A multistage tuberculosis vaccine that confers efficient protection before and after exposure

There is an essential need for vaccines that can prevent primary infection by Mycobacterium tuberculosis and control its reactivation in individuals with latent disease. Claus Aagaard et al. now report the development of a dual-function vaccine that shows protective efficacy in mice by both inhibiting infection upon initial pathogen exposure and by impairing reactivation of latent infection with M. tuberculosis. All tuberculosis vaccines currently in clinical trials are designed as prophylactic vaccines based on early expressed antigens. We have developed a multistage vaccination strategy in which the early antigens Ag85B and 6-kDa early secretory antigenic target (ESAT-6) are combined with the latency-associated protein Rv2660c (H56 vaccine). In CB6F1 mice we show that Rv2660c is stably expressed in late stages of infection despite an overall reduced transcription. The H56 vaccine promotes a T cell response against all protein components that is characterized by a high proportion of polyfunctional CD4+ T cells. In three different pre‐exposure mouse models, H56 confers protective immunity characterized by a more efficient containment of late-stage infection than the Ag85B-ESAT6 vaccine (H1) and BCG. In two mouse models of latent tuberculosis, we show that H56 vaccination after exposure is able to control reactivation and significantly lower the bacterial load compared to adjuvant control mice.