CAREER: An ImmunoBioEngineering Platform for Rapid and Scalable Biomanufacturing of Universal Viral Vaccines

流感流行每年造成25万至30万人死亡，300万至500万人患重病。不幸的是，目前的流感疫苗提供的保护有限，需要季节性流感疫苗，并且由于基于鸡蛋的制造技术的限制，造成大流行的易感性。因此，开发一种快速、可扩展的通用流感疫苗生物生产系统具有重大的社会影响。为了实现这一目标，本CAREER提案旨在开发一种基于酵母的系统，用于合成和工程人工流感样病毒（AILVs），能够诱导对流感病毒的普遍保护。它代表了一种新的方法，有可能从目前简单的自然病毒样颗粒合成方法转向复杂的设计病毒样颗粒工程，以开发下一代病毒疫苗。研究成果将用于加强本科和研究生课程，这些课程也将用于K-12的推广工作，并提高STEM领域的公众科学素养。由于一些分子和细胞的挑战，以前没有开发基于酵母的ailv。本提案将使用多学科方法结合蛋白质工程、免疫学、合成生物学、生物化学和生物统计学来解决这些问题。具体来说，我们将研究：(1)酵母是否能够生产和组装关键的流感病毒蛋白，使其成为功能性的ailv；(2)所产生的ailv是否能引发保护性抗体和t细胞反应；(3)具有普遍保护能力的ailv的分子设计。由此产生的基于酵母的ailv不仅将作为一个快速和可扩展的流感疫苗生物制造平台，而且还将用于探测免疫反应，以回答t细胞免疫学、蛋白质3D自组装等方面的核心问题。研究成果将用于加强本科和研究生课程，这些课程也将用于K-12的推广工作，并提高STEM领域的公众科学素养。PI计划开发适合各级教育工作者的创造性教学法，以改善学生的学习。

PI: Wen , FeiProposal No: 1653611Influenza epidemics result in 250,000-300,000 deaths and 3-5 million cases of severe illness annually. Unfortunately, current influenza vaccines offer limited protection requiring seasonal flu shots and pose pandemic susceptibility due to technological limitations of the egg-based manufacturing. Therefore, it is of great societal impact to develop a rapid and scalable system for biomanufacturing of universal flu vaccines. Towards this goal, this CAREER proposal aims to develop a yeast-based system for synthesizing and engineering artificial influenza-like viruses (AILVs) capable of inducing universal protection against influenza viruses. It represents a novel approach with the potential of shifting from current approach of simple natural virus-like particle synthesis to complex designer virus-like particle engineering for developing the next generation viral vaccines. Research findings will be used to strengthen the undergraduate and graduate curricula, which will also be used in K-12 outreach endeavors and increase public scientific literacy in the STEM fields.Yeast-based AILVs have not been previously developed due to several molecular and cellular challenges. This proposal will address these issues using a multi-disciplinary approach interfacing protein engineering, immunology, synthetic biology, biochemistry, and biostatistics. Specifically, we will investigate: (1) if yeast is capable of producing and assembling key influenza viral proteins into functional AILVs; (2) if the resulting AILVs can elicit protective antibody and T-cell responses; and (3) the molecular design of AILVs capable of universal protection. The resulting yeast-based AILVs will not only serve as a rapid and scalable influenza vaccine biomanufacturing platform, but also will be used to probe immune responses to answer central questions in T-cell immunology, 3D self-assembly of proteins, and more. Research findings will be used to strengthen the undergraduate and graduate curricula, which will also be used in K-12 outreach endeavors and increase public scientific literacy in the STEM fields. PI plans to develop creative pedagogies that are adaptable by educators at all levels for improved student learning.