Improving vaccines against tuberculosis. Neonatal BCG protection against leprosy: a study in Manaus, Brazilian Amazon. Influence of bacille Calmette-Guérin vaccination on size of tuberculin skin test reaction: to what size? Lower hookworm incidence, prevalence, and intensity of infection in children with a Bacillus Calmette-Guérin vaccination scar. Occupational risk of tuberculosis transmission in a low incidence area A case-control study of the effectiveness of BCG vaccine for preventing leprosy in Yangon, Myanmar. BCG and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. Timing and dose of BCG vaccination in infants as assessed by postvaccination tuberculin sensitivity. Effect of BCG revaccination on incidence of tuberculosis in school-aged children in Brazil: the BCG-REVAC cluster-randomised trial BCG vaccination in low birth weight newborns: analysis of lymphocyte proliferation, IL-2 generation and intradermal reaction to PPD. Long-term efficacy of BCG vaccine in American Indians and Alaska Natives: A 60-year follow-up study. Pathogenesis of tuberculosis and effectiveness of BCG vaccination. BCG vaccination protects against leprosy in Venezuela: a case-control study. Design of the Brazilian BCG-REVAC trial against tuberculosis: a large, simple randomized community trial to evaluate the impact on tuberculosis of BCG revaccination at school age.
Tuberculosis remains a major cause of mortality and physical and economic deprivation worldwide . There have been significant recent advances in our underst and ing of the Mycobacterium tuberculosis genome , mycobacterial genetics and the host determinants of protective immunity . Nevertheless , the challenge is to harness this information to develop a more effective vaccine than BCG , the attenuated strain of Mycobacterium bovis derived by Calmette and Guérin nearly 90 years ago . Some of the limitations of BCG include the waning of the protective immunity with time , reduced effectiveness against pulmonary tuberculosis compared to disseminated disease , and the problems of a live vaccine in immuno-compromised subjects . Two broad approaches to vaccine development are being pursued . New live vaccines include either attenuated strains of Mycobacterium tuberculosis produced by r and om mutagenesis or targeted deletion of putative virulence factors , or by genetic manipulation of BCG to express new antigens or cytokines . The second approach utilizes non-viable subunit vaccines to deliver immunodominant mycobacterial antigens . Both protein and DNA vaccines induce partial protection against experimental tuberculosis infection in mice , however , their efficacy has generally been equivalent to or less than that of BCG . The comparative effects of cytokine adjuvants and vaccines targeting antigen presenting cells on enhancing protection will be discussed . Coimmunization with plasmid interleukin-12 and a DNA vaccine expressing Antigen 85B , a major secreted protein , was as protective as BCG . The combination of priming with DNA-85B and boosting with BCG was superior to BCG alone . Therefore it is possible to achieve a greater level of protection against tuberculosis than with BCG , and this highlights the potential for new tuberculosis vaccines in humans There is clear evidence that BCG protects against leprosy , but cross-immunity with environmental mycobacteria can interfere with vaccination protection . Some have cast doubts whether BCG vaccination can offer a significant impact against leprosy in the Brazilian Amazon , which is an endemic area for leprosy and with a high prevalence of environmental mycobacteria . This study was design ed to estimate the  vaccine effectiveness  of neonatal BCG against leprosy in Amazon region , in Brazil . This is a cohort study nested in a r and omized community trial . The study had two main results . First , neonatal BCG vaccination in Brazilian Amazon elicited protection of 74 % ( 95 % CI 57 - 86 ) against all forms of leprosy cases . Second , the highest protection was observed for multibacillary cases , 93 % ( 95 % CI 71 - 98 ) . It is concluded that the study provides evidence that neonatal BCG may have an important and overlooked impact on the occurrence and transmission of leprosy , maybe even more in the future when the cohort which received a high coverage of BCG reaches the age of high incidence of leprosy BACKGROUND Previous bacillus Calmette-Guerin ( BCG ) vaccination can confound the results of a tuberculin skin test ( TST ) . We sought to determine a cutoff diameter of TST in duration beyond which the influence of BCG vaccination was negligible in evaluating potential Mycobacterium tuberculosis infection in a population