In vitro recapitulation of intramuscular mRNA vaccination with naive and recall antigens using a human lymphoid follicle chip platform

Predicting the efficacy and toxicity of mRNA vaccines remains challenging. We describe an in vitro human model that replicates immune responses to lipid nanoparticle (LNP)-based mRNA vaccines upon intramuscular injection. Vaccines are administered to human skeletal myoblasts and antigen-presenting cells (APCs). Non-amplifying mRNA (NAM) vaccines directly induce antigen expression in APCs, whereas self-amplifying mRNA (SAM) vaccines require muscle cell-APC contact. The transfer of APCs and soluble factors to a microfluidic human lymphoid follicle chip (LF Chip), to mimic lymphatic drainage, induces LF expansion, de novo immunoglobulin G (IgG) production against a naive antigen, and cytokine release, with responses varying by LNP type. Similar vaccination of LF chips with Moderna vaccine against SARS-CoV-2 spike recall antigen generates neutralizing antibodies and induces somatic hypermutation (SHM). These studies offer an all-human alternative for evaluating vaccine-induced immunity, limiting the need for non-human primates and accelerating vaccine development.