It is estimated that one-third of the world’s population is infected with Mycobacterium tuberculosis. Infection typically remains latent, but it can reactivate to cause clinical disease. The only vaccine, Mycobacterium bovis bacillus Calmette-Guérin (BCG), is largely ineffective, and ways to enhance its efficacy are being developed. Of note, the candidate booster vaccines currently under clinical development have been designed to improve BCG efficacy but not prevent reactivation of latent infection. Here, we demonstrate that administering a multistage vaccine that we term H56 in the adjuvant IC31 as a boost to vaccination with BCG delays and reduces clinical disease in cynomolgus macaques challenged with M. tuberculosis and prevents reactivation of latent infection. H56 contains Ag85B and ESAT-6, which are two of the M. tuberculosis antigens secreted in the acute phase of infection, and the nutrient stress–induced antigen Rv2660c. Boosting with H56/IC31 resulted in efficient containment of M. tuberculosis infection and reduced rates of clinical disease, as measured by clinical parameters, inflammatory markers, and improved survival of the animals compared with BCG alone. Boosted animals showed reduced pulmonary pathology and extrapulmonary dissemination, and protection correlated with a strong recall response against ESAT-6 and Rv2660c. Importantly, BCG/H56-vaccinated monkeys did not reactivate latent infection after treatment with anti-TNF antibody. Our results indicate that H56/IC31 boosting is able to control late-stage infection with M. tuberculosis and contain latent tuberculosis, providing a rationale for the clinical development of H56.
Philana Ling Lin, Jes Dietrich, Esterlina Tan, Rodolfo M. Abalos, Jasmin Burgos, Carolyn Bigbee, Matthew Bigbee, Leslie Milk, Hannah P. Gideon, Mark Rodgers, Catherine Cochran, Kristi M. Guinn, David R. Sherman, Edwin Klein, Christopher Janssen, JoAnne L. Flynn, Peter Andersen
Title and authors | Publication | Year |
---|---|---|
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Intracellular Cytokine Staining and Flow Cytometry: Considerations for Application in Clinical Trials of Novel Tuberculosis Vaccines
SG Smith, K Smits, SA Joosten, KE van Meijgaarden, I Satti, HA Fletcher, N Caccamo, F Dieli, F Mascart, H McShane, HM Dockrell, TH Ottenhoff, TJ Scriba |
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Mucosal vaccination with attenuated Mycobacterium tuberculosis induces strong central memory responses and protects against tuberculosis
D Kaushal, TW Foreman, US Gautam, X Alvarez, T Adekambi, J Rangel-Moreno, NA Golden, AM Johnson, BL Phillips, MH Ahsan, KE Russell-Lodrigue, LA Doyle, CJ Roy, PJ Didier, JL Blanchard, J Rengarajan, AA Lackner, SA Khader, S Mehra |
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Tuberculosis vaccines: barriers and prospects on the quest for a transformative tool
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Immunological Reviews | 2015 |
Immunology studies in non-human primate models of tuberculosis
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Protection against Mycobacterium tuberculosis Infection Offered by a New Multistage Subunit Vaccine Correlates with Increased Number of IFN-γ+IL-2+ CD4+ and IFN-γ+ CD8+ T Cells
X Wang, J Zhang, J Liang, Y Zhang, X Teng, X Yuan, X Fan, MM Rodrigues |
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Protein Energy Malnutrition during Vaccination Has Limited Influence on Vaccine Efficacy but Abolishes Immunity if Administered during Mycobacterium tuberculosis Infection
T Hoang, EM Agger, JP Cassidy, JP Christensen, P Andersen, S Ehrt |
Infection and immunity | 2015 |
A multi-scale approach to designing therapeutics for tuberculosis
JJ Linderman, NA Cilfone, E Pienaar, C Gong, DE Kirschner |
Integrative Biology | 2015 |
Recent advances in the development of vaccines for tuberculosis
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Therapeutic advances in vaccines | 2015 |
Synthetic Long Peptide Derived from Mycobacterium tuberculosis Latency Antigen Rv1733c Protects against Tuberculosis
M Coppola, SJ van Eeden, L Wilson, KL Franken, TH Ottenhoff, A Geluk, DW Pascual |
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S Aboutorabian, J Hakimi, F Boudet, S Montano, A Dookie, C Roque, SF Ausar, N Rahman, RH Brookes |
Human Vaccines & Immunotherapeutics | 2015 |
Transformative tools for tackling tuberculosis
JL Gardiner, CL Karp |
Journal of Experimental Medicine | 2015 |
Evaluation of Humoral Immunity to Mycobacterium tuberculosis -Specific Antigens for Correlation with Clinical Status and Effective Vaccine Development
M Niki, M Suzukawa, S Akashi, H Nagai, K Ohta, M Inoue, M Niki, Y Kaneko, K Morimoto, A Kurashima, S Kitada, S Matsumoto, K Suzuki, Y Hoshino |
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A Novel MVA-Based Multiphasic Vaccine for Prevention or Treatment of Tuberculosis Induces Broad and Multifunctional Cell-Mediated Immunity in Mice and Primates
S Leung-Theung-Long, M Gouanvic, CA Coupet, A Ray, E Tupin, N Silvestre, JB Marchand, D Schmitt, C Hoffmann, M Klein, P Seegren, MC Huaman, AD Cristillo, G Inchauspé, AA Izzo |
PloS one | 2015 |