Immunopeptidomics-based design of highly effective mRNA vaccine formulations against Listeria monocytogenes

Listeria monocytogenes is a foodborne intracellular bacterial pathogen leading to human listeriosis. Despite a high mortality rate and increasing antibiotic resistance no clinically approved vaccine against Listeria is available. To identify antigens for this bacterial pathogen that can be encoded in mRNA vaccine formulations, we screened for Listeria epitopes presented on the surface of infected human cell lines by mass spectrometry-based immunopeptidomics. In between more than 15,000 human self-peptides, we detected 68 Listeria epitopes from 42 different bacterial proteins, including several known antigens. Peptide epitopes presented on different cell lines were often derived from the same bacterial surface proteins, classifying these antigens as potential vaccine candidates. Encoding these highly presented antigens in lipid nanoparticle mRNA vaccine formulations resulted in high levels of protection in vaccination challenge experiments in mice. Our results pave the way for the development of a clinical mRNA vaccine against Listeria and demonstrate the power of immunopeptidomics for next-generation bacterial vaccine development.

单核细胞增生李斯特菌（Listeria monocytogenes）是一种食源性胞内细菌病原体，可引发人类李斯特菌病。尽管该菌致死率高且抗生素耐药性问题日益突出，但目前尚无获批的临床抗李斯特菌疫苗。为鉴定可编码于mRNA疫苗制剂中的该细菌抗原，我们通过基于质谱的免疫肽组学（immunopeptidomics），筛选了感染人类细胞系表面呈递的李斯特菌表位。在逾15000种人类自身肽中，我们从42种不同细菌蛋白中检测到68种李斯特菌表位，其中包含多种已知抗原。不同细胞系呈递的肽表位通常源自同一细菌表面蛋白，据此可将这些抗原归类为潜在疫苗候选物。将这类高呈递抗原编码至脂质纳米颗粒（lipid nanoparticle）mRNA疫苗制剂后，在小鼠疫苗攻毒实验中实现了高水平的免疫保护。本研究成果为抗李斯特菌临床mRNA疫苗的开发铺平了道路，同时证明了免疫肽组学在下一代细菌疫苗开发中的应用价值。