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A multistage tuberculosis vaccine that confers efficient protection before and after exposure

Nature Medicine volume 17, pages 189–194 (2011)Cite this article

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Abstract

All tuberculosis vaccines currently in clinical trials are designed as prophylactic vaccines based on early expressed antigens. We have developed a multistage vaccination strategy in which the early antigens Ag85B and 6-kDa early secretory antigenic target (ESAT-6) are combined with the latency-associated protein Rv2660c (H56 vaccine). In CB6F1 mice we show that Rv2660c is stably expressed in late stages of infection despite an overall reduced transcription. The H56 vaccine promotes a T cell response against all protein components that is characterized by a high proportion of polyfunctional CD4+ T cells. In three different pre‐exposure mouse models, H56 confers protective immunity characterized by a more efficient containment of late-stage infection than the Ag85B-ESAT6 vaccine (H1) and BCG. In two mouse models of latent tuberculosis, we show that H56 vaccination after exposure is able to control reactivation and significantly lower the bacterial load compared to adjuvant control mice.

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Figure 1: Immunogenicity and protective efficacy of H56 and its components.
Figure 2: Immune responses and vaccine efficacy of H56 compared to H1.
Figure 3: Evaluation of H56 as a BCG booster.
Figure 4: Vaccination with H56 after exposure.

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Acknowledgements

We thank the Bill and Melinda Gates Foundation (GC12 #37885), EC-FP6: TB-VAC (LSHP-CT-2003-503367), the US National Institutes of Health and National Institute of Allergy and Infectious Diseases (HHSN266200400091c) and the TB Vaccine Testing and Research Materials Contract (NOI-AI-40091). Thanks to N. Caceres for her contribution on the model of latent tuberculosis, to L. Rasmussen, M. Henriksen, J. Brady and V. Andersen for excellent technical help and to E.M. Agger for critical reading of the manuscript.

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Author notes

  1. Claus Aagaard and Truc Hoang: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Infectious Disease Immunology, Statens Serum Institut, Copenhagen, Denmark

    Claus Aagaard, Truc Hoang, Jes Dietrich, Rolf Billeskov & Peter Andersen

  2. Unitat de Tuberculosi Experimental, Institut per a la Investigació en Ciències de la Salut Germans Trias i Pujol, Universitat Autònoma de Barcelona, Badalona, Catalonia, Spain

    Pere-Joan Cardona

  3. Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, Colorado, USA

    Angelo Izzo

  4. Department of Microbiology and Immunology, Stanford University School of Medicine, California, USA

    Gregory Dolganov & Gary K Schoolnik

  5. Veterinary Sciences Centre, School of Agriculture, Food Science and Veterinary Medicine, University College Dublin, Belfield, Dublin, Ireland

    Joseph P Cassidy

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Contributions

C.A. conceived of the study, produced H56, conducted pre‐exposure vaccine studies and prepared the manuscript. T.H. developed the CB6F1 latency model and conducted latency studies in this model. J.D. conducted the BCG boost studies. P.-J.C. developed the C57BL/6 latency model and conducted latency studies in this model. A.I. conducted pre‐exposure vaccine studies. G.D. designed and performed gene expression analyses. G.K.S. designed and performed gene expression analyses. J.P.C. performed histological evaluation of lung specimens. R.B. contributed to the latency vaccine studies. P.A. conceived of the study and prepared the manuscript. All authors discussed the results and commented on the manuscript at all stages.

Corresponding authors

Correspondence to Claus Aagaard or Peter Andersen.

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Competing interests

C.A. and P.A. are co-inventors on a patent application to the Danish patent office covering the use of H56 as a vaccine. All rights have been assigned to Statens Serum Institut, a Danish not-for-profit governmental institute.

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Aagaard, C., Hoang, T., Dietrich, J. et al. A multistage tuberculosis vaccine that confers efficient protection before and after exposure. Nat Med 17, 189–194 (2011). https://doi.org/10.1038/nm.2285

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