Adjuvants for swine vaccines: Mechanisms of actions and adjuvant effects

This review deals with mechanisms of actions (MOA) and adjuvant effects of various types of adjuvants for swine vaccines. A number of different types of adjuvants have been tested with swine vaccines, including oil emulsion, particulate antigen (Ag) carrier, cytokines, pathogen-associated molecular patterns and immune ligands, saponins, and bacterial cells and toxins. In addition, there are a number of chemicals and natural products that possess adjuvant activities when tested with swine vaccines, and are grouped as miscellaneous in this review. The MOA of adjuvants can be generally divided into two categories: delivery vehicles and immunostimulants. Adjuvants serving as delivery vehicle can act as a depot, help deliver Ag to the draining lymph nodes, promote Ag uptake by antigen-presenting cells (APCs), and protect Ag from harsh conditions. Adjuvants possessing immunostimulatory activities may help recruit and activate APCs and T cells, enhance APC functions, and direct T cell differentiation and immunoglobulin isotype switching. Success of adjuvant use on improving immunogenicity and protective efficacy of swine vaccines depends on several factors, including type and stability of vaccine Ag, dose and schedule of vaccination, MOA of adjuvant, route, dose and schedule of adjuvant administration, type of immune response required, and safety from adverse reactions. In addition to the above mentioned factors, cost effectiveness is of concern. Further studies of swine vaccine adjuvants may need to focus on characterization of their MOA and search for more potential adjuvant candidates that can induce mucosal immune response.     

Efficient mucosal vaccination of a novel classical swine fever virus E2-Fc fusion protein mediated by neonatal Fc receptor

Classical swine fever (CSF) remains one of the most important highly contagious and fatal viral disease of swine with high morbidity and mortality. CSF is caused by classical swine fever virus (CSFV), a small, enveloped RNA virus of the genus Pestivirus. The aim of this study was to construct the a novel CSFV Fc-fusion recombinant protein and evaluate the efficacy as a vaccine against CSFV. Here, we obtained a novel subunit vaccine expressing CSFV E2 recombinant fusion protein in CHO-S cells. Functional analysis revealed that CSFV Fc-fusion recombinant protein (CSFV-E2-Fc) could bind to FcγRI on antigen-presenting cells (APCs) and significantly increase IgA levels in serum and feces, inducing stronger mucosal immune response in swine. Additionally, CSFV-E2-Fc immunization enhanced CSFV-specific T cell immune response with a Th1-like pattern of cytokine secretion, remarkably stimulated the Th1-biased cellular immune response and humoral immune response. Further, the protective effects of CSFV-E2-Fc subunit vaccines were confirmed. The data suggest that CSFV E2-Fc recombinant fusion protein may be a promising candidate subunit vaccine to elicit immune response and protect against CSFV.     

The immune response to poliovirus-specific synthetic peptides: effects of adjuvants and test animal species

Carrier protein conjugates of five synthetic peptides containing amino acid sequences specific to capsid proteins VP1 and VP2 of poliovirus type 1 were tested for their abilities to elicit an immune response in the presence of either of two adjuvants and in several animal species. Freund's adjuvant induced significantly higher level anti-peptide antibody titers than A1(OH)3. However, no difference was noted between the two adjuvants in their abilities to aid in the induction of cross-reactive virus neutralizing antibody. The latter antibody was more readily produced by rabbits than by guinea pigs in spite of equivalent anti-peptide titers. Rats failed to produce neutralizing antibodies and their anti-peptide antibody levels were generally lower. The significance of these results for studies involving the development of synthetic peptide immunogens is discussed.     

大剂量胸腺素对类风湿关节炎临床症状及免疫指标的影响

目的 :研究大剂量胸腺素对类风湿关节炎的临床症状及免疫指标的影响。方法 :将 5 2例类风湿关节炎病人随机分胸腺素组和对照组 ,均给予甲氨蝶呤及双氯芬酸治疗。胸腺素组同时给予胸腺素80～ 12 0mg ,iv ,gtt,qd× 8wk。结果 :胸腺素组与对照组比较在休息痛、晨僵时间、关节肿胀数、医生评估、α 酸性糖蛋白、血红蛋白、CD4 /CD8、病人评估等方面有明显改善 ,其中晨僵时间缩短值和CD4 /CD8增加值 ,胸腺素组为 (98± 5 3)min和 0 .5± 0 .3,对照组为 (70± 38)min和 0 .3± 0 .4 (P <0 .0 5 )。结论 :大剂量胸腺素对类风湿关节炎治疗作用肯定 ,无不良反应 ,可以作为一种辅助治疗     

Extrinsic Phagocyte-Dependent STING Signaling Dictates the Immunogenicity of Dying Cells

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The cationic liposomal adjuvants CAF01 and CAF09 formulated with the major outer membrane protein elicit robust protection in mice against a Chlamydia muridarum respiratory challenge

