Encapsulation of an EP67-Conjugated CTL Peptide Vaccine in Nanoscale Biodegradable Particles Increases the Efficacy of Respiratory Immunization and Affects the Magnitude and Memory Subsets of Vaccine-Generated Mucosal and Systemic CD8+T Cells in a Diameter-Dependent Manner.
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. We then compared total magnitude, effector/central memory (CD127/KRLG1/CD62L), and IFN-γ/TNF-α/IL-2 secreting subsets of pp89-specific CD8+T cells as well as protection of naive female BALB/c mice against primary respiratory infection with MCMV 21 days after respiratory immunization. We found that decreasing the diameter of encapsulating particle from ∼5.4 μm to ∼350 nm (i) increased the magnitude of pp89-specific CD8+T cells in the lungs and spleen; (ii) partially changed CD127/KLRG1 effector memory subsets in the lungs but not the spleen; (iii) changed CD127/KRLG1/CD62L effector/central memory subsets in the spleen; (iv) changed pp89-responsive IFN-γ/TNF-α/IL-2 secreting subsets in the lungs and spleen; (v) did not affect the extent to which encapsulation increased efficacy against primary MCMV respiratory infection over unencapsulated pp89-RR-EP67. Thus, although not observed under our current experimental conditions with MCMV, varying the diameter of nanoscale biodegradable particles may increase the efficacy of mucosal immunization with coencapsulated immunostimulant/subunit vaccines against certain pathogens by selectively increasing memory subset(s) of CD8+T cells that correlate the strongest with protection.
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.
Bala V K
BVK
Karuturi
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.
Shailendra B
SB
Tallapaka
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.
Pravin
P
Yeapuri
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.
Stephen M
SM
Curran
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.
Sam D
SD
Sanderson
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.
Joseph A
0000-0003-2446-9797
JA
Vetro
D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000378:metabolism*; D003587:Cytomegalovirus / Q000276:immunology; D005260:Female; D018928:Immunity, Mucosal / Q000276:immunology; D051379:Mice; D008807:Mice, Inbred BALB C; D041681:NIH 3T3 Cells; D053758:Nanoparticles / Q000737:chemistry*; D054118:Nanospheres / Q000737:chemistry*; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D022223:Vaccines, Subunit / Q000737:chemistry* / Q000276:immunology
D014409:Tumor Necrosis Factor-alpha; D022223:Vaccines, Subunit
correlate of protection; host-derived immunostimulant; microparticle; microsphere; mucosal adjuvant; mucosal vaccine; murine cytomegalovirus; nanoparticle; nanosphere; vaccine delivery