Tuberculosis (TB) continues to ravage humanity, causing 2 million deaths per year. A vaccine against TB more potent than the current live vaccine, bacillus Calmette-Gué rin (BCG), is desperately needed. Using two commercially available strains of BCG as host strains, BCG Connaught and Tice, we have constructed two recombinant BCG vaccines stably expressing and secreting the 30-kDa major secretory protein of Mycobacterium tuberculosis (M. tb.), the primary causative agent of TB. We have tested the efficacy of the two strains in the highly susceptible guinea pig model of pulmonary TB, a model noteworthy for its close resemblance to human TB. Animals immunized with the recombinant BCG vaccines and challenged by aerosol with a highly virulent strain of M. tb. had 0.5 logs fewer M. tb. bacilli in their lungs and 1 log fewer bacilli in their spleens on average than animals immunized with their parental conventional BCG vaccine counterparts. Statistically, these differences were highly significant. Paralleling these results, at necropsy, animals immunized with the recombinant BCG vaccines had fewer and smaller lesions in the lung, spleen, and liver and significantly less lung pathology than animals immunized with the parental BCG vaccines. The recombinant vaccines are the first vaccines against TB more potent than the current commercially available BCG vaccines, which were developed nearly a century ago.

SummaryGlutamine synthetases (GS) are ubiquitous enzymes that play a central role in every cell's nitrogen metabolism. We have investigated the expression and activity of all four genomic Mycobacterium tuberculosis GS -GlnA1, GlnA2, GlnA3 and GlnA4 -and four enzymes regulating GS activity and/or nitrogen and glutamate metabolism -adenylyl transferase (GlnE), γ γ γ γ -glutamylcysteine synthase (GshA), UDP-N -acetylmuramoylalanine-D -glutamate ligase (MurD) and glutamate racemase (MurI). All eight genes are located in multigene operons except for gln A1, and all are transcribed in M. tuberculosis ; however, some are not translated or translated at such low levels that the enzymes escape detection. Of the four GS, only GlnA1 can be detected. Each of the eight genes, as well as the gln A1-gln E-gln A2 cluster, was expressed separately in Mycobacterium smegmatis , and its gene product was characterized and assayed for enzymatic activity by analysing the reaction products. In

Tuberculosis is the leading cause of death in AIDS patients

The current drug regimens for treating tuberculosis are lengthy and onerous, and hence complicated by poor adherence leading to drug resistance and disease relapse. Previously, using an output-driven optimization platform and an in vitro macrophage model of Mycobacterium tuberculosis infection, we identified several experimental drug regimens among billions of possible drug-dose combinations that outperform the current standard regimen. Here we use this platform to optimize the in vivo drug doses of two of these regimens in a mouse model of pulmonary tuberculosis. The experimental regimens kill M. tuberculosis much more rapidly than the standard regimen and reduce treatment time to relapse-free cure by 75%. Thus, these regimens have the potential to provide a markedly shorter course of treatment for tuberculosis in humans. As these regimens omit isoniazid, rifampicin, fluoroquinolones and injectable aminoglycosides, they would be suitable for treating many cases of multidrug and extensively drug-resistant tuberculosis.

To generate an inexpensive readily manufactured COVID-19 vaccine, we employed the LVS ΔcapB vector platform, previously used to generate potent candidate vaccines against Select Agent diseases tularemia, anthrax, plague, and melioidosis. Vaccines expressing SARS-CoV-2 structural proteins are constructed using the LVS ΔcapB vector, a highly attenuated replicating intracellular bacterium, and evaluated for efficacy in golden Syrian hamsters, which develop severe COVID-19-like disease. Hamsters immunized intradermally or intranasally with a vaccine co-expressing the Membrane and Nucleocapsid proteins and challenged 5 weeks later with a high dose of SARS-CoV-2 are protected against severe weight loss and lung pathology and show reduced viral loads in the oropharynx and lungs. Protection correlates with anti-Nucleocapsid antibody. This potent vaccine should be safe; inexpensive; easily manufactured, stored, and distributed; and given the high homology between Membrane and Nucleocapsid proteins of SARS-CoV and SARS-CoV-2, potentially serve as a universal vaccine against the SARS subset of pandemic causing β-coronaviruses.