A Nanoparticle-Based Multivalent Rotavirus Vaccine

基于纳米颗粒的多价轮状病毒疫苗

• 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
• 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

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) 会导致儿童严重腹泻，并导致较高的发病率和死亡率。虽然目前直播 口服 RV 疫苗在发达国家非常有效，但在发展中国家其功效受到损害， RV 发病率和死亡率仍然最高，因此最需要 RV 疫苗。因素 导致功效受损的因素包括微生物群失调、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都会影响肠道状况，从而影响疫苗的功效 口服 RV 疫苗。因此，人们呼吁采用肠外 RV 疫苗方法来提高 RV 疫苗的功效。 发展中国家。为此，我们开发了一种基于纳米颗粒的创新型 S60-VP8* RV 疫苗 会满足这样的呼吁。我们疫苗的重组、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预防 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-VP8* 纳米颗粒可轻松自组装 生产的、高度稳定且具有极高的免疫原性，因此是一种优秀的 RV 候选疫苗。每个 S60-VP8* 纳米颗粒含有 60 价诺如病毒内壳和 60 个表面展示的 RV VP8* 抗原。 病毒受体结合 VP8* 是理想的 RV 疫苗靶标，因为自然 RV 感染会引发抗体 大多数是 VP8* 特异性的，并且绝大多数 VP8* 定向抗体可以中和 RV 感染。作为证明 概念，我们展示了 S60-VP8* 纳米粒子的高免疫原性、中和性和保护性 显示小鼠模型中的主要 P[8] RV VP8*。在此应用中，我们将生产鸡尾酒 S60-VP8* 显示全球主要 P[8]、P[4]、P[6] 和 P[11] RV 的 RV VP8* 的纳米颗粒疫苗，并定义 使用小鼠和高度相关的限菌 (Gn) 猪验证其安全性、免疫原性和保护功效 模型。这是第一种基于纳米颗粒的混合型 RV 疫苗，涵盖所有四种主要 P 型 RV 和 因此将为发达国家和发展中国家提供针对 RV 感染的广泛保护。这 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-VP8* 纳米颗粒疫苗的试验。在此应用中将进行两个主要的实验。 首先，我们将生产涵盖四种主要 RV P 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 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， 混合纳米颗粒疫苗的交叉 P 型免疫原性和广泛中和/保护作用比较 目前在 Gn 猪人 RV 攻击模型中实施的活 RV 疫苗。机理研究 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 凭借出色的生产力记录，我们将实现该项目的目标。

项目成果

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
• 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.

• DOI: 10.3390/vaccines11111650
• 发表时间: 2023-10-27
• 期刊: Vaccines
• 影响因子: 7.8
• 作者: Xia M;Huang P;Vago F;Jiang W;Tan M
• 通讯作者: Tan M

Norovirus Vaccines: Current Clinical Development and Challenges.

• DOI: 10.3390/pathogens10121641
• 发表时间: 2021-12-19
• 期刊: Pathogens (Basel, Switzerland)
• 作者: Tan M