Cancer vaccines entering Phase III clinical trials

The last 10 years have seen a growth in the number of tumour antigens identified from immune responses raised in patients. The discovery that tumours can be recognised by the immune system stimulated a great deal of work characterising the molecular mechanisms underlying immune recognition. This in turn has led to an impressive array of immunological approaches to the generation of cancer vaccines; these range from molecularly defined T cell epitopes, antibody-based vaccines, cytokine therapies, immune modulators and DNA vaccines, to whole cell vaccines and, more recently, combinations of these methods. Many of these approaches have entered Phase I/II trials and have shown interesting clinical results. Moreover, they have extended our knowledge of the immune system and our understanding of the mechanisms required to design a successful cancer vaccine. This review outlines some of the approaches that have led to some of these vaccines entering Phase III clinical trials, discusses their modes of action and reports on their current status in trial.     

Cancer vaccines entering Phase III clinical trials

The last 10 years have seen a growth in the number of tumour antigens identified from immune responses raised in patients. The discovery that tumours can be recognised by the immune system stimulated a great deal of work characterising the molecular mechanisms underlying immune recognition. This in turn has led to an impressive array of immunological approaches to the generation of cancer vaccines; these range from molecularly defined T cell epitopes, antibody-based vaccines, cytokine therapies, immune modulators and DNA vaccines, to whole cell vaccines and, more recently, combinations of these methods. Many of these approaches have entered Phase I/II trials and have shown interesting clinical results. Moreover, they have extended our knowledge of the immune system and our understanding of the mechanisms required to design a successful cancer vaccine. This review outlines some of the approaches that have led to some of these vaccines entering Phase III clinical trials, discusses their modes of action and reports on their current status in trial.     

Prospects for development of vaccines against fungal diseases.

Despite recent additions to our antifungal drug armamentarium, success rates for many mycoses remain unacceptably low and antifungal drug therapy is often limited by toxicity, resistance and high cost. To circumvent these difficulties, alternative approaches to prevention and treatment are being developed, including vaccines and passive immunotherapy. Here, we review the progress of current research in this field, discuss some of the potential obstacles to developing and marketing a protective antifungal vaccine, and summarize two clinical trials of monoclonal antibodies as adjunctive treatment of established mycoses. In animal models of fungal infections, protective responses have been elicited with vaccines composed of whole organisms, soluble cell free fractions, purified proteins, glycans and nucleic acids. Methods to boost the immune response to vaccination include the use of adjuvants and antigen-loaded dendritic cells (DCs). A significant challenge to the development of effective vaccines will be to elicit immune responses in immunocompromised individuals who are most at risk for invasive fungal infections.     

Immune modulators with defined molecular targets: cornerstone to optimize rational vaccine design

Vaccination remains the most valuable tool for preventing infectious diseases. However, the performance of many existing vaccines should be improved and there are diseases for which vaccines are still not available. The use of well-defined antigens for the generation of subunit vaccines has led to products with an improved safety profile. However, purified antigens are usually poorly immunogenic, making essential the use of adjuvants. Despite the fact that adjuvants have been used to increase the immunogenicity of vaccines for more than 70 years, only a handful has been licensed for human use (e.g., aluminium salts, the micro-fluidized squalene-in-water emulsion MF59 and monophosphoryl lipid A). Thus, the development of new adjuvants which are able to promote broad and sustained immune responses at systemic and mucosal levels still remains as a major challenge in vaccinology. Recent advances in our understanding of the immune system have facilitated the identification of new biological targets for screening programs aimed at the discovery of novel immune stimulators. This resulted in the identification of new candidate adjuvants, which made possible the modulation of the immune responses elicited according to specific needs. A number of promising adjuvants which are currently under preclinical or clinical development will be described in this review.     

Application of DNA vaccine technology to aquaculture

The aquaculture industry needs to augment its global production and efficiency to meet the increasing consumer needs for fish and shellfish products. Unfortunately, infectious diseases have been a major impediment to the development and profitability of fish farms. While vaccines offer the most efficient way to control infectious pathogens, current products have only been successful against some diseases. These are mostly bacterial, and there are still several important diseases, mainly of viral and parasitic origin, for which no prophylactic treatment exists. DNA vaccines, compared to traditional antigen vaccines, have several practical and immunological advantages that make them very attractive for the aquaculture industry. The early success of DNA vaccines in animal models was very encouraging, but fish are unique in many aspects, and findings with other classes of vertebrate, namely mammals and birds, do not necessarily apply to aquatic animals. However, more recent studies with reporter genes showed that fish cells efficiently express foreign proteins encoded by eukaryotic expression vectors. A piscine-specific backbone vector might eventually improve immune responses to DNA vaccines, but there is already strong direct evidence for the induction of protective immunity with currently available plasmids. Immune responses to plasmid DNA injected intramuscularly (IM) into fish are characterized by the production of antibodies, which have been shown to be neutralizing in two different viral disease models. There is also indirect evidence suggesting the induction of cell-mediated immunity. Despite this evidence, immune responses to DNA vaccines have only been poorly characterized in fish because of the limited knowledge of the piscine immune system, and the small number of studies on the subject. Apart from optimizing the efficiency of DNA vaccines, other important issues, such as safety and production cost will be determinants for the potential application of this technology in commercial fish farms. Alternative methods of administration will also have to be developed for small fish and low-valued species, for which IM injection is not practical and/or cost effective.     

