Subunit vaccine protects against a clinical isolate of Mycobacterium avium in wild type and immunocompromised mouse models

Abstract

The nontuberculous mycobacteria (NTM) Mycobacterium avium is a clinically significant pathogen that can cause a wide range of maladies, including tuberculosis-like pulmonary disease. An immunocompromised host status, either genetically or acutely acquired, presents a large risk for progressive NTM infections. Due to this quietly emerging health threat, we evaluated the ability of a recombinant fusion protein ID91 combined with GLA-SE [glucopyranosyl lipid adjuvant, a toll like receptor 4 agonist formulated in an oil-in-water stable nano-emulsion] to confer protection in both C57BL/6 (wild type) and Beige (immunocompromised) mouse models. We optimized an aerosol challenge model using a clinical NTM isolate: M. avium 2-151 smt, observed bacterial growth kinetics, colony morphology, drug sensitivity and histopathology, characterized the influx of pulmonary immune cells, and confirmed the immunogenicity of ID91 in both mouse models. To determine prophylactic vaccine efficacy against this M. avium isolate, mice were immunized with either ID91 + GLA-SE or bacillus Calmette–Guérin (BCG). Immunocompromised Beige mice displayed a delayed influx of innate and adaptive immune cells resulting in a sustained and increased bacterial burden in the lungs and spleen compared to C57BL/6 mice. Importantly, both ID91 + GLA-SE and BCG vaccines significantly reduced pulmonary bacterial burden in both mouse strains. This work is a proof-of-concept study of subunit vaccine-induced protection against NTM.

Vaccination inducing durable and robust antigen-specific Th1/Th17 immune responses contributes to prophylactic protection against Mycobacterium avium infection but is ineffective as an adjunct to antibiotic treatment in chronic disease

“…However, it should be noted that the degree of lung inflammation is not plainly associated with the efficacy of immunization. Our observations are consistent with previous reports [ 25 , 34 , 75 ] in which lung pathology scores did not correlate with the bacterial loads in the context of Mav infection, suggesting that protective immune responses minimally require some immune cell components and antigen-specific but vigorous immune responses.…”

“…Although the protective immune correlates of the host against MAC infection have not been fully elucidated to date, two studies recently documented that ID91 and Ag85B antigen-specific multiple cytokine-expressing CD4 + T cells [ 25 ] or the reciprocal induction of both antigen-specific Th1 and Th17 cells are important for the control of Mav infection [ 39 ].…”

RNA-based vaccine demonstrates prophylactic efficacy against Mycobacterium tuberculosis challenge in a mouse model

“…Statistical analyses were performed using GraphPad Prism 7 software. Significant differences are labeled accordingly in the figures where * p < 0.05, ** p < 0.01, *** p < 0.001 and **** p < 0.0001, with methodology used previously by our group 68,70 .…”

Protective Efficacy of BCG Vaccine against Mycobacterium leprae and Non-Tuberculous Mycobacterial Infections

“…In an experiment involving immunocompromised beige mice that were deficient in B and T lymphocytes, natural killer cells, and had reduced bactericidal activity, administration of the BCG vaccine showed reduced pulmonary bacterial burden in the lungs and spleen of these mice compared to C57BL/6 mice when both were challenged with M. avium. As a result, this study demonstrated that prophylactic immunization with the BCG vaccine tended to lower immunopathology within beige mice infected with M. avium [ 78 ]. Furthermore, the use of DNA plasmids and recombinant forms of the BCG vaccine encoding single mycobacterial genes has been shown to provide great protective effects against M. avium infection.…”