Safety and immunogenicity of boosting BCG vaccinated subjects with BCG: comparison with boosting with a new TB vaccine, MVA85A.

Journal article

OBJECTIVES: 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. DESIGN: 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. RESULTS AND 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. TRIAL REGISTRATION: ClinicalTrials.gov NCT00654316 NCT00427830.

Authors: Whelan, K; Pathan, A; Sander, C; Fletcher, H; Poulton, I

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Public Library of Science
• Journal: PloS one
• Volume: 4
• Issue: 6
• Article number: e5934
• Publication date: 2009-01-01
• DOI: 10.1371/journal.pone.0005934
• EISSN: 1932-6203
• ISSN: 1932-6203
• Language: English
• Keywords: CD8-Positive T-Lymphocytes; Antigens, Bacterial; Time Factors; Flow Cytometry; Interferon-gamma; Enzyme-Linked Immunosorbent Assay; Peptides; Humans; Male; Tuberculosis Vaccines; BCG Vaccine; Adult; Acyltransferases; Dendritic Cells; Middle Aged; Female