Non- Inferiority Fractional-doses Trial for Yellow Fever Vaccine
试验速览
- 阶段
- 4 期
- 状态
- 已完成
- 入组人数
- 900
- 试验地点
- 3
- 主要终点
- The proportion of vaccinees that seroconverts as measured by Plaque Reduction Neutralisation Test (PRNT-50)
研究概览
简要总结
In the recent past there has been a number of large urban Yellow Fever outbreaks in sub-Saharan Africa, tropical South Americas, The demand for Yellow Fever vaccines in response to the large urban outbreaks occurring concurrently and the risk of further spread through Africa and to Asia was larger than the available global supply. In this situation, the World Health Organisation (WHO) developed recommendations for the use of fractional doses of Yellow Fever vaccine as a dose-sparing strategy. These recommendations were based on data from a limited number of clinical trials, none of which had been conducted in Africa. This was due to the uncertainties on the minimum dose requirement.
Our study complements a study which is comparing full standard dose to 1/5th of standard dose of all four WHO-prequalified YF vaccines in adults (ClinicalTrials.gov number: NCT02991495), and is currently ongoing at KEMRI CGMRC and Epicentre, Mbarara which is designed to answer questions on the use of current stock of YF vaccines with a potency as close as possible to each manufacturers' minimum release. Data from this trial will inform a WHO recommendation on using 1/5th of the current standard dose of vaccine for outbreak control. However, since many vials will contain excess YF vaccine such that 1/5th of a vial is likely to be substantially above the current minimum potency requirements, these data may not be scientifically explanatory regarding the minimum dose required for preventive use.
The new complementary study, aims to determine the lowest YF vaccine dose that is non-inferior to the current standard full dose among populations in sub-Saharan Africa. The study will be conducted in Kenya (KEMRI Center for Geographical Medicine Research-Coast (CGMR-C), Kilifi) and Uganda (Epicentre, Mbarara) with trial participants recruited at both sites, using vaccine from one WHO-prequalified manufacturer (Institut Pasteur de Dakar, Senegal (IPD)).
详细描述
Yellow fever (YF) is a disease caused by a mosquito-borne flavivirus that is endemic in sub-Saharan Africa and tropical South America. Ninety percent of YF cases are in Africa where YF virus is transmitted by different mosquito genera in three recognized transmission cycles. A sylvatic cycle involves transmission between forest-dwelling mosquitoes (Haemagogus spp) and non-human primate reservoirs, with sporadic incidental transmission to humans (e.g. forest workers). An intermediate cycle, occurring only in Africa, involves mosquito transmission between non-human primates and humans, or human-to-human transmission among humans living or working close to forested areas. An urban cycle involves transmission between humans and urban mosquito vectors, primarily Aedes aegypti, and occurs when a viraemic person, infected in the sylvatic or intermediate cycle, introduces YF virus to areas with a large non-immune population and A. aegypti vectors resulting in disease outbreaks.
Infection with YF virus is characterised by a wide range of manifestations, ranging from subclinical infection with mild and non-specific symptoms, to severe, life-threatening illness with jaundice, renal failure and haemorrhage.
A highly effective vaccine is available for use against YF in adults and children aged ≥9 months. The vaccine is a freeze-dried preparation of live attenuated YF virus strain 17D, which was developed in 1937 and is produced by four WHO-prequalified manufacturers. A single dose of YF vaccine is considered sufficient to confer life-long protective immunity against all seven known genotypes of wild-type YF virus. Protective levels of YF virus neutralizing antibodies are developed in 80-100% vaccine recipients within 10 days after vaccination, and in 99% within a month.
Although fractional dosing has recently been used in vaccination campaigns in Kinshasa and Brazil in 2016, 2017 and 2018, WHO recommendations were based on a limited number of clinical studies and important data gaps remain.
fractional vaccine dosing is compounded by the uncertainty surrounding minimum dose requirements.
研究设计
- 研究类型
- Interventional
- 分配方式
- Randomized
- 干预模型
- Parallel
- 主要目的
- Prevention
- 盲法
- Triple (Participant, Investigator, Outcomes Assessor)
盲法说明
Investigators and participants will be blinded to the allocations. Only the pharmacist and the nurse administering the vaccine will be unblinded. The allocation will be to one of the four treatment arms per a computer-generated randomization schedule. Allocations will be concealed until a member of the unblinded study team scratches the randomization booklet to reveal the participants' randomization arm.
入排标准
- 年龄范围
- 9 Months 至 59 Years（Child, Adult）
- 性别
- All
- 接受健康志愿者
- 是
入选标准
- •Individuals aged ≥18 - <60 years of age.
- •Children aged between 9 months and 12 months.
- •HIV negative on serological screening OR HIV positive adults and children aged > 18 months on serological testing, and no symptoms suggestive of current clinical immunosuppression and cluster of differentiation-4 (CD4) count>200 (for adults) and CD4% > 25% (for children aged 9-12 months) within the last 6 months.
- •Ability to provide informed consent to participate in the study
排除标准
- •Known contraindications to YF vaccination such as allergies to egg protein and chicken products or any component of the vaccine (including gelatin, eggs, eggs products or chicken products), immunodeficiency, known thymus disorder, such as thymoma and myasthenia gravis
- •Using corticosteroids or other immunosuppressive therapy
- •Thymus disorder, such as thymoma and myasthenia gravis
- •Acute febrile disease on the day of vaccination with temperature >37.5 degrees Celsius is a temporal contraindication.
- •Previous YF vaccination
- •Previous YF infection as determined from history
- •Pregnancy (as determined by a urine test on the proposed day of vaccination) and lactating women
- •Planning to migrate out of the study areas before the end of the study follow-up
- •Planning to travel to a country requiring YF vaccination certificate within the first year after vaccination.
- •Any condition or criteria, including acute or chronic clinically significant abnormality that in the opinion of the investigator might compromise the wellbeing of the volunteer or interfere with the outcome of the study.
结局指标
主要结局
The proportion of vaccinees that seroconverts as measured by Plaque Reduction Neutralisation Test (PRNT-50)
时间窗: 28 days post vaccination
PRNT-50 will be used to quantify functional antibodies by neutralisation of the virus
次要结局
- Other flavivirus antibodies interference as tested by neutralisation tests(Baseline and 28 days after vaccination)
- Duration of immunity as measured by PRNT(10 days, 28 days, 1 year and 2 years (adults))
- Change in the geometric mean fold of the antibody titre as measured by PRNT(Baseline and 28 days after vaccination)
- Post-vaccination viremia as measured by quantitative Polymerase Chain Reaction (PCR)(baseline, and on days 2, 3, 4, 5, 6, 7 and 10 after vaccination)
- Changes in cellular immunology(baseline and days 10 and 28 post-vaccination.)
- Changes in biomarkers(Baseline, and on days 2, 3, 4, 5, 6, 7,10 and 28 after vaccination)
- Safety of different doses as described by the occurrence of adverse events (AE) and serious adverse events.(28 days after vaccination and an average of 1 year for the adult study and two years for the children study. .)
研究者
George Warimwe, PhD
Professor
University of Oxford