THE RUTI VACCINE / The dynamic hypothesis
The dynamic hypothesis
Contrary to prior belief, evidence has now been found to show that in the latent infection caused by Mycobacterium tuberculosis the bacilli are not ‘dormant’ but waging an ongoing war against the host. Once the primary lesion has been caused (1), the multiplying bacilli are spread through the blood or, locally, through the bronchial tree (2). On multiplying, the bacillus destroys the alveolar macrophages (AM) and produces a necrotic extracellular medium, in which it ends up. This medium is extremely stressful for the bacillus, which stops growing and replicating.
This non-replicative state can revert when the bacillus is phagocytosed by a non-activated AM. If it is phagocytosed by an activated AM, the non-replicative state allows it to resist the bactericide mechanisms of the macrophage.

Following the immune response, in which all infected AM are activated, bacillary multiplication ends. In order to survive the bacillus must remain in its non-replicative state in the necrotic tissue of the lesion (granulome) or inside the AM which drain the remains of necrotic cells into the alveolar space. Carried along by the alveolar fluid, the non-replicative bacilli arrive in the upper bronchial space to be swallowed and destroyed in the stomach (3). However, this space is where the aerosols that condition the cold, dry air that we breathe in are generated, which means that the non-replicative bacilli can be inhaled back into the pulmonary alveoli where they infect new inactive AM and generate a new lesion (4).
In this process of continuous reinfection, the new infective source can develop in the upper pulmonary lobules where the inflammatory response is slow and disproportionate, leading to the destruction of tissues and the formation of the typical TB cavities (5).

Hipòtesi dinàmica

Treatment of latent TB is currently based on isoniazid, an antibiotic that kills the bacilli in the active multiplication phase. This avoids constant reinfection and ends up draining the non-replicative bacilli (3t-5t). Nevertheless, the draining process is slow which means that the treatment must go on for nine months. Any less than this is not efficient because in order to remove the risk of reinfection, all of the non-replicative bacilli must be drained from the necrotic tissue. Furthermore, by killing the replicative bacilli, any specific circulating T-lymphocytes, which identify incipient sources of reinfection, are eradicated.

A new combined therapy which does not prevent the specific immune response is under study: administration of a vaccine after a short course of antibiotics (isoniazid). The vaccine developed (RUTI ®) is manufactured from fragments of non-replicative bacilli and enables recognition of antigens of bacilli in replication or non-replicative bacilli, thereby controlling reinfection more efficiently. The course of treatment can be cut from nine months to only one. This new form of therapy is currently in clinical development. Its lack of toxicity in humans and immunogenic power have already been demonstrated (phase I) and at least five years are required to demonstrate the efficacy of the treatment (phases II and III).

Investigación y Ciencia