Secretome,surfome and immunome: emerging approaches for the discovery of new vaccine candidates against bacterial infections

Functional genomics has made possible advanced structure-to-function investigation of pathogens and helped characterize virulence mechanisms. Proteomics has been become a tool for large-scale identification of proteins involved during invasion and infection by the pathogens. Bacterial surface and secreted proteins play key role in the interaction between the bacterial cell and the host environment. Thus exoproteome and surface proteome of a microorganism are hypothesized to contain components of effective vaccines. Surfome and exoproteome analysis strategy facilitates identification of novel vaccine antigen and overall helps in progress of discovery of vaccine. The study of the antibody response can advance how proteomics is used, because it investigates antibody–antigen interactions and also unravel the relationship of antibody responses to pathogen and host characteristics. System immunology integrating with proteome i.e. immunoproteomics is applicable to those infections that are having tendency of diverse antibody target recognition and thus accurately reflects progression of the infection.     

Immune response against Mycobacterium tuberculosis: implications for vaccine development

Tuberculosis remains a major health problem globally. Although this threat would best be controlled by a combination of chemotherapy and vaccination, satisfactory vaccines are not available yet. Rational design of a novel vaccine generation against tuberculosis has become possible on the basis of recent achievements in molecular genetics of the pathogen and immunology of the host. Currently, two different strategies are pursued. First, the subunit vaccine approach attempting to induce efficacious immunity by unique antigens in defined adjuvants. Second, the whole bacterial vaccine approach relying on multiple antigens and built-in adjuvanticity. Time will tell which type of vaccine is best suited for eradication of tuberculosis.     

DC-SIGN与免疫调节

树突状细胞(DC)是目前所知体内功能最强大的专职抗原递呈细胞,它既能启动初始免疫应答,也能负向调控免疫反应,具有独特的免疫调节功能。DC-SIGN属于DC表面C型凝集素受体超家族成员,它既是DC病原体模式识别和黏附受体,又作为DC特征性多功能免疫分子,参与DC免疫调节作用。DC-SIGN在调节DC黏附迁移及炎症反应,激活初始T细胞及启动免疫应答,以及病原体与肿瘤的免疫逃逸等诸多方面发挥重要作用,已日益受到人们的关注。而对DC-SIGN在天然免疫和获得性免疫中调节作用及其相关机制的更深入研究,可为临床相关疾病机制探讨与防治进一步提供新的有力依据和干预途径。     

Giardia vaccination

Recently, a Giardia vaccine has become commercially available in the USA for prevention of clinical signs of giardiasis and reduction of cyst shedding in dogs and cats. The vaccine is based upon the current state of knowledge of Giardia antigenicity and immunology. Here, Merle Olson, Howard Ceri and Douglas Morck describe studies that led to the development of this vaccine and subsequent efficacy studies. Immunoprophylaxis and immunotherapeutic application of the vaccine are discussed.     

The top five "game changers" in vaccinology: toward rational and directed vaccine development

Despite the tremendous success of the classical "isolate, inactivate, and inject" approach to vaccine development, new breakthroughs in vaccine research are increasingly reliant on novel approaches that incorporate cutting edge technology and advances in innate and adaptive immunology, microbiology, virology, pathogen biology, genetics, bioinformatics, and many other disciplines in order to: (1) deepen our understanding of the key biological processes that lead to protective immunity, (2) observe vaccine responses on a global, systems level, and (3) directly apply the new knowledge gained to the development of next-generation vaccines with improved safety profiles, enhanced efficacy, and even targeted utility in select populations. Here we highlight five key components foundational to vaccinomics efforts: applied immunogenomics, next generation sequencing and other cutting-edge "omics" technologies, advanced bioinformatics and analysis techniques, and finally, systems biology applied to immune profiling and vaccine responses. We believe these "game changers" will play a critical role in moving us toward the rational and directed development of new vaccines in the 21st century.     

