Distinct T-cell responses when BCG vaccination is delayed from birth to 6 weeks of age in Ugandan infants.

BACKGROUND In Uganda, the tuberculosis vaccine BCG is administered on the first day of life. Infants delivered at home receive BCG vaccine at their first healthcare facility visit at 6 weeks of age. Our aim was to determine the effect of this delay in BCG vaccination on the induced immune response. METHODS We assessed CD4(+) and CD8(+) T-cell responses with a 12-hour whole-blood intracellular cytokine/cytotoxic marker assay, and with a 6-day proliferation assay. RESULTS We enrolled 92 infants: 50 had received BCG vaccine at birth and 42 at 6 weeks of age. Birth vaccination was associated with (1) greater induction of CD4(+) and CD8(+) T cells expressing either interferon γ (IFN-γ) alone or IFN-γ together with perforin and (2) induction of proliferating cells that had greater capacity to produce IFN-γ, tumor necrosis factor α (TNF-α), and interleukin 2 together, compared with delayed vaccination. CONCLUSIONS Distinct patterns of T-cell induction occurred when BCG vaccine was given at birth and at 6 weeks of age. We propose that this diversity might impact protection against tuberculosis. Our results differ from those of studies of delayed BCG vaccination in South Africa and the Gambia, suggesting that geographical and population heterogeneity may affect the BCG vaccine-induced T-cell response.

[1]  G. Kaplan,et al.  Longitudinal changes in CD4(+) T-cell memory responses induced by BCG vaccination of newborns. , 2013, The Journal of infectious diseases.

[2]  G. Bancroft,et al.  Blockade of IL-10 Signaling during Bacillus Calmette-Guérin Vaccination Enhances and Sustains Th1, Th17, and Innate Lymphoid IFN-γ and IL-17 Responses and Increases Protection to Mycobacterium tuberculosis Infection , 2012, The Journal of Immunology.

[3]  J. Casanova,et al.  Mycobacterial Disease and Impaired IFN-γ Immunity in Humans with Inherited ISG15 Deficiency , 2012, Science.

[4]  F. Verreck,et al.  Prime-Boost Vaccination with rBCG/rAd35 Enhances CD8+ Cytolytic T-Cell Responses in Lesions from Mycobacterium Tuberculosis-Infected Primates , 2012, Molecular medicine.

[5]  M. Tameris,et al.  A phase IIa trial of the new tuberculosis vaccine, MVA85A, in HIV- and/or Mycobacterium tuberculosis-infected adults. , 2012, American journal of respiratory and critical care medicine.

[6]  B. Landry,et al.  A recombinant adenovirus expressing immunodominant TB antigens can significantly enhance BCG-induced human immunity. , 2012, Vaccine.

[7]  J. Lieberman,et al.  Perforin pores in the endosomal membrane trigger release of endocytosed granzyme B to the cytosol of target cells , 2011, Nature Immunology.

[8]  H. Whittle,et al.  Randomized trial of BCG vaccination at birth to low-birth-weight children: beneficial nonspecific effects in the neonatal period? , 2011, The Journal of infectious diseases.

[9]  S. Rowland-Jones,et al.  Immunogenicity of the Tuberculosis Vaccine MVA85A Is Reduced by Coadministration with EPI Vaccines in a Randomized Controlled Trial in Gambian Infants , 2011, Science Translational Medicine.

[10]  T. Tylleskär,et al.  Perinatal Mortality in Eastern Uganda: A Community Based Prospective Cohort Study , 2011, PloS one.

[11]  Victoria Nankabirwa,et al.  Is vaccination coverage a good indicator of age-appropriate vaccination? A prospective study from Uganda. , 2011, Vaccine.

[12]  Mario Roederer,et al.  SPICE: Exploration and analysis of post‐cytometric complex multivariate datasets , 2011, Cytometry. Part A : the journal of the International Society for Analytical Cytology.

[13]  G. Kaplan,et al.  Induction of Granulysin and Perforin Cytolytic Mediator Expression in 10-Week-Old Infants Vaccinated with BCG at Birth , 2010, Clinical & developmental immunology.

[14]  S. Self,et al.  Ontogeny of Toll-Like Receptor Mediated Cytokine Responses of Human Blood Mononuclear Cells , 2010, PloS one.

[15]  T. Scriba,et al.  Novel application of Ki67 to quantify antigen-specific in vitro lymphoproliferation , 2010, Journal of immunological methods.

[16]  G. Kaplan,et al.  Specific T cell frequency and cytokine expression profile do not correlate with protection against tuberculosis after bacillus Calmette-Guérin vaccination of newborns. , 2010, American journal of respiratory and critical care medicine.

[17]  S. Rowland-Jones,et al.  Delaying Bacillus Calmette-Guérin Vaccination from Birth to 4 1/2 Months of Age Reduces Postvaccination Th1 and IL-17 Responses but Leads to Comparable Mycobacterial Responses at 9 Months of Age , 2010, The Journal of Immunology.

[18]  M. Tameris,et al.  The novel tuberculosis vaccine, AERAS-402, induces robust and polyfunctional CD4+ and CD8+ T cells in adults. , 2010, American journal of respiratory and critical care medicine.

