A Nanoparticle-Based Multivalent Rotavirus Vaccine

轮状病毒（RV）引起儿童严重腹泻，具有显著的发病率和死亡率。虽然目前的生活 口服RV疫苗在发达国家非常有效，在发展中国家其效力受到损害， 大多数RV发病率和死亡率仍然存在，因此最需要RV疫苗的地方。因素 导致效力受损的因素包括微生物群生态失调、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会影响肠道状况，因此， 口服RV疫苗。因此，需要肠胃外RV疫苗方法来改善在免疫缺陷中的功效。 发展中国家为此，我们开发了一种基于纳米颗粒的创新S60-VP 8 * RV疫苗 能够满足这些要求的。我们的疫苗的重组，非复制性质及其肠胃外递送 该方法还将降低疫苗生产成本，并防止RV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-VP 8 * 纳米颗粒是自组装的，很容易 生产的，高度稳定的和极强的免疫原性，因此是一种优秀的RV候选疫苗。每个 S60-VP 8 * 纳米粒含有60价的诺如病毒内壳和60个表面展示的RV VP 8 * 抗原。 结合病毒受体的VP 8 * 是RV疫苗的理想靶点，因为抗体是由自然RV感染引起的， 大多数是VP 8 * 特异性的，并且绝大多数VP 8 * 定向的抗体中和RV感染。作为服务的证明 概念，我们已经显示了S60-VP 8 * 纳米颗粒的高免疫原性、中和性和保护性 显示小鼠模型中主要的P[8] RV VP 8 *。在此应用中，我们将生产鸡尾酒S60-VP 8 * 展示全球主要的P[8]、P[4]、P[6]和P[11] RV的RV VP 8 * 的纳米颗粒疫苗，并定义了 其安全性、免疫原性和使用小鼠和高度相关的无菌（Gn）猪的保护效力 模型这是第一个基于纳米颗粒的鸡尾酒RV疫苗，覆盖所有四种主要的P型RV， 因此，将在发达国家和发展中国家提供广泛的保护，防止RV感染。的 来自小型和大型动物模型的结果将证明其有用性，从而促进未来的临床 我们的S60-VP 8 * 纳米颗粒疫苗的临床试验。在本申请中将进行两个主要的实验。 首先，我们将生产覆盖四种主要RV P类型的混合物S60-VP 8 * 纳米颗粒疫苗 (P[8]/P[4]/P[6]/P[11]），并评估交叉P型免疫应答、中和和保护，以及 描述了鸡尾酒疫苗在小鼠中的免疫机制。其次，我们将确定安全性， 交叉P型免疫原性，和广泛的中和/保护的鸡尾酒纳米颗粒疫苗相比 目前在Gn猪人RV攻毒模型中实施的活RV疫苗。机理研究 也将进行，以了解广泛的免疫反应和中和/保护的鸡尾酒 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， 凭借卓越的生产力往绩，我们定能达到这项计划的目标。

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.