Mucosal Influenza Vector Vaccine Carrying TB10.4 and HspX Antigens Provides Protection against Mycobacterium tuberculosis in Mice and Guinea Pigs.

Mariia Sergeeva,Yana Zabrodskaya,Kirill Vasilyev,Artem Fadeev,Janna Buzitskaya,Andrey Vasin,Ekaterina Romanovskaya-Romanko,Anastasia Pulkina,Natalia Zabolotnyh,Marina A Stukova,Tatiana I Vinogradova,Anna Polina Shurigina

doi:10.3390/vaccines9040394

Abstract

New strategies providing protection against tuberculosis (TB) are still pending. The airborne nature of Mycobacterium tuberculosis (M.tb) infection assumes that the mucosal delivery of the TB vaccine could be a more promising strategy than the systemic route of immunization. We developed a mucosal TB vaccine candidate based on recombinant attenuated influenza vector (Flu/THSP) co-expressing truncated NS1 protein NS1(1–124) and a full-length TB10.4 and HspX proteins of M.tb within an NS1 protein open reading frame. The Flu/THSP vector was safe and stimulated a systemic TB-specific CD4+ and CD8+ T-cell immune response after intranasal immunization in mice. Double intranasal immunization with the Flu/THSP vector induced protection against two virulent M.tb strains equal to the effect of BCG subcutaneous injection in mice. In a guinea pig TB model, one intranasal immunization with Flu/THSP improved protection against M.tb when tested as a vaccine candidate for boosting BCG-primed immunity. Importantly, enhanced protection provided by a heterologous BCG-prime → Flu/THSP vector boost immunization scheme was associated with a significantly reduced lung and spleen bacterial burden (mean decrease of 0.77 lg CFU and 0.72 lg CFU, respectively) and improved lung pathology 8.5 weeks post-infection with virulent M.tb strain H37Rv.

Highlights

Tuberculosis (TB) is one of the most significant causes of morbidity and mortality among all infectious diseases
We explored the characteristics of attenuated influenza vectors expressing TB10.4 and HspX antigens to induce mucosal immunity after intranasal administration
The ORF’s of M. tuberculosis TB10.4 and HspX antigens were inserted in the NS1 ORF of A/PR/8/34 virus after the 124 amino acid codon; the insert was terminated by a three-stop codon cassette, the NEP ORF was left unchanged (Figure 1)

Summary

Introduction

Tuberculosis (TB) is one of the most significant causes of morbidity and mortality among all infectious diseases. The only currently used TB vaccine, Mycobacterium bovis Bacillus Calmette–Guerin (BCG), is effective in the protection of newborns and infants against serious forms of disseminated childhood TB (miliary disease and meningitis) but has highly variable efficacy against pulmonary TB in adolescents and adults—the most widespread and transmissible form of TB [4,5]. The limited success of the BCG vaccine in the control of adult tuberculosis has been attributed at least in part to the fact that immune protection by BCG wanes over age and may last for only 10 to 15 years [6]. The reasons why BCG fails to protect against pulmonary TB could be due to co-infections (e.g., helminths) preventing the development of a protective immune response in the lungs or the lack of an adequate immune response in the respiratory tract after parenteral immunization [7]

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Conclusion