High dose aerosol challenge with Mycobacterium tuberculosis fails to overcome BCG vaccination-induced protection in cynomolgus macaques of Chinese origin: implications of natural resistance for TB vaccine evaluation.

Abstract

This study describes the use of cynomolgus macaques of Chinese origin (CCM) to evaluate the efficacy and immunogenicity of the BCG vaccine against high dose aerosol Mycobacterium tuberculosis challenge. Progressive disease developed in three of the unvaccinated animals within ten weeks of challenge, whereas all six vaccinated animals controlled disease for 26 weeks. Three unvaccinated animals limited disease progression, highlighting the intrinsic ability of this macaque species to control disease in comparison to macaques of other species and genotypes. Low levels of IFNγ were induced by BCG vaccination in CCM suggesting that IFNγ alone does not provide a sufficiently sensitive biomarker of vaccination in this model. An early response after challenge, together with the natural bias towards terminal effector memory T-cell populations and the contribution of monocytes appears to enhance the ability of CCM to naturally control infection. The high dose aerosol challenge model of CCM has value for examination of the host immune system to characterise control of infection which would influence future vaccine design. Although it may not be the preferred platform for the assessment of prophylactic vaccine candidates, the model could be well suited for testing post-exposure vaccination strategies and drug evaluation studies.

TB and SIV Coinfection; a Model for Evaluating Vaccine Strategies against TB Reactivation in Asian Origin Cynomolgus Macaques: A Pilot Study Using BCG Vaccination

“…An increase in PPD-specific IFNγ-secreting cells was observed in the animals in group 1 after BCG vaccination, although the response was lower and more short-lived than those observed after BCG vaccination in studies conducted with rhesus macaques [ 23 , 25 , 31 ]. However, the response profiles were similar to those we observed in cynomolgus macaques of Chinese origin, which were able to control a high-dose aerosol challenge of M. tb [ 32 ] and may point to other mechanisms of immune protection afforded by BCG in these cynomolgus macaque populations. Following M. tb infection, an increase in CFP10- and ESAT6-specific IFNγ-producing cells was measured in all animals.…”

“…The frequency of responses to these diagnostic antigens is considered to be a biomarker reflective of disease progression, TB disease burden [ 33 ] and antigen load, with high frequencies associated with a poorer postchallenge outcome [ 24 , 25 ]. In the initial period following M. tb challenge and before infection with SIV, ESAT6 and CFP10 responses were lowest in the BCG-vaccinated animals, suggesting that TB disease was more controlled, in line with observations from efficacy assessments of BCG vaccination performed in rhesus [ 24 , 25 ] and cynomolgus macaques of Chinese origin [ 32 ]. The increase in frequency of M. tb-specific IFNγ-secreting cells measured following SIV infection is in line with Diedrich et al, who reported an increase after coinfection with SIV after a latent TB infection [ 11 ], thought to be related to reactivation of TB, reflecting a breakdown in control of TB infection.…”