[19]  T. Scriba,et al.  Delaying BCG vaccination from birth to 10 weeks of age may result in an enhanced memory CD4 T cell response. , 2009, Vaccine.

[20]  G. Schoolnik,et al.  Immunogenicity of Novel DosR Regulon-Encoded Candidate Antigens of Mycobacterium tuberculosis in Three High-Burden Populations in Africa , 2009, Clinical and Vaccine Immunology.

[21]  S. Ehlers,et al.  Autocrine IL-10 Induces Hallmarks of Alternative Activation in Macrophages and Suppresses Antituberculosis Effector Mechanisms without Compromising T Cell Immunity1 , 2009, The Journal of Immunology.

[22]  R. Davies,et al.  Safety and immunogenicity of a new tuberculosis vaccine, MVA85A, in Mycobacterium tuberculosis-infected individuals. , 2009, American journal of respiratory and critical care medicine.

[23]  A. Hill,et al.  Multifunctional, High-Level Cytokine-Producing Th1 Cells in the Lung, but Not Spleen, Correlate with Protection against Mycobacterium tuberculosis Aerosol Challenge in Mice , 2008, The Journal of Immunology.

[24]  J. Wilschut,et al.  Alum boosts TH2-type antibody responses to whole-inactivated virus influenza vaccine in mice but does not confer superior protection. , 2008, Vaccine.

[25]  G. Rook Th2 cytokines in susceptibility to tuberculosis. , 2007, Current molecular medicine.

[26]  G. Pantaleo,et al.  Functional and phenotypic characterizationof tetanus toxoid‐specific human CD4+ T cellsfollowing re‐immunization , 2007, European journal of immunology.

[27]  A. Prusa,et al.  Immaturity of infection control in preterm and term newborns is associated with impaired toll-like receptor signaling. , 2007, The Journal of infectious diseases.

[28]  C. Dye,et al.  Effect of BCG vaccination on childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of cost-effectiveness , 2006, The Lancet.

[29]  R. Ortíz,et al.  Assessment by Flow Cytometry of Cytokine Production in Malnourished Children , 2005, Clinical Diagnostic Laboratory Immunology.

[30]  G. Pantaleo,et al.  Phenotypic heterogeneity of antigen‐specific CD4 T cells under different conditions of antigen persistence and antigen load , 2004, European journal of immunology.

[31]  P. Haslett,et al.  Novel application of a whole blood intracellular cytokine detection assay to quantitate specific T-cell frequency in field studies. , 2004, Journal of immunological methods.

[32]  G. Carcelain,et al.  Distinct Time Effects of Vaccination on Long-Term Proliferative and IFN-γ–producing T Cell Memory to Smallpox in Humans , 2004, The Journal of experimental medicine.

[33]  Maria Yazdanbakhsh,et al.  Allergy, parasites, and the hygiene hypothesis. , 2002, Science.

[34]  G. Hussey,et al.  Neonatal mycobacterial specific cytotoxic T‐lymphocyte and cytokine profiles in response to distinct BCG vaccination strategies , 2002, Immunology.

[35]  B. Petros,et al.  Effect of deworming on human T cell responses to mycobacterial antigens in helminth‐exposed individuals before and after bacille Calmette–Guérin (BCG) vaccination , 2001, Clinical and experimental immunology.

[36]  T. Ottenhoff,et al.  Human deficiencies in type-1 cytokine receptors reveal the essential role of type-1 cytokines in immunity to intracellular bacteria. , 2000, Advances in experimental medicine and biology.

[37]  E. Butcher,et al.  Chemokines in tissue-specific and microenvironment-specific lymphocyte homing. , 2000, Current opinion in immunology.

[38]  F. Sallusto,et al.  Two subsets of memory T lymphocytes with distinct homing potentials and effector functions , 1999, Nature.

[39]  H. Dockrell,et al.  Characterization of Human Mycobacterium bovis Bacille Calmette-Guérin-Reactive CD8+T Cells , 1999, Infection and Immunity.

[40]  M. Newport,et al.  Newborns develop a Th1-type immune response to Mycobacterium bovis bacillus Calmette-Guérin vaccination. , 1999, Journal of immunology.

[41]  C. Pitcher,et al.  Determination of antigen-specific memory/effector CD4+ T cell frequencies by flow cytometry: evidence for a novel, antigen-specific homeostatic mechanism in HIV-associated immunodeficiency. , 1997, The Journal of clinical investigation.

[42]  Kenneth M. Murphy,et al.  Functional diversity of helper T lymphocytes , 1996, Nature.

[43]  H Stein,et al.  Cell cycle analysis of a cell proliferation-associated human nuclear antigen defined by the monoclonal antibody Ki-67. , 1984, Journal of immunology.

[44]  H. Maecker,et al.  Bacillus Calmette Guerin Vaccination of Human Newborns Induces a Specific, Functional CD8 T Cell Response , 2006 .

[45]  BCG vaccine. WHO position paper. , 2004, Releve epidemiologique hebdomadaire.