Balance between Protection and Pathogenic Response to Aerosol Challenge with Mycobacterium tuberculosis (Mtb) in Mice Vaccinated with TriFu64, a Fusion Consisting of Three Mtb Antigens.

Sadaf Sulman,Obolbek Turapov,Benjamin O Savidge,Neda Nezam Abadi,Andrea May Cooper,Kawther Alqaseer,M Waheed Akhtar,John E Pearl,Mrinal K Das,Galina V Mukamolova

doi:10.3390/vaccines9050519

Abstract

Tuberculosis vaccines capable of reducing disease worldwide have proven difficult to develop. BCG is effective in limiting childhood disease, but adult TB is still a major public health issue. Development of new vaccines requires identification of antigens that are both spatially and temporally available throughout infection, and immune responses to which reduce bacterial burden without increasing pathologic outcomes. Subunit vaccines containing antigen require adjuvants to drive appropriate long-lived responses. We generated a triple-antigen fusion containing the virulence-associated EsxN (Rv1793), the PPE42 (Rv2608), and the latency associated Rv2628 to investigate the balance between bacterial reduction and weight loss in an animal model of aerosol infection. We found that in both a low pattern recognition receptor (PRR) engaging adjuvant and a high PRR-engaging adjuvant (MPL/TDM/DDA) the triple-antigen fusion could reduce the bacterial burden, but also induced weight loss in the mice upon aerosol infection. The weight loss was associated with an imbalance between TNFα and IL-17 transcription in the lung upon challenge. These data indicate the need to assess both protective and pathogenic responses when investigating subunit vaccine activity.

Highlights

Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), remains a leading cause of death from a single infectious agent and is estimated to kill approximately 1.2 million people every year [1]
To investigate the ability of artificially combined triple-antigen fusion to influence the immune response to Mtb challenge, it was necessary to produce the proteins in amounts sufficient to deliver to mice and to ensure that the preparations did not result in nonspecific activation of the immune response
We found that delivery of TriFu64 in mono-phosphoryl lipid A (MPL)/trehalose dicoryno-mycolate (TDM)/dioctadecylammonium bromide (DDA) resulted in2∆∆Ct value for TNFα and IL-17 determined (iii); the ratio of TNFα to IL-17 signal was determined within each sample (iv)

Summary

Introduction

Tuberculosis (TB), caused by the intracellular pathogen Mycobacterium tuberculosis (Mtb), remains a leading cause of death from a single infectious agent and is estimated to kill approximately 1.2 million people every year [1]. Vaccination is a key tool in the cost-effective control of infectious disease; development of a TB vaccine has proven difficult, some progress is being made recently [3]. In TB, vaccines can be designed to stop infection, to prevent development of disease or to reduce the consequences of disease [4]. In the case of vaccines capable of stopping infection, antigen choice is straightforward but, due to the nature of Mtb infection [5], it is likely that vaccines that prevent disease rather than infection will be more achievable and, in this situation, antigen choice is critical. A key factor, that will define the efficacy of any one antigen is the temporal and spatial availability of the antigen throughout infection

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Conclusion