Mycobacterium bovis BCG is widely used as a vaccine against tuberculosis (TB), 
despite its variable protective efficacy. Relatively little is known about the 
immune response profiles following BCG vaccination in relation to protection 
against TB. Here we tested whether BCG vaccination results in immune responses 
to DosR (Rv3133c) regulon-encoded proteins. These so-called TB latency antigens 
are targeted by the immune system during persistent Mycobacterium tuberculosis 
infection and have been associated with immunity against latent M. tuberculosis 
infection. In silico analysis of the DosR regulon in BCG and M. tuberculosis 
showed at least 97% amino acid sequence homology, with 41 out of 48 genes being 
identical. Transcriptional profiling of 14 different BCG strains, under hypoxia 
and nitric oxide exposure in vitro, revealed a functional DosR regulon similar 
to that observed in M. tuberculosis. Next, we assessed human immune responses to 
a series of immunodominant TB latency antigens and found that BCG vaccination 
fails to induce significant responses to latency antigens. Similar results were 
obtained with BCG-vaccinated BALB/c mice. In contrast, responses to latency 
antigens were observed in individuals with suspected exposure to TB (as 
indicated by positive gamma interferon responses to TB-specific antigens ESAT-6 
and CFP-10) and in mice vaccinated with plasmid DNA encoding selected latency 
antigens. Since immune responses to TB latency antigens have been associated 
with control of latent M. tuberculosis infection, our findings support the 
development of vaccination strategies incorporating DosR regulon antigens to 
complement and improve the current BCG vaccine.