title: Improving the Th1 cellular efficacy of the lead Yersinia pestis rF1-V subunit vaccine using SA-4-1BBL as a novel adjuvant.
abstract: The lead candidate plague subunit vaccine is the recombinant fusion protein rF1-V adjuvanted with alum. While alum generates Th2 regulated robust humoral responses, immune protection against Yersinia pestis has been shown to also involve Th1 driven cellular responses. Therefore, the rF1-V-based subunit vaccine may benefit from an adjuvant system that generates a mixed Th1 and humoral immune response. We herein assessed the efficacy of a novel SA-4-1BBL costimulatory molecule as a Th1 adjuvant to improve cellular responses generated by the rF1-V vaccine. SA-4-1BBL as a single adjuvant had better efficacy than alum in generating CD4(+) and CD8(+) T cells producing TNFα and IFNγ, signature cytokines for Th1 responses. The combination of SA-4-1BBL with alum further increased this Th1 response as compared with the individual adjuvants. Analysis of the humoral response revealed that SA-4-1BBL as a single adjuvant did not generate a significant Ab response against rF1-V, and SA-4-1BBL in combination with alum did not improve Ab titers. However, the combined adjuvants significantly increased the ratio of Th1 regulated IgG2c in C57BL/6 mice to the Th2 regulated IgG1. Finally, a single vaccination with rF1-V adjuvanted with SA-4-1BBL+alum had better protective efficacy than vaccines containing individual adjuvants. Taken together, these results demonstrate that SA-4-1BBL improves the protective efficacy of the alum adjuvanted lead rF1-V subunit vaccine by generating a more balanced Th1 cellular and humoral immune response. As such, this adjuvant platform may prove efficacious not only for the rF1-V vaccine but also against other infections that require both cellular and humoral immune responses for protection.
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, United States; Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, United States.
authors.forename: Gunes
authors.initials: G
authors.lastname: Dinc
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, United States; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY 40202, United States.
authors.forename: Jarrod M
authors.initials: JM
authors.lastname: Pennington
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, United States; Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, United States.
authors.forename: Esma S
authors.initials: ES
authors.lastname: Yolcu
authors.affiliation: Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, United States; Center for Predictive Medicine for Biodefense and Emerging Infectious Diseases, University of Louisville, Louisville, KY 40202, United States. Electronic address: matt.lawrenz@louisville.edu.
authors.forename: Matthew B
authors.initials: MB
authors.lastname: Lawrenz
authors.affiliation: Institute for Cellular Therapeutics, University of Louisville, Louisville, KY 40202, United States; Department of Microbiology and Immunology, University of Louisville, Louisville, KY 40202, United States. Electronic address: haval.shirwan@louisville.edu.
authors.forename: Haval
authors.initials: H
authors.lastname: Shirwan
mesh_terms: D053330:4-1BB Ligand / Q000494:pharmacology*; D000276:Adjuvants, Immunologic / Q000494:pharmacology*; D000818:Animals; D000907:Antibodies, Bacterial / Q000097:blood; D000917:Antibody Formation; D001428:Bacterial Vaccines / Q000276:immunology*; D005260:Female; D007111:Immunity, Cellular; D007074:Immunoglobulin G / Q000097:blood; D008810:Mice, Inbred C57BL; D010930:Plague / Q000517:prevention & control; D018417:Th1 Cells / Q000276:immunology*; D022223:Vaccines, Subunit / Q000276:immunology; D015010:Yersinia pestis
chemical_list: D053330:4-1BB Ligand; D000276:Adjuvants, Immunologic; D000907:Antibodies, Bacterial; D001428:Bacterial Vaccines; D007074:Immunoglobulin G; D022223:Vaccines, Subunit
keywords: 4-1BB; 4-1BBL; Adjuvant; Alum; CD137; Costimulation; Plague; SA-4-1BBL; Subunit vaccine; Th(1) response; rF1-V