| Epitope vaccine, which is designed by using epitopes, reduces the by-effects of traditional vaccines, and increases their safety and immunity. It is a promising study domain of vaccine study, which aims to cure infective diseases and cancers to date. But a HLA restricted epitope vaccine generally cannot provoke immune response in all individuals in targeted populations due to extreme diversity of HLA moleculer. That is to say multi-epitope vaccine, which carries several targeted antigen epitopes, is very important in vaccine design study, when the targeted population of this vaccine shows evident genetic diversity in HLA loci. Because each epitope is designed to target some populations, the well designed multi-epitope vaccine as a whole can be combined by multiple HLA moleculers, and further can be much more effective as a result. It means that the diversity of HLA moleculer must be fully considered, when the primary goal is to design multi-epitope vaccines with high theoretical immune response rates for targeted populations. However, currently, studies aiming at designing multi-epitope vaccines based on analyzing characteristics of population genetic structure of Chinese populations are rare. Hence, it is necessary to study the prediction system of the theoretical immune response rate of multi-epitope vaccine in China, because it is useful to direct vaccines designers. The results of previous studies revealed that the population genetic structure of Chinese populations showed evident spatial heterogeneity and spatial structure. Thus, traditional statistical methods are hard to describe its internal rules. The only way is to use methods of spatial genetics and spatial statistics to perform study. Consequently, with the support of geographic information system, the forecasting system of theoretical immune response rate of HLA-A-B loci restricted multi-epitope vaccines in Chinese population is built. It is based on analyzing spatial genetic structure of HLA-A-B loci in Chinese populations by combining the theoretical population genetics, molecular genetics, molecular immunology, spatial genetics and geostatistics. The purpose of the study is to direct Chinese vaccine designer to develope HLA-A-B loci restricted multi-epitope vaccines (including DNA vaccines), and to evaluate or predict their immune effects in Chinese populations. It is highly possible that this forecasting system will attract a lot of users and have favorable perspective in the future. It will bing economic benefits and social benefits undoubtedly. The whole dissertation includes the following five chapters:Chapter 1 The molecular immunology foundation of multi-epitope vaccine: Introduce the structural characteristics of HLA and its effect on immune response of epitope vaccines. The following aspects are introduced in a big way: the genetic structure and inherit character of HLA loci and the gene expression products of HLA- I complex. Futhermore, the immune function of HLA- I complex related to multi-epitope vaccines, and the typing rule of HLA and its influence on studies of multi-epitope vaccines are described. Besides, the molecular immunology foundation of multi-epitope vaccine is also introduced in this chapter including the methods of screening and identifying epitopes and the process of constructing epitope vaccines.Chapter 2 The data collection and the spatial database: The population genetic data of HLA-A-B loci, which could be classified into three batches namely HLA serology data, HLA supertype data and HLA haplotype data, are chosen to build the spatial genetic databases of HLA frequency. Besides, administration and analysis platform based on Chinese population genetic structure of HLA loci is built by using arcGIS9.0 of Environment System Research Institute in US as well. It is the base of analyzing the spatial genetic characteristics of HLA and building the forecasting system of theoretical immune response rate of HLA-A-B loci restricted multi-epitope vaccines in Chinese populationChapter 3 Study on characteristics of spatial genetic structure of HLA-A-B loci in Chinese population based on geographical information system: Based on geographical information system, principle component analysis and canonical trend surface analysis are used to perform quantitative analysis on spatial genetic structure. Futher, the inverse distance weighted algorithm of spatial interpolate techniques is used to perform spatial prediction. The contour maps are used, with the purpose of showing the characteristics of spatial genetic structure of HLA-A-B loci in Chinese population. Study results show that the genetic structure of HLA-A-B loci in Chinese population expresses evident spatial heterogeneity and spatial structure characteristics: ①As a whole, the genetic structure of majority Han and that of other minorities are similar, which form special spatial structure regions. But the genetic structure of northern Han and southern Han are entirely different from each other, and the difference is similar with that between northern minorities and southern minorities. Thus the obvious northern and southern spatial structure regions are formed, and the evident geographic genetic grads along north to south orientation can be observed consequently.