Potential health effects from non‐specific stimulation of the immune function in early age: The example of BCG vaccination

There is increasing, but still inconsistent evidence that vaccinations and childhood infections may play a role in the normal maturation of the immune system, and in the development and balance of immune regulatory pathways, both of which might impact health later in life. This review covers the epidemiological evidence regarding the role of Bacillus Calmette–Guérin (BCG) vaccination on the following inflammatory or autoimmune diseases: asthma and allergic diseases, Crohn’s disease (CD), insulin‐dependent diabetes mellitus (IDDM), and specific cancers. The literature is more comprehensive for asthma and allergic diseases, with 16 studies reporting the absence of an association while seven rather suggest a protective effect of BCG. We found insufficient evidence on CD to conclude at this point. Overall, the evidence for IDDM based on four studies leans towards no association, although some effects were observed in population subsets. Five epidemiological investigations provide evidence on a possible link with cancer incidence or mortality at various sites, with indications of both increased and decreased risks. Given the potential public health implications, it is imperative to acquire a better understanding of how BCG vaccination could influence the development of such chronic health conditions in the population.

[1]  J Siemiatycki,et al.  Bacille Calmette-Guérin Vaccination and Incidence of IDDM in Montreal, Canada , 1997, Diabetes Care.

[2]  D. Strachan,et al.  Immunization and symptoms of atopic disease in children: results from the International Study of Asthma and Allergies in Childhood. , 2001, American journal of public health.

[3]  Donna Spiegelman,et al.  Childhood social environment and Hodgkin's lymphoma: new findings from a population-based case-control study. , 2004, Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology.

[4]  Annette Pfahlberg,et al.  Inverse association between melanoma and previous vaccinations against tuberculosis and smallpox: results of the FEBIM study. , 2002, The Journal of investigative dermatology.

[5]  P. Grosjean,et al.  Antigen-specific and persistent tuberculin anergy in a cohort of pulmonary tuberculosis patients from rural Cambodia , 2002, Proceedings of the National Academy of Sciences of the United States of America.

[6]  R. Gie,et al.  Inverse association between Mycobacterium tuberculosis infection and atopic rhinitis in children , 2005, Allergy.

[7]  T. Annus,et al.  Atopic disorders among Estonian schoolchildren in relation to tuberculin reactivity and the age at BCG vaccination , 2004, Allergy.

[8]  G. Walraven,et al.  Absence of association between delayed type hypersensitivity to tuberculin and atopy in children in The Gambia , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[9]  B. Niggemann,et al.  Messages from the German Multicentre Allergy Study , 2002, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[10]  G. Hems,et al.  B.C.G. AND LEUKÆMIA , 1971 .

[11]  I. Annesi-Maesano,et al.  Does childhood immunization against infectious diseases protect from the development of atopic disease? , 2005, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[12]  Shaheen,et al.  Early BCG vaccination and reduction in atopy in Guinea‐Bissau , 2000, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[13]  Jean Weissenbach,et al.  Mapping of a susceptibility locus for Crohn's disease on chromosome 16 , 1996, Nature.

[14]  D. Snider,et al.  Efficacy of BCG vaccination in prevention of cancer: an update. , 1978, Journal of the National Cancer Institute.

[15]  U. Wahn,et al.  BCG infection suppresses allergic sensitization and development of increased airway reactivity in an animal model. , 1998, The Journal of allergy and clinical immunology.

[16]  Ethan M. Shevach,et al.  CD4+CD25+ Regulatory T Cells Can Mediate Suppressor Function in the Absence of Transforming Growth Factor β1 Production and Responsiveness , 2002, The Journal of experimental medicine.

[17]  Sergio Romagnani,et al.  The increased prevalence of allergy and the hygiene hypothesis: missing immune deviation, reduced immune suppression, or both? , 2004, Immunology.

