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

• Published in: PloS one Vol. 4; no. 6; p. e5934
• Main Authors: Whelan, Kathryn T, Pathan, Ansar A, Sander, Clare R, Fletcher, Helen A, Poulton, Ian, Alder, Nicola C, Hill, Adrian V S, McShane, Helen
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 16.06.2009; Public Library of Science (PLoS)
• Subjects: Acyltransferases - chemistry; Acyltransferases - immunology; Adult; Adults; Antigens; Antigens, Bacterial - chemistry; Antigens, Bacterial - immunology; Antitubercular agents; Bacillus Calmette-Guerin vaccine; BCG; BCG Vaccine - administration & dosage; BCG Vaccine - chemistry; Biological response modifiers; CD4 antigen; CD8 antigen; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - virology; Clinical trials; Cytometry; Dendritic cells; Dendritic Cells - virology; Disease; Enzyme-Linked Immunosorbent Assay; Female; Flow cytometry; Flow Cytometry - methods; HIV; Hospitals; Human immunodeficiency virus; Humans; Immune response; Immune response (cell-mediated); Immunogenicity; Immunology; Immunology/Immunity to Infections; Infections; Infectious Diseases/Bacterial Infections; Infectious Diseases/Respiratory Infections; Interferon; Interferon-gamma - metabolism; Lymphocytes; Lymphocytes T; Male; Middle Aged; Mycobacterium bovis; Mycobacterium tuberculosis; Neutrophils; Newborn babies; Peptides; Peptides - chemistry; Peripheral blood mononuclear cells; Safety; T cell receptors; T cells; Time Factors; Tuberculin; Tuberculosis; Tuberculosis Vaccines - chemistry; Vaccination; Vaccines; γ-Interferon
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0005934

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. 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. 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. ClinicalTrials.gov NCT00654316 NCT00427830.