Present and future of lung cancer vaccines

New approaches are needed to improve the current treatment of lung cancer. Inducing an immune response against lung tumour cells with vaccines represents an attractive therapy. However, lung tumours had not been considered good targets for vaccine therapy and, therefore, immune approaches have not been studied extensively in this setting. Current experimental strategies for antitumour vaccines include the generation of active immune responses against specific tumour antigens. Understanding the mechanisms of antitumour immunity and identifying relevant tumour-specific antigens will probably improve therapeutic strategies and provide avenues for the future of lung cancer therapy. There have been a number of preclinical immunotherapy trials suggesting activity, and a smaller number of human clinical trials using various vaccines in lung cancer. Initial data from these trials have shown preliminary evidence of induction of immune responses and suggest clinical activity. This paper reviews some of the most important developments in vaccines for lung cancer.     

Present and future of lung cancer vaccines

New approaches are needed to improve the current treatment of lung cancer. Inducing an immune response against lung tumour cells with vaccines represents an attractive therapy. However, lung tumours had not been considered good targets for vaccine therapy and, therefore, immune approaches have not been studied extensively in this setting. Current experimental strategies for antitumour vaccines include the generation of active immune responses against specific tumour antigens. Understanding the mechanisms of antitumour immunity and identifying relevant tumour-specific antigens will probably improve therapeutic strategies and provide avenues for the future of lung cancer therapy. There have been a number of preclinical immunotherapy trials suggesting activity, and a smaller number of human clinical trials using various vaccines in lung cancer. Initial data from these trials have shown preliminary evidence of induction of immune responses and suggest clinical activity. This paper reviews some of the most important developments in vaccines for lung cancer.     

Considerations for non-clinical safety studies of therapeutic peptide vaccines

Guidelines for non-clinical studies of prophylactic vaccines against infectious diseases have been published widely, but similar guidelines for therapeutic vaccines, and especially therapeutic peptide vaccines, have yet to be established. The approach to non-clinical safety studies required for therapeutic vaccines differs from that for prophylactic vaccines due to differences in the risk–benefit balance and the mechanisms of action. We propose the following guidelines for non-clinical safety studies for therapeutic peptide vaccines. (i) Since the main safety concern is related to the immune response that might occur at normal sites that express a target antigen, identification of these possible target sites using in silico human expression data is important. (ii) Due to the strong dependence on HLA, it is not feasible to replicate immune responses in animals. Thus, the required non-clinical safety studies are characterized as those detecting off-target toxicity rather than on-target toxicity.     

Recent advances in immunological adjuvants: the development of particulate antigen delivery systems

New generation vaccines, including those based on recombinant proteins, are safer than traditional vaccines, but are less immunogenic. Therefore, there is an urgent need for the development of new and improved vaccine adjuvants. A number of potent immunostimulatory molecules obtained from bacterial cells or plants have been extensively evaluated as adjuvants. However, a number of these molecules have displayed significant toxicity, both in preclinical animal models and in human clinical trials. An alternative approach to the development of novel adjuvants involves the preparation of particulate antigen delivery systems of similar dimensions to natural pathogens. In the absence of additional immunostimulatory molecules, emulsion droplets and microparticles have been shown to be potent adjuvants for the induction of both humoral and cell-mediated immune responses following systemic administration. Moreover, particulate delivery systems have been shown to display an acceptable toxicity profile in a number of clinical trials. Particulate antigen delivery systems also have the potential to function as potent adjuvants following administration by mucosal routes, including oral and intranasal. An alternative approach to the mucosal delivery of vaccines involves the use of genetically detoxified mutant toxins, e.g., LT-K63, as mucosal adjuvants. The use of novel adjuvants and antigen delivery systems is likely to extend the use of vaccines into the area of therapeutics, involving the eradication of infectious diseases and cancers, or the amelioration of autoimmune disorders.     

