Reactogenicity to major tuberculosis antigens absent in BCG is linked to improved protection against Mycobacterium tuberculosis

Nacho Aguilo,Regine Audran,Ana Belen Gomez,Jesus Gonzalo-Asensio,Ralf Spallek,François Spertini,Samuel Alvarez-Arguedas,Mahavir Singh,Santiago Uranga,Carlos Martin,Dessislava Marinova

doi:10.1038/ncomms16085

Abstract

MTBVAC is a live-attenuated Mycobacterium tuberculosis vaccine, currently under clinical development, that contains the major antigens ESAT6 and CFP10. These antigens are absent from the current tuberculosis vaccine, BCG. Here we compare the protection induced by BCG and MTBVAC in several mouse strains that naturally express different MHC haplotypes differentially recognizing ESAT6 and CFP10. MTBVAC induces improved protection in C3H mice, the only of the three tested strains reactive to both ESAT6 and CFP10. Deletion of both antigens in MTBVAC reduces its efficacy to BCG levels, supporting a link between greater efficacy and CFP10- and ESAT6-specific reactogenicity. In addition, MTBVAC (but not BCG) triggers a specific response in human vaccinees against ESAT6 and CFP10. Our results warrant further exploration of this response as potential biomarker of protection in MTBVAC clinical trials.

Highlights

MTBVAC is a live-attenuated Mycobacterium tuberculosis vaccine, currently under clinical development, that contains the major antigens ESAT6 and CFP10
We subcutaneously immunized with MTBVAC C57BL/6, BALB/c or C3H/HeNRj mouse strains, each expressing a different haplotype of the major histocompatibility complex (MHC); H-2b, H-2d and H-2k, respectively
We found that Bacille Calmette–Guerin (BCG) did not induce any response to ESAT6 or CFP10 stimulation irrespective of the MHC alleles

Summary

Introduction

MTBVAC is a live-attenuated Mycobacterium tuberculosis vaccine, currently under clinical development, that contains the major antigens ESAT6 and CFP10. These antigens are absent from the current tuberculosis vaccine, BCG. Even though MTBVAC has demonstrated improved protection compared to BCG in adult and newborn animal models[9,14,16], the mechanisms underlying its protective efficacy have not been characterized Elucidating these mechanisms remain crucial for the identification of vaccine-specific biomarkers, which would accelerate the clinical development of MTBVAC and would help anticipate results from other TB vaccine candidates in the preclinical and clinical pipeline

Methods

Results

Conclusion