Delivery of Chlamydia vaccines

The plethora of ocular, genital and respiratory diseases of Chlamydia, including nongonococcal urethritis, cervicitis pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, conjunctivitis, blinding trachoma and interstitial pneumonia, and chronic diseases that may include atherosclerosis, multiple sclerosis, adult onset asthma and Alzheimer's disease, still pose a considerable public health challenge to many nations. Although antibiotics are effective against Chlamydia when effectively diagnosed, asymptomatic infections are rampart, making clinical presentation of complications often the first evidence of an infection. Consequently, the current medical opinion is that an effective prophylactic vaccine would constitute the best approach to protect the human population from the most severe consequences of these infections. Clinical and experimental studies have demonstration that Chlamydia immunity in animals and humans is mediated by T cells and a complementary antibody response, and the completion of the genome sequencing of several isolates of Chlamydia is broadening our knowledge of the immunogenic antigens with potential vaccine value. Thus, major advances have been made in defining the essential elements of a potentially effective subunit vaccine design and parameters for evaluation. However, the challenge to develop effective delivery systems and human compatible adjuvants that would boost the immune response to achieve long-lasting protective immunity remains an elusive objective in chlamydial vaccine research. In response to evolving molecular and cellular technologies and novel vaccinology approaches, considerable progress is being made in the construction of novel delivery systems, such as DNA and plasmid expression systems, viral vectors, living and nonliving bacterial delivery systems, the use of chemical adjuvants, lipoprotein constructs and the codelivery of vaccines and specific immuno-modulatory biological agonists targeting receptors for chemokines, Toll-like receptors, and costimulatory molecules. The application of these novel delivery strategies to Chlamydia vaccine design could culminate in timely achievement of an efficacious vaccine.     

Delivery of Chlamydia vaccines

The plethora of ocular, genital and respiratory diseases of Chlamydia, including nongonococcal urethritis, cervicitis pelvic inflammatory disease, ectopic pregnancy, tubal factor infertility, conjunctivitis, blinding trachoma and interstitial pneumonia, and chronic diseases that may include atherosclerosis, multiple sclerosis, adult onset asthma and Alzheimer’s disease, still pose a considerable public health challenge to many nations. Although antibiotics are effective against Chlamydia when effectively diagnosed, asymptomatic infections are rampart, making clinical presentation of complications often the first evidence of an infection. Consequently, the current medical opinion is that an effective prophylactic vaccine would constitute the best approach to protect the human population from the most severe consequences of these infections. Clinical and experimental studies have demonstration that Chlamydia immunity in animals and humans is mediated by T cells and a complementary antibody response, and the completion of the genome sequencing of several isolates of Chlamydia is broadening our knowledge of the immunogenic antigens with potential vaccine value. Thus, major advances have been made in defining the essential elements of a potentially effective subunit vaccine design and parameters for evaluation. However, the challenge to develop effective delivery systems and human compatible adjuvants that would boost the immune response to achieve long-lasting protective immunity remains an elusive objective in chlamydial vaccine research. In response to evolving molecular and cellular technologies and novel vaccinology approaches, considerable progress is being made in the construction of novel delivery systems, such as DNA and plasmid expression systems, viral vectors, living and nonliving bacterial delivery systems, the use of chemical adjuvants, lipoprotein constructs and the codelivery of vaccines and specific immuno-modulatory biological agonists targeting receptors for chemokines, Toll-like receptors, and costimulatory molecules. The application of these novel delivery strategies to Chlamydia vaccine design could culminate in timely achievement of an efficacious vaccine.     

