A Randomized Phase I Clinical Trial of HydroVax-YFV, a Novel Inativated Yellow Fever Vaccine

新型灭活黄热病疫苗 HydroVax-YFV 的随机 I 期临床试验

• 批准号: 10404272
• 负责人: Ian James Amanna
• 金额: $ 99.97万
• 依托单位: NAJIT TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-07-01 至 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10404272
• 关键词: Acute; Address; Adult; Adverse event; Age; Age-Months; Age-Years; Allergy to eggs; Attenuated; Attenuated Vaccines; Award; Breast Feeding; Case Fatality Rates; Centers for Disease Control and Prevention (U.S.); Cessation of life; Clinical; Clinical Protocols; Clinical Research; Clinical Trials; Country; Data; Data Analyses; Development; Disease; Disease Outbreaks; Dose; Double-Blind Method; Ebola; Elderly; Encephalitis; Enrollment; FDA approved; Female; Fever; Flavivirus; Goals; Grant; Hemorrhage; Hepatitis; Hospitalization; Human Milk; Hydrogen Peroxide; Immunization; Incidence; Individual; Infant; Infrastructure; Institutes; Investigational Drugs; Investigational New Drug Application; Kidney Failure; Laboratories; Medical; Modeling; Mothers; National Institute of Allergy and Infectious Disease; Nausea and Vomiting; Outcome Measure; Package Insert; Patients; Peroxides; Phase; Phase I Clinical Trials; Phase I and II Vaccine Trials; Placebos; Pregnant Women; Prevention; Production; Protocols documentation; Randomized; Reporting; Research Personnel; Risk; Safety; Savings; Seizures; Serious Adverse Event; Signs and Symptoms; Societies; Technology; Test Result; Testing; Time; Toxic effect; Toxicology; United States National Institutes of Health; Vaccination; Vaccines; Veterans; Virus; Vulnerable Populations; West Nile virus; Woman; Wood material; Yellow Fever; Yellow Fever Vaccine; Yellow fever virus; age group; base; burden of illness; cGMP production; clinically relevant; disability; hemorrhagic fever virus; immune function; immunogenic; immunogenicity; male; man; member; mortality; mosquito-borne; mosquito-borne pathogen; nervous system disorder; nonhuman primate; novel; nursing mothers; phase I trial; pre-clinical; pregnant; primary endpoint; protective efficacy; public health relevance; safety assessment; secondary endpoint; seroconversion; stability testing; vaccine access; vaccine candidate; vaccine development; vaccine trial; viral transmission

Abstract Yellow fever virus (YFV) is a mosquito-borne emerging/re-emerging hemorrhagic fever virus that causes 20- 60% mortality and is endemic in >40 countries. The current live attenuated YFV vaccine was developed in 1936 and has proven to be effective at saving millions of lives from this devastating disease. Nevertheless, this is a live-attenuated vaccine that is contraindicated in healthy people who have egg allergies as well as vulnerable populations including young infants, pregnant or breastfeeding women, and the elderly. During recent outbreaks, these at-risk groups have had no alternatives to live yellow fever vaccination and our goal is to produce a vaccine that is safe for both healthy and vulnerable populations. According to the CDC, live YFV vaccines cause 47 serious adverse events (SAE) per million vaccinations (SAE defined as resulting in hospitalization, long-term disability, or death). Vaccine-associated neurological disease occurs at a rate of up to 1 case per 10,000 vaccinations. YFV vaccination of infants <9 months of age has been contraindicated since the 1960’s due to excessively high rates of vaccine-associated encephalitis in this age group. More recently, live YFV vaccination has been contraindicated in breastfeeding mothers due to documented cases of virus transmission via breastmilk to infants who later developed YFV-associated neurological disease including seizures. In patients >60 years of age, YFV vaccination causes severe viscerotropic disease at an incidence rate of approximately 1:50,000 with a mortality rate of >50%. The overall mortality rate following YFV vaccination (all ages) is estimated at 1 to 2 deaths per million doses. Despite these clear gaps in vaccination coverage, there is currently no commercial vaccine available for these vulnerable populations. To address this critical unmet need, we have discovered a safe and immunogenic peroxide-inactivated yellow fever vaccine, HydroVax-YFV. Importantly, this advanced vaccine is safe and provides complete protection against lethal viscerotropic yellow fever in a robust non-human primate model. Here, we propose a double-blind, randomized, placebo-controlled Phase I dose escalation trial to evaluate the preliminary safety and immunogenicity of HydroVax-YFV. Our goal is to eventually expand vaccine coverage to a broader range of patients and the successful completion of this study will represent a key milestone in the advancement of a clinically relevant vaccine against yellow fever and provide a much-needed approach to protect the most susceptible members of society including infants, elderly, and those with potentially compromised immune functions.

摘要 黄热病病毒（YFV）是一种由蚊子传播的新发/再发出血热病毒，导致20- 60%的死亡率，在40多个国家流行。目前的YFV减毒活疫苗是在1936年开发的，已被证明可以有效地挽救数百万人的生命。然而，这是一种减毒活疫苗，禁忌用于对鸡蛋过敏的健康人群以及脆弱人群，包括幼儿，孕妇或哺乳期妇女和老年人。在最近的疫情中，这些高危人群除了黄热病活疫苗接种外别无选择，我们的目标是生产一种对健康和脆弱人群都安全的疫苗。根据CDC的数据，每百万次接种活YFV疫苗会导致47起严重不良事件（SAE）（SAE定义为导致住院，长期残疾或死亡）。疫苗相关性神经系统疾病的发生率高达每10，000次疫苗接种1例。自20世纪60年代以来，由于9个月以下婴儿的疫苗相关性脑炎发生率过高，因此禁止对该年龄段的婴儿接种YFV疫苗。最近，母乳喂养的母亲禁忌接种YFV活疫苗，因为有记录的病例表明，病毒通过母乳传播给婴儿，婴儿后来患上了YFV相关的神经系统疾病，包括癫痫发作。在>60岁的患者中，YFV疫苗接种导致严重的内脏嗜性疾病，发病率约为1：50，000，死亡率> 50%。接种YFV疫苗后的总死亡率（所有年龄）估计为每百万剂1至2例死亡。尽管在疫苗接种覆盖率方面存在明显差距，但目前还没有可供这些脆弱人群使用的商业疫苗。为了解决这一关键的未满足的需求，我们发现了一种安全且具有免疫原性的过氧化物灭活黄热病疫苗HydroVax-YFV。重要的是，这种先进的疫苗是安全的，并在一个强大的非人灵长类动物模型中提供针对致死性嗜内脏性黄热病的完全保护。在此，我们提出了一项双盲、随机、安慰剂对照的I期剂量递增试验，以评估HydroVax-YFV的初步安全性和免疫原性。我们的目标是最终将疫苗覆盖范围扩大到更广泛的患者，这项研究的成功完成将代表黄热病临床相关疫苗发展的一个关键里程碑，并提供一种急需的方法来保护最易感的社会成员，包括婴儿，老年人和那些免疫功能可能受损的人。