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

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13万儿童死亡。两种疫苗最近在世界范围内推出，并已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中效果较差。这意味着轮状病毒仍然是腹泻住院的主要原因，即使在它们引入之后。为了应对这一挑战，我们需要下一代轮状病毒疫苗，以克服低收入国家有效口服疫苗的障碍。这些疫苗正在开发中。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和免疫相关的保护（CoP），可以用作替代试验终点尚未确定。对照人类感染研究，其中参与者故意暴露于野生型或减毒感染，在新疫苗的临床开发和关于其使用的全球建议方面发挥着越来越大的作用。我们建议使用一种已获许可的口服轮状病毒减毒活疫苗（Rotarix）作为赞比亚婴儿的受控人类感染挑战，以研究一种单独使用或与口服疫苗联合使用的新型可注射轮状病毒疫苗。这是一个令人兴奋的机会，看看这种可注射的VP8亚单位疫苗是否可以克服口服免疫的障碍，以及它的有效性是否通过与口服疫苗联合使用得到改善。与野生型感染相比，使用减毒活疫苗作为攻击剂具有许多优势，包括其已建立的安全性，高度监管（GMP）的生产和适用于儿童。这种感染模式的相关性最近的研究结果表明，对轮状病毒的获得性免疫主要通过预防感染而不是降低感染后的疾病风险来支持这种疫苗（而不是临床疾病），并将通过与正在进行的该疫苗有效性的3期临床试验结果进行比较来进一步验证。这种人类感染模型还将使我们能够研究肠道（本发明的目的是在口服和肠胃外免疫后检测免疫原性（例如，粘膜）免疫，并有效地探索针对感染的保护（CoP）的潜在免疫相关性，所述保护（CoP）可以在疫苗接种后从婴儿采集的血液或唾液样品中测量。这些研究将基于我们对轮状病毒免疫学的最新进展，重点关注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时间表更有效，这将支持进一步的研究和项目评估，最终可能导致非洲和亚洲疫苗接种对轮状病毒疾病和死亡率产生更大的影响。在本项目结束时，我们还将提高对疫苗诱导的轮状病毒免疫的理解，并在非洲婴儿中建立减毒活轮状病毒感染模型，该模型可用于评估正在开发的新轮状病毒疫苗。

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.