Defining the Immunogenicity and Efficacy of a Durable BCG Vaccine Strategy Optimized for Preventing TB in Pediatric HIV Infection

PROJECT SUMMARY Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb) remains a major cause of morbidity and mortality worldwide and HIV+ individuals are particularly susceptible. The only licensed TB vaccine is the live attenuated Bacillus Calmette-Guerin (BCG) that is given intradermally to infants. While BCG provides substantial protection against non-pulmonary TB in childhood, it has little impact on pulmonary TB rates in adults. Recent studies in macaques have elicited striking protection from TB by instead delivering BCG intravenously or mucosally. However, BCG can cause disease in immunosuppressed recipients, including HIV+ children. Recently, a more attenuated BCG strain, BCG𝚫1419c, has been shown to be safe in athymic mice, immunogenic in both mice and guinea pigs, and more efficacious than BCG in both murine and guinea pigs models of TB. In this proposal, we will use our pediatric Mauritian cynomolgus macaque (MCM) model of TB to test both BCG and BCG𝚫1419c when given by the more clinically translatable mucosal route. Using MCM 1-2 years of age more closely resembles the pediatric population currently targeted for BCG vaccination. We will characterize the immunogenicity of BCG and BCG𝚫1419c in these young MCM using a suite of powerful assays, including multiparameter flow cytometry, single cell RNAseq, serology, and epigenetic analysis. We will determine the protective efficacy of these vaccines by challenging the animals with virulent Mtb and then assessing protection using our well-established and quantitative PET/CT imaging, pathology, and Mtb burden measures. In Aim 2, we will use a similar approach to define the safety, immunogenicity and protective efficacy of both BCG and BCG𝚫1419c in SIV+ juvenile MCM, modeling HIV+ children who could most benefit from an improved TB vaccine. We will test our hypothesis that this more attenuated BCG𝚫1419c will be safe, immunogenic, and protect from Mtb when administered mucosally to juvenile MCM with and without pre-existing SIV infection. This multi-PI proposal assembles a team of three established scientists with complimentary expertise in the fields of TB, HIV and SIV, immunology, and pediatric infectious diseases. Furthermore, we already have an established productive and collaborative relationship, ensuring successful completion of this important project.