The role of "go no-go" decisions in TB vaccine development

"Go no-go" decisions play a critical role in the product development plan of any TB vaccine at several points. Go no-go decisions are designed to serve the fundamental maxim in vaccine development that killing a bad vaccine project as early as possible is the hallmark of a successful overall program; in development, unlike in basic research, costs and skilled manpower requirements rise exponentially as the program proceeds. The opportunity costs in resources, manpower and equipment utilized on bad vaccine projects are unavailable to other vaccine programs. The go no-go decision is a fundamental piece of the process that balances risk, time and resources. An example of a go no-go decision development program is presented.     

Preclinical development of an in vivo BCG challenge model for testing candidate TB vaccine efficacy

There is an urgent need for an immunological correlate of protection against tuberculosis (TB) with which to evaluate candidate TB vaccines in clinical trials. Development of a human challenge model of Mycobacterium tuberculosis (M.tb) could facilitate the detection of such correlate(s). Here we propose a novel in vivo Bacille Calmette-Guérin (BCG) challenge model using BCG immunization as a surrogate for M.tb infection. Culture and quantitative PCR methods have been developed to quantify BCG in the skin, using the mouse ear as a surrogate for human skin. Candidate TB vaccines have been evaluated for their ability to protect against a BCG skin challenge, using this model, and the results indicate that protection against a BCG skin challenge is predictive of BCG vaccine efficacy against aerosol M.tb challenge. Translation of these findings to a human BCG challenge model could enable more rapid assessment and down selection of candidate TB vaccines and ultimately the identification of an immune correlate of protection.     

Beyond BCG: the potential for a more effective TB vaccine.

The 'Bacille Calmette-Guerin' (BCG) vaccine has been used throughout most parts of the world for the majority of the century. It is safe to use and cheap to produce, but there have been increasing doubts about its effectiveness. These doubts could not come at a worse time, as tuberculosis (TB) rates continue to rise, compounded by the AIDS epidemic, and outbreaks of tuberculosis caused by multidrug-resistant strains are more common even in advanced countries. As a result, there is now a concerted research effort to produce new TB vaccine candidates. These include DNA vaccines, recombinant and auxotrophic vaccines and subunit vaccines, all of which hold promise. The real difficulty will probably arise at the clinical trial level, when a decision must be made either to replace BCG or to boost existing BCG-induced immunity using these new-generation vaccines.     

New technologies for vaccine development

Despite important success of preventive vaccination in eradication of smallpox and in reduction in incidence of poliomyelitis and measles, infectious diseases remain the principal cause of mortality in the world. Technologies used in the development of vaccines used so far, mostly based on empirical approaches, are limited and insufficient to fight diseases like malaria, acquired immunodeficiency syndrome (AIDS) or adult tuberculosis. Until recently, technologies for making vaccines were based on live attenuated microorganisms, whole killed microorganisms and subunit vaccines such as purified toxoids. Fortunately, the recent advances in the understanding of host-pathogen interaction as well as our increasing knowledge of how immune responses are triggered and regulated have opened almost unlimited possibilities of developing new immunization strategies based on recombinant microorganisms or recombinant polypeptides or bacterial or viral vectors, synthetic peptides, natural or synthetic polysaccharides or plasmid DNA. Thus, considering the expending number of technologies available for making vaccines, it becomes possible for the first time in the history of vaccinology to design vaccines based on a rational approach and leading to increased efficacy and safety.     

Proteomics for development of vaccine

The success of genome projects has provided us with a vast amount of information on genes of many pathogenic species and has raised hopes for rapid progress in combating infectious diseases, both by construction of new effective vaccines and by creating a new generation of therapeutic drugs. Proteomics, a strategy complementary to the genomic-based approach, when combined with immunomics (looking for immunogenic proteins) and vaccinomics (characterization of host response to immunization), delivers valuable information on pathogen-host cell interaction. It also speeds the identification and detailed characterization of new antigens, which are potential candidates for vaccine development. This review begins with an overview of the global status of vaccinology based on WHO data. The main part of this review describes the impact of proteomic strategies on advancements in constructing effective antibacterial, antiviral and anticancer vaccines. Diverse aspects of disease mechanisms and disease preventions have been investigated by proteomics.     

