VACCINATION AND THE EVOLUTIONARY DYNAMICS OF PNEUMOCOCCI

抗原多样性病原体，如肺炎双球菌提出了新的疫苗设计的进化挑战。针对可变抗原的疫苗的使用可以引起并且已经引起不携带疫苗中包括的抗原变体的病原体类型的增加。链球菌肺炎（肺炎球菌）群体对疫苗诱导的选择性压力的这种进化反应，称为“血清型替换”，可能反过来导致疾病模式的转变。血清型替换可能是有益的，也可能是有害的，这取决于替换类型引起疾病的能力。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，并利用这些知识预测疫苗广泛使用时人群的反应。小鼠肺炎球菌携带的实验模型和流行病学数据分析将用于表征肺炎球菌多样性和种群生物学的生态机制，这些机制将被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。具体目标是：1）定量表征鼻内携带的实验室小鼠模型中肺炎球菌菌株之间的群体生物学相互作用。2)描述天然肺炎球菌携带引起的抗体介导的免疫力的发展以及这种免疫力对肺炎球菌动力学的影响，使用这些模型，通过描述接种疫苗后肺炎球菌种群的变化，使用分子流行病学分型方法，确定现有传播模式的基础机制。

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.