Genetic Vaccines: Strategies for Optimization

Vaccination with attenuated or killed microbes, purified or recombinant subunit proteins and synthetic peptides is often hampered by toxicity, the presence of infectious agents, weak immune responses and prohibiting costs, especially in the developing world. Such problems may be circumvented by genetic immunization which has recently emerged as an attractive alternative to conventional vaccines. Numerous studies have already shown that immunization of experimental animals with plasmid DNA encoding antigens from a wide spectrum of bacteria, viruses, protozoa and cancers leads to protective humoural and cell-mediated immunity. This review deals with the background and progress made so far with DNA vaccines and their theoretical and practical advantages as well as potential risks, discusses proposed mechanisms of DNA transfection of cells and induction of immune responses to the produced vaccine antigen, and evaluates strategies for the control and optimization of such responses.     

DNA疫苗佐剂的研究进展

DNA疫苗是一种很有希望的免疫方法,经多途径接种质粒DNA能引起有效的免疫应答,重复给予不会产生抗载体免疫.然而,质粒DNA疫苗在小型实验动物中诱导的免疫应答远强于在人类和其他非人灵长类动物中.已设计多种佐剂通过直接刺激免疫系统或增强DNA表达来提高疫苗的免疫原性,这些佐剂包括免疫协同刺激分子、细胞因子、补体分子、脂质体、核酸、聚合物、纳米粒和微粒类佐剂.此文对DNA疫苗佐剂的研究进展作一综述.     

对多糖类疫苗免疫应答的研究进展

某些有荚膜的细菌,如b型流感嗜血杆菌、脑膜炎球菌和肺炎链球菌,其荚膜多糖可以开发成疫苗,但对儿童的免疫原性低,只有短期保护作用.多糖与蛋白质结合成为结合疫苗可以部分改善多糖疫苗的缺陷.此文回顾了对结合和非结合的多糖类疫苗的免疫应答研究进展,特别是关于人体对这些疫苗的异常应答的研究,以了解对多糖类疫苗的应答机制,从而有助于解决多糖类疫苗的低效和异常应答问题.     

DNA疫苗佐剂的研究进展

DNA疫苗是一种很有希望的免疫方法,经多途径接种质粒DNA能引起有效的免疫应答,重复给予不会产生抗载体免疫.然而,质粒DNA疫苗在小型实验动物中诱导的免疫应答远强于在人类和其他非人灵长类动物中.已设计多种佐剂通过直接刺激免疫系统或增强DNA表达来提高疫苗的免疫原性,这些佐剂包括免疫协同刺激分子、细胞因子、补体分子、脂质体、核酸、聚合物、纳米粒和微粒类佐剂.此文对DNA疫苗佐剂的研究进展作一综述.     

Peptide-based subunit nanovaccines

Classical vaccines incorporating live or attenuated microorganisms possess several disadvantages and cannot be applied against cancer and some pathogens. Modern vaccines utilizing immunogenic subunits derived from a particular pathogen are able to overcome these obstacles but need a specific delivery system for their efficacy. Nanotechnology has opened a new window into these delivery methodologies. A nano-sized formulation of subunit vaccines has been proven to be very effective in inducing cellular and humoral immune responses. Here, we review a number of peptide vaccine delivery strategies based on nanoparticles composed of polymers, peptides, lipids, and inorganic materials.     

The central role played by peptides in the immune response and the design of peptide-based vaccines against infectious diseases and cancer

Vaccines are one of the most cost effective methods of improving public health thereby increasing the quality of life. Prophylactic and therapeutic treatment by vaccines can prevent infectious diseases and some cancers and could also be used in the treatment of autoimmune disorders. An appreciation of this potential has resulted in a burgeoning literature which not only describes the scientific efforts being made into designing new and improved vaccines but also drives the efforts being made by public health organizations world-wide in delivering vaccines to the community. At the forefront of technologies being applied to the design of vaccines is the use of synthetic peptides; the chemical technologies used to assemble peptides have made great strides over the last decade and assembly of hi-fidelity peptides which can be of high molecular weight, multimeric or even branched is now almost routine. Together with the advances in peptide technology our understanding of the molecular events that are necessary to induce immune responses has also made great strides. The central role that peptides play in immune recognition is now recognised and rules are emerging that are being applied to the construction of peptide-based vaccines that, in the right context, can induce humoral (antibody) and cellular (cytotoxic and helper T cell) immune responses. Synthetic peptides are exquisitely placed to answer questions about immune recognition and along the way to provide us with new and improved vaccines.     

