Abstract
ObjectivesTo 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.DesignPhase 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-γ) ELISpot assay and flow cytometry.Results and ConclusionsBCG 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 IFNγ (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 RegistrationClinicalTrials.gov NCT00654316 NCT00427830
Highlights
It is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (M. tb.) [1]
Bacille Calmette-Guerin (BCG) revaccination (BCG-BCG) was well tolerated, and boosting of pre-existing purified protein derivative (PPD)-specific T cell responses was observed. When these results were compared with data from a previous clinical trial, where BCG was boosted with Modified Vaccinia Ankara expressing antigen 85A (MVA85A) (BCG-MVA85A), MVA85A induced significantly higher levels (.2-fold) of antigen 85-specific CD4+ T cells than boosting with BCG, up to 52 weeks post-vaccination (p = 0.009)
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
Summary
It is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (M. tb.) [1]. In 2007, there were estimated to be 9.2 million new cases of tuberculosis (TB) and in 2006, there were 0.5 million cases of multi-drug resistant TB [1]. The only available vaccine against TB, Mycobacterium bovis Bacille Calmette-Guerin (BCG), has variable efficacy. When BCG is administered at birth, it confers consistent and reliable protection against disseminated disease in childhood in the developing world [2,3]. BCG fails to protect against pulmonary disease in these regions [4]. Any improved vaccine regime against TB should include BCG, administered in infancy, in order to retain the protective effects against severe childhood disease [5,6,7]
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