免疫新策略:经皮免疫

经皮免疫是一种将抗原和佐剂局部应用于皮肤诱导产生全身免疫反应的一种新方法。皮肤不但是组织外源性物质包括病原体进入体内的物理屏障,还是复杂有效的免疫系统,因此皮肤是重要的免疫接种靶标。在人类和多种动物的实验中,经皮免疫的效果已经得到了证实。经皮免疫是一种免疫的新策略,有着广阔的实际应用前景。     

Subunit vaccines of the future: the need for safe, customized and optimized particulate delivery systems

A major challenge for current vaccine development is the fact that many new subunit vaccines based on highly purified recombinant proteins are poorly immunogenic and mobilize insufficient immune responses for protective immunity. Adjuvants are therefore needed in vaccine formulations to enhance, direct and maintain the immune response to vaccine antigens. Few adjuvants are currently approved for human use that mainly induce humoral immunity, and there is therefore an unmet medical need for development of effective and safe adjuvants that in addition can stimulate cellular or mucosal immunity, or combinations thereof, depending on the requirements for protection against the specific disease. Vaccine delivery systems are important components of adjuvants that allow proper delivery of antigens to antigen-presenting cells. Moreover, they often possess intrinsic immunopotentiating activity and/or can be customized towards a given immunological profile by the appropriate combination with immunopotentiating compounds. This article reviews the current status of human-tailored vaccine delivery with special focus on how to design safe particulate vaccine delivery systems with respect to composition, physicochemical properties, antigen association and choice of administration route, in order to better customize vaccine formulations towards specific diseases in the future.     

Schistosomiasis vaccines

Schistosomiasis is a major neglected tropical disease of public health importance to a billion people. An estimated 200 million people are currently infected; an additional 779 million individuals are at risk to acquire the infection in 74 countries. Despite many years of implementation of mass anti-parasitic drug therapy programs and other control measures, this disease has not been contained and continues to spread to new geographic areas. The discovery of a protective vaccine still remains the most potentially effective means for the control of this disease, especially if the vaccine provides long-term immunity against the infection. A vaccine would contribute to the reduction of schistosomiasis morbidity through induced immune responses leading to decrease in parasite load and reduced egg production. This vaccine could be administered to children between the ages of 3 and 12 years to prevent severe infection in a particularly high risk population. This review summarizes the current status of schistosomiasis vaccine development.     

Vaccines for parasitic diseases

Significant effort and progress has occurred over the last several years in the development of vaccines against three main tropical parasitic diseases (malaria, leishmaniases and schistosomiasis). However, an effective vaccine is not yet available. The difficulties in developing a vaccine against parasitic disease are complicated not only by the necessity to identify (and produce) appropriate, protective antigens but also a lack of complete understanding of the types of immune responses needed for protection. Despite these hurdles, several candidate vaccines are under development for each disease; at least one promising vaccine candidate exists that is in late stage clinical testing.     

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.     

Molecular basis for improved anthrax vaccines

The current vaccine for anthrax has been licensed since 1970 and was developed based on the outcome of human trials conducted in the 1950s. This vaccine, known as anthrax vaccine adsorbed (AVA), consists of a culture filtrate from an attenuated strain of Bacillus anthracis adsorbed to aluminum salts as an adjuvant. This vaccine is considered safe and effective, but is difficult to produce and is associated with complaints about reactogenicity among users of the vaccine. Much of the work in the past decade on generating a second generation vaccine is based on the observation that antibodies to protective antigen (PA) are crucial in the protection against exposure to virulent anthrax spores. Antibodies to PA are thought to prevent binding to its cellular receptor and subsequent binding of lethal factor (LF) and edema factor (EF), which are required events for the action of the two toxins: lethal toxin (LeTx) and edema toxin (EdTx). The bacterial capsule as well as the two toxins are virulence factors of B. anthracis. The levels of antibodies to PA must exceed a certain minimal threshold in order to induce and maintain protective immunity. Immunity can be generated by vaccination with purified PA, as well as spores and DNA plasmids that express PA. Although antibodies to PA address the toxemia component of anthrax disease, antibodies to additional virulence factors, including the capsule or somatic antigens in the spore, may be critical in development of complete, sterilizing immunity to anthrax exposure. The next generation anthrax vaccines will be derived from the thorough understanding of the interaction of virulence factors with human and animal hosts and the role the immune response plays in providing protective immunity.     

