Evaluating a multi-valent aerosol booster tb vaccine for adolescents and young adults in diverse african settings: T5 tbvac

In this proposal we will move beyond state-of-the-art in 3 ways. First, we will diversify the TB vaccine pipeline by developing the first multivalent recombinant viral vector TB vaccine candidate, ChAdOx1 T5, as a subunit booster vaccine for adolescents and young adults. We will compare immunogenicity between contrasting UK, West and East African settings. Second, ChAdOx1 T5 will be the first candidate TB vaccine delivered by aerosol in sub-Saharan Africa with bronchoscopic monitoring of lung immunity. Third, we will transfer an established and validated controlled human infection model (CHIM) to Uganda to compare ChAdOx1 T5 protective efficacy between rural and urban Uganda and the UK.ChAdOx1 T5 expresses 5 mycobacterial antigens, each protective when delivered alone. Boosting prior BCG with ChAdOx1 T5 confers significant protection in mice and non-human primates. We will manufacture GMP ChAdOx1 T5 and conduct a UK first-in-human phase 1 clinical trial, followed by phase 2a trials in Senegal and Uganda, to determine the safety and immunogenicity of ChAdOx1 T5 when delivered either by aerosol or intramuscularly. We will use the skin BCG CHIM to evaluate the efficacy of ChAdOx1 T5 after either aerosol or intramuscular delivery in Uganda and the UK. Using a CHIM will significantly de-risk future, late-stage development of this and other candidate TB vaccines. A comprehensive analysis of immunological samples taken prior to BCG challenge will allow identification of immune correlates of protection which will support development of this and other candidate vaccines. Community engagement and involvement will guide our research processes and build population preparedness for new TB vaccine implementation. Capacity strengthening will be embedded in all that we do.This proposal will develop the next generation TB subunit aerosol booster vaccine, de-risk its late-stage development and establish a strong South-South-North collaborative partnership for future TB vaccine R&D.