Protective Immunity to Human Cholera in Bangladesh

该项目是由麻省总医院-哈佛医学院和国际合作

This project is a collaboration between Massachusetts General Hospital-Harvard Medical School andthe International Centre for Diarrhoeal Disease Research in Bangladesh (ICDDR,B), focused on definingprotective immunity to V. cholerae infection and developing an improved cholera vaccine. The central hypothesis of this project is that V. cholerae expresses specific proteins during early infection, whichgenerate immuneresponses that are protective on subsequent exposure; an ancillary hypothesis is that these proteins are not adequately expressed duringcolonization with available vaccine strains, and that these differences may explain the lessened efficacy of currentvaccines. There are five specific aims in this project. In Specific Aim #1, the investigators will determine the genes and proteins expressed during humaninfection with V. cholerae in Bangladesh, utilizing gene expression profiling by microarray in samples of stool and vomit, as well as proteomicanalysis of these samples. In Specific Aim #2, the investigators will identify proteins that are immunogenic following human infection with V.cholerae, as well as following vaccination with cholera vaccine strain Peru-15, in order to determine whether differences in gene expression between wild-type V.cholerae and Peru-15 may be correlated with differences in specific immuneresponses. In Specific Aim #3, the investigators will assess the durationof immunity to key cholera antigens followingboth cholera and Peru-15 vaccination over a one year follow-up period. Theduration of immunity will be evaluated in serum, feces, and duodenal biopsies, as well as with a newlydescribed methodology for measuring circulating, antigen-specific memoryB cells. In Specific Aim #4, the investigators will examine which of the immune responses to in v/vo-expressed proteins are protective following exposure to V.cholerae in household contacts utilizing: baseline antibody liters to key antigens in serum and feces; the increase in baseline to day 3immunologic responses (as a markerof an anamnestic response), and the numberof circulating, antigen-specific memoryB cells at baseline. In Specific Aim #5, the investigators will evaluate selected host factors for correlation with development of immune responses followingcholera or Peru-15 vaccination, as well as with susceptibility to symptomatic cholera following exposure in household contacts. The long term goals of this project are to developthe theoretical underpinnings for an improved vaccine for prevention of cholera, and to accomplish substantial technologytransfer and capacity building at the ICDDR.B.