A Nanoparticle-Based Multivalent Rotavirus Vaccine

轮状病毒(RV)导致儿童严重腹泻，发病率和死亡率很高。在当前的生活中 口服轮状病毒疫苗在发达国家非常有效，但在发展中国家其效力受到损害， 那里的轮状病毒发病率和死亡率最高，因此最需要轮状病毒疫苗的地方。因素 导致疗效受损的原因包括微生物区系失调、同时使用脊髓灰质炎病毒和其他口服药物 疫苗，肠道病毒感染和营养不良，影响肠道状况，从而影响疫苗的有效性 口服RV疫苗。因此，肠外轮状病毒疫苗方法被称为提高疗效的方法。 发展中国家。为此，我们开发了一种创新的、基于纳米颗粒的S60-VP8*RV疫苗 这将满足这样的呼声。我们疫苗的重组、非复制性及其非肠道递送 该方法还将降低疫苗生产成本，防止轮状病毒活疫苗的肠套叠风险 更好的安全性和成本效益。生物工程S60-VP8*纳米粒子可以很容易地自我组装 生产的，高度稳定，极具免疫原性，因此，是一个优秀的轮状病毒疫苗候选。每个人 S60-VP8*纳米粒包含一个60价的诺如病毒内壳和60个表面展示的RV VP8*抗原。 与病毒受体结合的VP8*是理想的轮状病毒疫苗靶标，因为自然轮状病毒感染会引发抗体 大多数是VP8*特异性的，绝大多数VP8*导向的抗体能中和轮状病毒感染。作为证明 概念，我们已经展示了S60-VP8*纳米颗粒的高免疫原性、中和和保护作用 在小鼠模型中显示优势的P[8]RV VP8*。在此应用程序中，我们将生产鸡尾酒S60-VP8* 显示全球占优势的P[8]、P[4]、P[6]和P[11]RV的RV VP8*S的纳米疫苗并定义 它的安全性、免疫原性和在小鼠和高度相关的灵芝(Gn)猪身上的保护效果 模特们。这是第一个基于纳米颗粒的鸡尾酒RV疫苗，覆盖了所有四种主要的P型RV和 因此，将为发达国家和发展中国家预防轮状病毒感染提供广泛的保护。这个 小动物模型和大动物模型的结果都将证明其有效性，从而促进未来的临床 我们的S60-VP8*纳米颗粒疫苗的试验。在此应用程序中将执行两个主要的实验。 首先，我们将生产覆盖四种主要轮状病毒类型的鸡尾酒S60-VP8*纳米颗粒疫苗 (P[8]/P[4]/P[6]/P[11])，并评估交叉P型免疫反应、中和和保护 AS描绘了鸡尾酒疫苗在小鼠身上的免疫机制。第二，我们会确定它的安全性， 交叉P型免疫原性与广谱中和/保护鸡尾酒纳米粒疫苗的比较 与目前在Gn猪人RV挑战模型中实施的活RV疫苗进行比较。机械学研究 还将执行以了解鸡尾酒的广泛免疫反应和中和/保护 Gn猪的疫苗。鉴于我们强大的初步数据和研究团队的长期合作历史 凭借出色的生产率记录，我们将实现该项目的目标。

Rotavirus (RV) causes severe diarrhea in children with significant morbidity and mortality. While the current live oral RV vaccines are highly effective in developed nations, their efficacies are impaired in developing countries, where most RV morbidity and mortality remain and thus where RV vaccines are needed the most. Factors leading to the impaired efficacies include microbiota dysbiosis, concurrent uses of poliovirus and other oral vaccines, enterovirus infections, and malnutrition that impact intestinal conditions and thus the efficacies of the oral RV vaccines. As a result, parenteral RV vaccine approaches are called to improve the efficacy in the developing countries. To this end, we have developed an innovative, nanoparticle-based S60-VP8* RV vaccine that would meet such calls. The recombinant, nonreplicating nature of our vaccine and its parenteral delivery method will also reduce vaccine production cost and prevent intussusception risk of the live RV vaccines for better safety and cost-effectiveness. The bioengineered S60-VP8* nanoparticle is self-assembled, easily produced, highly stable, and extremely immunogenic, and therefore, an excellent RV vaccine candidate. Each S60-VP8* nanoparticle contains a 60-valent norovirus inner shell and 60 surface-displayed RV VP8* antigens. The viral receptor-binding VP8* is an ideal RV vaccine target, because antibodies elicited by nature RV infections are mostly VP8*-specific and vast majority of VP8*-directed antibodies neutralized RV infections. As a proof of concept, we have shown the high immunogenicity, neutralization, and protection of the S60-VP8* nanoparticle displaying the predominant P[8] RV VP8* in mouse model. In this application we will produce a cocktail S60-VP8* nanoparticle vaccine displaying RV VP8*s of the globally predominant P[8], P[4], P[6], and P[11] RVs and define its safety, immunogenicity, and protective efficacy using the mouse and the highly relevant gnotobiotic (Gn) pig models. This is the first nanoparticle-based cocktail RV vaccine covering all four predominant P type RVs and therefore will provide a broad protection against RV infections in both developed and developing nations. The outcomes from both small and large animal models will prove the usefulness and thus facilitate future clinical trials of our S60-VP8* nanoparticle vaccine. Two major lines of experiments will be performed in this application. First, we will produce the cocktail S60-VP8* nanoparticle vaccine covering the four predominant RV P types (P[8]/P[4]/P[6]/P[11]) and evaluate the cross-P type immune responses, neutralizations and protections, as well as delineate the immune mechanisms of the cocktail vaccine in mice. Second, we will determine the safety, cross-P type immunogenicity, and broad neutralization/protection of the cocktail nanoparticle vaccine compared with the currently implemented live RV vaccines in the Gn pig human RV challenge model. Mechanistic study will also be performed to understand the broad immune response and neutralization/protection of the cocktail vaccine in Gn pigs. Given our strong preliminary data and the long collaboration history of the research team with outstanding productivity track records, we will fulfill the goals of this project.