权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Human live-attenuated rotavirus to assess next-genchallenge with eration rotavirus vaccines in Africa

人类减毒活轮状病毒用于评估非洲轮状病毒疫苗的下一代挑战

基本信息

批准号：
MR/T030321/1
负责人：
Nicholas Grassly
金额：
$ 129.41万
依托单位：
Imperial College London
依托单位国家：
英国
项目类别：
Research Grant
财政年份：
2020
资助国家：
英国
起止时间：
2020 至无数据
项目状态：
已结题

来源：
https://gtr.ukri.org/projects?ref=MR%2FT030321%2F1
关键词：
Human live attenuated rotavirus assess

项目摘要

Rotavirus infection causes severe diarrhoea and is responsible for about 130,000 child deaths every year in low-income countries in Africa and Asia. Two vaccines have recently been introduced worldwide and have started to reduce the burden of rotavirus disease. Unfortunately, these orally administered vaccines are less effective in the low-income countries where they are needed compared with high-income countries. This means rotavirus remains the main cause of hospitalisation for diarrhoea even after their introduction. To tackle this challenge, we need a next-generation of rotavirus vaccines that overcome the barrier to effective oral vaccines in low-income countries. These vaccines are in the development pipeline. However, their assessment in clinical trials is challenging because comparison with placebo is no longer considered ethical and immune correlates of protection (CoP) that could be used as alternative trial endpoints have not been identified.Controlled human infection studies, where participants are deliberately exposed to wild-type or attenuated infections, are increasingly playing a role in the clinical development of new vaccines and global recommendations concerning their use. We propose to use a licensed live-attenuated oral rotavirus vaccine (Rotarix) as a controlled human infection challenge in infants in Zambia to investigate a novel injectable rotavirus vaccine used alone or in combination with oral vaccination. This is an exciting opportunity to see whether this injectable VP8 subunit vaccine can overcome the barrier to oral immunisation and whether its effectiveness is improved through combined use with oral vaccine.Use of a live-attenuated vaccine as a challenge agent has many advantages compared with wild-type infection, including its established safety profile, highly regulated (GMP) manufacture and its suitability for use in children. The relevance of this infection model (rather than clinical disease) is supported by recent findings showing acquired immunity to rotavirus acts primarily by preventing infection rather than reducing the risk of disease following infection and will be further validated by comparison with results from an ongoing phase 3 clinical trial of the efficacy of this vaccine.This human infection model will also allow us to investigate the development of intestinal (mucosal) immunity following oral and parenteral immunisation and to efficiently explore potential immune correlates of protection (CoP) against infection that can be measured in blood or saliva samples taken from infants after vaccination. These will be based on recent advances in our understanding of rotavirus immunology and focus on systemic and mucosal antibodies targeting different rotavirus antigens.If we find that combined use of an oral and injectable vaccine is more effective than current schedules, this will support further studies and programmatic evaluation that could ultimately lead to a greater impact of vaccination in Africa and Asia on rotavirus disease and mortality. At the end of this project, we will also have improved our understanding of vaccine-induced rotavirus immunity and established a live-attenuated rotavirus infection model in African infants that can be used to assess new rotavirus vaccines under development.

轮状病毒感染导致严重腹泻，每年在非洲和亚洲低收入国家造成约13万名儿童死亡。最近在世界范围内引进了两种疫苗，并开始减轻轮状病毒疾病的负担。不幸的是，与高收入国家相比，这些口服疫苗在需要它们的低收入国家的效果较差。这意味着轮状病毒即使在引入后仍然是腹泻住院治疗的主要原因。为了应对这一挑战，我们需要新一代轮状病毒疫苗，以克服在低收入国家获得有效口服疫苗的障碍。这些疫苗正在研发中。然而，它们在临床试验中的评估是具有挑战性的，因为与安慰剂的比较不再被认为是伦理的，而且可以用作替代试验终点的免疫相关保护（CoP）尚未确定。对照人类感染研究在参与者故意暴露于野生型或减毒型感染的情况下，在新疫苗的临床开发和关于其使用的全球建议中发挥着越来越大的作用。我们建议在赞比亚的婴儿中使用经许可的减毒口服轮状病毒活疫苗（Rotarix）作为受控的人类感染挑战，以研究一种新的可注射轮状病毒疫苗单独使用或与口服疫苗联合使用。这是一个令人兴奋的机会，可以看到这种可注射的VP8亚单位疫苗是否可以克服口服免疫的障碍，以及通过与口服疫苗联合使用是否可以提高其有效性。与野生型感染相比，使用减毒活疫苗作为攻毒剂具有许多优势，包括其已确立的安全性、严格监管的生产以及适用于儿童。最近的研究结果支持了这种感染模型（而不是临床疾病）的相关性，这些发现表明，对轮状病毒的获得性免疫主要是通过预防感染而不是减少感染后的疾病风险，并将通过与正在进行的该疫苗功效的3期临床试验的结果进行比较进一步验证。这种人类感染模型还将使我们能够研究口服和肠外免疫后肠道（粘膜）免疫的发展，并有效地探索接种疫苗后婴儿血液或唾液样本中可测量的感染保护（CoP）的潜在免疫相关性。这些将基于我们对轮状病毒免疫学的理解的最新进展，并侧重于针对不同轮状病毒抗原的全身和粘膜抗体。如果我们发现口服和注射疫苗的联合使用比目前的计划更有效，这将支持进一步的研究和规划评价，最终可能导致非洲和亚洲的疫苗接种对轮状病毒疾病和死亡率产生更大的影响。在这个项目结束时，我们还将提高我们对疫苗诱导的轮状病毒免疫的理解，并在非洲婴儿中建立一个减毒轮状病毒感染模型，该模型可用于评估正在开发的新的轮状病毒疫苗。