CSF or control vector Addl70-3, the immunogenicity of BCG vaccine was evaluated by type 1 IFN-γ production from lymphocytes of various lymphoid tissues upon mycobacterial antigen stimulation ex vivo. While mycobacterial antigen-specific IFN-γ production was slightly enhanced by co-immunization BCG with Addl70-3 as compared to BCG immunization alone, a marked increase both in the magnitude and longevity of anti-mycobacterial type 1 immunity was observed in the local draining lymph nodes and spleens by immunization with AdGM-CSF-adjuvanted BCG. Furthermore, there was a significant increase in the number of mycobacterial antigen-specific IFN-γ releasing CD4 T cells in mice immunized with AdGM-CSF-adjuvanted BCG vaccine. Consistent with these enhanced T-cell immunity and memory responses, AdGM-CSF-adjuvanted BCG vaccine significantly improved immune protection against secondary mycobacterial challenge. Our results suggest that GM-CSF transgene-based adjuvant formulation is an effective way to improve the immunogenicity of BCG vaccine.

Screening and treatment for latent tuberculosis infection among asylum seekers entering Switzerland.

To evaluate the compliance of doctors and patients with the current recommendations for screening and preventive treatment of immigrants with a positive tuberculin skin test (TST) suggestive of latent tuberculosis infection (LTBI). Retrospective cohort study of all asylum seekers entering Switzerland between 1 January 1993 and 31 December 1993 and assigned to the cantons of Aargau, Fribourg, Geneva, Neuchâtel, Valais and Vaud, who underwent a TST at the border. The medical documents of all individuals with a TST size suggestive of LTBI (> or = 10 mm in children <15 years, > or = 18 mm in young adults aged 15-25 years) were reviewed for final diagnosis, therapeutic decision, compliance with treatment if prescribed, and notification for tuberculosis within the next 3 years. Among 2515 asylum seekers, 172 had a positive TST suggestive of LTBI. The documents of 93 persons were available. The final diagnosis was LTBI in 71 cases, possible tuberculosis in 10 cases, an effect of BCG immunisation in 10 cases, and other diagnoses in 2 cases. Among 82 individuals with normal chest X-ray or no radiological examination, only 37 (46%) received a preventive treatment and one a full course of antituberculosis drugs. Among 11 persons with an abnormal chest X-ray, 2 received a full course of antituberculosis drugs, 7 a preventive therapy and 2 had no treatment prescribed. Among the 44 subjects in whom a preventive treatment was prescribed, 30 adhered to the treatment regimen. One case (without prescribed treatment) was notified for tuberculosis two years after entry. Compliance of doctors and patients with current recommendations for examination and treatment of immigrants with a TST suggestive of LTBI is unsatisfactory. New guidelines are needed to provide a clearer definition of the indications and explain the benefits of treating LTBI.

Screening and treatment for latent tuberculosis infection among asylum seekers entering Switzerland.

To evaluate the compliance of doctors and patients with the current recommendations for screening and preventive treatment of immigrants with a positive tuberculin skin test (TST) suggestive of latent tuberculosis infection (LTBI). Retrospective cohort study of all asylum seekers entering Switzerland between 1 January 1993 and 31 December 1993 and assigned to the cantons of Aargau, Fribourg, Geneva, Neuchâtel, Valais and Vaud, who underwent a TST at the border. The medical documents of all individuals with a TST size suggestive of LTBI (> or = 10 mm in children <15 years, > or = 18 mm in young adults aged 15-25 years) were reviewed for final diagnosis, therapeutic decision, compliance with treatment if prescribed, and notification for tuberculosis within the next 3 years. Among 2515 asylum seekers, 172 had a positive TST suggestive of LTBI. The documents of 93 persons were available. The final diagnosis was LTBI in 71 cases, possible tuberculosis in 10 cases, an effect of BCG immunisation in 10 cases, and other diagnoses in 2 cases. Among 82 individuals with normal chest X-ray or no radiological examination, only 37 (46%) received a preventive treatment and one a full course of antituberculosis drugs. Among 11 persons with an abnormal chest X-ray, 2 received a full course of antituberculosis drugs, 7 a preventive therapy and 2 had no treatment prescribed. Among the 44 subjects in whom a preventive treatment was prescribed, 30 adhered to the treatment regimen. One case (without prescribed treatment) was notified for tuberculosis two years after entry. Compliance of doctors and patients with current recommendations for examination and treatment of immigrants with a TST suggestive of LTBI is unsatisfactory. New guidelines are needed to provide a clearer definition of the indications and explain the benefits of treating LTBI.

