Blood Distribution\nof SARS-CoV‑2 Lipid Nanoparticle\nmRNA Vaccine in Humans

Lipid nanoparticle mRNA vaccines are an exciting but\nemerging technology\nused in humans. There is limited understanding of the factors that\ninfluence their biodistribution and immunogenicity. Antibodies to\npoly(ethylene glycol) (PEG), which is on the surface of the lipid\nnanoparticle, are detectable in humans and boosted by human mRNA vaccination.\nWe hypothesized that PEG-specific antibodies could increase the clearance\nof mRNA vaccines. To test this, we developed methods to quantify both\nthe vaccine mRNA and ionizable lipid in frequent serial blood samples\nfrom 19 subjects receiving Moderna SPIKEVAX mRNA booster immunization.\nBoth the vaccine mRNA and ionizable lipid peaked in blood 1–2\ndays post vaccination (median peak level 0.19 and 3.22 ng mL<sup>–1</sup>, respectively). The vaccine mRNA was detectable and quantifiable\nup to 14–15 days postvaccination in 37% of subjects. We measured\nthe proportion of vaccine mRNA that was relatively intact in blood\nover time and found that the decay kinetics of the intact mRNA and\nionizable lipid were identical, suggesting the intact lipid nanoparticle\nrecirculates in blood. However, the decay rates of mRNA and ionizable\nlipids did not correlate with baseline levels of PEG-specific antibodies.\nInterestingly, the magnitude of mRNA and ionizable lipid detected\nin blood did correlate with the boost in the level of PEG antibodies.\nFurthermore, the ability of a subject’s monocytes to phagocytose\nlipid nanoparticles was inversely related to the rise in PEG antibodies.\nThis suggests that the circulation of mRNA lipid nanoparticles into\nthe blood and their clearance by phagocytes influence the PEG immunogenicity\nof the mRNA vaccines. Overall, this work defines the pharmacokinetics\nof lipid nanoparticle mRNA vaccine components in human blood after\nintramuscular injection and the factors that influence these processes.\nThese insights should be valuable in improving the future safety and\nefficacy of lipid nanoparticle mRNA vaccines and therapeutics.