[18]  M. Blennerhassett,et al.  The increasing prevalence of Crohn's disease in industrialized societies: the price of progress? , 2005, Canadian journal of gastroenterology = Journal canadien de gastroenterologie.

[19]  J. Holloway,et al.  Infection of Mice with Mycobacterium bovis–Bacillus Calmette-Guérin (BCG) Suppresses Allergen-induced Airway Eosinophilia , 1998, The Journal of experimental medicine.

[20]  R. Schreiber,et al.  IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity , 2001, Nature.

[21]  D. Umetsu,et al.  Regulatory T cells control the development of allergic disease and asthma. , 2003, The Journal of allergy and clinical immunology.

[22]  G. Dahlquist,et al.  Indications that maternal coxsackie B virus infection during pregnancy is a risk factor for childhood-onset IDDM , 1995, Diabetologia.

[23]  O. Stutman Chemical carcinogenesis in nude mice: comparison between nude mice from homozygous matings and heterozygous matings and effect of age and carcinogen dose. , 1979, Journal of the National Cancer Institute.

[24]  S. Pek,et al.  Prevention of Insulitis and Diabetes Onset by Treatment With Complete Freund's Adjuvant in NOD Mice , 1991, Diabetes.

[25]  I. M. Neiman,et al.  [Inflammation and cancer]. , 1974, Patologicheskaia fiziologiia i eksperimental'naia terapiia.

[26]  S. Salvi,et al.  Could administration of bacille Calmette‐Guérin vaccination at birth protect from the development of asthma and allergic diseases in the western world? Has this question been adequately investigated? , 2002, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[27]  A. Buist,et al.  Absence of relationship between tuberculin reactivity and atopy in BCG vaccinated young adults , 2000, Thorax.

[28]  M. Greaves Infection, immune responses and the aetiology of childhood leukaemia , 2006, Nature Reviews Cancer.

[29]  I. Fortier,et al.  Markers of infection, breast-feeding and childhood acute lymphoblastic leukaemia , 2000, British Journal of Cancer.

[30]  S. Rosenthal Cancer precursors and their control by BCG. , 1986, Developments in biological standardization.

[31]  Impact of Mycobacterium vaccae immunization on lung histopathology in a murine model of chronic asthma , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[32]  M. Abreu,et al.  Defects in mucosal immunity leading to Crohn's disease , 2005, Immunological reviews.

[33]  M. Jacobsen,et al.  Mechanisms of bacillus Calmette-Guerin mediated natural killer cell activation. , 2004, The Journal of urology.

[34]  A. Pahari,et al.  BCG, tuberculin skin-test results and asthma prevalence in school children in North London. , 2002, Indian pediatrics.

[35]  N. Petrovsky,et al.  Prevention of Autoimmune Diabetes through Immunostimulation with Q Fever Complement‐Fixing Antigen , 2003, Annals of the New York Academy of Sciences.

[36]  Mph Dr. Robert S. Sandler MD,et al.  Childhood infections and the risk of inflammatory bowel disease , 2005, Digestive Diseases and Sciences.

[37]  R. Greenstein Is Crohn's disease caused by a mycobacterium? Comparisons with leprosy, tuberculosis, and Johne's disease. , 2003, The Lancet. Infectious diseases.

[38]  B. Niggemann,et al.  Early childhood infectious diseases and the development of asthma up to school age: a birth cohort study , 2001, BMJ : British Medical Journal.

[39]  C. Akdis,et al.  Role of interleukin 10 in specific immunotherapy. , 1998, The Journal of clinical investigation.

[40]  M. Melbye,et al.  Age at bacille Calmette–Guérin vaccination and risk of allergy and asthma , 2003, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[41]  É. Lerebours,et al.  Environmental risk factors in paediatric inflammatory bowel diseases: a population based case control study , 2005, Gut.

[42]  G. Le Gros,et al.  Development of an asthma vaccine: research into BCG. , 2000, Drugs.

