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

基本信息

批准号：
10443905
负责人：
Ian James Amanna
金额：
$ 99.77万
依托单位：
NAJIT TECHNOLOGIES, INC.
依托单位国家：
美国
项目类别：
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/10443905
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 Persons Phase Phase I Clinical Trials Phase I and II Vaccine Trials Placebo Control 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 formulation vaccine platform vaccine trial viral transmission

项目摘要

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.

抽象的黄热病病毒（YFV）是一种蚊子传播/重新出现的出血性发烧病毒，导致20-60％的死亡率，并且在> 40个国家/地区具有内在。当前的现场衰减YFV疫苗于1936年开发，事实证明，有效地从这种毁灭性疾病中挽救了数百万生命。尽管如此，这是一种活体侵蚀的疫苗，在患有卵过敏的健康人以及脆弱的人群中被禁忌，包括年轻婴儿，孕妇或母乳喂养妇女以及年龄较大。在最近的暴发期间，这些高危人群没有其他选择黄热病疫苗的选择，我们的目标是生产一种对健康和脆弱人群安全的疫苗。根据疾病预防控制中心（CDC）的说法，活的YFV疫苗会导致每百万疫苗47个严重的不良事件（SAE）（SAE定义为导致住院，长期残疾或死亡）。与疫苗相关的神经系统疾病以每10,000次接种疫苗的最高1例发生。自1960年代以来，由于该年龄段的疫苗相关性脑炎的发生率极高，因此<9个月大的婴儿的YFV疫苗已被禁忌。最近，由于记录在母乳喂养的母亲中，活的YFV疫苗因通过母乳传播的病例传播给母乳喂养而禁忌，这些病毒通过母乳传播给后来患有YFV相关的神经系统疾病，包括癫痫发作。在60岁以上的患者中，YFV疫苗以大约1：50,000的发病率导致严重的内脏疾病，死亡率> 50％。 YFV疫苗（所有年龄）之后的总死亡率估计为每百万剂量1至2次死亡。尽管在疫苗覆盖范围内存在这些明显的差距，但目前尚无这些脆弱人群的商业疫苗。为了满足这种关键的未满足需求，我们发现了一种安全且免疫原性的过氧化物灭活的黄热疫苗Hydrovax-YFV。重要的是，这种先进的疫苗是安全的，并在强大的非人类私有型号中提供了完全保护致命的内脏黄热病。在这里，我们提出了一项双盲，随机，安慰剂对照的I期升级试验，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，而这项研究的成功完成将是临床相关疫苗抵抗黄热病的关键里程碑，并提供了一种急需的方法来保护社会上最敏感的成员，包括婴儿，年龄较大，具有潜在损害免疫性损害的人。