Modular Evaluation of Multi-Platform Human In vitro Systems (MEMPHIS): A Methodological Advancement in Vaccinology 2260451

Abstract Introduction Vaccination is an effective strategy to reduce the burden of infectious diseases. Pre-clinical vaccine development has traditionally relied on animal models, limiting access to human-specific data necessary for rapid clinical translation. With the FDA’s Modernization Act endorsing human in vitro approaches for pre-clinical evaluation of novel vaccine candidates, we developed MEMPHIS — a suite of complementary human immune profiling modules designed to characterize age- and population-specific innate and adaptive immune responses to vaccine adjuvants and formulations. Methods Consisting of six complementary in vitro modules, MEMPHIS is designed to assess the ability of adjuvant formulations to influence innate immune activation, cell migration and fate, as well as antigen-specific B- and T-cell activation. MEMPHIS includes the assessment of type and magnitude of cellular immune memory to pathogens of interest, such that pre-exposure history can be factored into the assessment of new candidate vaccine formulations. Together, these modules enable comprehensive assessment of how adjuvants influence innate immune activation and adaptive immune programming. All MEMPHIS assays have been optimized to use minimal input — requiring only 100 mL of blood from adults or 20 mL from children — allowing integrated testing from a single donor sample. Results In this study, we demonstrate that MEMPHIS accurately modeled the type and magnitude of response to adjuvanted protein-based vaccine, mRNA vaccine, and small-molecule adjuvants, and defined molecular differences in mode of action between these stimuli. In addition, we report on the technical and biological variance of data generated with our modules, and present novel strategies for cross-platform data integration. Conclusion In summary, this system provides a powerful translational platform to inform adjuvant selection and vaccine design by defining potency, reactogenicity, and the breadth, diversity, and durability of immune responses across populations. Funding Source Department Innovation Award Topic Categories Technological Innovations in Immunology (TECH)