菌影作为新型疫苗递送载体的研究进展

尽管基于重组蛋白或DNA的新型疫苗的开发以指数级上升,但是其免疫原性常弱于传统疫苗,缺少有效的递送系统是其应用的主要限制因素,因此迫切需要开发新型改良的递送系统和佐剂.菌影(bacterial ghost,BG)系统正是这类载体系统,它能将结合的抗原靶向APC,并具有佐剂活性.BG是一种无生命的革兰阴性菌包膜,无胞质内容物,但保留了细胞形态和天然表面抗原结构.由于BG具有颗粒特性并包含许多已知的免疫刺激成分,因此BG能增强抗其传递的靶抗原的免疫应答.作为一种新型的疫苗递送载体,菌影将被用于人用和兽用疫苗的生产.     

菌影用作粘膜抗原传递的载体和导向系统

菌影系统是一种新的疫苗传递系统,具有内在佐剂性.菌影是一种无生命的革兰阴性菌包膜,无胞质内容物,但保持了细胞形态和天然表面抗原结构,包括生物粘附特性.用PhiX 174蛋白E裂解革兰阴性菌能获得菌影.菌影制剂的内在佐剂性能增强抗包膜结合抗原的免疫应答,包括T细胞活化和粘膜免疫.由于在E介导的裂解之前,天然和外源性抗原能在菌影包膜复合物上表达,因此多种来源的抗原可同时递呈给免疫系统.而且,扩展的菌影系统为将DNA编码的抗原特异性导向抗原递呈细胞提供了技术平台.菌影系统作为一项新的技术具有发展潜力,且安全、价廉,特别适用于联合疫苗.     

菌影用作粘膜抗原传递的载体和导向系统

菌影系统是一种新的疫苗传递系统，具有内在佐剂性。菌影是一种无生命的革兰阴性菌包膜，无胞质内容物，但保持了细胞形态和天然表面抗原结构，包括生物粘附特性。用PhiX174蛋白E裂解革兰阴性菌能获得菌影。菌影制剂的内在佐剂性能增强抗包膜结合抗原的免疫应答，包括T细胞活化和粘膜免疫。由于在E介导的裂解之前，天然和外源性抗原能在菌影包膜复合物上表达，因此多种来源的抗原可同时递呈给免疫系统。而且，扩展的菌影系统为将DNA编码的抗原特异性导向抗原递呈细胞提供了技术平台。菌影系统作为一项新的技术具有发展潜力，且安全、价廉，特别适用于联合疫苗。     

菌影在蛋白亚单位疫苗和DNA疫苗递送中的应用

菌影（bacterialghost,BG）是由噬菌体ФX174E基因表达蛋白介导革兰阴性菌裂解所形成的空胞,无胞质内容物,但保留了天然的胞壁结构。由于BG具有颗粒特性并含有天然表面抗原组分,因此易于被抗原呈递细胞识别并激发体液和细胞免疫应答。BG可负载外源蛋白和DNA,并可通过各种免疫途径进行接种。因此,BG是一种有潜力的疫苗递送系统。     

疫苗透皮免疫的研究进展

疫苗透皮免疫是一种新型的无针免疫接种途径,系将抗原和佐剂应用于完整皮肤表面,通过表皮的朗格汉斯细胞识别、处理抗原并将其呈递给T细胞,从而引发强烈的体液免疫和细胞免疫.这种安全有效的接种方式具有显著的免疫学优势和实用价值.本文综述了疫苗透皮免疫技术的历史背景、作用机制,透皮免疫给药系统中所用的佐剂、吸收促进剂和药物载体等,以及透皮疫苗目前的研发情况.     

壳聚糖衍生物在口鼻黏膜疫苗中的应用

壳聚糖是一种有效的黏膜疫苗佐剂和递送载体,但因其水溶性差,应用受到一定限制.通过对壳聚糖进行不同的化学修饰可得到各类壳聚糖衍生物,这些衍生物不仅溶解性较好,而且保持了壳聚糖良好的生物相容性、生物降解性、免疫刺激活性等优势,为黏膜疫苗,尤其是经口、鼻途径递送的疫苗提供了新型候选佐剂和递送载体.此文对修饰壳聚糖的主要方法以及其衍生物在口鼻黏膜疫苗中的应用做一综述.     