[43]  A. Frappier,et al.  B.C.G. vaccination and leukaemia mortality. , 1970, Lancet.

[44]  L. Cohn Mucus in chronic airway diseases: sorting out the sticky details. , 2006, The Journal of clinical investigation.

[45]  G. Rook,et al.  Inhibition of an established allergic response to ovalbumin in BALB/c mice by killed Mycobacterium vaccae , 1998, Immunology.

[46]  L Davignon,et al.  B.C.G. VACCINATION AND LEUKqMIA MORTALITY , 1971 .

[47]  B. Björkstén,et al.  Immune deviation and the hygiene hypothesis: A review of the epidemiological evidence , 2003, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[48]  C. Huber,et al.  Immmunotherapy of cancer: from vision to standard clinical practice , 2004, Journal of Cancer Research and Clinical Oncology.

[49]  M. Yılmaz,et al.  Correlation between atopic diseases and tuberculin responses , 2000, Allergy.

[50]  G. Draper,et al.  B.C.G. vaccination and leukaemia mortality. , 1971, Lancet.

[51]  C. Hawrylowicz,et al.  A defect in corticosteroid-induced IL-10 production in T lymphocytes from corticosteroid-resistant asthmatic patients. , 2002, The Journal of allergy and clinical immunology.

[52]  A. Gulsvik,et al.  Absence of relationship between tuberculin reactivity and asthmatic symptoms, level of FEV1 and bronchial hyperresponsiveness in BCG vaccinated young adults , 2002, Allergy.

[53]  L. Kinlen,et al.  Evidence from population mixing in British New Towns 1946-85 of an infective basis for childhood leukaemia , 1990, The Lancet.

[54]  O. Gefeller,et al.  Impact of vaccinations and infectious diseases on the risk of melanoma--evaluation of an EORTC case-control study. , 2003, European journal of cancer.

[55]  M. Langman,et al.  Childhood factors in ulcerative colitis and Crohn's disease. An international cooperative study. , 1987, Scandinavian journal of gastroenterology.

[56]  G. Pershagen,et al.  Early BCG vaccination and development of atopy , 1997, The Lancet.

[57]  M. Melbye,et al.  BCG vaccination and risk of atopy. , 2003, JAMA.

[58]  S. Franceschi,et al.  Medical history and risk of Hodgkin's and non‐Hodgkin's lymphomas , 2000, European journal of cancer prevention : the official journal of the European Cancer Prevention Organisation.

[59]  U. Wahn,et al.  Delayed hypersensitivity to tuberculin, total immunoglobulin E, specific sensitization, and atopic manifestation in longitudinally followed early Bacille Calmette-Guérin-vaccinated and nonvaccinated children. , 2001, Pediatrics.

[60]  U. Wahn,et al.  Is early BCG vaccination associated with less atopic disease? An epidemiological study in German preschool children with different ethnic backgrounds , 2002, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[61]  T. Haahtela,et al.  Immunization and atopy: possible implications of ethnicity. , 2004, The Journal of allergy and clinical immunology.

[62]  E. Sarinho,et al.  BCG scar diameter and asthma: a case-control study. , 2000, The Journal of allergy and clinical immunology.

[63]  R. Logan,et al.  Appendicectomy, childhood hygiene, Helicobacter pylori status, and risk of inflammatory bowel disease: a case control study , 1998, Gut.

[64]  S. Burdach,et al.  Reduced expression of transforming growth factor β1 exacerbates pathology in an experimental asthma model , 2005, European journal of immunology.

[65]  J. Castro‐Rodriguez,et al.  Siblings, day-care attendance, and the risk of asthma and wheezing during childhood. , 2000, The New England journal of medicine.

[66]  Shimon Sakaguchi,et al.  IL-10 is involved in the suppression of experimental autoimmune encephalomyelitis by CD25+CD4+ regulatory T cells. , 2004, International immunology.

[67]  M. Sadelain,et al.  Prevention of Type I Diabetes in NOD Mice by Adjuvant Immunotherapy , 1990, Diabetes.

