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    Timing of exposure explains variation in BCG effectiveness: a systematic review and meta-analysis. Trauer James M,Kawai Andrew,Coussens Anna K,Datta Manjula,Williams Bridget M,McBryde Emma S,Ragonnet Romain Thorax RATIONALE:The heterogeneity in efficacy observed in studies of BCG vaccination is not fully explained by currently accepted hypotheses, such as latitudinal gradient in non-tuberculous mycobacteria exposure. METHODS:We updated previous systematic reviews of the effectiveness of BCG vaccination to 31 December 2020. We employed an identical search strategy and inclusion/exclusion criteria to these earlier reviews, but reclassified several studies, developed an alternative classification system and considered study demography, diagnostic approach and tuberculosis (TB)-related epidemiological context. MAIN RESULTS:Of 21 included trials, those recruiting neonates and children aged under 5 were consistent in demonstrating considerable protection against TB for several years. Trials in high-burden settings with shorter follow-up also showed considerable protection, as did most trials in settings of declining burden with longer follow-up. However, the few trials performed in high-burden settings with longer follow-up showed no protection, sometimes with higher case rates in the vaccinated than the controls in the later follow-up period. CONCLUSIONS:The most plausible explanatory hypothesis for these results is that BCG protects against TB that results from exposure shortly after vaccination. However, we found no evidence of protection when exposure occurs later from vaccination, which would be of greater importance in trials in high-burden settings with longer follow-up. In settings of declining burden, most exposure occurs shortly following vaccination and the sustained protection observed for many years thereafter represents continued protection against this early exposure. By contrast, in settings of continued intense transmission, initial protection subsequently declines with repeated exposure to or other pathogens. 10.1136/thoraxjnl-2020-216794
    A century of BCG: Impact on tuberculosis control and beyond. Ahmed Asma,Rakshit Srabanti,Adiga Vasista,Dias Mary,Dwarkanath Pratibha,D'Souza George,Vyakarnam Annapurna Immunological reviews BCG turns 100 this year and while it might not be the perfect vaccine, it has certainly contributed significantly towards eradication and prevention of spread of tuberculosis (TB). The search for newer and better vaccines for TB is an ongoing endeavor and latest results from trials of candidate TB vaccines such as M72AS01 look promising. However, recent encouraging data from BCG revaccination trials in adults combined with studies on mucosal and intravenous routes of BCG vaccination in non-human primate models have renewed interest in BCG for TB prevention. In addition, several well-demonstrated non-specific effects of BCG, for example, prevention of viral and respiratory infections, give BCG an added advantage. Also, BCG vaccination is currently being widely tested in human clinical trials to determine whether it protects against SARS-CoV-2 infection and/or death with detailed analyses and outcomes from several ongoing trials across the world awaited. Through this review, we attempt to bring together information on various aspects of the BCG-induced immune response, its efficacy in TB control, comparison with other candidate TB vaccines and strategies to improve its efficiency including revaccination and alternate routes of administration. Finally, we discuss the future relevance of BCG use especially in light of its several heterologous benefits. 10.1111/imr.12968
    A review of the BCG vaccine and other approaches toward tuberculosis eradication. Cho Thomas,Khatchadourian Christopher,Nguyen Huy,Dara Yash,Jung Shuna,Venketaraman Vishwanath Human vaccines & immunotherapeutics Despite aggressive eradication efforts, Tuberculosis (TB) remains a global health burden, one that disproportionally affects poorer, less developed nations. The only vaccine approved for TB, the Bacillus of Calmette and Guérin (BCG) vaccine remains controversial because it's stated efficacy has been cited as anywhere from 0 to 80%. Nevertheless, there have been exciting discoveries about the mechanism of action of the BCG vaccine that suggests it has a role in immunization schedules today. We review recent data suggesting the vaccine imparts protection against both tuberculosis and non-tuberculosis pathogens via a newly discovered immune system called trained immunity. BCG's efficacy also appears to be tied to its affect on granulocytes at the epigenetic and hematopoietic stem cell levels, which we discuss in this article at length. We also write about how the different strains of the BCG vaccine elicit different immune responses, suggesting that certain BCG strains are more immunogenic than others. Finally, our review delves into how the current vaccine is being reformulated to be more efficacious, and track the development of the next generation vaccines against TB. 10.1080/21645515.2021.1885280