铁纳米颗粒佐剂的应用研究进展

与传统灭活疫苗相比,多肽等亚单位疫苗的免疫原性较差,一般需额外添加佐剂.近年来有关新型疫苗佐剂的研究不少,但仍然只有极少数佐剂被获批人类使用.纳米颗粒被认为有望替代传统佐剂,其中金属纳米颗粒是最有前途的一类疫苗佐剂,同时也是适宜的抗原递送系统.铁纳米颗粒作为新型疫苗佐剂的可能性正越来越受到关注.铁纳米颗粒的理化特性包括...     

纳米递送系统在mRNA肿瘤疫苗中的研究进展

肿瘤疫苗是肿瘤免疫治疗中极具发展前景的治疗策略之一,其通过递送肿瘤抗原促进抗原递呈过程,进而激活抗肿瘤免疫反应。信使RNA (messenger RNA, mRNA)疫苗是一种新型疫苗,通过向体内递送特定抗原的mRNA序列并表达相应抗原蛋白,从而激活机体免疫系统达到免疫治疗的目的。mRNA疫苗与传统疫苗相比具有生产周期短、有效性高和免疫原性强等优势,近年来mRNA疫苗在肿瘤免疫治疗中的应用引起广泛关注,但mRNA的不稳定性和低递送效率限制了其应用。纳米递送系统能有效解决mRNA疫苗递送的难题,极大地促进mRNA肿瘤疫苗的研究进程和临床应用,已成为mRNA疫苗研究的热点。本文对mRNA肿瘤疫苗进行介绍,重点对纳米递送系统在mRNA肿瘤疫苗中的应用进行综述,以期为mRNA肿瘤疫苗高效递送及肿瘤免疫治疗提供新思路和新方法。     

亚单位疫苗佐剂研究进展

接种疫苗是预防、控制甚至消灭传染病最有效的方法。近年来,随着DNA重组技术的发展,重组亚单位疫苗等新型疫苗的研究取得快速发展。亚单位疫苗由病原体的免疫活性片段制备而成,具有制备简单、安全性高等优点,成为新型疫苗的研究开发热点。然而,亚单位疫苗抗原的免疫原性较弱,常需添加佐剂系统增强其免疫作用。因此,本文将对亚单位疫苗中的常用佐剂和新型佐剂研究进展进行综述与分析,旨在为亚单位疫苗的研发提供理论依据。     

基于脂质载体的mRNA疫苗递送系统研究进展

转录信使RNA（mRNA）具有安全有效的蛋白质表达谱,在遗传病新疗法、表达功能性蛋白和抗体、疫苗或基因编辑的开发上具有良好的应用前景。随着病原生物学与免疫学的发展,mRNA疫苗凭借其高效性与稳定性而愈发被重视。目前,有效的体内递送手段是mRNA疫苗所面临的较大挑战,脂质载体的mRNA疫苗递送系统具有靶向性强、包封率高、细胞亲和性好的特点,部分脂质载体能够使mRNA疫苗在体内以非侵入性的方式进行靶向递送。从mRNA疫苗递送的主要难点、脂质载体在mRNA疫苗递送中的研究现状以及针对新型冠状病毒（SARS-CoV-2）的mRNA脂质载体疫苗开发进展,共3个方面总结了目前基于脂质载体的mRNA疫苗递送系统研究进展,并对未来的基因疫苗递送系统研究方向进行展望。     

Bacterial ghosts as antigen delivery vehicles

The bacterial ghost system is a novel vaccine delivery system unusual in that it combines excellent natural intrinsic adjuvant properties with versatile carrier functions for foreign antigens. The efficient tropism of bacterial ghosts (BG) for antigen presenting cells promotes the generation of both cellular and humoral responses to heterologous antigens and carrier envelope structures. The simplicity of both BG production and packaging of (multiple) target antigens makes them particularly suitable for use as combination vaccines. Further advantages of BG vaccines include a long shelf-life without the need of cold-chain storage due to their freeze-dried status, they are safe as they do not involve host DNA or live organisms, they exhibit improved potency with regard to target antigens compared to conventional approaches, they are versatile with regards to DNA or protein antigen choice and size, and as a delivery system they offer high bioavailability.     

