Surface Modification of Biodegradable Microparticles with the Novel Host-Derived Immunostimulant CPDI-02 Significantly Increases Short-Term and Long-Term Mucosal and Systemic Antibodies against Encapsulated Protein Antigen in Young Naïve Mice after Respiratory Immunization

Jacob E Parriott; Jason P Stewart; D David Smith; Stephen M Curran; Christopher D Bauer; Todd A Wyatt; Joy A Phillips; Elizabeth Lyden; Geoffrey M Thiele; Joseph A Vetro

doi:10.3390/pharmaceutics14091843

Surface Modification of Biodegradable Microparticles with the Novel Host-Derived Immunostimulant CPDI-02 Significantly Increases Short-Term and Long-Term Mucosal and Systemic Antibodies against Encapsulated Protein Antigen in Young Naïve Mice after Respiratory Immunization

Pharmaceutics. 2022 Sep 1;14(9):1843. doi: 10.3390/pharmaceutics14091843.

Authors

Jacob E Parriott¹, Jason P Stewart¹, D David Smith², Stephen M Curran¹, Christopher D Bauer^{3

4

5}, Todd A Wyatt^{3

4

5}, Joy A Phillips⁶, Elizabeth Lyden⁷, Geoffrey M Thiele^{3

8}, Joseph A Vetro^{1

9}

Affiliations

¹ Department of Pharmaceutical Sciences, College of Pharmacy, 986020 University of Nebraska Medical Center, Omaha, NE 68198, USA.
² Department of Biomedical Sciences, Creighton University, 2500 California Plaza, Omaha, NE 68178, USA.
³ Research Service, Department of Veterans Affairs Omaha-Western Iowa Health Care System, Omaha, NE 68105, USA.
⁴ Pulmonary, Critical Care and Sleep, Department of Internal Medicine, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁵ Department of Environmental, Agricultural and Occupational Health, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁶ Donald P. Shiley BioScience Center, San Diego State University, San Diego, CA 92182, USA.
⁷ Department of Biostatistics, College of Public Health, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁸ Department of Internal Medicine, Division of Rheumatology & Immunology, University of Nebraska Medical Center, Omaha, NE 68198, USA.
⁹ Center for Drug Delivery and Nanomedicine, 985830 University of Nebraska Medical Center, Omaha, NE 68198, USA.

Abstract

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. We found that, compared to MP surface-modified with inactive, scrambled scCPDI-02 (scCPDI-02-MP), intranasal administration of CPDI-02-MP in 50 μL sterile PBS greatly increased titers of short-term (14 days post-immunization) and long-term (90 days post-immunization) antibodies against encapsulated LPS-free OVA in nasal lavage fluids, bronchoalveolar lavage fluids, and sera of young, naïve female C57BL/6 mice with minimal lung inflammation. Thus, surface modification of ~1 μm biodegradable microparticles with CPDI-02 is likely to increase long-term mucosal and systemic antibodies against encapsulated protein antigen after respiratory and possibly other routes of mucosal immunization.

Keywords: C5a1R; C5aR1; CD88; EP54; EP67; M cell targeting; administration volume; dendritic cell targeting; mucosal immunization; mucosal vaccine; targeted vaccines; vaccine delivery.

Abstract

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