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

Sasha Larsen,Susan Baldwin,Natasha Dubois Cauwelaert,Mark Orr,Rhea Coler,Valerie Reese,Tiffany Pecor,Brian Granger,Brendan Podell

doi:10.3390/vaccines6020030

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.

Highlights

Tuberculosis (TB), caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb), was the leading cause of death from a single pathogen for the third year in a row, killing 1.3 millionVaccines 2018, 6, 30; doi:10.3390/vaccines6020030 www.mdpi.com/journal/vaccinesHIV-negative people in 2016 [1]
We noted significantly improved lung pathology in groups that received ID93/glucopyranosyl lipid adjuvant (GLA)-stable nano-emulsion (SE) in the context of drug treatment, which may be directly responsible for the enhanced survival seen in this highly-susceptible
We have demonstrated that therapeutic immunizations with anti-Mtb vaccine candidate

Summary

Introduction

Tuberculosis (TB), caused by the intracellular bacterium Mycobacterium tuberculosis (Mtb), was the leading cause of death from a single pathogen for the third year in a row, killing 1.3 millionVaccines 2018, 6, 30; doi:10.3390/vaccines6020030 www.mdpi.com/journal/vaccinesHIV-negative people in 2016 [1]. Up to 16% of people infected with TB die from the disease each year and the WHO reported 6.3 million new TB cases in 2016, up from 6.1 million in 2015. While BCG provides limited protection through adolescence from disseminated disease, it fails to protect individuals from adult pulmonary disease, which is the most transmissible form of the disease [2]. This puts the burden of disease control on complex 6+ month multidrug treatment regimens [3]. Extensive schedules of poorly-tolerated drugs can limit patient compliance and promote the development of drug resistance, requiring even longer drug treatment regimens, and perpetuate infectious distribution. Novel treatments and preventative vaccines effective against drug-sensitive (DS) and drug-resistant (DR) strains would significantly impact the global burden of this disease

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