Multicomponent vaccines for Staphylococcus aureus

Boston Children'S Hospital, Boston MA

Investigators

Abstract

The goal of Research Project 1 in the “Immunization against Multidrug-resistant Pathogens: Activating T Cell Immunity” Center of Excellence for Translational Research (IMPACT-CETR) is to develop a multicomponent Staphylococcus aureus vaccine formulated with conserved antigens using the new and innovative Multiple Antigen Presenting System (MAPS) platform. Staphylococcus aureus is a major cause of community-acquired and healthcare-associated infections, including skin and soft tissue infections, surgical site and wound infections, pneumonia, bacteremia, and endocarditis. In particular, the emergence of methicillin-resistant S. aureus (MRSA) is associated with significantly increased mortality and morbidity. Previous vaccine development efforts against S. aureus have been focused exclusively on the generation of antibodies to the pathogen; all attempts in clinical trials have failed. Recent evidence strongly suggests that T-cell-mediated immunity, rather than antibodies, is required for host defense against S. aureus. This team at BCH developed MAPS, a novel vaccine platform to generate highly immunogenic protein and polysaccharide complexes via strong affinity coupling of biotin and the avidin-like protein rhizavidin. MAPS promotes the generation of antibodies and multipronged systemic and tissue-resident T-cell responses to the target protein antigens. A candidate S. aureus MAPS (SA MAPS) vaccine targets four conserved staphylococcal proteins and confers broad and enhanced protection in mouse models of S. aureus infection or colonization, including in models where antibody-based vaccines fail to protect. Published studies showed that SA MAPS-induced cellular immunity, more specifically, the tissue-resident memory T cells (TRMs), play a primary role in mediating immune defense against S. aureus in the skin and on mucosal surfaces. The objective of this project is to advance this candidate vaccine by characterizing the cellular and molecular mechanisms of protection, identifying surrogate markers that correlate with protection, and evaluating immunological responses in NHPs. Aim 1 is to elucidate SA MAPS vaccine-induced adaptive cellular defense network in skin tissues. Single-cell spatial profiling analysis and evaluation in genetically modified mouse stains will be used to define the spatial organization, molecular signatures, and intercellular interaction and signaling of SA MAPS-induced TRMs in skin tissues after S. aureus infection and to identify specific T-cell populations or signaling pathways that are responsible for protection. Aim 2 will evaluate potential surrogate markers that correlate with protection following SA MAPS immunization. Aim 3 will evaluate the immunogenicity of the SA MAPS vaccine in NHPs, refine the surrogate markers identified in Aim 2, characterize the vaccine-induced cellular defense network in skin, and compare the findings from NHPs and mice. Successful completion of this project will result in the characterization of cell-mediated adaptive host defense mechanisms and comprehensive preclinical data in mice and NHPs to support the advancement of this vaccine to future Phase 1 clinical studies.