Mycobacterium tuberculosis and dendritic cells: recognition, activation and functional implications

The highly complex nature of interactions of Mycobacterium tuberculosis with cells of the immune system has puzzled researchers the world-over in understanding the pathogenesis and immunology associated with tuberculosis (TB). This has contributed to the delay in development of effective vaccine(s) for TB. Several excellent studies have provided only a glimpse of the kind and degree of immune responses elicited following infection by mycobacteria. Preferred entry via respiratory route results in the capture of mycobacteria by alveolar macrophages that eventually become their long-term hosts. Since the pathogen is rarely cleared this has resulted in the human population serving as a large reservoir for mycobacteria. Owing to their unique ability to prime na?ve and memory T cells, dendritic cells (DCs) play important and indispensable roles in the initiation and maintenance of protective immune responses following infection. The kind of immune response initiated by DCs with respect to mycobacteria determines the character of immune responses mounted by the host against the pathogen. The profile of cytokines and chemokines secreted as a result of infection of DCs by mycobacteria further plays an important role in defining the course of infection. This minireview attempts to highlight key interactions of mycobacteria with dendritic cells. We discus the uptake of mycobacteria by DCs followed by DC activation and the spectrum of immune responses initiated by infected/activated DCs, followed by numerous ways the pathogen has devised to subvert protective responses.     

Discovery of T cell antigens by high-throughput screening of synthetic minigene libraries

The identification of novel T cell antigens is central to basic and translational research in autoimmunity, tumor immunology, transplant immunology, and vaccine design for infectious disease. However, current methods for T cell antigen discovery are low throughput, and fail to explore a wide range of potential antigen-receptor interactions. To overcome these limitations, we developed a method in which programmable microarrays are used to cost-effectively synthesize complex libraries of thousands of minigenes that collectively encode the content of hundreds of candidate protein targets. Minigene-derived mRNA are transfected into autologous antigen presenting cells and used to challenge complex populations of purified peripheral blood CD8+ T cells in multiplex, parallel ELISPOT assays. In this proof-of-concept study, we apply synthetic minigene screening to identify two novel pancreatic islet autoantigens targeted in a patient with Type I Diabetes. To our knowledge, this is the first successful screen of a highly complex, synthetic minigene library for identification of a T cell antigen. In principle, responses against the full protein complement of any tissue or pathogen can be assayed by this approach, suggesting that further optimization of synthetic libraries holds promise for high throughput antigen discovery.     

增强乙型肝炎疫苗免疫效果的研究进展

乙肝疫苗对于控制乙型肝炎病毒感染十分重要.近年人们仍在根据免疫学理论和生物工程技术进展不断研发更加科学有效的新型乙肝疫苗.就新型乙肝疫苗设计的免疫机制和提高免疫效果的关键因素作出综述.     

Cancer immunotherapy: moving beyond current vaccines

Great progress has been made in the field of tumor immunology in the past decade, but optimism about the clinical application of currently available cancer vaccine approaches is based more on surrogate endpoints than on clinical tumor regression. In our cancer vaccine trials of 440 patients, the objective response rate was low (2.6%), and comparable to the results obtained by others. We consider here results in cancer vaccine trials and highlight alternate strategies that mediate cancer regression in preclinical and clinical models.     

Cellular and molecular mechanisms of vaccine-induced protection against retroviral infections

More than 15 years after the discovery of human immunodeficiency virus (HIV), researchers are still struggling to design a protective AIDS vaccine. A remaining problem is a lack of basic knowledge about the immunological requirements for protection against retroviruses. Infection of macaque monkeys with simian immunodeficiency virus is still the best model for HIV vaccine research. However, in this model it remains difficult to determine protective immunological mechanisms because of limited numbers of experimental animals and their genetic heterogeneity. Thus, fundamental concepts in retroviral immunology have to be defined in other ways such as mouse models. This minireview summarizes new findings on cellular and molecular mechanisms in protection of mice against Friend murine retrovirus infection. It has been shown that complex immune responses, including B and T cell responses, are required for efficient protection in this model. Multiple viral antigens are necessary to elicit such broad immune reactivity. Efficacious vaccines must protect not only against acute disease, but also against the establishment of persistent infections or the host is at serious risk of virus reactivation. The minireview closes with a discussion on the relevance of findings from the mouse model on the design of a protective vaccine against HIV.     