Bioadhesive delivery systems for mucosal vaccine delivery

Mucosal vaccine delivery potentially induces mucosal as well as systemic immune responses and may have advantages particularly for optimal protection against pathogens that infect the host through mucosal surfaces. However, the delivery of antigens through mucosal membranes remains a major challenge due to unfavorable physiological conditions (pH and enzymes) and significant biological barriers, which restrict the uptake of antigens. To improve mucosal vaccine delivery, the use of bioadhesive delivery systems offers numerous advantages, including protection from degradation, increasing concentration of antigen in the vicinity of mucosal tissue for better absorption, extending their residence time, and/or targeting them to sites of antigen uptake. Although some bioadhesives have direct immune stimulating properties, it appears most likely that successful mucosal vaccination will require the addition of vaccine adjuvants for optimal immune responses, particularly if they are to be used in an unprimed population. Thus, complex vaccine formulations and delivery strategies have to be carefully designed to appropriately stimulate immune response for the target pathogen. In addition, careful consideration is needed to define the “best” route for mucosal immunization for each individual pathogen.     

Prospects for a human Toxoplasma vaccine

Human toxoplasmosis is usually benign, but may occasionally lead to severe or lethal damages when combined with immunosuppressive states or when transmitted to the fetus during pregnancy. Only a vaccine could prevent these harmful effects. The oral route is the natural portal of entry of T. gondii. A protective immune response at the mucosal level is required to kill the parasite as soon as it penetrates the intestinal barrier thus preventing toxoplasma from invading the host and settling into tissues. The probable major roles played by both CD8 T cells and antibodies, specially IgA, suggest that the best strategy would be to stimulate both the cellular and humoral arms of the mucosal immune system. Mucosal dendritic cells have been shown to induce good protection against oral toxoplasma challenge. Our hypothesis is that an acceptable and effective human vaccine would have to carry the optimized synthetic vaccine (subunit, DNA or replicon) plus an appropriate adjuvant and to target the mucosal dendritic cells by means of an inert delivery system such as polymer microparticles, which can be endocytosed by M cells of the gut or nasal-associated lymphoid tissues.     

Designing Vaccines to Neutralize Effective Toxin Delivery by Enterotoxigenic Escherichia coli

Enterotoxigenic Escherichia coli (ETEC) are a leading cause of diarrheal illness in developing countries. Despite the discovery of these pathogens as a cause of cholera-like diarrhea over 40 years ago, and decades of vaccine development effort, there remains no broadly protective ETEC vaccine. The discovery of new virulence proteins and an improved appreciation of the complexity of the molecular events required for effective toxin delivery may provide additional avenues to pursue in development of an effective vaccine to prevent severe diarrhea caused by these important pathogens.     

Nanotechnology-based manipulation of dendritic cells for enhanced immunotherapy strategies

Dendritic cells (DCs) are potent antigen-presenting cells capable of initiating a primary immune response and possess the ability to activate T cells and stimulate the growth and differentiation of B cells. DCs provide a direct connection between innate and adaptive immune response, and arise from bone marrow precursors that are present in immature forms in peripheral tissues, where they are prepared to capture antigens. DCs migrate from the peripheral tissues to the closest lymph nodes through afferent lymphatic vessels to present the foreign antigens, stimulating T-cell activation and initiating a cellular immune response. Moreover, it is known that DCs have an important role in various diseases and conditions involving the immune system, particularly in cancer and autoimmune disorders. For these reasons, targeting nanoparticles (NPs) to DCs provides a promising strategy for developing an efficient balanced and protective immune response. NPs can modulate the immune response and might be potentially useful as effective vaccine adjuvants for infectious disease and cancer therapy. The objective of this review is to present the latest advances in NP delivery methods targeting DCs, the mechanisms of action, potential effects, and therapeutic results of these systems and their future applications, such as improved vaccination strategies, cancer immunotherapy, and immunomodulatory treatments.From the Clinical EditorDendritic cells (DCs) are potent antigen-presenting cells capable of initiating a primary immune response and activating T and B cells. The role of DC-s can be considered as a bridge between innate and adaptive immunity. Targeting nanoparticles (NPs) to DCs can modulate the immune response and might be useful as vaccine adjuvants in infectious disease and cancer therapy.     

