Previous exposure to dengue as a risk factor for Zika during pregnancy

怀孕期间接触登革热是寨卡病毒的危险因素

• 批准号: 10078931
• 负责人: Matthew T Aliota
• 金额: $ 63.22万
• 依托单位: UNIVERSITY OF MINNESOTA
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-01-01 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10078931
• 关键词: 9 year old; Adult; Americas; Amino Acids; Antibodies; Area; Binding; Brazil; Cells; Complication; Conflict (Psychology); Congenital Abnormality; Costa Rica; Country; Data; Dengue; Dengue Infection; Dengue Vaccine; Dengue Virus; Dengvaxia; Development; Disease; Dose; El Salvador; Epidemic; Epidemiology; Exposure to; Fc Receptor; Fetal Development; Flavivirus; Goals; Government; Guillain Barré Syndrome; Immune; Immune response; Immunity; Immunization; Immunize; Immunology; Incidence; Individual; Infection; International; Laboratories; Lead; Licensure; Life; Link; Location; Macaca; Mexico; Microcephaly; Modeling; Mus; Neonatal; Neurologic; Outcome; Paraguay; Pathogenesis; Philippines; Pregnancy; Prevalence; Primary Infection; Public Health; Reporting; Research; Risk; Risk Factors; Role; Serotyping; Severities; Structure; Syndrome; T memory cell; United States National Institutes of Health; Vaccinated; Vaccination; Viral Pathogenesis; Viremia; Virion; Virus; Virus Activation; Virus Diseases; Virus Replication; West Nile virus; World Health Organization; Yellow Fever; Yellow fever virus; ZIKA; ZIKV disease; ZIKV infection; Zika Virus; adverse outcome; aged; co-infection; cross reactivity; cytokine release syndrome; env Gene Products; experimental study; fetal; health/scientific organization; neonate; neutralizing antibody; nonhuman primate; pathogenic virus; pregnant; public health emergency; response; secondary infection; translational model; vaccine candidate; vector; virology

Project Summary Dengue virus (DENV) is endemic in many regions of the Americas where Zika virus (ZIKV) is emerging. These two viruses are closely related genetically and antigenically, so immunity to DENV may influence the outcome of ZIKV infection. The goal of this project is to understand the impact of pre-existing DENV immunity induced by infection or vaccination on ZIKV infection during pregnancy. This question is important because it has been hypothesized that the unexpectedly high rate of adverse consequences associated with ZIKV infection during pregnancy may be the result of previous infection with one of the four DENV serotypes. Primary infection with one DENV serotype is protective against secondary infection with the same serotype. Secondary infection with a different serotype can lead to enhanced disease because cross-reactive, inadequately neutralizing, antibodies can facilitate enhanced viral replication and skewed immune responses. DENV and ZIKV are similar enough in the envelope protein (the major target of these enhancing antibodies) that ZIKV could theoretically function as a “fifth” DENV serotype. This has been explored to some degree, but controversy remains, as some groups have reported cross-protection while others have reported the potential for enhanced disease. Critically, interactions between DENV and ZIKV have not been explored in the setting of pregnancy, even though congenital ZIKV infection is associated with birth defects. Accordingly, through this NIH/ NIAD R01 we will use our nonhuman primate model of ZIKV infection to evaluate whether the severity of maternal and fetal ZIKV infection during pregnancy are enhanced by previous exposure to DENV. There are two Specific Aims: Specific Aim 1. Define the impact of prior DENV infection on the severity of maternal and neonatal ZIKV infection in pregnant macaques. Specific Aim 2. Define the impact of prior DENV vaccination on the severity of maternal and neonatal ZIKV infection in pregnant macaques. In these studies, we will contrast maternal viremia, immune responses, and fetal outcomes with those in DENV-naive individuals infected identically with ZIKV. Our strategy to induce DENV-specific immune responses includes exposure to both wildtype DENV and a leading DENV vaccine candidate, Sanofi Pasteur’s Dengvaxia®. These studies are critically important because 1) ZIKV is circulating in many locations where DENV is hyperendemic and 2) Dengvaxia® is currently licensed for use, and licensure of other DENV vaccines is imminent, in areas where ZIKV is circulating. By definition, large-scale vaccination campaigns will increase the prevalence of DENV immunity. Whether immunization with Dengvaxia®—which simultaneously exposes an individual to all four DENV serotypes—can lead to more severe ZIKV disease is unknown. The results from these experiments will provide important answers to an epidemiologically relevant question; is it safe to vaccinate against dengue where ZIKV also is co-endemic?

项目摘要 登革热病毒(DENV)在美洲许多地区流行，寨卡病毒(ZIKV)正在这些地区出现。这些 这两种病毒在基因和抗原性上密切相关，因此对DENV的免疫可能会影响结果 寨卡病毒感染的可能性。这个项目的目标是了解预先存在的DENV免疫诱导的影响 孕期通过感染或接种寨卡病毒感染。这个问题很重要，因为它已经 假设与寨卡病毒感染相关的不良后果的出人意料的高比率 怀孕可能是先前感染了四种DENV血清型之一的结果。原发感染 一种DENV血清型对同一血清型的二次感染具有保护作用。继发感染 具有不同血清型的抗体可能会导致疾病加重，因为交叉反应、中和不足的抗体可以促进病毒复制增强和免疫反应扭曲。DENV和ZIKV相似 在包膜蛋白(这些增强抗体的主要目标)中足够多，理论上ZIKV可以 作为第五种DENV血清型。这在某种程度上已经被探索过了，但争议仍然存在，因为 一些群体报告了交叉保护，而另一些群体则报告了疾病增强的可能性。 关键的是，DENV和ZIKV之间的相互作用在怀孕期间还没有被探索过， 尽管先天性ZIKV感染与出生缺陷有关。因此，通过这一NIH/ NIAD R01我们将使用我们的ZIKV感染的非人灵长类动物模型来评估孕期母婴ZIKV感染的严重性是否因先前接触DENV而增加。有两个 具体目标： 明确目标1.明确以前的DENV感染对产妇和新生儿的严重程度的影响 妊娠猕猴中的寨卡病毒感染。 具体目标2.确定之前接种DENV疫苗对产妇和新生儿严重程度的影响 妊娠猕猴中的寨卡病毒感染。 在这些研究中，我们将比较母体病毒血症、免疫反应和胎儿结局 DENV-感染相同ZIKV的幼稚个人。我们诱导DENV特异性免疫反应的策略包括接触野生型DENV和领先的DENV候选疫苗，赛诺菲巴斯德 登革热®。这些研究是至关重要的，因为1)寨卡病毒在许多地方传播， DENV是高度流行的，2)Dengvaxia®目前获得了使用许可，并获得了其他DENV疫苗的许可 迫在眉睫，在寨卡病毒流行的地区。根据定义，大规模的疫苗接种活动将增加 登革热病毒免疫力的流行情况。是否接种登革热®-同时暴露于 一个人对所有四种DENV血清型--是否会导致更严重的ZIKV疾病尚不清楚。结果来自于 这些实验将为一个与流行病学相关的问题提供重要答案；在寨卡病毒也共同流行的地方接种登革热疫苗安全吗？