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) 是一种由蚊子传播的新发/复发出血热病毒，导致 20-60% 的死亡率，在超过 40 个国家流行。目前的减毒活疫苗于 1936 年开发，已被证明是有效的。然而，这是一种减毒活疫苗，对鸡蛋过敏的健康人以及包括幼儿在内的弱势群体是禁忌的。根据疾病预防控制中心的说法，在最近的疫情爆发期间，这些高危人群没有其他选择，可以接种活黄热病疫苗，而我们的目标是生产一种对健康人群和弱势人群都安全的疫苗。每百万次疫苗接种中，YFV 活疫苗会导致 47 起严重不良事件 (SAE)（SAE 定义为导致住院、长期残疾或死亡），每 10,000 次疫苗接种中，发生与疫苗相关的神经系统疾病的比例高达 1 例。自 20 世纪 60 年代以来，9 个月以下婴儿的 YFV 疫苗接种一直被禁止，因为该年龄段的疫苗相关脑炎发病率过高。最近，由于有记录的病毒通过病毒传播的病例，母乳喂养的母亲也禁止接种 YFV 活疫苗。母乳喂养后来患上 YFV 相关神经系统疾病（包括癫痫发作）的婴儿在 60 岁以上的患者中，YFV 疫苗接种会导致严重的内脏疾病，发病率约为1:50,000，死亡率 >50%，YFV 疫苗接种（所有年龄段）后的总体死亡率估计为每百万剂 1 至 2 人死亡，尽管疫苗接种覆盖率存在明显差距，但目前尚无可用于该疫苗的商业疫苗。为了解决这一未满足的关键需求，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，并提供针对致命内脏性的全面保护。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。我们的目标是最终扩大疫苗覆盖范围。这项研究的成功完成将代表临床相关黄热病疫苗进展的一个关键里程碑，并提供一种急需的方法来保护社会最易受影响的成员，包括婴儿、老年人和儿童。免疫系统可能受损的人功能。