②In some special geographic regions, the genetic structure of majority Han shows unconspicuous spatial heterogeneity and obvious spatial structure characteristics.③In southern China, there exists obvious geographic isolation between Han and minorities, while in northern China geographic isolation is not obvious between Han and minorities.④In northern China, the genetic structure of minorities shows unconspicuous spatial heterogeneity and obvious spatial structure characteristics. But in southern China, the genetic structure of minorities shows obvious spatial heterogeneity and the internal structure is very complex. The analysis results indicate that spatial genetic structure of HLA-A-B serology data and HLA-A-B supertype data in Chinese population expresses obvious spatial heterogeneity characteristics, which should be considered by vaccine designers when the purpose is to design multi-epitope vaccine in China. That is to say, before the design of multi-epitope vaccine, Chinese vaccine designers must consider the difference of the immunal effects of studied vaccines in different regions.Chapter 4 Construction of the forecasting system of theoretical immune response rate of HLA-A-B loci restricted multi-epitope vaccines in Chinese population: On the basis of the former analysis of spatial genetic structure of HLA-A-B loci in China, the forecasting system of theoretical immune response rates of multi-epitope vaccines is built based on GIS.Major study methods and implement plan:①Build the mathematical model of theoretical immune response rate of multi-epitope vaccine;②According to the mathematical model, write the computer codes and programs used to calculate theoretical immune response rate(CPF) of multi-epitope vaccine on serology level and supertype level. The CPF of vaccines can be calculated automaticly from HLA serology and supertype database;③By using spatial statistical analysis methods, the spatial distribution characteristics of CPF of HLA-A-B loci restricted multi-epitope vaccine in Chinese population are analyzed with the support of spatial analysis module of GIS. Further, the forecasting system of theoretical immune response rate of HLA-A-B loci restricted multi-epitope vaccines in Chinese population is built;④The design strategy of multi-epitope vaccine is brought forward;⑤Based on arcGIS 9.0, the calculation of CPF is made to be programed, stanalized, and visualized.Major study results:①The spatial distribution of CPF of HLA-A-B loci restricted multi-epitope vaccines in China shows evident spatial heterogeneity and spatial structure characteristics;②the new CPF calculation method, which estimates upper and lower limit of real CPF works successfully to estimate the immunal effects of multi-epitope vaccine without the existence of haplotype data;③HLA-A loci restricted epitopes are first choices for multi-epitope vaccine designers;④Supertype typing techniques do reduce the difficulty of choosing epitopes and overcome the restriction of HLA-epitope mapping to some extent.The significance and the appliance of predicting system: In all, the forecasting system of theoretical immune response rate of HLA-A-B loci restricted multi-epitope vaccines in Chinese population is of significant meaning to direct Chinese vaccine designer to design HLA-A-B restricted vaccine in China and evaluate their effects.Chapter 5 Web exhibition system of spatial prediction results of CPF: For making the predicted results of CPF programed, standalized, and visualized, ASP language is used to develope exhibition system of forecasting system of theoretical immune response rate of HLA loci restricted multi-epitope vaccines in Chinese population. The website is built.Current system realizes following functions:①The contour maps of spatial prediction result of theoretical immune response rates of HLA restricted multi-epitope vaccines could be exhibited on-line. Through this system, user can browse and search for the CPF of certain epitope combination they need on system's mainpage;②Website maintenance personnels can use background management page to initialize system setup and update contents of the website conveniently;③The website, which offers platform for communication and cooperation, supplies a lot of knowledge and information of multi-epitope vaccine;④The web exhibition of predicting results of CPF is realized;⑤The demand of Chinese vaccine designer, which is to search for the CPF of any epitope combination they need in any region of China, is satisfied.
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