Despite widespread use, the only licensed tuberculosis (TB) vaccine available for human use, M. bovis Bacille Calmette-Guerin (BCG), has not been able to prevent TB from becoming a global health emergency. To achieve the 2030 targets of the WHO End TB Program, a new TB vaccine strategy is needed. For optimal effect, such a strategy will need to offer both improved efficacy following vaccination of TB-nave infants, as well as vaccine efficacy in the population of M. tuberculosis (Mtb)-exposed adolescents/adults in endemic regions. Advances in our understanding of TB immunology and vaccinology allow for a more tailored vaccine designed for this dual function. Based on specific antigen selection and adjuvanted administration, we have developed a novel single vaccine with dual use as a co-vaccine alongside BCG for nave individuals and as a standalone vaccine for previously exposed/infected individuals. This designed hybrid protein subunit vaccine (ESX1-Vax) is composed specifically of secreted ESX-1 related antigens that are missing from BCG, including ESAT-6 whose targeting is uniquely protective against re-growth of pre-existing infection. The hybrid protein is delivered with the CAF01 adjuvant that is highly effective in promoting T cell responses with defined TB-protective phenotype and function. Co-administration of ESX1-Vax/CAF01 with BCG does not hinder BCG effects. Instead, it acts synergistically to complement BCG vaccination by priming differentiation-resistant T cells targeting ESX-1 virulence factor antigens. As a non-replicative subunit vaccine, ESX1-Vax is also readily boostable. Furthermore, administration of ESX1-Vax/CAF01 in a post-exposure setting is highly efficacious against bacterial re-growth. In this proposal, we aim to optimize the immunogencity and efficacy of this ESX1-Vax through molecular modifications to maximize the T cell response against ESAT-6 epitopes. We will compare the modified constructs for efficacy and immunogenicity after BCG co-vaccination and in standard and newly-established post-exposure vaccination models to select the optimal ESX1-Vax construct. The selected construct will then be developed for production as a final GMP-produced ESX1/CAF01 product, verified for vaccine activity and assessed for toxicology. The overall outcome of this product development is, thus, a single boostable vaccine that is uniquely designed to work both together with BCG prophylactically in non-infected neonates, as well as when delivered post Mtb exposure in latently infected individuals, and that is ready for progress to clinical trials.

Public Health Relevance

We have developed a tuberculosis (TB) vaccine with dual function as a co-vaccine alongside BCG for nave individuals and as a standalone vaccine for previously exposed/infected individuals. Inspired by recent advances in TB immunology, we aim to further optimize and develop this vaccine using molecular modifications and testing in advanced animal models. Our final optimized product will be GMP produced and documented for progression towards clinical trials.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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Special Emphasis Panel (ZAI1)
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Eichelberg, Katrin
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Statens Serum Institute
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