Tuberculosis

An infectious disease at global scale

In this world today about every 20 seconds a person dies as the result of infection with Mycobacterium tuberculosis, despite the use of BCG (Bacille Calmette-Guérin) as a vaccine for many decades now. Although efficacious against childhood forms of the disease, BCG is insufficiently protective against pulmonary tuberculosis at later stages. By estimation one-third of the world's population is latently infected. Thus, mycobacteria 'hijack' a large proportion of the human population, not causing overt disease but posing a threat of tuberculosis outbreaks constantly.

BPRC - A granuloma, in the lung of an TB infected monkey
Histology reveals pathology, cq. a granuloma, in the lung of an
infected monkey that is indistinguishable from human TB.

New therapies urgently required

A better vaccine or an improved regimen with better prophylactic and/or, ideally, therapeutic or sterilising efficacy, is urgently required to fight the TB pandemic. Antibiotics are available but require months of regime compliance because of their ineffective action rates. Multi- and extreme drug resistant strains show an increasing prevalence and, also, better antibiotic therapies are urgently required. However, the field is facing some knowledge gaps with regard to both (naturally acquired and vaccine induced) protective host mechanisms as well as mycobacterial pathogenesis and immune evasion strategies. This lack of insight heavily compromises a swift development of improved therapies.

TB and primate models in perspective

Like other monkeys, macaques show marked similarities to man. Not only by genetics and immunity, but also their suscpetibility to M.tuberculosis infection and the manifestation of clinical symptoms and pathology is reminiscent of human TB. These non-human primates - more than any other available animal model - can be expected to have a high predictive validity towards human disease and therapy. The same seems true for BCG vaccination, which can protect rhesus and cynomolgus macaques from severe TB disease, but fails to prohibit infection. It is noted that macaque populations can differ with regard to their protective response to BCG treatment. There is room for improvement, which provides a perspective for pre-clinical evaluation of new therapies better than BCG in these non-human primate (NHP) models.

Towards improved treatment and better insight

Thus, macaque models can provide a relevant role in the development of improved prophylactic or therapeutic vaccines against TB. They can contribute to rational downselection of the number of candidates to progress towards advanced clinical efficacy testing, which is costly and time-consuming. But perhaps more importantly, these primates can provide controled conditions to study and unravel complex interactions between pathogen and host, which may increase our knowledge base for rationalised design and accellerated development of better TB therapies.