of health care workers with a high vaccination rate and low incidence of tuberculosis . METHODS From 1991 through 1998 , all new employees at the University Hospital of Lausanne , Switzerl and , underwent a 2-step TST at entry visit . We also gathered information on demographic characteristics , along with factors commonly associated with tuberculin positivity , including previous BCG vaccination , history of latent M. tuberculosis infection , and predictors for M. tuberculosis infection . RESULTS Among the 5117 investigated subjects , we found that influence of BCG vaccination  on TST results varied across categories of age ( likelihood ratio test , 0.0001 ) . Prior BCG vaccination had a strong influence on skin test results of < or=18 mm in diameter among persons < 40 years old , compared with the influence of factors predictive of M. tuberculosis infection . Prior latent M. tuberculosis infection and travel or employment in a country in which tuberculosis is endemic also had significant influences . CONCLUSIONS Interpretation of TST reactions of < or=18 mm among BCG-vaccinated persons < 40 years of age must be done with caution in areas with a low incidence of tuberculosis . In such a population , except for persons who have never been vaccinated , TST reactions of < or=18 mm are more likely to be the result of prior vaccination than infection and should not systematic ally lead to preventive treatment Bacillus Calmette-Guérin ( BCG ) , the most common vaccine worldwide , has broad effects on the immune system . Hookworm infections are a major source of morbidity . In response to a preliminary report of BCG vaccination protection against nematodes in human immunodeficiency virus-infected adults , data from an ongoing prospect i ve study were analyzed to determine the intensity ( eggs per gram of stool ) , prevalence , and incidence of different helminths in children with and without a BCG vaccination scar . Adjusted prevalence and incidence ratios were estimated by using logistic regression . Children with a BCG vaccination scar were found to have statistically significantly lower hookworm prevalence ( 41 % ) , incidence ( 37 % ) , and mean egg counts ( 39 % ) , after controlling for age , sex , and socioeconomic factors . There was no BCG association with incidence , prevalence , or intensity of infection with Schistosoma mansoni , Ascaris lumbricoides , or Trichuris trichiura . Such protection would have implication s for public health and for research on mechanisms behind human immunological responses to hookworm Background To investigate the occupational risk of tuberculosis ( TB ) infection in a low-incidence setting , data from a prospect i ve study of patients with culture-confirmed TB conducted in Hamburg , Germany , from 1997 to 2002 were evaluated . Methods M. tuberculosis isolates were genotyped by IS6110 RFLP analysis . Results of contact tracing and additional patient interviews were used for further epidemiological analyses . Results Out of 848 cases included in the cluster analysis , 286 ( 33.7 % ) were classified into 76 clusters comprising 2 to 39 patients . In total , two patients in the non-cluster and eight patients in the cluster group were health-care workers . Logistic regression analysis confirmed work in the health-care sector as the strongest predictor for clustering ( OR 17.9 ) . However , only two of the eight transmission links among the eight clusters involving health-care workers had been detected previously . Overall , conventional contact tracing performed before genotyping had identified only 26 ( 25.2 % ) of the 103 contact persons with the disease among the clustered cases whose transmission links were epidemiologically verified . Conclusion Recent transmission was found to be strongly associated with health-care work in a setting with low incidence of TB . Conventional contact tracing alone was shown to be insufficient to discover recent transmission chains . The data presented also indicate the need for establishing improved TB control strategies in health-care setting BACKGROUND Five r and omized trials , a follow-up study , and six case-control investigations of BCG vaccine 's effectiveness ( VE ) for preventing leprosy have been conducted internationally , with widely varying estimates of VE . Because of the difficulty of generalizing from disparate results , local estimates of VE are needed for health planning purpose s and are currently particularly relevant , given the World Health Organization 's ( WHO ) goal to eliminate leprosy by the year 2000 . METHODS We conducted a case-control study in Yangon , Myanmar . Residents of Yangon between the ages of 6 years and 24 years