title: Safety and immunogenicity of boosting BCG vaccinated subjects with BCG: comparison with boosting with a new TB vaccine, MVA85A.
abstract: OBJECTIVE
  To investigate the safety and immunogenicity of a booster BCG vaccination delivered intradermally in healthy, BCG vaccinated subjects and to compare with a previous clinical trial where BCG vaccinated subjects were boosted with a new TB vaccine, MVA85A.
  
  
  METHODS
  Phase I open label observational trial, in the UK. Healthy, HIV-negative, BCG vaccinated adults were recruited and vaccinated with BCG. The primary outcome was safety; the secondary outcome was cellular immune responses to antigen 85, overlapping peptides of antigen 85A and tuberculin purified protein derivative (PPD) detected by ex vivo interferon-gamma (IFN-gamma) ELISpot assay and flow cytometry.
  
  
  CONCLUSIONS
  BCG revaccination (BCG-BCG) was well tolerated, and boosting of pre-existing PPD-specific T cell responses was observed. However, when these results were compared with data from a previous clinical trial, where BCG was boosted with MVA85A (BCG-MVA85A), MVA85A induced significantly higher levels (>2-fold) of antigen 85-specific CD4+ T cells (both antigen and peptide pool responses) than boosting with BCG, up to 52 weeks post-vaccination (p = 0.009). To identify antigen 85A-specific CD8+ T cells that were not detectable by ex vivo ELISpot and flow cytometry, dendritic cells (DC) were used to amplify CD8+ T cells from PBMC samples. We observed low, but detectable levels of antigen 85A-specific CD8+ T cells producing IFNgamma (1.5% of total CD8 population) in the BCG primed subjects after BCG boosting in 1 (20%) of 5 subjects. In contrast, in BCG-MVA85A vaccinated subjects, high levels of antigen 85A-specific CD8+ T cells (up to 14% total CD8 population) were observed after boosting with MVA85A, in 4 (50%) of 8 subjects evaluated. In conclusion, revaccination with BCG resulted in modest boosting of pre-existing immune responses to PPD and antigen 85, but vaccination with BCG-MVA85A induced a significantly higher response to antigen 85 and generated a higher frequency of antigen 85A-specific CD8+ T cells.
  
  
  BACKGROUND
  ClinicalTrials.gov NCT00654316 NCT00427830.
authors.affiliation: Jenner Institute, University of Oxford, Churchill Hospital, Oxford, United Kingdom.
authors.forename: Kathryn T
authors.initials: KT
authors.lastname: Whelan
authors.forename: Ansar A
authors.initials: AA
authors.lastname: Pathan
authors.forename: Clare R
authors.initials: CR
authors.lastname: Sander
authors.forename: Helen A
authors.initials: HA
authors.lastname: Fletcher
authors.forename: Ian
authors.initials: I
authors.lastname: Poulton
authors.forename: Nicola C
authors.initials: NC
authors.lastname: Alder
authors.forename: Adrian V S
authors.initials: AV
authors.lastname: Hill
authors.forename: Helen
authors.initials: H
authors.lastname: McShane
mesh_terms: D000217:Acyltransferases / Q000737:chemistry / Q000276:immunology*; D000328:Adult; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology*; D001500:BCG Vaccine / Q000008:administration & dosage* / Q000737:chemistry; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism / Q000821:virology; D003713:Dendritic Cells / Q000821:virology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D008297:Male; D008875:Middle Aged; D010455:Peptides / Q000737:chemistry; D013997:Time Factors; D032581:Tuberculosis Vaccines / Q000737:chemistry*
chemical_list: D000942:Antigens, Bacterial; D001500:BCG Vaccine; D010455:Peptides; D032581:Tuberculosis Vaccines; D007371:Interferon-gamma; D000217:Acyltransferases; C112580:antigen 85A, Mycobacterium tuberculosis