Serology as a measure of exposure and duration of infection in malaria trials

描述(由申请人提供)：血清学作为疟疾试验中暴露和感染持续时间的衡量标准，疟疾是全世界儿科发病率和死亡率的主要原因之一。全球对疟疾负担的认识增加了对疟疾控制的投资，甚至提高了在某些地区消灭疟疾的可能性。在疟疾传播迅速变化和大规模扩大控制努力的时代，准确衡量疟疾感染和疾病负担随时间和空间的变化的工具至关重要。衡量传播强度的金标准是昆虫学接种率(EIR)，它根据叮咬率和携带寄生虫的媒介的比例来衡量估计的每人每年被蚊子叮咬的次数。寄生虫流行率(PR)，即在横断面调查中携带无症状感染的人的比例，通常被用来量化感染的负担，也被用作传播强度的替代指标。疟疾引起的发热发作的数量或发生率、严重住院疟疾病例和疟疾导致的死亡是衡量临床疾病负担的重要指标。这些指标中的每一项--EIR、PR和发病率--都衡量了疟疾寄生虫在生命周期的不同时间点上的成功程度，而这些指标之间的关系却鲜为人知。因此，比较针对寄生虫生命周期不同阶段的干预措施是具有挑战性的。例如，减少蚊子数量的干预措施(如杀幼虫或室内滞留喷洒)预计将降低EIR。然而，一种有效药物的引入可能不会降低EIR，但会减少感染持续时间、严重疾病的发生率和死亡率。如何才能最好地比较这些干预措施的影响？对疟疾抗原的抗体从第一次接触血液期寄生虫开始发展，但抗体反应的大小和寿命与感染持续时间和再次感染的频率有关。因此， 从疟疾-NA到暴露于疟疾的血清转换与传播强度和感染持续时间有关。最近的研究表明，血清学技术可用于在横断面调查中快速评估人群水平的暴露情况。已有研究表明，随着年龄的增长，血清阳性率的增加与EIR成正比。年龄-血清阳性率曲线的拐点被假设为反映最近在人群中传播的减少。这些技术尚未在干预试验的背景下进行前瞻性测试，并与疟疾负担的其他衡量标准进行比较。我们建议将疟疾的血清学措施纳入一项大规模、整群随机的疟疾干预试验。Mvmer o试验旨在比较媒介控制和诊断干预的影响，并在拉丁方设计中检测两者之间的协同作用。拟议的工作将确定人口年龄-血清阳性率和年龄滴度曲线是否反映了在短时间尺度上的人口水平感染的变化 干预试验以及绝对抗体滴度和血清阳性率是否可以区分减少感染暴露的干预措施(ITN、杀幼虫、国税局)和缩短感染持续时间的干预措施(诊断试验、有效药物、早期治疗和活动性病例检测)。 公共卫生相关性：疟疾的血清学测量可以将流行病学参数与昆虫学参数联系起来，是疟疾监测工具箱的有力补充。我们建议在一项前瞻性、整群随机、多干预试验中扩大对血清学措施如何反映针对寄生虫生命周期不同阶段的干预措施的影响的理解。

DESCRIPTION (provided by applicant): Serology as a measure of exposure and duration of infection in malaria trials Malaria is one of the leading causes of pediatric morbidity and mortaliy worldwide. Global awareness about the burden of malaria has led to increased investment in malaria control and has even raised the prospect of elimination in some areas. In an era of rapidly changing malaria transmission and mass scale-up of control efforts, tools to accurately measure changes in the burden of malaria infection and disease over time and space are crucial. The gold standard for measuring transmission intensity is the entomological inoculation rate (EIR) which measures the estimated number of infectious mosquito bites per person per year based on the biting rate and proportion of vectors carrying parasites. Parasite prevalence (PR), or the fraction of people carrying asymptomatic infections in a cross-sectional survey, is often used to quantify the burden of infection and is also used as a proxy for transmission intensity. The number or incidence of febrile episodes due to malaria, severe hospitalized malaria cases, and malaria- attributable deaths are important measures of the burden of clinical disease. Each of these indicators - EIR, PR and incidence - measures the success of the parasite at a different point in the malaria parasite's life-cycle and the relationship between these measures is poorly understood. Therefore, comparing interventions that target different stages of the parasite's life- cycle is challenging. For example, interventions that reduce the number of mosquitoes (such as larviciding or indoor residual spraying) would be expected to reduce the EIR. However, the introduction of an effective drug may not be expected to reduce EIR but will reduce the duration of infections, incidence of severe disease, and death. How can the impact of these interventions best be compared? Antibodies to malaria antigens begin to develop from the first exposure to blood-stage parasites, but the magnitude and longevity of the antibody response is related to the duration of infection and frequency of re-infection. Therefore, seroconversion from malaria-na¿ve to malaria exposed is related to the intensity of transmission and duration of infection. Recent studies have shown that serological techniques can be used to rapidly assess exposure at a population level in cross-sectional surveys. It has been shown that the increase in seroprevalence with increasing age is directly proportional to EIR. Inflections in the age-seroprevalence curve are hypothesized to reflect recent reduction in transmission in a population. These techniques have not yet been tested prospectively in the context of an intervention trial and compared alongside other measures of malaria burden. We propose to incorporate serological measures of malaria into a large, cluster-randomized malaria intervention trial. The Mvomero trial is designed to compare the impact of a vector control and a diagnostic intervention and to detect synergies between the two in a latin squares design. The work proposed will determine whether population age- seroprevalence and age-titer profiles reflect changes in population-level exposure to infection on short time scales in the context of an intervention trial and whether absolute antibody titers and seroprevalence can distinguish between interventions that reduce exposure to infection (ITN, larviciding, IRS) and interventions that reduce the duration of infection (diagnostic tests, effective drugs, early treatment and activ case detection). PUBLIC HEALTH RELEVANCE: Serological measures of malaria can relate epidemiologic parameters to entomologic parameters and are a powerful addition to the malaria surveillance toolbox. We propose to extend the understanding of how serological measures reflect the impact of interventions that target different stages of the parasite life- cycle in a prospective, cluster randomized, multi-intervention trial.