Lymphocyte recruitment and protective efficacy against pulmonary mycobacterial infection are independent of the route of prior Mycobacterium bovis BCG immunization.

Mycobacterium tuberculosis infects humans through the lung, and immunity to this chronic infection is mediated primarily by CD4(+) T lymphocytes. Recently we have demonstrated that the recruitment of lymphocytes to the lung during primary aerosol M. tuberculosis infection in mice occurs predominantly through the interaction of alpha(4)beta(1) integrin on CD4(+) T cells and vascular cell adhesion molecule-1 on the pulmonary endothelium. To investigate the effect of route of immunization with Mycobacterium bovis BCG on the pattern of T-cell recruitment to the lung, we have analyzed the differences in expression of integrins on activated memory CD4(+) T cells infiltrating the lung following primary BCG immunization by aerosol, intravenous, and subcutaneous routes and after subsequent aerosol challenge with M. tuberculosis. There were marked differences in the patterns of recruitment of activated CD4(+) T cells to the lung following primary immunization by the three routes. Expansion of CD44(hi) CD62L(low) CD4(+) T cells in the lung occurred following aerosol and intravenous BCG immunizations, and the lymphocyte recruitment was proportional to the pulmonary bacterial load. The majority of infiltrating CD4(+) T cells expressed alpha(4)beta(1) integrin. On subsequent exposure to aerosol BCG rapid expansion of gamma interferon-secreting alpha(4)beta(1)(+) CD4(+) T cells occurred to the same extent in all immunized mice, regardless of the route of immunization. Similar expansion of alpha(4)beta(1)(+) CD4(+) memory T cells occurred following M. tuberculosis challenge. The three routes of BCG immunization resulted in the same level of protection against aerosol M. tuberculosis or BCG challenge in both the lungs and spleen. Therefore, recruitment of effector T lymphocytes and protective efficacy against pulmonary mycobacterial infection are independent of the route of prior BCG immunization.

Immune Response to Heat Shock Protein-65 following BCG Immunisation Accelerates Atherosclerosis in the Cholesterol-Fed Rabbit

Immune Response to Heat Shock Protein-65 following BCG Immunisation Accelerates Atherosclerosis in the Cholesterol-Fed Rabbit

Interventions to reduce tuberculosis mortality and transmission in low- and middle-income countries.

Tuberculosis is among the top ten causes of global mortality and affects low-income countries in particular. This paper examines, through a literature review, the impact of tuberculosis control measures on tuberculosis mortality and transmission, and constraints to scaling-up. It also provides estimates of the effectiveness of various interventions using a model proposed by Styblo. It concludes that treatment of smear-positive tuberculosis using the WHO directly observed treatment, short-course (DOTS) strategy has by far the highest impact. While BCG immunization reduces childhood tuberculosis mortality, its impact on tuberculosis transmission is probably minimal. Under specific conditions, an additional impact on mortality and transmission can be expected through treatment of smear-negative cases, intensification of case-finding for smear-positive tuberculosis, and preventive therapy among individuals with dual tuberculosis-HIV infection. Of these interventions, DOTS is the most cost-effective at around US$ 5-40 per disability-adjusted life year (DALY) gained. The cost for BCG immunization is likely to be under US$ 50 per DALY gained. Treatment of smear-negative patients has a cost per DALY gained of up to US$ 100 in low-income countries, and up to US$ 400 in middle-income settings. Other interventions, such as preventive therapy for HIV-positive individuals, appear to be less cost-effective. The major constraint to scaling up DOTS is lack of political commitment, resulting in shortages of funding and human resources for tuberculosis control. However, in recent years there have been encouraging signs of increasing political commitment. Other constraints are related to involvement of the private sector, health sector reform, management capacity of tuberculosis programmes, treatment delivery, and drug supply. Global tuberculosis control could benefit strongly from technical innovation, including the development of a vaccine giving good protection against smear-positive pulmonary tuberculosis in adults; simpler and shorter drug regimens for treatment of tuberculosis disease and infection; and improved diagnostics for tuberculosis infection and disease.

Will BCG immunization affect the clinical expression of an established asthmatic?

Will BCG immunization affect the clinical expression of an established asthmatic?

A study of neonatal BCG immunization within an acute hospital trust.

