Evaluation of a human BCG challenge model to assess antimycobacterial immunity induced by BCG and a candidate tuberculosis vaccine, MVA85A, alone and in combination

Stephanie A Harris, Joel Meyer, Iman Satti, Leanne Marsay, Ian D Poulton, Rachel Tanner, Angela M Minassian, Helen A Fletcher, Helen McShane, Stephanie A Harris, Joel Meyer, Iman Satti, Leanne Marsay, Ian D Poulton, Rachel Tanner, Angela M Minassian, Helen A Fletcher, Helen McShane

Abstract

Background: A new vaccine is urgently needed to combat tuberculosis. However, without a correlate of protection, selection of the vaccines to take forward into large-scale efficacy trials is difficult. Use of bacille Calmette-Guérin (BCG) as a surrogate for human Mycobacterium tuberculosis challenge is a novel model that could aid selection.

Methods: Healthy adults were assigned to groups A and B (BCG-naive) or groups C and D (BCG-vaccinated). Groups B and D received candidate tuberculosis vaccine MVA85A. Participants were challenged with intradermal BCG 4 weeks after those who received MVA85A. Skin biopsies of the challenge site were taken 2 weeks post challenge and BCG load quantified by culture and quantitative polymerase chain reaction (qPCR).

Results: Volunteers with a history of BCG showed some degree of protective immunity to challenge, having lower BCG loads compared with volunteers without prior BCG, regardless of MVA85A status. There was a significant inverse correlation between antimycobacterial immunity at peak response after MVA85A and BCG load detected by qPCR.

Conclusion: Our results support previous findings that this BCG challenge model is able to detect differences in antimycobacterial immunity induced by vaccination and could aid in the selection of candidate tuberculosis vaccines for field efficacy testing.

Trial registration: ClinicalTrials.gov NCT01194180.

Keywords: MVA85A; human BCG challenge; tuberculosis; vaccine.

Figures

Figure 1.
Figure 1.
Consort diagram showing participant recruitment and follow-up. *One volunteer withdrew from group B for personal reasons after MVA85A vaccination but before bacille Calmette-Guérin challenge.
Figure 2.
Figure 2.
Quantification of bacterial load from punch biopsies 14 days post bacille Calmette-Guérin (BCG) challenge by culture on solid agar (A) and quantitative polymerase chain reaction (qPCR) (B). Individual values are shown for each volunteer. Horizontal bars indicate median values in each group. Significant differences between groups are as follows: *P ≤ .05, **P ≤ .01, ***P ≤ .001; Mann–Whitney U test. A significant positive correlation was observed between the culture and qPCR results (C).
Figure 3.
Figure 3.
Ex vivo interferon-gamma enzyme-linked immunosorbent spot (ELISpot) assay responses to purified protein derivative from Mycobacteriumtuberculosis for all groups (A) and to a single pool of Ag85A peptides for groups B and D (B). A value of 1667 spot-forming cells (SFCs)/1 × 106 peripheral blood mononuclear cells (PBMCs) represents a blackout in the ELISpot well. ** P < .01. Abbreviation: BCG, bacille Calmette-Guérin.
Figure 4.
Figure 4.
Correlation between ex vivo interferon-gamma enzyme-linked immunosorbent spot assay responses to purified protein derivative or Ag85A and estimated bacille Calmette-Guérin (BCG) copy number by polymerase chain reaction (PCR). Spearman R values are shown with asterisks indicating P values as follows: *P ≤ .05, **P ≤ .01, ***P ≤ .001. Abbreviations: PBMC, peripheral blood mononuclear cell; SFC, spot-forming cell.
Figure 5.
Figure 5.
Growth ratios obtained from the mycobacteria growth indicator tube assay (A) and correlation with estimated bacille Calmette-Guérin (BCG) copy number by quantitative polymerase chain reaction (PCR) (B).