who were listed in the National Leprosy Registry as being on active treatment for leprosy between December 1992 and April 1993 were eligible to participate in the study as cases . Control subjects were matched to the cases on age , sex , and neighbourhood . RESULTS One or more doses of BCG were associated with a VE of 66 % . The results show a significant trend of increasing VE with increasing number of BCG doses ( one dose , VE = 55 % ; two doses , VE = 68 % ; three doses , VE = 87 % ) . One dose of BCG vaccine appeared to provide protection substantially higher than that found in an earlier vaccine trial in Myanmar , but consistent with results from case-control studies in other countries . CONCLUSIONS These data suggest that BCG reduces the risk of leprosy  in Myanmar , and that BCG vaccination of infants , along with early case-finding and treatment , should be considered an important part of the leprosy intervention strategy The Medical Research Council 's trial of BCG and vole bacillus vaccines in the prevention of  tuberculosis in Great Britain has ended after 20 years ' follow-up of the 54 239 participants , who were aged 14 to 15 years when the entered the trial in 1950 - 2 . Participants who were tuberculin positive on entry were left unvaccinated ; those who were tuberculin negative were allocated at r and om to an unvaccinated or to a vaccinated group . The protective efficacy of each of the two vaccines , among those initially tuberculin negative , was 84 % during the first five years , and gradually decreased , averaging 77 % for each vaccine over the whole period . The incidence of tuberculosis decreased substantially in all groups during the trial , however , and of the total of 610 cases of tuberculosis only 27 developed between 15 and 20 years . Thus we can not make a reliable assessment of efficacy during this final period . The prevalence and incidence of tuberculosis in Great Britain have decreased radically since this trial began . The expected benefit from large-scale BCG-vaccination of children is now far less , and may decrease further if the incidence of tuberculosis continues to decline Tuberculosis is an important public health problem in developing countries and BCG plays an important role in preventing serious form of the disease in children . BCG induced tuberculin sensitivity is a quantitative characteristic and has been used to compare vaccine efficacy . The st and ard dose of BCG vaccine is 0.1 mg in 1 ml though manufacturers of certain strains of BCG , i.e. , Copenhagen 1331 recommend half dose in infants . There are also varying ideas about the optimum time to vaccinate babies and some studies suggest that late vaccination confers a high degree of protection . This study was carried out to evaluate tuberculin sensitivity and side effects following 0.05 ml and 0.1 ml of BCG at birth and 0.1 ml of BCG at 4 - 6 weeks of age . Two hundred and thirty eight newborns were vaccinated r and omly with 0.05 ml and 0.05 ml and 0.1 ml of BCG vaccine ( Copenhagen 1331 strain ) containing .69 million culturable particles per ml . One hundred and eight infants 4 - 6 weeks of age were vaccinated with 0.1 ml of BCG .  One hundred and fifty five ( 44.7 % ) infants were evaluated by Mantoux test using 1TU PPD RT23 10 - 12 weeks after vaccination and 105 ( 30.6 % ) followed up till 6 months for any side effects . No significant difference in mean tuberculin reaction , tuberculin positivity and mean scar size was observed in groups receiving 0.1 ml at birth or 4 - 6 weeks of age . However , the group receiving 0.05 ml at birth had a significantly lower mean tuberculin reaction , tuberculin positivity and mean scar size . No locoregional side effects were observed . Hence the present practice of giving 0.1 ml of BCG at birth should be continued BACKGROUND Many countries offer a second BCG vaccination to prevent tuberculosis , although there is little evidence of whether this confers additional protection . BCG vaccination is routine in Brazil but BCG revaccination procedures vary by state . We studied revaccination efficacy in two Brazilian cities with tuberculosis prevalence representative of Brazil . METHODS We did a cluster-r and omised trial of the protection against tuberculosis from BCG revaccination in school-aged children who had had one BCG vaccination as infants . 767 schools in the cities of Salvador and Manaus , Brazil , participated ; schools were the unit of r and omisation . The study was open label with no placebo . Cases of tuberculosis were identified through record linkage to the Tuberculosis Control Programme . Revaccination status was masked during linkage and validation of cases . The incidence of tuberculosis was the primary outcome . Analysis was by intention to treat . FINDINGS 386 schools ( 176,846 children ) were assigned BCG revaccination and 365 ( 171,293 children )  no revaccination .  