Background Tuberculosis remains one of the world's deadliest transmissible diseases despite the widespread use of BCG. MTBVAC is a new live tuberculosis vaccine based on a genetically attenuated phoP-/fadD26-deletion mutant of M. tuberculosis that expresses most antigens present in human isolates in contrast to BCG. Methods We conducted this randomized, double-blind, controlled phase I study at CHUV, Lausanne, Switzerland, to compare MTBVAC to BCG in healthy, PPD-negative adults. Primary outcome was safety in all vaccinated participants. Secondary outcome included whole blood cell mediated immune response to live MTBVAC and BCG as well as interferon-gamma release assay (IGRA) on peripheral blood mononuclear cells. Volunteers fulfilling the inclusion criteria were randomly allocated (on a 3:1 basis) in a dose-escalation manner to three cohorts. Each cohort included 9 subjects who were injected with MTBVAC 5x10 3 , 5x10 4 , or 5x10 5 colony forming units (CFU) in 0.1 mL and 3 subjects with BCG (single dose of 5x10 5 CFU in 0.1 mL). Each subject received a single intradermal injection in the non-dominant arm starting with the lowest MTBVAC dose. Findings Thirty-six volunteers were recruited. Vaccination with MTBVAC (5x10 3 , 5x10 4 , 5x10 5 CFU/0.1mL) was as safe as with BCG, and did not induce serious adverse events. All individuals were IGRA negative at the end of follow-up (D210). After whole blood stimulation with live MTBVAC or BCG, MTBVAC was immunogenic in a dosedependent manner. At the same dose level as BCG (5x10 5 CFU), although no

Swiss State Secretariat for Education, Research and Innovation (SERI), through the EU Horizon 2020 Research and Innovation Programme.

This trial was registered in clinicaltrials.gov (NCT01949909) and www.pactr.org (PACTR201310000683408).

Tau is a microtubule stabilizing protein that forms aggregates in Alzheimer’s disease (AD). Tau derived from AD patients’ brains induces tau aggregation in a prion-like manner when injected into susceptible mouse models. Here we investigated whether cerebrospinal fluid (CSF) collected from patients diagnosed with probable AD or mild cognitive impairment (MCI) likely due to AD harbors a prion-like tau seeding potential. CSF was injected intrahippocampally into young P301S tau transgenic mice. CSF obtained from AD or MCI patients increased hippocampal tau hyperphosphorylation and tau tangle formation in these mice at 4 months post-seeding. Tau pathology was also accentuated in the contralateral hippocampus, and in anterior and posterior directions, indicative of spreading. We provide first evidence for in vivo prion-like properties of AD patients’ CSF, accelerating tau pathology in susceptible tau transgenic mice. This demonstrates that biologically active tau seeds reach the CSF compartment in AD. Further studies may help to evaluate strain specific properties of CSF derived tau bioseeds, and to assess their diagnostic potential. Electronic supplementary material The online version of this article (10.1186/s40478-019-0725-3) contains supplementary material, which is available to authorized users.