The rational design of an AIDS vaccine

The extraordinary genetic diversity and immune evasion of human immunodeficiency virus (HIV) pose significant challenges for vaccine development. AIDS vaccine design requires a scientifically driven, rational approach that encompasses the latest advances in viral molecular genetics, structural biology, and immunology.     

Schistosomes: the road from host-parasite interactions to vaccines in clinical trials

Insights over recent years into the interactions between helminths, including schistosomes, and the immune system have generated new concepts in immunology and significant advances in vaccine strategies. Here, we report recent advances that substantially increase our understanding of the nature of the host innate and adaptive responses to schistosomes and on strategies elaborated by the parasite to manipulate such responses. We also describe the long road that has allowed us to move from the identification of an anti-schistosome vaccine candidate, a 28kDa glutathione-S-transferase, to its recent evaluation in human clinical trials.     

Current research status of immunology in the genomic era

This review updates the current status of immunology research under the influence of genomics, both conceptually and technologically. It particularly highlights the advantages of employing the high-throughput and large-scale technology, the large genomic database, and bioinformatic power in the immunology research. The fast development in the fields of basic immunology, clinical immunology (tumor and infectious immunology) and vaccine designing is illustrated with respect to the successful usage of genomic strategy. We also speculate the future research directions of immunology in the era of genomics and post-genomics. Supported by the National High-Tech Research and Development Program of China (Grant No.2006AA02A252), National Natural Science Foundation of China (Grant No.30771965) and Shanghai Pujiang Program (Grant No.07pj14066).     

CpG motifs: the active ingredient in bacterial extracts?

The use of bacteria and bacterial extracts for immunotherapy has a checkered past. Recent developments in immunology reveal that these nonspecific immune activators actually work by triggering specific receptors that are expressed by subsets of immune cells. Identification of these receptors and the molecular signaling pathways that they activate has enabled a new era of specific targeted immunotherapy using chemically synthesized mimics of pathogen molecules.     

Development and application of synthetic peptides as vaccines

Vaccination against bacterial and viral diseases has been one of the major achievements in medicine and immunology since the beginning of this century. Extensive vaccination programs have been able to control or, in the case of smallpox, virtually wipe out some of the most dangerous infectious diseases e.g. poliomyelitis, measles, whooping cough, diphtheria and tetanus. However, as this success has been limited mainly to the developed, affluent countries, infectious diseases still remain the worlds largest health problem. Furthermore, vaccines against human parasites are non-existent. Recent advances in immunology and molecular biology including recombinant DNA technology have provided the basis for new approaches to vaccine development.     

抗独特型抗体与T细胞记忆的关系

记忆T细胞作为人体免疫系统中的一个组成部分,在免疫应答中发挥着至关重要的作用,因此利用抗独特型抗体制备诱导产生记忆T细胞的疫苗是免疫学领域的一个重要方向。抗独特型抗体Fab段具有与特异性抗原相似的抗原决定簇的结构,其作为抗原替代物制备的疫苗所激发机体产生的记忆T细胞具有特异性强和安全性高的特点,成为一种比较理想的疫苗.就抗独特型抗体与T细胞记忆之间的联系及其应用效果作一简要综述。     

Vaccination Strategies against Highly Pathogenic Arenaviruses: The Next Steps toward Clinical Trials

