Monophosphoryl-Lipid A (MPLA) is an Efficacious Adjuvant for Inactivated Rabies Vaccines.

Chen Chen,Haoqi Li,Zongmei Wang,Ling Zhao,Yueming Yuan,Ming Zhou,Ruiming Li,Chengguang Zhang,Zhenfang Fu

doi:10.3390/v11121118

Chen Chen, Haoqi Li + Show 7 more

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https://doi.org/10.3390/v11121118

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Journal: Viruses	Publication Date: Dec 3, 2019
Citations: 30	License type: CC BY 4.0

Affiliation: Huazhong Agricultural University, University of Georgia

Abstract

Rabies, as one of the most threatening zoonoses in the world, causes a fatal central nervous system (CNS) disease. So far, vaccination with rabies vaccines has been the most effective measure to prevent and control this disease. At present, inactivated rabies vaccines are widely used in humans and domestic animals. However, humoral immune responses induced by inactivated rabies vaccines are relatively low and multiple shots are required to achieve protective immunity. Supplementation with an adjuvant is a practical way to improve the immunogenicity of inactivated rabies vaccines. In this study, we found that monophosphoryl-lipid A (MPLA), a well-known TLR4 agonist, could significantly promote the maturation of bone marrow-derived dendritic cells (BMDC) through a TLR4-dependent pathway in vitro and the maturation of conventional DCs (cDCs) in vivo. We also found that MPLA, serving as an adjuvant for inactivated rabies vaccines, could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, and plasma cells (PCs), consequently enhancing the production of RABV-specific total-IgG, IgG2a, IgG2b, and the virus-neutralizing antibodies (VNAs). Furthermore, MPLA could increase the survival ratio of mice challenged with virulent RABV. In conclusion, our results demonstrate that MPLA serving as an adjuvant enhances the intensity of humoral immune responses by activating the cDC–Tfh–GC B axis. Our findings will contribute to the improvement of the efficiency of traditional rabies vaccines.

Highlights

Rabies virus (RABV), a single negative-strand RNA virus, belonging to the Lyssavirus genus within the Rhabdoviridae family, is still responsible for 59,000–61,000 human deaths annually, mostly in developing countries [1,2,3]
In order to evaluate the ability of monophosphoryl-lipid A (MPLA) to activate DCs in vitro, bone marrow-derived dendritic cells (BMDC) from wild type (WT) mice and TLR4 knock-out (TLR4−/− )
BMDC cells derived from WT mice or TLR4−/− mice were transferred into the 12-well plates and treated with MPLA (100 μL of 1 μg), BPL-inactivated LBNSE (100 μL of 1 × 107 FFU), and DMEM (100 μL), respectively

Summary

Introduction

Rabies virus (RABV), a single negative-strand RNA virus, belonging to the Lyssavirus genus within the Rhabdoviridae family, is still responsible for 59,000–61,000 human deaths annually, mostly in developing countries [1,2,3]. The RABV genome encodes five structural proteins, including nucleocapsid protein (N), phosphoprotein (P), matrix protein (M), glycoprotein (G), and large polymerase (L) [4]. After auto-cleaving the first 19 amino acids (aa), defined as the signal peptide (sp) of the G protein precursor, the mature G protein (1–505 aa), which is comprised of the ectodomain at the 50 end (et, 1–439 aa), the transmembrane domain (tm, 440–461 aa) and the cytoplasmic tail (ct, 462–505 aa), accesses the virion surface [5,6]. The G protein is the only protein on the virion surface, and it is mainly responsible for the interaction with receptors expressed on the cell surface [7,8]. The G protein is the only protein to induce virus-neutralizing antibodies (VNA) [4].

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