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Vaccines 2018, 6(2), 30; https://doi.org/10.3390/vaccines6020030

Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment

1
Infectious Disease Research Institute, Seattle, WA 98102, USA
2
Department of Global Health, University of Washington, Seattle, WA 98195, USA
3
Department of Microbiology, Immunology and Pathology, Colorado State University, Fort Collins, CO 80523, USA
4
PAI Life Sciences Inc., Seattle, WA 98102, USA
*
Author to whom correspondence should be addressed.
Received: 30 April 2018 / Revised: 18 May 2018 / Accepted: 22 May 2018 / Published: 24 May 2018
(This article belongs to the Collection Vaccines Against Chronic and Persistent Bacterial Infections)
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Abstract

It is estimated that one third of the world’s population is infected with Mycobacterium tuberculosis (Mtb). This astounding statistic, in combination with costly and lengthy treatment regimens make the development of therapeutic vaccines paramount for controlling the global burden of tuberculosis. Unlike prophylactic vaccination, therapeutic immunization relies on the natural pulmonary infection with Mtb as the mucosal prime that directs boost responses back to the lung. The purpose of this work was to determine the protection and safety profile over time following therapeutic administration of our lead Mtb vaccine candidate, ID93 with a synthetic TLR4 agonist (glucopyranosyl lipid adjuvant in a stable emulsion (GLA-SE)), in combination with rifampicin, isoniazid, and pyrazinamide (RHZ) drug treatment. We assessed the host inflammatory immune responses and lung pathology 7–22 weeks post infection, and determined the therapeutic efficacy of combined treatment by enumeration of the bacterial load and survival in the SWR/J mouse model. We show that drug treatment alone, or with immunotherapy, tempered the inflammatory responses measured in brochoalveolar lavage fluid and plasma compared to untreated cohorts. RHZ combined with therapeutic immunizations significantly enhanced TH1-type cytokine responses in the lung over time, corresponding to decreased pulmonary pathology evidenced by a significant decrease in the percentage of lung lesions and destructive lung inflammation. These data suggest that bacterial burden assessment alone may miss important correlates of lung architecture that directly contribute to therapeutic vaccine efficacy in the preclinical mouse model. We also confirmed our previous finding that in combination with antibiotics therapeutic immunizations provide an additive survival advantage. Moreover, therapeutic immunizations with ID93/GLA-SE induced differential T cell immune responses over the course of infection that correlated with periods of enhanced bacterial control over that of drug treatment alone. Here we advance the immunotherapy model and investigate reliable correlates of protection and Mtb control. View Full-Text
Keywords: therapeutic vaccine; Mycobacterium tuberculosis; tuberculosis; immunotherapy; adjuvant; GLA-SE; ID93 therapeutic vaccine; Mycobacterium tuberculosis; tuberculosis; immunotherapy; adjuvant; GLA-SE; ID93
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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Larsen, S.E.; Baldwin, S.L.; Orr, M.T.; Reese, V.A.; Pecor, T.; Granger, B.; Dubois Cauwelaert, N.; Podell, B.K.; Coler, R.N. Enhanced Anti-Mycobacterium tuberculosis Immunity over Time with Combined Drug and Immunotherapy Treatment. Vaccines 2018, 6, 30.

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