NANOBAC · Antibody-guided design of multivalent nanoparticle vaccines against bacterial pathogens

Vaccines are the most effective single measure to protect populations against infectious diseases without promoting antimicrobial resistance (AMR). In this proposal, I intend to harness the rapid developments in protein design and quantitative and structural mass spectrometry to i) enable detailed molecular characterization of circulating serum antibody repertories, ii) establish a generalizable framework for antibody-guided design of next-generation nanoparticle vaccines against bacteria and iii) use the developed nanoparticle vaccines to investigate structural properties of protective antibody responses required for immunity. The planned work relies on identifying and producing protective antigen-specific monoclonal antibodies from immune individuals. These antibodies are used to structurally characterize conserved epitopes in their correct three-dimensional conformation. The structural information is then harnessed to design multivalent nanoparticle vaccine candidates. The planned work is focused on i) determining the optimal combination of epitopes that generates the highest level of protection using Streptococcus pyogenes as a model system, ii) determine the molecular properties of the circulating serum antibody response that mediates the protection and iii) modify the epitope design to target conserved structural motifs typically found within protein families to produce immunogens that confer cross-pathogen protection.The work will be novel as it will for the first time, demonstrate the design of a protective vaccine candidate against a protein family associated with distinct bacterial pathogens and infections. The concept will be extendable to other protein families and bacterial pathogens to aid in the combat against AMR.