[68]  M. Sadelain,et al.  Prevention of diabetes in the BB rat by early immunotherapy using Freund's adjuvant. , 1990, Journal of autoimmunity.

[69]  G. Comstock BCG vaccination and cancer. , 1991, Tubercle.

[70]  D. Classen,et al.  THE TIMING OF PEDIATRIC IMMUNIZATION AND THE RISK OF INSULIN-DEPENDENT DIABETES MELLITUS , 1997 .

[71]  G. Comstock,et al.  BCG vaccination and the subsequent development of cancer in humans. , 1981, Journal of the National Cancer Institute.

[72]  G. Hems,et al.  B.C.G. and leukaemia. , 1971, The Lancet.

[73]  I. Barlan,et al.  Effect of pre‐immunization by killed Mycobacterium bovis and vaccae on immunoglobulin E response in ovalbumin‐sensitized newborn mice , 1999, Pediatric allergy and immunology : official publication of the European Society of Pediatric Allergy and Immunology.

[74]  H. Storm,et al.  Hematopoietic and lymphatic cancers in relatives of patients with infectious mononucleosis. , 2002, Journal of the National Cancer Institute.

[75]  Bhagirath Singh,et al.  BCG vaccination prevents insulin-dependent diabetes mellitus (IDDM) in NOD mice after disease acceleration with cyclophosphamide. , 1997, Journal of autoimmunity.

[76]  J. Satoh,et al.  Streptococcal Preparation (OK-432) Inhibits Development of Type I Diabetes in NOD Mice , 1986, Diabetes.

[77]  P. Gourdy,et al.  Specific abrogation of transforming growth factor-beta signaling in T cells alters atherosclerotic lesion size and composition in mice. , 2003, Blood.

[78]  J. Palefsky,et al.  Immunosuppression and co-infection with HIV , 2003 .

[79]  C. Tam,et al.  Asthma, atopy and tuberculin responses in Chinese schoolchildren in Hong Kong , 2001, Thorax.

[80]  O. Gefeller,et al.  Prior immunisation of patients with malignant melanoma with vaccinia or BCG is associated with better survival. An European Organization for Research and Treatment of Cancer cohort study on 542 patients. , 2005, European journal of cancer.

[81]  S. Phipps,et al.  A role for eosinophils in airway remodelling in asthma. , 2004, Trends in immunology.

[82]  Mourad Sahbatou,et al.  Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn's disease , 2001, Nature.

[83]  I. Strannegård,et al.  Prevalence of allergy in children in relation to prior BCG vaccination and infection with atypical mycobacteria , 1998, Allergy.

[84]  B. Norlén,et al.  5-year followup of a randomized prospective study comparing mitomycin C and bacillus Calmette-Guerin in patients with superficial bladder carcinoma. Swedish-Norwegian Bladder Cancer Study Group. , 1999, The Journal of urology.

[85]  R. Flavell,et al.  Transforming growth factor-beta in T-cell biology. , 2002, Nature reviews. Immunology.

[86]  N. Høiby,et al.  Results of Multiple Diagnostic Tests forMycobacterium avium subsp. paratuberculosis in Patients with Inflammatory Bowel Disease and in Controls , 2000, Journal of Clinical Microbiology.

[87]  William D. Lees,et al.  Defective acute inflammation in Crohn's disease: a clinical investigation , 2006, The Lancet.

[88]  B. Tönshoff,et al.  Adenotonsillar hypertrophy and post-transplant lymphoproliferative disorder in pediatric renal transplant recipients , 2004, Pediatric Nephrology.

[89]  H. Waaler B.C.G. and leukaemia mortality. , 1970, Lancet.

[90]  D. Coggon,et al.  Inflammatory bowel disease and domestic hygiene in infancy , 1994, The Lancet.