Chronicles in drug discovery

Chronicles in Drug Discovery features special interest reports on advances in drug discovery. This month we highlight new options to prevent oral mucositis, a treatment-limiting adverse effect of chemotherapy. Studies are currently focusing on mechanism-based therapies to prevent or repair DNA damage to epithelial and submucosal cells and the cascade or events that follow to cause tissue damage or analgesics to ease the associated oral cavity pain. Therapeutic limitations also exist for the use of the highly effective antibiotic gentamicin, as it evokes acute renal failure. Mechanistic investigations have shed some light on potential targets: the kallikreins, peroxynitrite-related pathways, superoxide production and the accumulation of aminoglycosides. New antibiotic strategies for trachoma, the leading cause of preventable blindness, are also explored along with studies to aid the development of vaccine candidates. Finally, we discuss the utility of allosteric-potentiating ligands to modulate nicotinic acetylcholine receptors, mimicking the reward/addictive effects of nicotine, as potential strategies for smoking cessation.     

Campylobacter vaccine development:a key to controlling enteric diseases

Worldwide, Campylobacter jejuni is a major cause of diarrhoea and dysentery, with approximately 400 million cases occurring annually. Control of the disease through public health and antibiotic measures is insufficient, and vaccination offers the most promising solution. Infection produces immunity from disease, suggesting that vaccination may produce similar protection. Epidemiological data suggest that there are conserved antigens among serotypes; immunity against which protects against disease. Therefore a monovalent serotype vaccine seems practical. Several antigens on Campylobacter have been found to be immunogenic and, in some cases, associated with virulence. However, none of these proteins have been produced recombinantly in the proper conformation, nor have they been protective in preclinical models. For this reason, live attenuated or inactivated Campylobacter whole cell (CWC) vaccines may be the best approach. Development of an attenuated strain of Campylobacter has been complicated by the fact that the organism is highly transformable. Rec A mutants of Campylobacter have recently been constructed in an attempt to avoid this trait. Such mutants have been made defective in various virulence properties and are being evaluated for safety in preclinical models. Antex Biologics has made an inactivated CWC vaccine using the Company's patented NST (nutriment signal transduction) technology, whereby the cells are grown using physiologically logical conditions to maximise the expression of antigens associated with in vivo virulence. This vaccine has been shown to be safe, immunogenic, and protective in preclinical models of infection. Inclusion of a mucosal adjuvant in the vaccine increases the immunological response to the antigen. Recent Phase I and Phase II clinical trials, using the CWC vaccine formulated with an adjuvant and orally administered, show that the vaccine is safe and immunogenic in human volunteers. The approach used to develop this inactivated whole cell Campylobacter vaccine is also applicable for the rapid development of new vaccines against a variety of mucosal pathogens.     

Current trachoma treatment methodologies: focus on advancements in drug therapy

Currently, there are approximately 6 million people with irreversible blindness as a result of chronic follicular conjunctivitis with subsequent corneal scarring caused by Chlamydia trachomatis, also known as trachoma. On the basis of the clinical studies evaluated, the most widely tested effective pharmacological treatments for trachoma today are topical tetracycline 1% to be applied to both eyes twice daily for 6 weeks or a single oral dose of azithromycin 20 mg/kg (up to 1g). Although chemotherapy can generate prompt therapeutic response and surgery can reverse the repercussions of these infections, these conditions will persist through reinfections. Implementing proper personal hygiene and environmental improvement measures for the control of infection transmission will be essential in reducing the potentially devastating results of trachoma infections.     

Starch microparticles as vaccine adjuvant

The demand for new vaccine adjuvants is well documented. New purified antigens from parasites, bacterial or viral pathogens, as well as recombinant subunit antigens and synthetic peptides, are often inherently weak immunogens; therefore, they need some kind of adjuvant to help initiate an immune response. In addition, there are very few adjuvants using the potential of the mucosal immune system, which may play an important role in the defence against air- and food-borne infections. Starch is a natural biocompatible and biodegradable polymer that is suitable for the production of various particulate adjuvant formulations, which can induce mucosal as well as systemic immune responses. This review gives an account of the different starch adjuvants used in immunisation studies. In particular, the properties of polyacryl starch microparticles as an oral vaccine adjuvant that induce protective immune responses in mice challenge experiments are summarised. In addition, a diphtheria booster vaccine has been proposed to be used to proving the concept in man and the possibilities to design an efficient vaccine formulation for human use are discussed.     