新型结核病疫苗及其评价方法的研究进展

结核病是由结核分枝杆菌感染引起的慢性传染病,严重危害人类健康,卡介苗对儿童粟粒性结核和结核性脑膜炎保护效果较好,但对成人肺结核保护效果却不确定。过去十余年,众多研究人员一直致力于新型结核病疫苗的研发,但至今尚未成功。结核病的致病和免疫机制还不完全清楚,缺乏可以预测临床保护效果的指标和动物模型,动物实验结果常与临床试验结果不符,临床试验耗时漫长、成本昂贵、且需要大量结核病患者,这些都严重阻碍了结核病疫苗的研发。近年来,研究人员研发了一些新方法进行结核病疫苗临床前评价,从而缩短了进入临床试验的时间,加快了结核病疫苗的发展。综述了新型结核病疫苗的研究进展及其保护力评价方法,特别是临床前评价新方法。     

Epitope-driven TB vaccine development: a streamlined approach using immuno-informatics, ELISpot assays, and HLA transgenic mice

New vaccine candidates that might better control the worldwide prevalence of Mycobacterium tuberculosis (Mtb) have yet to be described. Strong CD4+ T cell-mediated immune response (CMI) is correlated with protection from the development of TB disease; however, the selection of suitable vaccine antigens has been thwarted by the size and complexity of the (Mtb) proteome, and by the relative difficulty of delivering these antigens in the right immunological context. One possible solution is to develop immunotherapeutic vaccines for TB that are based on T cell epitopes representing multiple antigens. This text illustrates the stepwise development of epitope-driven vaccines from in silico epitope mapping to testing the vaccine in a live Mtb challenge model. First, we used the whole genome Mtb microarray to identify bacterial proteins expressed under the conditions thought to model Mtb survival and replication in human macrophages. Eighteen of these proteins were also found by Behr et al. to be absent from at least one strain of BCG; the sequences of these eighteen proteins were then screened for T-cell epitopes using the immuno-informatics algorithm, EpiMatrix. Of the seventeen representative epitopes evaluated in ELISpot assays, all seventeen were confirmed to elicit interferon (IFN)-gamma secretion by PBMC from Mtb-exposed subjects. A parallel live Mtb challenge study in mice showed prototype epitope-based TB vaccines to be robustly immunogenic but not as effective as BCG. These experiments illustrate the use of immuno-informatics tools for vaccine development and describe a pathway for the development of a more effective, epitope-driven, immunotherapeutic vaccine for TB.     

Functional proteomics: The goalposts are moving

Holistic understanding of protein function is a primary goal of the post-genome sequencing era. Functional genomic approaches are powerful and relatively straightforward but produce an incomplete picture at the protein level. Proteomics offers physiologically enriched insights to protein function, and ongoing advances are enabling proteome analyses to proceed with increased depth and efficiency. Exciting discoveries have emerged recently amidst growing awareness of the power of proteomics. However, while proven as a potent discovery tool, proteomics is under pressure to provide improved functional value particularly in concert with other investigative approaches. As reviewed here for ERp29, a recently discovered endoplasmic reticulum protein, the role of novel proteins can remain elusive even after substantial information has accrued. Thousands more proteins of uncertain function will be unveiled in the near future. Consequently, the goalposts are moving for proteomics both through increasing demand for high-value functional information and improving capacity to deliver.     

Post-genomic vaccine development

For over a century, vaccines were developed according to Pasteur's principles of isolating, inactivating and injecting the causative agent of an infectious disease. The availability of a complete microbial genome sequence in 1995 marked the beginning of a genomic era that has allowed scientists to change the paradigm and approach vaccine development starting from genomic information, a process named reverse vaccinology. This can be considered as one of the most powerful examples of how genomic information can be used to develop therapeutic interventions, which were difficult or impossible to tackle with conventional approaches. As the genomic era progressed, it became apparent that multi-strain genome analysis is fundamental to the design of universal vaccines. In the post-genomic era, the next challenge of the vaccine biologist will be the merging of the vaccinology with structural biology.     

Optimizing vaccine development

Optimizing the development of modern molecular vaccines requires a complex series of interdisciplinary efforts involving basic scientists, immunologists, molecular biologists, clinical vaccinologists, bioinformaticians and epidemiologists. This review summarizes some of the major issues that must be carefully considered. The intent of the authors is to briefly describe key components of the development process to give the reader an overview of the challenges faced from vaccine concept to vaccine delivery. Every vaccine requires unique features based on the biology of the pathogen, the nature of the disease and the target population for vaccination. This review presents general concepts relevant for the design and development of ideal vaccines protective against diverse pathogens.