42,053 children in the vaccine group and 47,006 in the control group were absent from school on the day of the visit and were excluded . 31,163 and 27,146 , respectively were also excluded because they had no BCG scar , two or more scars , or a doubtful scar on assessment . The crude incidence of tuberculosis in the intervention group was 29.3 per 100,000 person years and in the control group 30.2 per 100,000 person-years ( crude-rate ratio 0.97 ; 95 % CI 0.76 - 1.28 ) . The efficacy of BCG revaccination was 9 % ( -16 to 29 % ) . INTERPRETATION Revaccination given to children aged 7 - 14 years in this setting does not provide substantial additional protection and should not be recommended . Follow-up is ongoing and needed to assess the effect of other factors on revaccination efficacy : time since vaccination , age at vaccination , and high or low prevalence of environmental mycobacteria OBJECTIVE To study vaccinal scar formation and post-vaccinal immune response in newborns with birth weight ranging from 2000 to 2499 g vaccinated in the first week of life with intradermal bacille Calmette-Guérin ( BCG ) ( Moreau-Rio de Janeiro strain ) . METHOD Specific immune response to PPD was assessed in 30 low birth weight newborns ( mean birth weight = 2311.7 + /- 122.1 g ; mean gestational age = 38.1 + /- 1.8 weeks ) in comparison to 56 control infants ( mean birth weight = 3198.9 + /- 267.2 g ; mean gestational age = 38.5 + /- 1.2 weeks . RESULTS Low birth weight infants have an efficient immune response to vaccinal stimulus when compared to control infants as judged by specific in vitro lymphocyte proliferation ( mean SI = 9.7 + /- 12.9 vs SI = 8.8 + /- 10.0 , P = 0.72 ) and IL-2 production ( mean SI = 3.1 + /- 3.4 vs SI = 2.6 + /- 2.0 , P = 0.38 ) . Intradermal reaction to PPD was also comparable in both groups ( mean in duration diameter = 9.5 + /- 5.1 mm vs 9.6 + /- 5.0 mm , P = 0.94 ) . CONCLUSION These data suggest that low birth weight newborns show a good immune response to BCG , thus reinforcing the inclusion of such infants in regular vaccination programs with intradermal BCG CONTEXT The duration of protection from tuberculosis of BCG vaccines is not known . OBJECTIVE To determine the long-term duration of protection of a BCG vaccine that was previously found to be efficacious . DESIGN Retrospective record review using Indian Health Service records , tuberculosis registries , death certificates , and supplemental interviews with trial participants . SETTING AND PARTICIPANTS Follow-up for the period 1948 - 1998 among American Indians and Alaska Natives who participated in a placebo-controlled BCG vaccine trial during 1935 - 1938 and who were still at risk of developing tuberculosis . Data from 1483 participants in the BCG vaccine group and 1309 in the placebo group were analyzed . MAIN OUTCOME MEASURES Efficacy of BCG vaccine  , calculated for each 10-year interval using a Cox regression model with time-dependent variables based on tuberculosis events occurring after December 31 , 1947 ( end of prospect i ve case finding ) . RESULTS The overall incidence of tuberculosis was 66 and 138 cases per 100 000 person-years in the BCG vaccine and placebo groups , respectively , for an estimate of vaccine efficacy of 52 % ( 95 % confidence interval , 27%-69 % ) . Adjustments for age at vaccination , tribe , subsequent BCG vaccination , chronic medical illness , isoniazid use , and bacille Calmette-Guérin strain did not substantially affect vaccine efficacy . There was slight but not statistically significant waning of the efficacy of BCG vaccination over time , greater among men than women . CONCLUSION In this trial , BCG vaccine efficacy persisted for 50 to 60 years , suggesting that a single dose of an effective BCG vaccine can have a long duration of protection Among the hypotheses offered to explain the conflicting results of various trials of  BCG vaccination  , the one invoking gross differences in the immunogenic properties of the various BCG vaccines ( strains ) has received most attention . Indeed , for many years research in BCG vaccination has been directed almost entirely towards improving the quality of vaccines . the anticipated benefit of this work , however , is not borne out by the results of the latest trial in India . Whereas it can not be excluded that technological advances may have result ed in the worst vaccines ever , it also remains possible that the basic hypothesis was less relevant than