Tuberculosis is a re-emerging problem in the United Kingdom. BCG immunization administered in the neonatal period is protective. National guidelines and locally published standards identify infants for whom BCG immunization is recommended. The study aimed to calculate the rate of identification of infants 'at risk' by parental ethnic group and/or family history of tuberculosis, to determine subsequent immunization uptake, and to describe characteristics associated with missed BCG immunization. A retrospective audit was conducted. Demographic data were collected from a computer database of antenatal booking data, for 2043 pregnancies delivering between 1 October 1998 and 30 April 1999. A cohort of infants 'at risk' was defined, and infants referred for BCG immunization were identified. A manual search of immunization records determined immunization uptake. A cohort of 247 (12 per cent pregnancies) was 'at risk'. Fifty-five per cent of the cohort 'at risk' was correctly identified and 42 per cent correctly identified and immunized. The largest subgroup of the cohort, 48 per cent, was Caucasian and at risk because of a positive family history of tuberculosis. Family history of tuberculosis was the most important risk factor, and was missed in 86 per cent of cases. Despite the local publication of established guidelines, 58 per cent of infants 'at risk' failed to be immunized. Family history of tuberculosis was more important than parental ethnic group in predicting risk for the cohort, and was missed in the majority of cases. Appropriate guidelines alone do not guarantee good practice. Guidelines should be introduced in conjunction with regular audit to ensure effective implementation.

Are infections protecting from atopy?

The 'Hygiene Hypothesis' proposes that overcrowding and unhygienic contacts early in life may protect from atopic diseases by facilitating exposure to microbes. Longitudinal studies have recently shown that among subjects exposed early in life to other children at home, or at day care, the risk of wheezing steadily declined with age to levels significantly lower than controls. Evidences supporting a protective role of respiratory infections or BCG immunization on the development of allergic asthma are still insufficient. By contrast, the observation of a lower prevalence of atopic sensitization among children raised on a farm has been consistently reproduced. Several new studies have recently investigated the role of changes of human microbial flora, declining exposure to foodborne and orofecal infections, to helminths and to environmental sources of endotoxin as putative contributors to the rise of allergy and asthma cases among populations living with a western lifestyle.

Are infections protecting from atopy?

The ‘Hygiene Hypothesis’ proposes that overcrowding and unhygienic contacts early in life may protect from atopic diseases by facilitating exposure to microbes. Longitudinal studies have recently shown that among subjects exposed early in life to other children at home, or at day care, the risk of wheezing steadily declined with age to levels significantly lower than controls. Evidences supporting a protective role of respiratory infections or BCG immunization on the development of allergic asthma are still insufficient. By contrast, the observation of a lower prevalence of atopic sensitization among children raised on a farm has been consistently reproduced. Several new studies have recently investigated the role of changes of human microbial flora, declining exposure to foodborne and orofecal infections, to helminths and to environmental sources of endotoxin as putative contributors to the rise of allergy and asthma cases among populations living with a western lifestyle.

Risk factors for latent tuberculosis infection among children in New York City.

Although identification and appropriate treatment of children with latent tuberculosis (TB) infection (LTBI) is considered critical to the control and elimination of TB in the United States, there are limited data on risk factors for LTBI in pediatric populations. To further improve targeted screening for LTBI, we performed a matched case-control study from September 1996 to December 1998. We actively surveyed 24 primary care clinics serving Northern Manhattan and Harlem twice monthly for case participants 1 to 5 years old with LTBI, defined as a child with a Mantoux tuberculin skin test (TST) >/=10 mm and a normal chest radiograph. Two age- and clinic-matched control participants with TSTs equal to 0 mm were enrolled per case. To determine risk factors for LTBI, a bilingual research worker reviewed the medical records of study participants and administered a questionnaire to the parents of participants. We enrolled 96 cases and 192 controls whom did not differ by age, gender, ethnicity, and race; overall, the mean age of participants was 2.9 years, 51% were male, 80% were Hispanic, and 9% black. Logistic regression analysis demonstrated that contact with an adult with active TB, foreign birth, foreign travel, and a relative with a positive TST were predictive of case status. In contrast, a history of a previous negative TST proved protective and BCG immunization was not an independent risk factor for a positive TST, suggesting that boosting was not important in this population. We identified several risk factors for LTBI in children that can be used to refine targeted surveillance for TB among Hispanic immigrant populations in the United States.