Real-time benefit-risk assessment of influenza vaccine exposure across a nationally representative primary care sentinel network

关键词：疫苗接种和剂量、疫苗不良反应、人类流感、流感疫苗、远程医疗、疫苗可预防的疾病、免疫监测、哨点监测、公共卫生信息学、临床信息学流感疫苗接种方面的创新使每年能够发布多种流感疫苗以对抗季节性流感，每种疫苗都有其独特的特点。这可以跨越活的减毒方法与灭活方法、鸡蛋与细胞培养方法、三价(对三种菌株的保护)与四价(对四种菌株的保护)成分和佐剂(添加成分以最大限度地提高免疫反应)与高剂量给药方法。有必要监测和比较这些疫苗在每个季节的表现及其特点；实时监测和比较甚至可能导致季节性而不是季后性成分变化，最大限度地提高国内和国际流感应对的有效性。同样，今年为对抗与新型冠状病毒(新冠肺炎)相关的危重疾病而取得的前所未有的疫苗开发速度也伴随着对其随时间推移的有效性和相关不良事件的严格审查。相比之下，流感疫苗从来没有积累过如此程度的公众关注、犹豫和政治化。在这种情况下，比以往任何时候都更加重要的是，监测疫苗的保护性如何以及何时减弱，并确定感兴趣的不良事件和疫苗迟疑的高危人口统计数据；根据疫苗品牌、批次和特征区分这些指标将是告知未来疾病准备和应对的关键。因此，在可靠的原创研究和严格的文献综述的基础上，这项工作的主要成果将是开发一个实时流感疫苗效益-风险(V-BR)平台，能够监测与不同类型和品牌的流感疫苗相关的效力、吸收和不良反应。该平台将利用牛津-皇家全科医生研究和监测中心的数据(每周两次摘录约15,000,000份匿名患者记录，链接到UKHSA病毒学数据库以及医院和死亡记录)，其支持的临床信息学和结果研究小组的专业知识，以及EMIS‘Patient Access’APP(约1,000万注册用户)提供的日常摘录和直接问卷数据的组合。得益于RCGP RSC监测、仪表板和观察站55年的强大遗产，以及通过Patient Access应用程序托管的患者经验调查提供的丰富数据，这一学生群体将处于独特的地位，可以生成一个世界级的流感V-BR平台。这项工作也符合MRC的研究重点(最突出的是健康信息学、疾病预防、分层医学和流行病学以及公共卫生)，因为它能够洞察流感疫苗接种情况、不良反应和疗效在不同人群之间可能存在的差异。此外，通过阐明疫苗接种率最低的地方、效力不稳定的地方和/或接种后不良影响最明显的地方，这一平台将有助于减少疫苗迟疑和拒绝接种的努力--这是世卫组织和ECDC的优先事项。最后，这个平台可能揭示的个体差异也将为未来探索更个性化的疫苗接种方法提供强有力的理由。除了负责这个平台的持续维护和运行外，到学员结束时，学生将成为疫苗研究领域的专家，熟练掌握R、SQL、Tableau和PowerBI，并将撰写或共同撰写一系列高级研究成果和出版物

Key terms: Vaccine administration and dosage, vaccine adverse effects, human influenza, influenza vaccine, telemedicine, vaccine-preventable diseases, immunologic surveillance, sentinel surveillance, public health informatics, clinical informatics Innovation within influenza vaccination has enabled the release of a number of flu vaccine types to counter seasonal flu each year, each with their own unique characteristics. This can span live attenuated vs inactivated methodologies, egg vs cell cultures, trivalent (protective against three strains) vs quadrivalent (protective against four strains) composition and adjuvanted (added ingredients to maximise immune response) vs high-dosage delivery methods. It is necessary to monitor and compare how these vaccines and their characteristics perform each season; doing so in real-time can even lead to in-season rather than post-season composition changes, maximising the effectiveness of flu response both nationally and internationally. Equally, the unprecedented speed of vaccine development achieved this year to counteract critical illness associated with the novel coronavirus (COVID-19) has also been accompanied with intense levels of scrutiny related to their effectiveness over time and associated adverse events of interest (AEI). Influenza vaccines have never amassed this level of public attention, hesitation and politicisation by comparison. In this context, it will be more important than ever to monitor how and when protectiveness of vaccines wane and to identify at-risk demographics for both adverse events of interest and vaccine hesitancy; differentiating these metrics by vaccine brands, batches and characteristics will be key for informing both disease preparedness and response going forwards. As such, informed by robust original research and rigorous literature review, the primary output of this work will be to develop a real-time influenza vaccine benefit-risk (V-BR) platform capable of monitoring the efficacy, uptake and adverse effects associated with different types and brands of influenza vaccines. This platform will leverage data from the Oxford-Royal College of General Practitioners Research and Surveillance Centre (twice weekly extracts of ~ 15,000,000 pseudoanonymised patient records linked to UKHSA virology databases and hospital and death records), the expertise of its underpinning Clinical Informatics and Outcomes Research Group and a combination of daily extracts and direct questionnaire data supplied by the EMIS 'Patient Access' app (~ 10 million registered users).Benefitting from both the 55-year strong legacy of RCGP RSC surveillance, dashboards and observatories and the richness of data offered through patient experience surveys hosted on the Patient Access app, this studentship will be uniquely positioned to generate a world-class influenza V-BR platform. This work also aligns with MRC research priorities (most notably health informatics, disease prevention, stratified medicine and epidemiology and public health) due to its ability to provide insight into how influenza vaccine uptake, adverse effects and efficacy may differ between population groups. Further, by illuminating where vaccine uptake is lowest, where efficacy wavers and/or where post-vaccination adverse effects are most pronounced, this platform will contribute to efforts to reduce vaccine hesitancy and refusal - a WHO and ECDC priority. Finally, the individual differences that may be revealed by this platform will also make a strong case for exploring a more personalised approach to vaccination in the future. As well as becoming responsible for the ongoing maintenance and actioning of this platform, by the studentship's end the student will have established themselves as an expert within the field of vaccine research, will have upskilled in R, SQL, Tableau and PowerBI and will have authored or co-authored a range of high-level research outputs and publications