Elsevier

Vaccine

Volume 35, Issue 51, 18 December 2017, Pages 7088-7094
Vaccine

Long-term humoral immunity induced by CVC1302-adjuvanted serotype O foot-and-mouth disease inactivated vaccine correlates with promoted T follicular helper cells and thus germinal center responses in mice

https://doi.org/10.1016/j.vaccine.2017.10.094Get rights and content

Highlights

  • CVC1302 adjuvanticity is mediated through potent induction of GC responses.

  • CVC1302 adjuvanticity is mediated through the induction of TFH cells.

  • CVC1302 adjuvanticity is mediated through master regulators of B cell identity.

Abstract

Long-lasting humoral immunity is one of the necessary criteria for a successful vaccine. In our previous study, it was demonstrated that the immunopotentiator CVC1302 could improve the humoral immunity induced by the foot and mouth disease virus (FMDV) killed vaccine (KV) with only one dose. Significantly higher FMDV-specific antibody titers and more persistent antibody responses were observed in pigs receiving CVC1302-adjuvanted KV (KV-CVC1302) than in those inoculated with KV alone. In this study, we show that CVC1302 enhances murine IgG responses to FMDV by promoting a potent T follicular helper cell (TFH) response, which directly controls the magnitude of the germinal center (GC) B cell response. These results indicate a need for studies to assess the capacity of CVC1302 to enhance the efficacy of FMDV KV immunization in pigs, and provide new insights into the development of FMDV vaccines.

Introduction

Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals, which causes substantial economic losses in the swine industry worldwide [1]. FMD was listed at the head of the class A diseases of the animal health code by the International Organization of Animal Health (OIE).

Foot-and-mouth disease virus (FMDV), the causative agent of FMD, belongs to the genus Aphthovirus of the family Picornaviridae, containing seven serotypes (A, O, C, Asia I, and Southern African Territories (SAT) 1, 2, and 3) [2]. In China, serotype O of FMDV is currently prevalent, and its control still relies mainly on vaccination with inactivated vaccines [3]. However, one dose of the available commercial FMDV inactivated vaccines cannot induce efficient humoral immunity against FMDV infection, which not only causes economic loss, but also inhibits the progress of FMD prevention and control.

In our previous study, an immunopotentiator CVC1302, containing muramyl dipeptide (MDP), Monophosphoryl lipid A (MPL), and β-glucan, was determined to successfully improve the efficacy of serotype O FMDV killed vaccine.

Long-term humoral immunity was observed by the detection of liquid-phase blocking antibody titers in pigs after receiving just one dose of KV-CVC1302. One of the criteria for successful vaccines is the generation of long-lived antibody responses to provide protection against subsequent infection, which in turn relies on a robust germinal center (GC) response [4]. The size and quality of the GC response are directed by T follicular helper (TFH) cells, which provide growth and differentiation signals to GC B cells and mediate the positive selection of high-affinity B cell clones in the GC, thereby determining which B cells exit the GC as long-lived plasma cells (LLPCs) and memory B cells (MBCs) [5]. Studies in mice indicate that LLPCs, localized primarily in specialized niches in the bone marrow (BM), can survive up to the lifetime of the mice, even in the absence of regeneration by B cells [6].

MF59, an adjuvant used in human vaccines, is known to induce persistent high-affinity functional Ab titers. Recent studies have indicated that MF59 mediates its B cell adjuvanticity by promoting TFH cells and thus GC responses [7], [8], [9]. Hence, in this study, we aimed to decipher the molecular and cellular mechanisms whereby CVC1302 induces a long-term humoral immune response and whether CVC1302 directly, or indirectly, mediates GC responses to induce long-term antibody immunity. This knowledge may improve the rational design of FMDV vaccine candidates.

Section snippets

Mice

Six-week-old BALB/c female mice were purchased from Yang Zhou University. The study and protocol were approved by the Science and Technology Agency of Jiangsu Province. The approval ID is NKYVET 2015-0066, granted by the Jiangsu Academy of Agricultural Sciences Experimental Animal ethics committee. All animal studies were performed in strict accordance with the guidelines of Jiangsu Province Animal Regulations (Government Decree No. 45).

Vaccine, adjuvants, and immunizations

Commercially available serotype O FMDV inactivated vaccine

Serotype O FMDV-specific functional IgG and isotype antibody responses in mice induced by KV-CVC1302

Serotype O FMDV-specific humoral responses were characterized in mice inoculated with PBS, KV, or KV-CVC1302. Significant differences in the level of serotype O FMDV-specific LPB IgG antibody titers could be observed between the groups immunized with KV-CVC1302 and KV at each sampling point (P < .05, P < .01 or P < .001) (Fig. 1A). KV-CVC1302 induces, not only higher FMDV-specific LPB IgG antibody titers, but also longer persistence of humoral responses compared with KV. No detectable LPB IgG

Discussion

FMD, one of the most contagious viral diseases known, affects cloven-hoofed livestock and wild animals. FMD is epidemic in many regions of the world, causing substantial economic losses. In China, vaccination is the main approach for the control of FMD. However, the commercially available FMDV vaccine, based on an inactivated virus, requires about 7 days to induce short-term protective immunity, and requires periodical re-vaccination [28]. In our previous study, we successfully developed an

Acknowledgements

This work was supported by special fund for Jiangsu Agriculture Science and Technology Innovation Fund (JASTIF) (CX (15) 1062), special fund for Agro-scientific Research in the Public Interest (201303046). We thank Victoria Muir, PhD, from Liwen Bianji, Edanz Gryoup China (www.liwenbianji.cn/ac) for editing the English text of a draft of this manuscript.

Disclosures

The authors have no financial conflicts of interest.

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