Lessons learned about the therapeutic potential of the natural human immune response to lung cancer

Lung cancer is the leading cause of cancer deaths; patients with this disease often develop antibodies to their own tumour antigens. TB94 is one such human antibody, and was obtained from the natural immune response from a patient with lung cancer. The data generated so far on TB94 suggest that this human antibody may have clinical applications in the diagnosis and treatment of lung cancer. Since humans make antibodies to tumour antigens, the intelligence of the human immune response can be exploited for the discovery of potential novel antigens. These novel antigens can then be developed for vaccine applications. Creating effective strategies to analyse systematically the natural human immune response to tumour antigens will open up new areas of immunotherapy for the control and eradication of disease.     

Starch microparticles as vaccine adjuvant

The demand for new vaccine adjuvants is well documented. New purified antigens from parasites, bacterial or viral pathogens, as well as recombinant subunit antigens and synthetic peptides, are often inherently weak immunogens; therefore, they need some kind of adjuvant to help initiate an immune response. In addition, there are very few adjuvants using the potential of the mucosal immune system, which may play an important role in the defence against air- and food-borne infections. Starch is a natural biocompatible and biodegradable polymer that is suitable for the production of various particulate adjuvant formulations, which can induce mucosal as well as systemic immune responses. This review gives an account of the different starch adjuvants used in immunisation studies. In particular, the properties of polyacryl starch microparticles as an oral vaccine adjuvant that induce protective immune responses in mice challenge experiments are summarised. In addition, a diphtheria booster vaccine has been proposed to be used to proving the concept in man and the possibilities to design an efficient vaccine formulation for human use are discussed.     

疫苗相关不良事件研究综述

疫苗是预防传染病最有效的手段之一,据统计目前全球因为疫苗的使用,每年可使300余万人免于死亡,75万儿童免于残疾。疫苗可以刺激机体产生一定的保护物质,如免疫激素、生理活性物质、特殊抗体等,当机体再次接触到这种病原体时,机体免疫系统便会依循其原有的记忆,制造更多的保护物质来阻止病原菌的伤害。然而伴随疫苗的使用,很多疫苗相关不良事件的发生也引起了学者的高度关注。本文通过对既往有关疫苗不良反应的相关文献进行回顾,包括针对重症急性呼吸综合征冠状病毒（Severe aeute respiratory syndrome coronavirus,SARS-CoV）和中东呼吸综合征冠状病毒（Middle east respiratory syndrome coronavirus,MERS-CoV）疫苗相关不良反应进行总结分析,以期将来可以为新型冠状病毒肺炎疫苗临床的安全使用提供借鉴和参考。     

Current efforts on generation of optimal immune responses against HIV through mucosal immunisations

Currently, over 40 million HIV-infected individuals are found around the globe, with an additional 15,000 daily infections. There is a general consensus that the most effective way to prevent new infections is to introduce a prophylactic vaccine. It is also generally agreed that both cytotoxic T lymphocytes (CTLs) and neutralising antibodies are important to mediate protection. The neutralising antibodies must be broadly reactive to neutralise multiple primary isolates. There is also increasing agreement that CTLs and neutralising antibodies should be present at mucosal sites of HIV entry, the draining lymph nodes and systemically. The route of immunisation is important when determining the site where protection is desired, i.e. the female genitourinary tract versus the male or female rectum versus systemic tissues, as are the type of HIV-related antigens, immunopotentiating adjuvants and delivery systems. Finally, multiple vaccine delivery systems may be required to be administered through both mucosal and parenteral routes to induce optimal immune responses and protection against HIV infection through rectal, vaginal or systemic routes of transmission. This review discusses current efforts on the generation of optimal immune responses against HIV in the genitourinary and intestinal tracts using mucosal immunisations alone or combinations of mucosal and parenteral immunisations.