EP67 is a complement component 5a (C5a)-derived peptide agonist of the C5a receptor (CD88) that selectively activates DCs over neutrophils. Systemic administration of EP67 covalently attached to peptides, proteins, or attenuated pathogens generates TH1-biased immunogen-specific humoral and cellular immune responses with little inflammation. Furthermore, intranasal administration of EP67 alone increases the proportion of activated APCs in the airways. As such, we hypothesized that EP67 can act as a mucosal adjuvant. Intranasal immunization with an EP67-conjugated CTL peptide vaccine against protective MCMV epitopes M84 and pp89 increased protection of naïve female BALB/c mice against primary respiratory infection with salivary gland-derived MCMV and generated higher proportions of epitope responsive and long-lived memory precursor effector cells (MPEC) in the lungs and spleen compared to an inactive, scrambled EP67-conjugated CTL peptide vaccine and vehicle alone. Thus, EP67 may be an effective adjuvant for mucosal vaccines and warrants further study.
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http://dx.doi.org/10.1016/j.clim.2015.06.006 | DOI Listing |
Pharmaceutics
September 2022
Department of Pharmaceutical Sciences, College of Pharmacy, 986020 University of Nebraska Medical Center, Omaha, NE 68198, USA.
Generating long-lived mucosal and systemic antibodies through respiratory immunization with protective antigens encapsulated in nanoscale biodegradable particles could potentially decrease or eliminate the incidence of many infectious diseases, but requires the incorporation of a suitable mucosal immunostimulant. We previously found that respiratory immunization with a model protein antigen (LPS-free OVA) encapsulated in PLGA 50:50 nanoparticles (~380 nm diameter) surface-modified with complement peptide-derived immunostimulant 02 (CPDI-02; formerly EP67) through 2 kDa PEG linkers increases mucosal and systemic OVA-specific memory T-cells with long-lived surface phenotypes in young, naïve female C57BL/6 mice. Here, we determined if respiratory immunization with LPS-free OVA encapsulated in similar PLGA 50:50 microparticles (~1 μm diameter) surface-modified with CPDI-02 (CPDI-02-MP) increases long-term OVA-specific mucosal and systemic antibodies.
View Article and Find Full Text PDFACS Infect Dis
May 2020
Center for Drug Delivery and Nanomedicine, University of Nebraska Medical Center, Omaha, Nebraska 68198, United States.
EP67 is a second-generation, human C5a-derived decapeptide agonist of C5a receptor 1 (C5aR1/CD88) that selectively activates mononuclear phagocytes over neutrophils to potentiate protective innate and adaptive immune responses while potentially minimizing neutrophil-mediated toxicity. Pro and -methyl-Leu (Me-Leu) amino acid residues within EP67 likely induce backbone structural changes that increase potency and selective activation of mononuclear phagocytes over neutrophils versus first-generation EP54. The low coupling efficiency between Pro and Me-Leu and challenging purification by HPLC, however, greatly increase scale-up costs of EP67 for clinical use.
View Article and Find Full Text PDFInt J Pharm
June 2019
Center for Drug Delivery and Nanomedicine, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA; Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center, 986025 Nebraska Medical Center, Omaha, NE 68198-6025, USA. Electronic address:
Encapsulation of protein vaccines in biodegradable nanoparticles (NP) increases T-cell expansion after mucosal immunization but requires incorporating a suitable immunostimulant to increase long-lived memory T-cells. EP67 is a clinically viable, host-derived peptide agonist of the C5a receptor that selectively activates antigen presenting cells over neutrophils. We previously found that encapsulating EP67-conjugated CTL peptide vaccines in NP increases long-lived memory subsets of CTL after respiratory immunization.
View Article and Find Full Text PDFVaccine
October 2018
Department of Pathology and Laboratory Medicine, Medical Sciences I, Room D440, University of California, Irvine, Irvine, CA 92697-4800, USA. Electronic address:
Introduction: Chlamydial infections are spread worldwide and a vaccine is needed to control this pathogen. The goals of this study were to determine if the delivery of an adjuvant associated to the antigen, via a derivatized amphipol, and adjuvant combinations improve vaccine protection.
Methods: A novel approach, trapping the Chlamydia muridarum (Cm) native MOMP (nMOMP) with amphipols (A8-35), bearing a covalently conjugated peptide (EP67), was used.
Mol Pharm
May 2017
Center for Drug Delivery and Nanomedicine and §Department of Pharmaceutical Sciences, College of Pharmacy, University of Nebraska Medical Center , 986025 Nebraska Medical Center, Omaha, Nebraska 68198-6025, United States.
The diameter of biodegradable particles used to coencapsulate immunostimulants and subunit vaccines affects the magnitude of memory CD8 T cells generated by systemic immunization. Possible effects on the magnitude of CD8 T cells generated by mucosal immunization or memory subsets that potentially correlate more strongly with protection against certain pathogens, however, are unknown. In this study, we conjugated our novel host-derived mucosal immunostimulant, EP67, to the protective MCMV CTL epitope, pp89, through a lysosomal protease-labile double arginine linker (pp89-RR-EP67) and encapsulated in PLGA 50:50 micro- or nanoparticles.
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