Department of Microbiology and Immunology, Peter Doherty Institute for Infection and Immunity, The University of Melbourne, Melbourne, Victoria 3000, Australia.
Melbourne Sexual Health Centre and Department of Infectious Diseases, Alfred Hospital and Central Clinical School, Monash University, Melbourne, Victoria 3000, Australia.
ACS Nano. 2024 Oct 1;18(39):27077-27089. doi: 10.1021/acsnano.4c11652. Epub 2024 Sep 19.
Lipid nanoparticle mRNA vaccines are an exciting but emerging technology used in humans. There is limited understanding of the factors that influence their biodistribution and immunogenicity. Antibodies to poly(ethylene 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. To test this, we developed methods to quantify both the vaccine mRNA and ionizable lipid in frequent serial blood samples from 19 subjects receiving Moderna SPIKEVAX mRNA booster immunization. Both the vaccine mRNA and ionizable lipid peaked in blood 1-2 days post vaccination (median peak level 0.19 and 3.22 ng mL, respectively). The vaccine mRNA was detectable and quantifiable up to 14-15 days postvaccination in 37% of subjects. We measured the proportion of vaccine mRNA that was relatively intact in blood over time and found that the decay kinetics of the intact mRNA and ionizable lipid were identical, suggesting the intact lipid nanoparticle recirculates in blood. However, the decay rates of mRNA and ionizable lipids did not correlate with baseline levels of PEG-specific antibodies. Interestingly, the magnitude of mRNA and ionizable lipid detected in blood did correlate with the boost in the level of PEG antibodies. Furthermore, the ability of a subject's monocytes to phagocytose lipid nanoparticles was inversely related to the rise in PEG antibodies. This suggests that the circulation of mRNA lipid nanoparticles into the blood and their clearance by phagocytes influence the PEG immunogenicity of the 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 these processes. These insights should be valuable in improving the future safety and efficacy of lipid nanoparticle mRNA vaccines and therapeutics.
脂质纳米颗粒 mRNA 疫苗是一种令人兴奋但新兴的技术,已在人类中使用。人们对影响其体内分布和免疫原性的因素知之甚少。脂质纳米颗粒表面的聚乙二醇(PEG)抗体在人类中可检测到,并可被人类 mRNA 疫苗增强。我们假设 PEG 特异性抗体可增加 mRNA 疫苗的清除率。为了验证这一点,我们开发了方法来定量检测 19 名接受 Moderna SPIKEVAX mRNA 加强免疫接种的受试者频繁的连续血液样本中的疫苗 mRNA 和可离子化脂质。疫苗 mRNA 和可离子化脂质在接种后 1-2 天达到峰值(中位数峰值水平分别为 0.19 和 3.22ng/ml)。在 37%的受试者中,疫苗 mRNA 可检测到并定量至接种后 14-15 天。我们测量了随时间推移血液中相对完整的疫苗 mRNA 比例,发现完整 mRNA 和可离子化脂质的衰减动力学相同,提示完整的脂质纳米颗粒在血液中循环。然而,mRNA 和可离子化脂质的衰减率与基线 PEG 特异性抗体水平无关。有趣的是,在血液中检测到的 mRNA 和可离子化脂质的量与 PEG 抗体水平的升高相关。此外,受试者单核细胞吞噬脂质纳米颗粒的能力与 PEG 抗体的上升呈反比。这表明 mRNA 脂质纳米颗粒进入血液循环及其被吞噬细胞清除的能力影响 mRNA 疫苗的 PEG 免疫原性。总的来说,这项工作定义了肌肉内注射后脂质纳米颗粒 mRNA 疫苗成分在人血液中的药代动力学及其影响这些过程的因素。这些见解对于改善脂质纳米颗粒 mRNA 疫苗和治疗剂的未来安全性和疗效应该是有价值的。
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