Vaccination is one of the most valuable weapons against infectious diseases and has led to a significant reduction in mortality and morbidity. However, for most viral hemorrhagic fevers caused by arenaviruses, no prophylactic vaccine is available. This is particularly problematic as these diseases are notoriously difficult to diagnose and treat. Lassa fever is globally the most important of the fevers caused by arenaviruses, potentially affecting millions of people living in endemic areas, particularly in Nigeria. Annually, an estimated 300,000 humans are infected and several thousands succumb to the disease. The successful development of the vaccine “Candid#1” against Junin virus, the causative agent of Argentine hemorrhagic fever, proved that an effective arenavirus vaccine can be developed. Although several promising studies toward the development of a Lassa fever vaccine have been published, no vaccine candidate has been tested in human volunteers or patients. This review summarizes the immunology and other aspects of existing experimental arenavirus vaccine studies, discusses the reasons for the lack of a vaccine, and proposes a plan for overcoming the final hurdles toward clinical trials.     

Pasteur, Pastorians, and the dawn of immunology: the importance of specificity

Throughout his career, the problems that attracted Louis Pasteur almost invariably involved considerations of specificity of structure and/or of action. Thus, his work on asymmetric crystals showed that chemical form not only specifies crystalline structure, but affects the affinity of ferments as well. In his studies of diseases of silkworms, of beer, and of wine, he could unerringly distinguish with the microscope the specific agents of disease. From this emerged his concept of the specificity of species and against the nonspecificity of spontaneous generation, whence the germ theory of disease. It was in the new field of immunology, however, where the manifestations of an exquisite specificity were most clearly seen. Here, Pasteur's vaccines worked because he chose the specific pathogen in order to induce a specific immunity, and he succeeded each time. But the two most prominent Pastorian successors in immunology, Elie Metchnikoff and Jules Bordet, were not equally successful. Although each contributed significantly to the birth of immunology, each advanced a theory that neglected the principle of specificity and paid a price in consequence. Metchnikoff's phagocytic theory of immunity could not survive the demonstrable specificity of humoral antibodies, while Bordet's physical adsorptive concept of the antibody-cell interaction quickly fell to Paul Ehrlich's demonstration of the stereochemical determination of immunological specificity.     

Directions in the immune targeting of cancer: lessons learned from the cancer-testis Ag NY-ESO-1

Since the early 1990s, numerous cancer Ag have been defined and for a handful of these there is now some clinical experience, which has made it possible to assess their value as targets for cancer immunotherapy. The cancer-testis Ag have been particularly attractive because their expression is limited to cancer and virtually no non-malignant cells apart from germ cells and trophoblast. Among these, NY-ESO-1 has been the focus of our attention. The exceptional immunogenicity of this Ag coupled with its widespread distribution among many cancer types make it a very good vaccine candidate, with the potential to be used in vaccines against many types of malignancies. This article reviews emerging knowledge about the biology of NY-ESO-1 and experience with the early clinical development of vaccines directed against NY-ESO-1. These early studies have yielded a wealth of information about the immunology of NY-ESO-1 and set the scene for future clinical strategies for immune targeting of cancer.     

In silico identification of potential therapeutic targets in the human pathogen Helicobacter pylori

Availability of genome sequences of pathogens has provided a tremendous amount of information that can be useful in drug target and vaccine target identification. One of the recently adopted strategies is based on a subtractive genomics approach, in which the subtraction dataset between the host and pathogen genome provides information for a set of genes that are likely to be essential to the pathogen but absent in the host. This approach has been used successfully in recent times to identify essential genes in Pseudomonas aeruginosa. We have used the same methodology to analyse the whole genome sequence of the human gastric pathogen Helicobacter pylori. Our analysis revealed that out of the 1590 coding sequences of the pathogen, 40 represent essential genes that have no human homolog. We have further analysed these 40 genes by the protein sequence databases to list some 10 genes whose products are possibly exposed on the pathogen surface. This preliminary work reported here identifies a small subset of the Helicobacter proteome that might be investigated further for identifying potential drug and vaccine targets in this pathogen.