SHIGELLA CVD 25000G: PHASE 1, RANDOMIZED, DOUBLE-BLIND, PLACEBO-CONTROLLED, D

点击翻译按钮获取中文摘要

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Shigella and enterotoxigenic Escherichia coli (ETEC) are two of the most important causes of disease and death caused by diarrhea among infants and children living in poor countries of Asia and Africa. Soldiers and other travelers to these areas of the world can also become ill from these infections. Shigella and ETEC are spread by direct contact with people who have these infections and do not wash their hands well after using the toilet or by unclean food and water. As a result, it is hard to stop the spread of these infections in places where hygiene and sanitation are not good. In addition, antibiotics that worked well in the past can no longer cure some Shigella and ETEC infections. For these reasons, vaccines are being developed and tested for their ability to prevent diarrheal disease due to Shigella and ETEC. The experimental vaccine given in this study is made from an illness-causing strain of Shigella called Shigella flexneri 2a (or S. flexneri 2a) which is the most common type of Shigella that affects children living in the poorest countries. It was made by removing genes that normally allow Shigella to cause illness. Removing these genes is expected to weaken the vaccine to the point that it will only live for a few days in the intestine and will not cause diarrhea or fever. In addition, two ETEC genes were placed into the Shigella bacteria. One gene causes the Shigella bacteria to make tiny "hairs" on its surface called "colonization factor antigen type I", or "CFA/I". These "hairs" are made of protein and help the ETEC stick to the intestine. The second gene causes the Shigella to make a protein called "LTA2B". LTA2B does not cause diarrhea, but it is part of the ETEC protein called "heat labile toxin", or "LT" which can cause watery diarrhea. CFA/I and LT are commonly found in ETEC that cause diarrhea. It is hoped that the CVD 1208S(pCFA/I-LTA2B) vaccine will protect people from future infections with S. flexneri 2a and with ETEC that make CFA/I and LT. The objectives of the study are as follows: + To evaluate the safety and clinical tolerability of a single dose of CVD 1208S(pCFA/I-LThA2B), with particular attention to the occurrence of diarrhea, dysentery, or fever; + To assess the immunogenicity of a single dose of CVD 1208S(pCFA/I-LThA2B) by measuring the responses that are most likely to be associated with protective immunity. + To evaluate the dose response of CVD 1208S(pCFA/I-LThA2B) so that a well-tolerated and immunogenic dosage level can be selected for further development; + To evaluate the extent and duration of shedding of CVD 1208S(pCFA/I-LThA2B); + To evaluate preliminarily the transmissibility of CVD 1208S(pCFA/I-LThA2B) by determining whether the vaccine strain is acquired by placebo recipients living in close proximity on the Research Isolation Ward, as identified by stool culture. Three groups of about 13 volunteers each will be admitted to the General Clinical Research Center Isolation Ward for 13-day period for Ward acclimatization, vaccination and observation. Volunteers in Group 1 will receive either CVD 1208S(pCFA/I-LTA2B) vaccine at a low dose of 10 million bacteria or placebo. If the dose appears to be safe, then Group 2 will be admitted to the GCRC and receive either CVD 1208S(pCFA/I-LTA2B) vaccine at a medium dose of 100 million bacteria or placebo. If the dose appears to be safe, then Group 3 will be admitted to the GCRC and receive either CVD 1208S(pCFA/I-LTA2B) vaccine at a high dose of 1 billion bacteria or placebo. After discharge from the inpatient portion of the study, each group will return to clinic for follow-up on Days 14, 21, 28 and 42 for stool check, a blood draw and safety check. Finally, six months following vaccination, volunteers will contacted via telephone for a safety check.