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

ABSTRACT: 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.

INSTRUMENT(S): Orbitrap Fusion Lumos, Q Exactive HF

ORGANISM(S): Homo Sapiens (human) Listeria Monocytogenes Egd

TISSUE(S): Epithelial Cell, Cell Culture

DISEASE(S): Colon Cancer,Cervix Carcinoma

SUBMITTER: Rupert Mayer

LAB HEAD: Francis Impens

PROVIDER: PXD031451 | Pride | 2022-09-26

REPOSITORIES: Pride

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			Action	DRS
	F000188b_1p_uPAC8_CMB-514_FRIMP_ImPep_TMT-Fr-1_20190430103259.mgf	Mgf
	F000188b_1p_uPAC8_CMB-514_FRIMP_ImPep_TMT-Fr-1_20190430103259.raw	Raw
	F000189b_1p_uPAC8_CMB-514_FRIMP_ImPep_TMT-Fr-2.mgf	Mgf
	F000189b_1p_uPAC8_CMB-514_FRIMP_ImPep_TMT-Fr-2.raw	Raw
	F000190b_1p_uPAC8_CMB-514_FRIMP_ImPep_TMT-Fr-3.mgf	Mgf

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Project description:Background. Dendritic cell (DC)-based neoantigen vaccination holds potential as a safe and effective adjuvant therapy for patients with early-stage, resectable NSCLC, a tumor type typically characterized by high mutational loads. DCs have the unique ability to elicit robust antitumoral T-cell responses, while neoantigens are ideal targets to elicit high-affinity T cell responses with exquisite tumor specificity. Here, we present the results of a phase I clinical trial in which a novel DC vaccine targeting neoantigens was evaluated in six patients with early stage, resected NSCLC. Methods. Tumor samples were subjected to a comprehensive neoantigen identification approach encompassing genomics, transcriptomics and immunopeptidomics. Using genomics and transcriptopmics data, tumor-specific antigens were identified by a bioinformatics approach. Additionally, immunopeptidomics was performed by immunoprecipitation of human MHC class I molecule followed by immunopeptides enrichment and LC-MS/MS analysis. Two immunopeptidomics screens were performed. In the first immunopeptidomics screen, patient-derived tumors were analyzed to uncover neoepitopes specific for the patient. In the second, screen, patient-derived EBV-immortilized B cell lines overexpressing the selected neoepitopes were analyzed to verify that the predicted neoepitopes can bind to the HLA haplotypes of the patients. For anti-tumor vaccination, patients underwent leukapheresis for the manufacturing of monocyte-derived DCs loaded with neoantigens (Neo-mDCs) according to a four-day protocol. Neo-mDCs were injected intravenously following an intrapatient dose escalation scheme. Primary endpoint of the trial was safety. Secondary endpoints were feasibility, immunogenicity, and relapse-free survival. Results. In the first immunopeptidomics screen, one neoepitopes derived was identified from the tumor of one patient. In the second immunopeptidomics screen, several predicted neoepitopes were confirmed to be presented on the HLA haplotypes of the patients by analyzing the patient-derived EBV-immortilized B cell lines. Additionally, the vaccine was demonstrated to be feasible and safe. T cell responses were observed in 5 of 6 vaccinated patients and were dominated by CD8+ T cells, which could be detected ex vivo at high frequencies >1.5 years after the last dose. Furthermore, single cell analysis indicated that the CD8+ T cell responsive population was polyclonal and exhibited the near entire spectrum of T cell differentiation states, including a naïve-like state associated with long lasting memory but excluding exhausted cell states. Three of six vaccinated patients experienced disease relapse. Conclusion. Neo-mDC vaccination is safe and feasible. Vaccination induces large populations of neoantigen-specific T-cell responses containing long lasting memory and effector cells in early-stage NSCLC patients, suggesting clinical potential.

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

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