Two cationic liposomal adjuvants CAF01 and CAF09 were formulated with the native or the recombinant Chlamydia muridarum major outer membrane protein (nMOMP and rMOMP). BALB/c mice were immunized with the four vaccine formulations using the subcutaneous followed by the intranasal (i.n.) routes. As positive controls mice were inoculated i.n. with live C. muridarum and negative controls received i.n. minimal essential medium (MEM). Four weeks after the last immunization mice were challenged i.n. with 10⁴ inclusion forming units (IFU) of C. muridarum. Following the challenge the mice were weighed daily. At 10 days post-challenge the mice were euthanized, their lungs weighed and the number of C. muridarum IFU determined. Serum collected the day before the challenge showed that all four groups of mice immunized with CAF01, or CAF09 and MOMP had significant C. muridarum-specific antibody titers. As determined by a T-cell lymphoproliferative assay, these four groups of mice also mounted robust cell mediated immune responses with high production of IFN-γ and IL17 and low levels of IL-4. Following the challenge the four groups of mice lost significantly less body weight than the MEM-immunized group. Lungs of mice vaccinated with CAF01, or CAF09, and nMOMP were significantly lighter than those from mice immunized using rMOMP. The number of IFU recovered from the lungs of mice vaccinated with CAF01, or CAF09, and nMOMP was similar to the number of IFU recovered from mice immunized with live EB. Mice that received rMOMP had significantly higher numbers of IFU than other groups. In conclusion, CAF01 and CAF09 elicited very robust protective humoral and cellular immune responses and were equally effective at adjuntavizing the C. muridarum MOMP. Mice vaccinated with nMOMP were significantly better protected than those immunized with rMOMP, indicative of the importance of the structural conformation of this antigen in protection.     

New adjuvants in evolving vaccine strategies

Adjuvants are becoming the key players of vaccine formulations to enhance the immunogenicity of subunit (peptides, proteins, virus-like particles (VLPs)) and DNA vaccines, as well as to reach the current new goals of preventing and/or treating chronic infectious diseases and cancers. Induction of humoral response, in particular neutralizing antibodies able to inhibit the binding of pathogens to their cellular receptors, remains a major goal of vaccines targeted to prevent acute lytic infections; induction/modulation of cellular immunity is, however, critical to fight latently/chronically infected cells as well as cancer cells. The new adjuvants, included in vaccine preparations, are currently able to modify the presentation of epitopes to the immune system with a specific T_H1 versus T_H2 polarization efficacy. A paradigm of the relevance of these new adjuvants is the immunological result obtained with the inclusion of monophosphoryl lipid A in the formulation of L1-based human papillomavirus (HPV)-naked VLPs. In the May issue of this journal, Garcon and colleagues describe the highly enhanced humoral and memory B cellular immunity of the AS04-adjuvanted HPV vaccine, which results in a long-lasting and broad spectrum immunity.     

Analgesic adjuvants modulate morphine-induced immune effects in mice

BackgroundMacrophages, involved in the pathogenesis of pain, express a variety of receptors enabling responsiveness to certain medications, including adjuvant analgesics (AAs), that are effective in neuropathic pain and include drugs not primarily indicated for pain treatment, such as anticonvulsants or antidepressants. Their analgesic effects are likely associated with immunomodulatory activity, that remain undefined. Thus, current research aimed at examining the impact of AAs on morphine-induced effects exerted on mouse immunity.MethodsMacrophages from mice treated with morphine with or without gabapentin, amitriptyline or venlafaxine, were either subjected to phagocytosis assay, cultured to evaluate the generation of cytokines, or were pulsed with either corpuscular antigen or hapten and transferred to naive recipients to induce humoral or cellular response, respectively. Active contact hypersensitivity was also elicited in drug-treated mice.ResultsWe observed that repeatedly administered morphine and AAs reduced antigen phagocytosis by macrophages. Further, amitriptyline with morphine enhanced basal secretion of cytokines by macrophages, and all drugs tended to decrease LPS-stimulated release of pro-inflammatory cytokines. Morphine and AAs impacted the expression of phagocytosis and antigen-presentation markers on macrophages, which led to the reduced ability of morphine-affected macrophages to induce B-cell secretion of specific antibodies, and the addition of AAs strengthened this effect. Finally, gabapentin and venlafaxine suppressed the contact hypersensitivity reaction, while amitriptyline seemed to have the opposite effect.ConclusionsOur study demonstrated a significant anti-inflammatory activity of AAs across a broad spectrum of macrophage immune functions, which is likely critical to their analgesic activity supporting the beneficial effect of morphine.     

Molecular signatures of vaccine adjuvants

Mass vaccination has saved millions of human lives and improved the quality of life in both developing and developed countries. The emergence of new pathogens and inadequate protection conferred by some of the existing vaccines such as vaccines for tuberculosis, influenza and pertussis especially in certain age groups have resulted in a move from empirically developed vaccines toward more pathogen tailored and rationally engineered vaccines. A deeper understanding of the interaction of innate and adaptive immunity at molecular level enables the development of vaccines that selectively target certain type of immune responses without excessive reactogenicity. Adjuvants constitute an imperative element of modern vaccines. Although a variety of candidate adjuvants have been evaluated in the past few decades, only a limited number of vaccine adjuvants are currently available for human use. A better understanding of the mode of action of adjuvants is pivotal to harness the potential of existing and new adjuvants in shaping a desired immune response. Recent advancement in systems biology powered by the emerging cutting edge omics technology has led to the identification of molecular signatures rapidly induced after vaccination in the blood that correlate and predict a later protective immune response or vaccine safety. This can pave ways to prospectively determine the potency and safety of vaccines and adjuvants. This review is intended to highlight the importance of big data analysis in advancing our understanding of the mechanisms of actions of adjuvants to inform rational development of future human vaccines.