References

    1. WHO. Tuberculosis. Accessed 11 June 2013.
    1. Brennan MJ, Thole J. Tuberculosis. Vol. 92. Edinburgh: Elsevier; 2012. Tuberculosis vaccines: a strategic blueprint for the next decade; pp. S6–13.
    1. Stylianou E, Pepponi I, Van Dolleweerd CJ, Paul MJ, Ma JK, Reljic R. Exploring the vaccine potential of Dec-205 targeting in Mycobacterium tuberculosis infection in mice. Vaccine. 2011;29:2279–86.
    1. Williams A, Hatch GJ, Clark SO, et al. Evaluation of vaccines in the EU TB vaccine cluster using a guinea pig aerosol infection model of tuberculosis. Tuberculosis. 2005;85:29–38.
    1. Vordermeier HM, Villarreal-Ramos B, Cockle PJ, et al. Viral booster vaccines improve Mycobacterium bovis BCG-induced protection against bovine tuberculosis. Infect Immun. 2009;77:3364–73.
    1. Verreck FAW, Vervenne RAW, Kondova I, et al. MVA.85A boosting of BCG and an attenuated, phoP deficient M. tuberculosis vaccine both show protective efficacy against tuberculosis in rhesus macaques. PloS one. 2009;4:e5264.
    1. Worku S, Hoft DF. In vitro measurement of protective mycobacterial immunity antigen-specific expansion of T cells capable of inhibiting intracellular growth of bacille Calmette-Guerin. Clin Infect Dis. 2000;63110:257–61.
    1. Li Q, Whalen CC, Albert JM, et al. Differences in rate and variability of intracellular growth of a panel of Mycobacterium tuberculosis clinical isolates within a human monocyte model. Infect Immun. 2002;70:6489–93.
    1. Marsay L, Matsumiya M, Tanner R, et al. tb). Tuberculosis. Vol. 93. Edinburgh: Elsevier; 2013. Mycobacterial growth inhibition in murine splenocytes as a surrogate for protection against Mycobacterium tuberculosis (M; pp. 551–7.
    1. Sauerwein RW, Roestenberg M, Moorthy VS. Experimental human challenge infections can accelerate clinical malaria vaccine development. Nat Rev Immunol. 2011;11:57–64.
    1. Carrat F, Vergu E, Ferguson NM, et al. Time lines of infection and disease in human influenza: a review of volunteer challenge studies. Am J Epidemiol. 2008;167:775–85.
    1. Statler J, Mammen M, Lyons A, Sun W. Sonographic findings of healthy volunteers infected with dengue virus. J Clin Ultrasound. 2008;36:413–7.
    1. Marwick C. Volunteers in typhoid infection study will aid future vaccine development. JAMA. 1998;279:1423–4.
    1. Minassian AM, Satti I, Poulton ID, Meyer J, Hill AVS, McShane H. A human challenge model for Mycobacterium tuberculosis using Mycobacterium bovis bacille Calmette-Guerin. J Infect Dis. 2012;205:1035–42.
    1. McShane H, Brookes R, Gilbert SC, Hill AVS, Mmun INI. Enhanced immunogenicity of CD4+ T-cell responses and protective efficacy of a DNA-modified vaccinia virus Ankara prime-boost vaccination regimen for murine tuberculosis. Infect Immun. 2001;69:681–6.
    1. Minassian AM, Ronan EO, Poyntz H, Hill AVS, McShane H. Preclinical development of an in vivo BCG challenge model for testing candidate TB vaccine efficacy. PloS one. 2011;6:e19840.
    1. Talbot EA, Williams DL, Frothingham R, Talbot EA, Williams DL. PCR identification of Mycobacterium bovis PCR identification of Mycobacterium bovis BCG. J Clin Microbio. 1997;35:566.
    1. Meyer J, Harris SA, Satti I, et al. Comparing the safety and immunogenicity of a candidate TB vaccine MVA85A administered by intramuscular and intradermal delivery. Vaccine. 2013;31:1026–33.
    1. Wallis RS, Palaci M, Vinhas S, et al. A whole blood bactericidal assay for tuberculosis. J Infect Dis, 2001;183:1300–3.
    1. Cunha AJLA, Anna CCS, Mannarino R, Labanca TC, Ferreira S, March MFBP. Adverse effects of BCG revaccination: a report on 13 cases from Rio de Janeiro, Brazil. Int J Tuberc Lung Dis. 2002;6:1110–3.
    1. Dourado I, Rios MH, Pereira SMM, et al. Rates of adverse reactions to first and second doses of BCG vaccination: results of a large community trial in Brazilian school children. Int J Tuberc Lung Dis. 2003;7:399–402.
    1. Pathan AA, Minassian AM, Sander CR, et al. Effect of vaccine dose on the safety and immunogenicity of a candidate TB vaccine, MVA85A, in BCG vaccinated UK adults. Vaccine. 2012;30:5616–24.
    1. SSI. Description of BCG VACCINE SSI. . Accessed 12 June 2013.
    1. McShane H, Pathan AA, Sander CR, et al. Recombinant modified vaccinia virus Ankara expressing antigen 85A boosts BCG-primed and naturally acquired antimycobacterial immunity in humans. Nat Med. 2004;10:1240–4.
    1. Tameris MD, Hatherill M, Landry BS, et al. Safety and efficacy of MVA85A, a new tuberculosis vaccine, in infants previously vaccinated with BCG: a randomised, placebo-controlled phase 2b trial. Lancet. 2013;381:1021–8.
    1. Fletcher HA, Tanner R, Wallis R, et al. Inhibition of mycobacterial growth in vitro following primary but not secondary vaccination with BCG. Clin Vaccine Immunol. 2013;20:1683–9.
    1. Worku S, Hoft DF. Differential effects of control and antigen-specific T cells on intracellular mycobacterial growth. Infect Immun. 2003;71:1763–73.
    1. Kampmann B, Tena GN, Mzazi S, Eley B, Young DB, Levin M. Novel human in vitro system for evaluating antimycobacterial vaccines. Infect Immun. 2004;71:6401–7.
    1. Cheon S, Kampmann B, Hise AG, et al. Bactericidal activity in whole blood as a potential surrogate marker of immunity after vaccination against tuberculosis. Clin Diagn Lab Immunol. 2004;9:901–7.
    1. Williams A, Goonetilleke NP, Mcshane H, et al. Boosting with poxviruses enhances Mycobacterium bovis BCG efficacy against tuberculosis in guinea pigs. Infect Immun. 2005;73:3814–6.
    1. Goonetilleke NP, Mcshane H, Hannan CM, Anderson RJ, Brookes RH, Hill AVS. Enhanced immunogenicity and protective efficacy against Mycobacterium tuberculosis of bacille Calmette-Guérin vaccine using mucosal administration and boosting with a recombinant modified vaccinia virus Ankara. J Immunol. 2003;171:1602–9.
    1. B.C.G. and vole bacillus vaccines in the prevention of tuberculosis in adolescence and early adult life. Br Med J. 1963;1:973–8.

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