[91]  D. Liggitt,et al.  Viral-induced T helper type 1 responses enhance allergic disease by effects on lung dendritic cells , 2004, Nature Immunology.

[92]  M. Harada,et al.  Prevention of overt diabetes and insulitis in NOD mice by a single BCG vaccination. , 1990, Diabetes research and clinical practice.

[93]  G. Dahlquist,et al.  The cumulative incidence of childhood diabetes mellitus in Sweden unaffected by BCG-vaccination , 1995, Diabetologia.

[94]  R. Mitsuyasu,et al.  AIDS-related Kaposi's sarcoma: current treatment options, future trends. , 2000, Oncology.

[95]  R. Hoover,et al.  Risk of cancer in renal-transplant recipients. , 1973, Lancet.

[96]  R. Vile Faculty Opinions recommendation of IFNgamma and lymphocytes prevent primary tumour development and shape tumour immunogenicity. , 2001 .

[97]  C. Sanjeevi,et al.  BCG Vaccination and GAD65 and IA‐2 Autoantibodies in Autoimmune Diabetes in Southern India , 2002, Annals of the New York Academy of Sciences.

[98]  C. Hawrylowicz,et al.  Potential role of interleukin-10-secreting regulatory T cells in allergy and asthma , 2005, Nature Reviews Immunology.

[99]  P. Libby Inflammation in atherosclerosis , 2002, Nature.

[100]  A. Frappier,et al.  B.C.G. vaccination and leukemia mortality. , 1970, Lancet.

[101]  H Hjalgrim,et al.  Risk of Hodgkin's disease and other cancers after infectious mononucleosis. , 2000, Journal of the National Cancer Institute.

[102]  P. Sly,et al.  TH2‐polarized immunological memory to inhalant allergens in atopies is established during infaney and early childhood , 1997, Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology.

[103]  R. Townley,et al.  The effect of BCG vaccine at birth on the development of atopy or allergic disease in young children. , 2004, Annals of allergy, asthma & immunology : official publication of the American College of Allergy, Asthma, & Immunology.

[104]  B. Sander,et al.  Sequential production of Th1 and Th2 cytokines in response to live bacillus Calmette-Guérin. , 1995, Immunology.

[105]  E. Bonifacio,et al.  Neonatal Bacille Calmette-Guerin vaccination and type 1 diabetes. , 2005, Diabetes care.

[106]  A. Lalvani,et al.  Regulatory T cells are expanded in blood and disease sites in patients with tuberculosis. , 2006, American journal of respiratory and critical care medicine.

[107]  E. Seidman,et al.  Investigating the Hygiene Hypothesis as a Risk Factor in Pediatric Onset Crohn's Disease: A Case-Control Study , 2006, The American Journal of Gastroenterology.

[108]  J. Palefsky,et al.  Chapter 6: Immunosuppression and co-infection with HIV. , 2003, Journal of the National Cancer Institute. Monographs.

[109]  B. Toelle,et al.  The effect of neonatal BCG vaccination on atopy and asthma at age 7 to 14 years: an historical cohort study in a community with a very low prevalence of tuberculosis infection and a high prevalence of atopic disease. , 2003, The Journal of allergy and clinical immunology.

[110]  F. Guillén-Grima,et al.  BCG Immunization at Birth and Atopic Diseases in a Homogeneous Population of Spanish Schoolchildren , 2005, International Archives of Allergy and Immunology.

[111]  R. Coffman,et al.  TH1 and TH2 cells: different patterns of lymphokine secretion lead to different functional properties. , 1989, Annual review of immunology.

[112]  The Inverse Association Between Tuberculin Responses and Atopic Disorder , 1997, Science.

[113]  M. Barreto,et al.  Lower prevalence of reported asthma in adolescents with symptoms of rhinitis that received neonatal BCG , 2004, Allergy.

[114]  H. Adami,et al.  Perinatal risk factors for inflammatory bowel disease: a case-control study. , 1990, American journal of epidemiology.