HANTAVIRUS ECOLOGY AND DISEASE IN CHILE AND PANAMA

描述（由申请人提供）：汉坦病毒是NIH A类病原体，包括在北美，中美洲和南美洲引起汉坦病毒心肺综合征（HCPS）的病毒。智利（384例）和阿根廷（595例）报告的HCPS病例和死亡人数尽管人口少得多，但超过了美国（379例）报告的病例数，北美和南美的病死率仍为36-38%。目前尚无已知的有效治疗方法或疫苗。在项目1“安第斯和巧克力病毒生态学”中，我们将研究智利和巴拿马啮齿动物宿主的生态学，以建立预测模型并快速解释远程监测结果，以指导公共卫生干预。在项目2“HCPS的治疗和预防”中，我们将完成一项疑似HCPS患者在心肺期静脉注射甲基强的松龙的对照试验，继续通过血浆置换法收集安第斯病毒感染幸存者的血浆，并进行三项具有高滴度安第斯病毒中和活性（HIP）的免疫血浆的临床试验。HIP的首个试验将是I期剂量递增安全性和药代动力学试验，在a)正常成人和b) HCPS患者中进行。第二项试验将是对HCPS高风险人群（HCPS指数患者的性伴侣，发生HCPS的风险为20%）进行HIP的公开安全性和有效性试验。第三项试验将是在心肺期疑似HCPS患者中进行的HIP对照试验。在项目3中，我们将完善我们的研究，试图了解哪些因素使性伴侣比非性伴侣的家庭接触者感染风险明显更高。我们将a)前瞻性地跟踪性伴侣家庭接触者，b)实施问卷调查以评估诸如常见源暴露、性行为和深吻等风险，以及c)研究生殖器、口腔和皮肤分泌物，包括每天在家收集唾液拭子，以确定是否可以通过PCR识别安第斯病毒RNA，以及是否可以从PCR阳性样本中培养病毒。

DESCRIPTION (provided by applicant): Hantaviruses are NIH category A pathogens, including the viruses that cause hantavirus cardiopulmonary syndrome (HCPS) in North, Central and South America. Reported cases and deaths from HCPS in Chile (384) and Argentina (595), despite much smaller populations, outnumber cases reported in the United States (379), and case fatality rates remain at 36-38% in North and South America. There is no known effective treatment or vaccine. In Project 1, Ecology of Andes and Choclo Viruses, we will study the ecology of the rodent reservoirs in Chile and Panama to develop predictive models and rapid interpretation of results from remote monitoring to guide public health intervention. In Project 2, Treatment and Prevention of HCPS, we will complete a controlled trial of intravenous methylprednisolone in persons with suspected HCPS in the cardiopulmonary phase, continue collection of plasma by plasmapheresis of survivors of Andes virus infection and perform three clinical trials with immune plasma with high titers of Andes virus neutralizing activity (HIP). The first trial with HIP will be a phase I, dose-escalation safety and pharmacokinetics trial in a) normal adults and b) persons with HCPS. The second trial will be an open safety and efficacy trial of HIP in persons at high risk of developing HCPS (sex partners of index patients with HCPS who have a 20% risk of developing HCPS). The third trial will be a controlled trial of HIP in persons with suspected HCPS in the cardiopulmonary phase. In Project 3, we will refine our studies to try to learn what factors put sex partners at significantly higher risk of infection than nonsex partner household contacts. We will a) prospectively follow sex partner household contacts, b) administer questionnaires to assess risks such as common source exposure, sexual practices and deep kissing and c) study genital, oral and dermal secretions, including daily home collection of saliva swabs, to determine whether Andes virus RNA can be identified by PCR and whether virus can be cultured from PCR-positive samples. PROJECT 1: Ecology of Andes & Choclo Viruses (Glass, G.) PROJECT 1 DESCRIPTION (provided by applicant): Hantavirus cardiopulmonary syndrome resulting from any of a number of hantaviruses in the western hemisphere is thought to be contracted through inhalation of infected rodent excreta. In southern and central Chile, the Andes virus infects the sigmodontine rodent Oligoryzomys longicaudatus, and causes a rare but severe human infection with high mortality. In western Panama, the Choclo virus infects the rodent Oligoryzomys fulvescens and causes a common but usually mild or inapparent human infection with a low mortality rate. In both regions the risk of transmission appears to be influenced by many factors increasing the opportunity for close contact between infected rodents and susceptible humans. We will focus our investigations on three of these factors, with the goal of gaining insights critical for the design of future environmental interventions to decrease hantavirus transmission. First, recent investigations in Chile and Panama have associated risk of infection with selected vegetation habitats favored by the infected vector rodents. In Chile exposure risk can be predicted by remote sensing with satellite imagery analysis over 2/3 of the country. In Panama a micro scale analysis has suggested complex relationships between peridomestic infected rodents and agricultural activities. We propose to focus on spatial relationships between rodents and habitats over time, using mark-recapture trapping and radiotelemetry to mark rodent movements, particularly in peridomestic environments. Second we will create a dynamic model that extends our current static analysis of risk. The new model will apply graph theory to field collected data of rodent habitat preferences and movements within the landscape to predict the likely movement of infected rodents. We will test the model using data from sites different from those used to create the model. The temporal precision of the model will be improved by quantitating viral load in rodent blood, tissue, and urine in the winter (low transmission) and spring (high transmission) seasons. Finally, serial serosurveys of at-risk human populations in Panama will quantify the impact on human infection associated with spatial-temporal variations in rodent density and movement.