Mincle and STING-Stimulating Adjuvants Elicit Robust Cellular Immunity and Drive Long-Lasting Memory Responses in a Foot-and-Mouth Disease Vaccine.

Min Ja Lee,Sung Ho Shin,Jong-Hyeon Park,Hyundong Jo,Su-Mi Kim,Byounghan Kim,Hang Sub Shim

doi:10.3389/fimmu.2019.02509

Abstract

Conventional foot-and-mouth disease (FMD) vaccines exhibit several limitations, such as the slow induction of antibodies, short-term persistence of antibody titers, as well as low vaccine efficacy and safety, in pigs. Despite the importance of cellular immune response in host defense at the early stages of foot-and-mouth disease virus (FMDV) infection, most FMD vaccines focus on humoral immune response. Antibody response alone is insufficient to provide full protection against FMDV infection; cellular immunity is also required. Therefore, it is necessary to design a strategy for developing a novel FMD vaccine that induces a more potent, cellular immune response and a long-lasting humoral immune response that is also safe. Previously, we demonstrated the potential of various pattern recognition receptor (PRR) ligands and cytokines as adjuvants for the FMD vaccine. Based on these results, we investigated PRR ligands and cytokines adjuvant-mediated memory response in mice. Additionally, we also investigated cellular immune response in peripheral blood mononuclear cells (PBMCs) isolated from cattle and pigs. We further evaluated target-specific adjuvants, including Mincle, STING, TLR-7/8, and Dectin-1/2 ligand, for their role in generating ligand-mediated and long-lasting memory responses in cattle and pigs. The combination of Mincle and STING-stimulating ligands, such as trehalose-6, 6′dibehenate (TDB), and bis-(3′-5′)-cyclic dimeric guanosine monophosphate (c-di-GMP), induced high levels of antigen-specific and virus-neutralizing antibody titers at the early stages of vaccination and maintained a long-lasting immune memory response in pigs. These findings are expected to provide important clues for the development of a robust FMD vaccine that stimulates both cellular and humoral immune responses, which would elicit a long-lasting, effective immune response, and address the limitations seen in the current FMD vaccine.

Highlights

Foot-and-mouth disease (FMD) is a highly contagious viral disease that mainly affects cloven-hoofed livestock
Mouse experiments were performed to evaluate the potential of pattern recognition receptor (PRR) ligands and recombinant cytokines as FMD vaccine adjuvants and the induction of adjuvant-mediated memory immune response (Figure 1A)
As indicated by Structural Protein (SP) O ELISA, the group administered with PRR ligand and foot-and-mouth disease virus (FMDV) O Ag showed high antibody titers at 28 dpv (Figure 1B), and antibody titers were significantly elevated in the experimental groups treated with rmIFNα (p < 0.001), rmIFNγ+rmIL-2+rmTNFα (p < 0.05), rmIL-15+rmIL-18 (p < 0.05), TDB+c-di-GMP (p < 0.05), and R848+c-di-GMP (p < 0.01) compared to the positive control group

Summary

Introduction

Foot-and-mouth disease (FMD) is a highly contagious viral disease that mainly affects cloven-hoofed livestock. This disease causes serious economic losses to the livestock industry, due to a rapid spread and high livestock mortality, resulting in low livestock productivity [1]. Over 70 species of wildlife, including livestock ruminants such as cows, pigs, buffalos, camels, sheep, and goats, are susceptible to this disease. The efficacy of inactivated vaccines was improved by including oil adjuvants (double or single oil emulsions). These vaccines exhibited certain limitations, such as the slow induction of antibodies to levels allowing for defense, low antibody titers, short-term persistence of antibodies, and low immunogenicity in pigs

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Conclusion