Blood Distribution of SARS-CoV-2 Lipid Nanoparticle mRNA Vaccine in Humans

Lipid nanoparticle mRNA vaccines are an exciting but new technology used in humans. There is limited understanding of factors that influence their biodistribution and immunogenicity. Antibodies to polyethylene glycol (PEG), which is on the surface of the lipid nanoparticle, are detectable in humans and boosted by human mRNA vaccination. We hypothesized that PEG-specific antibodies could increase the clearance of mRNA vaccines. We developed methods to quantify both the mRNA and ionizable lipid in frequent serial blood samples from 19 subjects receiving Moderna SPIKEVAX mRNA booster immunization. Both the mRNA and ionizable lipid peaked in blood 1-2 days post vaccination (median peak level 0.19 and 3.22 ng mL ^-1 , respectively). The mRNA was detectable out to 14-28 days post-vaccination in most subjects. We measured the proportion of mRNA that was relatively intact in blood over time and found the decay kinetics of the intact mRNA and ionizable lipid were identical, suggesting the intact lipid nanoparticle recirculates in blood. However, mRNA and ionizable lipid decay rates did not correlate with baseline levels of PEG-specific nor spike-specific antibodies. The magnitude of mRNA and ionizable lipid detected in blood did correlate with the boost in PEG antibodies. Further, the ability of subject’s monocytes to phagocytose lipid nanoparticles had an inverse relationship with the rise in PEG antibodies. This suggests circulation of mRNA lipid nanoparticle vaccines into the blood and their ability to be cleared by phagocytes influence PEG immunogenicity of mRNA vaccines. Overall, this work defines the pharmacokinetics of lipid nanoparticle mRNA vaccine components in human blood after intramuscular injection and the factors that influence this. These insights should prove useful in improving the future safety and efficacy of lipid nanoparticle mRNA vaccines and therapeutics.