VACCINATION AND THE EVOLUTIONARY DYNAMICS OF PNEUMOCOCCI

抗原性多样的病原体，如肺炎球菌，对疫苗设计提出了新的进化挑战。使用针对可变抗原的疫苗可能导致，并且已经导致不携带疫苗中所含抗原变体的病原体类型增加。肺炎链球菌（肺炎球菌）群体对疫苗诱导的选择压力的这种进化反应，被称为“血清型替代”，可能反过来导致疾病模式的转变。血清型替代可能是有益的，也可能是有害的，这取决于替代型引起疾病的能力。本文提出的研究旨在确定未接种疫苗人群中观察到的肺炎球菌群体生物学的生物学机制，并利用这些知识来预测当疫苗被广泛使用时人群将如何反应。小鼠携带肺炎球菌的实验模型和流行病学数据分析将用于描述肺炎球菌多样性和种群生物学背后的生态机制，并将这些机制纳入肺炎球菌携带和传播的数学模型。该模型的预测将使用来自肺炎球菌结合疫苗社区随机试验的肺炎球菌分离株的分子流行病学研究。具体目的是：1)定量表征实验室小鼠鼻内运载模型中肺炎球菌菌株之间的群体-生物相互作用。2)通过分子流行病学分型方法表征接种后肺炎球菌种群的变化，表征天然携带肺炎球菌的抗体介导免疫的发展及其对肺炎球菌动力学的影响，利用这些模型确定现有传播模式的机制。

Antigenically diverse pathogens such as pneumococci present novel evolutionary challenges for vaccine design. The use of vaccines directed against variable antigens can cause, and has caused, increases in pathogen types not carrying the antigenic variants included in the vaccine. this evolutionary response of the population of streptococcus pneumonia (pneumococcus) to vaccine -induced selective pressure, known as "serotype replacement," may in turn cause a shift in patterns of disease. serotype replacement may be either beneficial or harmful, depending on the ability of the replacing types to cause disease. The research proposed here is to ascertain is designed to ascertain the biological mechanisms underlying the observed population biology of pneumococci in unvaccinated populations and to use this knowledge to predict how the population will respond when vaccines are widely used. Experimental models of pneumococcal carriage in mice and analysis of epidemiological data will be used to characterize the ecological mechanisms underlying pneumococcal diversity and population biology, and these mechanisms will be incorporated into a mathematical model of pneumococcal carriage and transmission. The predictions of this model will be using molecular epidemiological studies of pneumococcal isolates from community randomized trial of the pneumococcal conjugate vaccine. the specific aims are: 1) to characterize quantitatively the population- biological interactions between pneumococcal strains in a laboratory mouse model of intra nasal carriage. 2) to characterize the development of antibody-mediated immunity due to natural pneumococcal carriages and the impact of this immunity on dynamics of pneumococci, to use these models to identify the mechanisms underlying existing patterns of the transmission mathematical models by characterizing the changes in pneumococcal populations following vaccination, using molecular epidemiological typing methods.