Colloidal Manganese Salt Improves the Efficacy of Rabies Vaccines in Mice, Cats, and Dogs

Abstract

Rabies, caused by rabies virus (RABV), remains a serious threat to public health in most countries worldwide. At present, the administration of rabies vaccines has been the most effective strategy to control rabies. Herein, we evaluate the effect of colloidal manganese salt (Mn jelly, MnJ) as an adjuvant of rabies vaccine in mice, cats, and dogs. The results showed that MnJ promoted type I interferon (IFN-I) and cytokine production in vitro and the maturation of dendritic cells (DCs) in vitro and in vivo . Besides, MnJ serving as an adjuvant for rabies vaccines could significantly facilitate the generation of T follicular helper (Tfh) cells, germinal center (GC) B cells, plasma cells (PCs), and RABV-specific antibody-secreting-cells (ASCs), consequently improved the immunogenicity of rabies vaccines and provide better protection against virulent RABV challenge. Similarly, MnJ enhanced the humoral immune response in cats and dogs as well. Collectively, our results suggest that MnJ can facilitate the maturation of DCs during rabies vaccination, which can be a promising adjuvant candidate for rabies vaccines. IMPORTANCE Extending humoral immune response by using adjuvants is an important strategy for vaccine development. In this study, a novel adjuvant MnJ supplemented in rabies vaccines was evaluated in mice, cats, and dogs. Our results in the mouse model revealed that MnJ increased the numbers of mature DCs, Tfh cells, GC B cells, PCs, and RABV-specific ASCs, resulting in enhanced immunogenicity and protection rate of rabies vaccines. We further found MnJ had the same stimulative effect in cats and dogs. Our study provides the first evidence that MnJ serving as a novel adjuvant of rabies vaccines can boost immune response both in a mouse and pet model.

A Unique Combination of Mn2+ and Aluminum Adjuvant Acted the Synergistic Effect

“…A nanodepot of manganese (nanoMn) evokes M1 macrophage polarization and recruits monocytes into inflammatory foci, ameliorates coronavirus-induced tissue damage, and increases the development of virus-specific memory T cells through facilitating antigen presentation [ 35 ]. The administration of colloidal manganese salt (Mn jelly (MnJ)) as an adjuvant promoted the production of type I interferon (IFN-I) and the maturation of dendritic cells (DCs) and significantly facilitated the generation of T follicular helper (Tfh) cells, plasma cells (PCs), and RABV-specific antibody-secreting cells (ASCs), following the strengthening of the immunogenicity of rabies vaccines [ 13 ]. In addition, MnJ as a mucosal adjuvant induced high levels of secretory IgA.…”

“…Mn-deficient mice decreased cytokine production and were more vulnerable to DNA viruses, indicating that Mn is required for the host defense against DNA viruses. In addition, Mn 2+ exerts the function of immunologic adjuvant, for instance, colloidal manganese salt increases the efficacy of rabies vaccines in mice, cats, and dogs [ 13 , 14 ].…”

Recent progress on the activation of the cGAS–STING pathway and its regulation by biomolecular condensation

“…The ability of Mn 2+ to activate cGAS-dependent signaling makes it applicable to develop Mn 2+ -based antimicrobial/antitumor drugs or immune adjuvants for vaccines ( Van Herck et al., 2021 ). The nanoparticle and liposome-based Mn 2+ delivery strategies are of particular interest ( Hou et al., 2020 ; Wang et al., 2021c ). In fact, as a natural micronutrient necessary for diverse biological activities, Mn 2+ facilitates antigen uptake and presentation by the antigen-presenting cells (APCs), as well as germinal center formation in the adaptive immune responses ( Zhang et al., 2021 ).…”

“…The adjuvant effects of MnJ have been proved for various antigens, including proteins/peptides as T cell-dependent antigens and T cell-independent antigens such as the bacterial capsule polysaccharides, indicating that MnJ is a potent universal immune adjuvant ( Zhang et al., 2021 ). Importantly, besides MnJ, various Mn 2+ -containing nanoparticles have been formulated and significantly improved the efficacy of vaccines against influenza virus ( Cui et al., 2021 ), hepatitis B virus ( Lin et al., 2021 ), rabies virus ( Wang et al., 2021c ), and novel coronaviruses ( Sun et al., 2021b ; He et al., 2021 ; Wang et al., 2021b ) in different animal models.…”

Amino acid sequence determines the adjuvant potency of ad-tetra-peptide hydrogel

“…DCs break down protein antigens into peptides and present them in a complex with class I or class II major histocompatibility complex (MHC) molecules to CD4 + or CD8 + T cells respectively. [23][24][25][26][27] Upon maturation, DC upregulates the expression of MHC molecules that are important for antigen presentation. 28,29 Given the differential effects of six compounds on DC maturation, we next investigated their effect on DC antigen presentation.…”