Old and new vaccine approaches

The conventional, currently available vaccines, though quite successful, suffer from a few shortcomings which hamper future vaccine development. We present herewith some of the new approaches that are presently being pursued, including (1) the development of recombinant, or genetically engineered, vaccines which are based either on the expression of the relevant protective antigen and its formulation into vaccine, or the production of live vaccines, where an appropriate live vector (virus or bacterium) presents the foreign antigen. (2) The development of naked DNA vaccines that include the gene(s) coding for the relevant protective antigen(s). (3) Peptide vaccines that include defined B cell and T cell epitopes, either in a chemically synthesized molecule or in a synthetic recombinant construct. The efficacy of such vaccines is usually dependent on adequate presentation and delivery, namely, carrier/adjuvant technology. (4) Therapeutic vaccines, based on all of the above approaches, may be applied for chronic or long-term infections, or for noninfectious diseases including autoimmune diseases, various neurological disorders, allergy and cancer.     

Advanced subunit vaccine delivery technologies: From vaccine cascade obstacles to design strategies

Designing and manufacturing safe and effective vaccines is a crucial challenge for human health worldwide. Research on adjuvant-based subunit vaccines is increasingly being explored to meet clinical needs. Nevertheless, the adaptive immune responses of subunit vaccines are still unfavorable, which may partially be attributed to the immune cascade obstacles and unsatisfactory vaccine design. An extended understanding of the crosstalk between vaccine delivery strategies and immunological mechanisms could provide scientific insight to optimize antigen delivery and improve vaccination efficacy. In this review, we summarized the advanced subunit vaccine delivery technologies from the perspective of vaccine cascade obstacles after administration. The engineered subunit vaccines with lymph node and specific cell targeting ability, antigen cross-presentation, T cell activation properties, and tailorable antigen release patterns may achieve effective immune protection with high precision, efficiency, and stability. We hope this review can provide rational design principles and inspire the exploitation of future subunit vaccines.     

Advances in vaccine delivery: transcutaneous immunisation

Needle-free delivery of vaccines has become a global priority. Transcutaneous immunisation (TCI), topical application of vaccine antigens to the skin, can elicit systemic antibody and T-cell responses, suggesting that this new technique may provide a means for vaccination without needles. TCI requires the use of an adjuvant such as cholera toxin added to a vaccine antigen, such as diphtheria toxoid, to induce antibodies to diphtheria toxoid. The adjuvant and antigen are thought to target Langerhans cells, potent antigen-presenting cells found in the superficial layers of the skin. TCI appears to be a highly practical technique for delivery of vaccines that provides unique access to the immune system.     

Formulation and stabilization of recombinant protein based virus-like particle vaccines

Vaccine formulation development has traditionally focused on improving antigen storage stability and compatibility with conventional adjuvants. More recently, it has also provided an opportunity to modify the interaction and presentation of an antigen/adjuvant to the immune system to better stimulate the desired immune responses for maximal efficacy. In the last decade, there has been a paradigm shift in vaccine antigen and formulation design involving an improved physical understanding of antigens and a better understanding of the immune system. In addition, the discovery of novel adjuvants and delivery systems promises to further improve the design of new, more effective vaccines. Here we describe some of the fundamental aspects of formulation design applicable to virus-like-particle based vaccine antigens (VLPs). Case studies are presented for commercially approved VLP vaccines as well as some investigational VLP vaccine candidates. An emphasis is placed on the biophysical analysis of vaccines to facilitate formulation and stabilization of these particulate antigens.     

Uniqueness of the mucosal immune system for the development of prospective mucosal vaccine

The mucosal immune system acts as the first line of defense against microbial infection through a dynamic immune network based on innate and acquired mucosal immunity. To prevent infectious diseases, it is pivotal to develop effective mucosal vaccines that can induce both mucosal and systemic immune responses, especially secretory IgA (S-IgA) and plasma IgG, against pathogens. Recent advances in medical and biomolecular engineering technology and progress in cellular and molecular immunology and infectious diseases have made it possible to develop versatile mucosal vaccine systems. In particular, mucosal vaccines have become more attractive due to recent development and adaptation of new types of drug delivery systems not only for the protection of antigens from the harsh conditions of the mucosal environment but also for effective antigen delivery to mucosa-associated lymphoid tissues such as Peyer's patches and nasopharynx-associated lymphoid tissue, the initiation site for the induction of the antigen-specific immune response. In this review, we shed light on the dynamics of the mucosal immune system and recent advances toward the development of prospective mucosal antigen delivery systems for vaccines.     