ISCOMs and other saponin based adjuvants

Saponins are chemically a heterogeneous group of sterol glycosides and triterpene glycosides which are common constituents of plants. One source of triterpenoid saponins obtained from the bark of Quillaia saponaria Molina (the soap bark tree) have been known to cause substantial enhancement of immune responses since the 1920s. Despite their use in animal vaccines, the development of saponin-based formulations for human vaccines has been impeded by their complexity and concerns about toxicity. This review briefly covers the use of saponins for animal vaccines but focuses mainly on the development of these adjuvants for use in man. Important aspects include preparation of purified or highly defined saponin fractions, improved understanding of the relationships between adjuvant activity, toxicity and structure of saponins and formulation of saponins into structures with reduced toxicity such as ISCOMs. Recent developments in the understanding of cellular interactions, cytokine induction and the in vivo localisation of saponin containing formulations will also be reviewed.     

Uptake and adjuvant activity of orally delivered saponin and ISCOM vaccines

Saponins are a highly heterogenous group of glycosides which are common in plants and have been known to have adjuvant properties since the 1920s. The immunostimulating complex or ISCOM is a particulate adjuvant/antigen delivery system. ISCOMs are open cage-like complexes typically with a diameter of about 40 nm which are built up by cholesterol, lipid, immunogen and saponins from the bark of Quillaia saponaria Molina (soap bark tree). ISCOMs and saponins are used as adjuvants in some commercial veterinary vaccines and have been examined as adjuvants in a large number of human experimental vaccines. This review describes the current status and potential of saponin and ISCOMs as adjuvants for orally-administered vaccines with special reference to the induction of local and systemic immune responses and interactions with the intestinal epithelium. The structure and composition of saponins and ISCOMs will also be reviewed.     

治疗黑色素瘤的DC疫苗研究新进展

黑色素瘤是最具侵袭性的皮肤恶性肿瘤,易发生早期转移和治疗后复发。治疗性肿瘤疫苗是新兴的免疫疗法,具有毒性低以及可抑制肿瘤转移的特点。目前已有多个针对黑色素瘤治疗性疫苗的研究,其中黑色素瘤治疗性树突状细胞（DC）疫苗引起了广泛关注。虽然肿瘤治疗性DC疫苗在黑色素瘤中的疗效已被多项研究证实,但该类疫苗存在免疫效应不足、单独使用疗效不佳等问题,仍具有较大的改进空间。本文对黑色素瘤的治疗性DC疫苗的研究现状进行了综述,并对肿瘤治疗性DC肿瘤的研究重点及优化策略进行展望。     

对世界卫生组织预防传染病mRNA疫苗非临床评价技术要点的解析

目的：了解WHO最新发布的《预防传染病mRNA疫苗质量、安全及有效性评价法规考虑》中关于mRNA疫苗非临床评价的主要内容,为我国评价此类产品非临床研究提供参考。方法：分析mRNA疫苗的主要特点,对照《预防传染病mRNA疫苗质量、安全及有效性评价法规考虑》,梳理mRNA疫苗非临床研究特别是药效学和毒理学研究设计、实施和分析的关键要点。结果与结论：mRNA技术已成为疫苗研发的前沿技术,作为新型生物制品,mRNA疫苗具有诸多不同于传统生物制品的特点。WHO认为非临床研究的设计、实施和分析应充分考虑mRNA产品的技术特点,相关药效学和毒理学研究应着重解决免疫应答的持久性或持久性免疫细胞表型、Ⅰ型干扰素介导的固有免疫应答、mRNA和LNPs的生物分布和持久性、全身和局部的毒性和炎症反应、非自然修饰核苷的潜在毒性、脂质纳米颗粒中新型脂质的毒性等方面问题,并提出了在公共卫生突发事件背景下针对优先病原体的mRNA疫苗非临床加速评价的考虑要点,对我国非临床评价此类产品具有很好的指导作用和应用价值。     

Is There an Optimal Formulation and Delivery Strategy for Subunit Vaccines?

Modern vaccine design has moved away from attenuated or inactivated whole-pathogen vaccines to more pure and defined subunit vaccines. However subunit antigens have poor bioavailability and stability and lack immunogenicity. To overcome these issues subunit vaccines have to be administered in a suitable delivery system in combination with immune stimulants. Many different delivery systems have been developed and investigated each having different modes of action, for example increasing delivery and/or sustaining delivery of antigen to immune cells. In addition a number of different routes of immunization are possible and these can play a crucial role in determining the fate of an immune response. In this review the different strategies for the delivery of prophylactic and therapeutic subunit vaccines along with the impact of these on the immune responses generated are discussed.