presumed . the quality of the vaccine may be of little importance and a different explanation should be sought for the observed differences in protection . One possible lead is the observation that BCG vaccination consistently appeared to be of poor efficacy under conditions where , in a vaccination programme , even an effective vaccine would have little impact on the tuberculosis problem , i.e. where the majority of cases originated from the population already infected . The hypothesis offered is that in such population s the pathogenesis of tuberculosis is different from that prevailing under the clearly exceptional conditions under which BCG vaccination was effective . Rather than being the direct result of primary infection , tuberculous disease ( observed ) may be the result of reinfection . In this case BCG vaccination can not be expected to have a protective effect A total of 64,570 household and other close contacts of about 2000 leprosy cases were screened for eligibility for entry into a trial of a new leprosy vaccine .  The screening procedure included a clinical examination for leprosy and for the presence of BCG and lepromin scars . Ninety-five new cases of leprosy were identified , and the prevalence of BCG and lepromin scars among them was compared with similar data from matched controls selected from among those with no evidence of leprosy . The difference in the prevalence of BCG scars in the two groups was used to estimate the protection against leprosy conferred by BCG vaccination . One or more BCG scars was associated with a protective efficacy of 56 % ( 95 % confidence limits 27 % to 74 % ) . There was a trend of increasing protection with four or more BCG scars , but this was not statistically significant . There was no evidence that the efficacy of BCG  varied with age or according to whether or not the contact lived in the same household as a case . The protective effect was significantly higher among males , and was significantly greater for multibacillary than for paucibacillary leprosy This paper describes the design and baseline results of a large and simple r and omized controlled trial of the protection against tuberculosis of a dose of Bacillus Calmette Guerin ( BCG ) vaccination given to school children in a population with a high coverage of neonatal BCG ( The Brazilian BCG-REVAC trial ) . The study started in 1996 and is a pair-matched and stratified-cluster r and omized controlled trial with no placebo . The study population consists of children aged 7 - 14 years enrolled in 763 state schools from the cities of Salvador and Manaus , Brazil . Schools were the unit of r and omization . Identifying information was collected for 354,708 school children . The final study population , after exclusions on the basis of age , BCG scar readings and absence from school on the day of the study visit , consists of 242,401 children , of whom 125,403 are in intervention schools . Follow-up relies on ascertainment of cases diagnosed at the health services and notified to the tuberculosis control program surveillance system . Blindness is guaranteed during linkage and validation of cases . Analysis is planned for the next 12 months , where efficacy will be estimated by calculating incidence of tuberculosis in the vaccine and control groups , taking into consideration the cluster design . The intervention studied , a second BCG vaccination , is widely used , although the World Health Organization does not recommend it on the basis of absence of evidence of protection or lack of protection . The results of the trial will make it possible for BCG revaccination practice to be informed by evidence . This is an example of a large simple and relatively inexpensive effectiveness trial , result ing from good collaboration between academia and health and education services enabling developing countries to define policies that are relevant for their reality
OBJECTIVES To review the protective efficacy of the first and second doses of BCG vaccine and to assess its major indications and contraindications .
SUMMARY OF THE FINDINGS BCG vaccine has been used since 1921 .
However , the data concerning its use are variable and inconsistent .
The protective efficacy of the first dose of BCG vaccine against miliary tuberculosis or tuberculous meningitis is remarkably important .
CONCLUSIONS Despite the hope that a new vaccine against tuberculosis will be available in the future , BCG vaccine , in spite of its deficiencies , is today and will be for many years to come an important tool in controlling the harmful effects of tuberculosis , especially in countries where this disease has moderate to high levels of incidence