Immunological investigation for the implementation of Live Attenuated Influenza Vaccination

每年流感影响5-10%的成年人和20-30%的儿童，导致250- 500，000人死亡，并给卫生服务带来巨大压力。传统的灭活注射疫苗针对的是弱势群体，特别是老年人（死于流感的风险最高），但有效性只有50-60%。另一种可能更好的策略是以弱化流感病毒的形式接种活疫苗;它可以作为鼻喷雾剂方便地给药，对儿童有效率为80%。由于流感主要通过儿童在社区中传播，因此通过接种疫苗保护他们可以阻止传播，从而提供全社区的保护（称为“群体免疫”）。基于这一理由，英国卫生部（DH）启动了第一个由公共资金资助的全国性疫苗接种计划，每年向所有儿童提供这种疫苗，每年的费用为c。一亿英镑由英国公共卫生部（PHE）管理和监测的分阶段推广，于2013年开始，适用于2-3岁的儿童。自2003年以来，活疫苗已在美国使用，但自2010年以来，其有效性降低。去年的监测表明，它不再能保护儿童免受主要流感病毒的侵害，因此美国公共卫生机构停止了它的使用。在英国，研究结果显示，活疫苗一直透过群体免疫力，保护已接种疫苗的儿童及未接种疫苗的长者，但效果不如预期。卫生署、公共卫生署及世界卫生组织认为，找出疫苗效果下降（在美国则没有）的原因，是公共卫生的当务之急。该提案解决了这一问题，旨在回答最佳实施这种活疫苗的关键问题。国家卫生研究所（NIHR）呼吸道感染健康保护研究单位（HPRU）是帝国理工学院伦敦（IC）和PHE之间的合作伙伴关系。为了这个提议，我们的HPRU汇集了英国顶级的流感专家。我们密切合作，在我们的观察研究中招募并随访了接受活鼻喷雾疫苗的不同儿童群体。我们系统地储存了所有相关的血液和鼻拭子样本，创建了一个全球独一无二的“生物库”，使我们能够填补上述重要的知识空白。作为一种鼻喷雾剂，这种活疫苗会导致鼻子轻微的短暂感染，诱导广泛的免疫反应，类似于自然感染。与英国相比，大多数接受疫苗的美国儿童在前几年接受过疫苗。疫苗表现不佳的主要假设是，在已经多次接种减毒疫苗病毒的儿童中，诱导的免疫力足以预防局部短暂性鼻感染，但不足以保护免受自然流感感染。我们研究中的儿童包括从未接种过疫苗的儿童以及以前接种过疫苗的儿童（最多3次疫苗接种）。这使我们能够：-通过测量疫苗接种后从鼻子中流出的疫苗病毒量来评估，比较先前疫苗接种对疫苗诱导局部感染的影响-通过一系列血液测试来测量它刺激免疫力的程度-评估先前疫苗接种诱导的免疫应答预防这种有益的局部感染和免疫刺激。今年冬天，疫苗中的流感毒株已根据世卫组织对预计将占主导地位的新天然流感毒株的建议进行了替换。我们还将比较这种新疫苗株诱导的鼻复制和免疫刺激与以前的疫苗株诱导的。

Each year flu affects 5-10% of adults and 20-30% of children, causes 250-500,000 deaths and places a huge strain on health services. The conventional inactivated injectable vaccine is targeted to vulnerable groups, especially the elderly (who are at highest risk of dying from flu), but is only 50-60% effective. An alternative, potentially better strategy is a live vaccine in the form of a weakened flu virus; it is given conveniently as a nasal spray and is 80% effective in children. Since flu spreads across communities mostly through children, protecting them by vaccination can stem the spread, thereby providing community-wide protection (known as 'herd immunity'). With this rationale, the UK Department of Health (DH) launched the first publicly-funded nationwide vaccination programme with this vaccine, offering it yearly to all children at an annual cost of c. £100m. The phased roll-out, managed and monitored by Public Health England (PHE), started in 2013 with 2-3 year old children. The live vaccine has been used in the USA since 2003 but has become less effective since 2010. Last year surveillance indicated that it was no longer protecting children against the predominant flu strain, and the USA public health agency therefore discontinued its use. In the UK, results show that the live vaccine has so far been protecting vaccinated children and unvaccinated elderly through herd immunity, but it has been less effective than expected.Identifying the reasons for this reduced (and in the USA, absent) effectiveness is recognised by DH, PHE and the World Health Organization (WHO) as an urgent public health priority. This proposal addresses this issue and aims to answer the key questions for optimal implementation of this live vaccine.The National Institute for Health Research (NIHR) Health Protection Research Unit (HPRU) in Respiratory Infections is a partnership between Imperial College London (IC) and PHE. For this proposal, our HPRU brings together the UK's top flu experts. We have worked closely together to enrol and follow-up different groups of children receiving the live nasal spray vaccine into our observation studies. We have systematically stored all relevant blood and nasal swab samples, creating a globally unique 'biobank' which enables us to address the important knowledge gaps above.As a nasal spray, this live vaccine causes a mild transient infection in the nose inducing a wide range of immune responses, similar to natural infection. In contrast to the UK, most US children receiving the vaccine have received it in previous years. The leading hypothesis for the vaccine's underperformance is that in children who are already repeatedly vaccinated with the weakened vaccine virus, the immunity induced is sufficient to prevent the localised transient nasal infection, but is not strong enough to protect against infection by natural flu.The children in our studies include those never previously vaccinated as well as previously vaccinated children (up to 3 previous vaccinations). This enables us to:-compare the effect of prior vaccination on how well the vaccine induces a local infection, assessed by measuring the amount of vaccine virus shed from the nose after vaccination-measure how well it stimulates immunity by a range of blood tests-evaluate which immune responses induced by prior vaccination prevent this beneficial local infection and immune stimulation. For this winter, the strain of flu in the vaccine has been replaced in line with WHO's recommendation for the new natural flu strain that is expected to dominate. We will also compare nasal replication and immune stimulation induced by this new vaccine strain with that induced by the previous vaccine strain.