    BCG vaccination strategies against tuberculosis: updates and perspectives. Human vaccines & immunotherapeutics Bacillus Calmette-Guérin (BCG) is the only licensed vaccine against tuberculosis (TB). However, BCG has variable efficacy and cannot completely prevent TB infection and transmission. Therefore, the worldwide prevalence of TB calls for urgent development of a more effective TB vaccine. In the absence of other approved vaccines, it is also necessary to improve the efficacy of BCG itself. Intravenous (IV) BCG administration and BCG revaccination strategies have recently shown promising results for clinical usage. Therefore, it is necessary for us to revisit the BCG vaccination strategies and summarize the current research updates related to BCG vaccination. This literature review provides an updated overview and perspectives of the immunization strategies against TB using BCG, which may inspire the following research on TB vaccine development. 10.1080/21645515.2021.2007711
    Prevalence of Latent TB and Effectiveness of BCG Vaccination Against Latent Tuberculosis: An Observational Study. Trollfors Birger,Sigurdsson Vignir,Dahlgren-Aronsson Anna International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases OBJECTIVES:This study aimed to determine the prevalence of latent tuberculosis infection (LTBI) in immigrant children and adolescents (aged 0-17 years) living or recently arriving in Sweden. It also aimed to estimate the effectiveness of Bacillus Calmette-Guérin (BCG) against LTBI in immigrant children coming to Sweden from high-incidence countries, most of them being asylum seekers. LTBI was defined as a positive Quantiferon or a tuberculin skin test (TST) of ≥ 10 mm in small children from whom it was difficult to obtain 3 mL of blood. DESIGN:A typical BCG scar was used as a substitute for written documentation of BCG vaccination. The study comprised 1,404 immigrants aged 0-17 years. The arms and legs of all of them were inspected for a BCG scar, and Quantiferon or TST was performed. The study was a retrospective, observational, comparative cohort study. RESULTS:LTBI was found in 123 of 1,011 (12%) children with a BCG scar and in 116 of 393 (29.5%) without a BCG scar, giving an estimated vaccine effectiveness of 59%. CONCLUSIONS:LTBI was common among the immigrant children (17%). LTBI can progress to active TB and then spread in the immigrant population and to the general population if all immigrant arrivals are not tested and given prophylactic treatment if they have LTBI. The BCG vaccine was found to have a significant effect on LTBI (59%). 10.1016/j.ijid.2021.06.045
    A change in the timing of the Bacillus Calmette-Guérin vaccination in 2013 was associated with an increase in the incidence rate of infants with latent tuberculosis infection. Journal of infection and chemotherapy : official journal of the Japan Society of Chemotherapy BACKGROUND:A change in the timing of the Bacillus Calmette-Guérin (BCG) vaccination among infants in Japan appears to be associated with an increase in the incidence rate of latent tuberculosis infection (LTBI). METHODS:Data on both active and latent tuberculosis (TB) infections from 2007 to 2019, which were reported by the Japan Anti-Tuberculosis Association, were statistically analyzed by comparing TB incidence rates in 2007-2012 and 2013-2019. RESULTS:Although the incidence rate for active TB disease did not statistically increase nor decrease in the infant age group for either sex (and in fact decreased for some of the other age groups), the incidence rates of LTBI for both sexes were increased in the infant age group, while the incidence rates decreased in the other age groups. Between 2007 and 2012, the incidence rate of LTBI in females was statistically greater than those of males in the 1-4-year-old age group. From 2013 to 2019, the incidence rates of females were greater than those of males in both the infant and 1-4-year-old age groups, suggesting a growing preponderance of infections among female children in the youngest age groups. CONCLUSION:It may be that the change of BCG vaccination timing in Japan which took place in 2013 affected the infant incidence rate of LTBI, with a more prominent effect on females than males. In order to control TB infection, the ramifications of a change in vaccination timing therefore need careful exploration, as one such change appears associated with increased numbers of infants with LTBI, with disproportionate effects on females. 10.1016/j.jiac.2022.03.018
    Effectiveness of Bacillus Calmette-Guérin vaccination against severe childhood tuberculosis in China: a case-based, multicenter retrospective study. International journal of infectious diseases : IJID : official publication of the International Society for Infectious Diseases BACKGROUND:Evidence varies regarding the efficacy of Bacillus Calmette-Guérin (BCG) vaccine. Data on protection by BCG vaccination against severe tuberculosis (TB) among children in China remain unclear. METHODS:We conducted a case-based, multicenter retrospective study at three children's hospitals in China. Sociological factors affecting BCG vaccination and risk factors associated with disease types were analyzed using a multivariable model. RESULTS:A total 1701 children with active TB were enrolled. Children who were younger, female, residing in a rural area, living in the western regions, and with no BCG vaccination history were at higher risk of developing severe TB. Children with a BCG scar had significantly lower risk for severe TB (odds ratio [OR] 0.59, 95% confidence interval [CI] 0.51-0.67). Children with no BCG scar but who were vaccinated at birth still had lower risk of severe TB types, such as tuberculous meningitis (OR 0.88, 95% CI 0.80-0.97) and miliary TB (OR 0.77, 95% CI 0.69-0.87). CONCLUSIONS:Neonatal BCG vaccination could be an effective means to control TB. In the absence of a new, more effective TB vaccine, our results lend support to continued use of the BCG vaccine in China. 10.1016/j.ijid.2022.04.023