Evaluating mRNA-lipid nanoparticle platforms and adjuvants to overcome maternal antibody interference

Project Summary/Abstract This proposal presents a five-year research and career development training program focused on the potential of mRNA-lipid nanoparticles (mRNA-LNP) and lipid nanoparticle (LNP) adjuvants to overcome maternal antibody interference. The candidate is currently an Attending Physician and Postdoctoral Research Fellow in Adult and Pediatric Infectious Diseases at the University of Pennsylvania (Penn) and Children’s Hospital of Philadelphia (CHOP). The current proposal builds on the candidate’s previous research and clinical experience in innate and humoral immunology and adjuvant research with aims and training activities that emphasize the analysis of humoral and cellular immune responses to mRNA-LNP platforms and LNP adjuvants in the setting of maternal antibodies. The proposed aims and training plan will prepare the candidate with an array of skills that will accelerate and strengthen his transition to independence as a physician-scientist studying maternal-fetal factors impacting infant vaccine responses. Despite over a century of advances in vaccine technology, we still lack vaccines that effectively induce protective antibody (Ab) responses in young infants. This leaves a vulnerable group reliant on maternal antibodies (matAbs). MatAbs provide infants with early-life protection against pathogens. However, matAbs also interfere with Ab responses to vaccines. MatAb interference (MAI) has been a major barrier to early immunization against influenza (flu), measles, and others. The foundation of this proposal is our preliminary data showing that mRNA- lipid nanoparticle (mRNA-LNP) vaccines and protein-subunit vaccines administered with empty lipid nanoparticles (eLNP) overcome MAI in mice. However, the mechanism(s) that allow mRNA-LNP and eLNP- containing vaccines to overcome MAI, and the degree to which they could do so for other vaccine types, are not understood. The specific objective of this proposal is to use mouse models of MAI to determine the mechanism by which mRNA-LNP and eLNP-containing vaccines overcome MAI and to determine whether those properties could be more broadly applied to other vaccine types. My central hypothesis is that LNPs overcome MAI through interferon-alpha-dependent adjuvant activity. This hypothesis will be investigated in two aims. 1: Determine if mRNA-LNP and eLNP-adjuvanted flu vaccines alter intracellular B cell signaling pathways associated with MAI, 2: Determine if mRNA-LNP and eLNP-adjuvanted live attenuated vaccines can overcome MAI in a mouse model of measles vaccination. Successful completion of these aims will determine if adjuvant properties of LNP are important for overcoming MAI with the vision that the knowledge gained can inform new approaches to vaccine and adjuvant development that may impact rational vaccine design for newborns and young infants.