Viral kinetics, immunity and transmission of ZIKV: an exploratory analysis in preparation for vaccine development

摘要/概要 自2015年以来，我们的研究小组一直在跟踪ZIKV感染的受试者，包括孕妇和孕妇。 未怀孕的成年人、受感染妇女的性伴侣、儿童和其他家庭接触者，以及 婴儿出生的母亲与PCR证实ZIKV感染。我们有一个数据库和标本库， 5000份生物样本，包括来自356名孕妇的系列血清和尿液样本 疑似ZIKV感染的女性，200名非孕妇，200名性伴侣，150名家庭接触者 和ZIKV暴露的婴儿。其他标本包括唾液、胎盘组织、羊水、母乳和 尿液、唾液和血清。我们假设ZIKV的病毒动力学包括病毒载量 并且病毒脱落的持续时间在不同的身体隔室之间可能有很大的不同，所述不同的身体隔室包括血液，尿液， 母乳、羊水、胎盘和唾液，并且在患者人群之间也可能不同，包括 妊娠和非妊娠患者、性伴侣、儿童和ZIKV感染母亲的婴儿。我们也 假设病毒载量和发病机制可能会增强性暴露于病毒，除了 病媒接触，并可能导致疾病发病率和传播增加。我们也 假设中和抗体的发展提供了终身免疫力，但有些人 个体，包括先天性感染的婴儿，可能具有延迟的抗体应答， 脱落在成年人中，这可能不仅会导致病毒脱落时间延长和传播风险增加 而且还会反弹感染对其他虫媒病毒感染（包括登革热1-4）的潜在预先存在抗体 病毒和黄热病可能通过干扰病毒动力学改变ZIKV感染的过程， 中和抗体的产生延迟。我们建议调查病毒载量和病毒动力学， 不同人群中的不同区室，并将结果与症状的严重程度和潜在的 传播给伴侣和婴儿。我们将在一个子集中进行空斑减少中和试验， 受试者研究保护性免疫和与病毒动力学、传播和 感染的清除，以及预先存在的抗其他黄病毒抗体的作用。

Abstract/Summary Our group of researchers has been following subjects with ZIKV infection since 2015 including pregnant and non-pregnant adults, sexual partners of infected women, children and other household contacts as well as infants born to mothers with PCR proven ZIKV infection. We have a database and specimen bank with over 5000 biological specimens available including serial serum and urine specimens from over 356 pregnant women with suspected ZIKV infection, 200 non-pregnant women, 200 sexual partners, 150 household contacts and ZIKV-exposed infants. Other specimens include saliva, placental tissue, amniotic fluid, breast milk and urine, saliva and serum from exposed infants. We hypothesize that viral kinetics of ZIKV including virus load and duration of viral shedding may differ widely between different body compartments including blood, urine, breast milk, amniotic fluid, placenta and saliva, and also may differ between patient populations, including pregnant and non-pregnant patients, sexual partners, children, and infants of ZIKV-infected mothers. We also hypothesize that virus load and pathogenesis may be enhanced by sexual exposure to the virus in addition to vector exposure and that may contribute to enhanced disease morbidity and transmission. We also hypothesize that the development of neutralizing antibodies provides lifelong immunity, but that some individuals, including congenitally infected infants, may have delayed antibody responses with prolonged viral shedding. In adults this might translate not only into prolonged viral shedding and increased transmission risk but also rebound infection. Potentially pre-existing antibodies to other arboviral infections including dengue 1-4 viruses and yellow fever may modify the course of ZIKV infection through interference with viral kinetics or delayed development of neutralizing antibodies. We propose to investigate viral load and viral kinetics in different compartments in distinct populations and correlate findings with severity of symptoms and potential transmission to partners and infants. We will perform plaque reduction neutralization assays in a subset of subjects to investigate protective immunity and potential correlates with viral kinetics, transmission and clearance of infection, and the role of pre-existing antibodies to other flaviviruses.