Carbohydrate molecules: an expanding horizon in drug delivery and biomedicine

This review presents successful applications of carbohydrate molecules in drug delivery, vaccine development, cancer, HIV and various other diseases based on advances in glycobiology and glycochemistry. Carbohydrate-mediated delivery could be site specific/cell specific. Carbohydrate-based delivery system has been successfully utilized for the delivery of macromolecular drugs, antigen, and potential therapeutic drug candidates. Lectin, the high affinity carbohydrate-binding nonimmune glycoproteins has specific and noncovalent binding sites for defined carbohydrates. Endogenous surface lectins of cancer cells participate in the regulation of tumor cell growth. The oligosaccharides constitute potential recognition sites for carbohydrate-mediated interactions between cells and drug carriers bearing suitable site directing molecules. The recognition of carbohydrate immunodeterminants has created great attention in the development of carbohydrate-based vaccines. Peptide mimotopes provide a strategy to augment human immunodeficiency virus 1 (HIV-1) specific carbohydrate reactive immune responses. Experimental cancer and HIV vaccines are being developed in attempts to overcome weak immunological responses to carbohydrate-rich surface antigens using carriers, adjuvants, and novel carbohydrate antigen constructs. Current carbohydrate-based vaccines are used for prostate cancer, typhus, pneumonia, and meningitis; vaccines for malaria, anthrax, and leishmaniasis are under development. This article discusses the current research involved in the role of carbohydrate molecules in targeted controlled drug delivery, immunology, and vaccine development.     

M cell-targeted delivery of vaccines and therapeutics

BACKGROUND: M (microfold or membranous) cells are specialised epithelial cells responsible for antigen sampling at the interface of mucosal surfaces and the environment. Their high transcytotic ability make M cells an attractive target for mucosally delivered vaccines and therapeutics. OBJECTIVE: This brief review discusses the current state of M cell-targeted mucosal delivery systems and the potential of such delivery systems for the development of new vaccines and therapeutics against mucosal infectious and inflammatory diseases. SCOPE: A variety of synthetic microparticles/nanoparticles have been developed and tested as vehicles for M cell-targeted mucosal drug and vaccine delivery. beta1 integrins, pathogen recognition receptors, specific carbohydrate residues and other M cell surface antigens have been exploited as potential targets for the delivery of mucosal vaccines and therapeutics. CONCLUSION: Despite a considerable body of literature, much work still needs to be done before an effective M cell-targeted vaccine or therapeutic is developed.     

Recent developments in vaccine delivery systems

New generation vaccines, particularly those based on recombinant proteins and DNA, are likely to be less reactogenic than traditional vaccines, but are also less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. Adjuvants can be broadly separated into two classes, based on their principal mechanisms of action; vaccine delivery systems and 'immunostimulatory adjuvants'. Vaccine delivery systems are generally particulate e.g. emulsions, microparticles, iscoms and liposomes, and mainly function to target associated antigens into antigen presenting cells (APC), including macrophages and dendritic cells. This review will focus on recent developments in vaccine delivery systems. Immunostimulatory adjuvants are predominantly derived from pathogens and often represent pathogen associated molecular patterns (PAMP) e.g. LPS, MPL, CpG DNA, which activate cells of the innate immune system. Once activated, cells of innate immunity drive and focus the acquired immune response. In some studies, delivery systems and immunostimulatory agents have been combined for more effective delivery of the immunostimulatory adjuvant into APC. A rational approach to the development of new and more effective vaccine adjuvants will require much further work to better define the mechanisms of action of existing adjuvants. The discovery of more potent adjuvants may allow the development of vaccines against infectious agents such as HIV which do not naturally elicit protective immunity. New adjuvants and delivery system combinations may also allow vaccines to be delivered mucosally.