A Nanoparticle-Based Multivalent Rotavirus Vaccine

基于纳米颗粒的多价轮状病毒疫苗

基本信息

批准号：
10206373
负责人：
Ming Tan
金额：
$ 62.64万
依托单位：
CINCINNATI CHILDRENS HOSP MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-08-01 至 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10206373
关键词：
Adverse effects Animal Model Antibodies Antibody Response Antigens Biomedical Engineering Cessation of life Child Clinical Trials Collaborations Data Dendritic Cell Vaccine Developed Countries Developing Countries Diarrhea Disease Distal Economics Enterovirus Environment Epidemiology Family suidae Future Gnotobiotic Goals Head Hospitalization Human Human poliovirus Immune Immune response Immunization Immunize Immunologics Immunology Impairment Infection Intestines Intussusception Malnutrition Methods Modeling Monitor Morbidity - disease rate Mus Nature Neonatal Norovirus Oral Oranges Outcome Outpatients Physiological Productivity Proteins Recombinants Recording of previous events Records Research Risk Role Rotavirus Rotavirus Infections Rotavirus Vaccines Safety Surface Tissues Translations Vaccinated Vaccine Production Vaccines Virus Receptors Visit animal data base combat convict cost cost effectiveness dysbiosis experimental study immunogenic immunogenicity improved innovation microbiota mortality mouse model nanoparticle neutralizing antibody oral vaccine parenteral administration prevent protective efficacy receptor receptor binding sucking uptake vaccine candidate vaccine efficacy vaccine safety

项目摘要

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.

轮状病毒（RV）导致发病率明显和死亡率的儿童严重腹泻。当时现场直播口服RV疫苗在发达国家中非常有效，其效率在发展中国家受损，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。因素导致效力受损包括菌群营养不良，脊髓灰质炎病毒和其他口腔的同时使用影响肠道条件的疫苗，肠病毒感染和营养不良，从而影响肠道条件的疗效口服RV疫苗。结果，呼出了肠胃外的RV疫苗方法来提高发展中国家。为此，我们开发了一种创新的基于纳米颗粒的S60-VP8* RV疫苗那会遇到这样的电话。疫苗及其肠胃外交付的重组，不复制性质方法还将降低疫苗的生产成本，并防止肠suseptoseptions for the Live RV疫苗的风险更好的安全性和成本效益。生物工程的S60-VP8*纳米颗粒是自组装的，很容易产生，高度稳定且具有极高的免疫原性，因此是出色的RV疫苗候选者。每个 S60-VP8*纳米颗粒包含60个诺如病毒内壳和60个表面播放的RV VP8*抗原。病毒受体结合VP8*是理想的RV疫苗靶标，因为自然引起的RV感染引起的抗体主要是VP8* - 特异性和绝大多数VP8*指导的抗体中和RV感染。作为证明概念，我们显示了S60-VP8*纳米颗粒的高免疫原性，中和和保护在鼠标模型中显示主要P [8] RV VP8*。在此应用程序中，我们将生产鸡尾酒S60-VP8* 纳米颗粒疫苗显示出全球主要p [8]，p [4]，p [6]和p [11] RVS的RV VP8*s 使用小鼠和高度相关的gnotobiotic（GN）猪的安全性，免疫原性和保护功效型号。这是涵盖所有四种主要P型RV的基于纳米颗粒的鸡尾酒RV疫苗和因此，将为发达国家和发展中国家的RV感染提供广泛的保护。这小动物模型的结果都将证明其有用性，从而促进未来的临床我们的S60-VP8*纳米颗粒疫苗的试验。在此应用程序中将进行两条主要实验行。首先，我们将生产鸡尾酒S60-VP8*涵盖四种主要RV P类型的纳米颗粒疫苗（p [8]/p [4]/p [6]/p [11]），并评估跨P型免疫反应，中和化和保护措施如描述小鼠鸡尾酒疫苗的免疫机制。第二，我们将确定安全性比较鸡尾酒纳米颗粒疫苗的跨P型免疫原性和广泛的中和/保护在GN Pig Human RV挑战模型中，目前实施的现场RV疫苗。机械研究还将进行以了解鸡尾酒的广泛免疫反应和中和/保护 GN猪中的疫苗。考虑到我们强大的初步数据和研究团队的悠久合作历史凭借出色的生产力记录，我们将实现该项目的目标。

项目成果

期刊论文数量（4）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A New Gnotobiotic Pig Model of P[6] Human Rotavirus Infection and Disease for Preclinical Evaluation of Rotavirus Vaccines.

DOI：
10.3390/v14122803
发表时间：
2022-12-15
期刊：
Viruses
影响因子：
0
作者：
Nyblade C;Hensley C;Parreño V;Zhou P;Frazier M;Frazier A;Ramesh A;Lei S;Degiuseppe JI;Tan M;Yuan L
通讯作者：
Yuan L

Pseudovirus Nanoparticles Displaying Plasmodium Circumsporozoite Proteins Elicited High Titers of Sporozoite-Binding Antibody.