KSHV Subunit Vaccine Candidates to Elicit Potent Humoral Immune Reponses against KSHV Infection

KSHV 亚单位候选疫苗可引发针对 KSHV 感染的有效体液免疫反应

基本信息

批准号：
10559659
负责人：
Javier Gordon Ogembo
金额：
$ 85.1万
依托单位：
BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-03-22 至 2026-02-28
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10559659
关键词：
Adult Animal Model Animals Antibodies Antibody Response Antibody titer measurement B-Cell Lymphomas B-Lymphocytes CD34 gene Callithrix Callithrix jacchus jacchus Carcinogens Cells Child Classification Data Developed Countries Developing Countries Development Disease Dose Endothelium Enzyme-Linked Immunosorbent Assay Epithelium FK506 Fibroblasts Funding Future Glycoproteins Goals HIV/AIDS Herpesviridae Herpesviridae Infections Herpesvirus Vaccines Human Human Herpesvirus 8 Iatrogenesis Immune Immune response Immunization Immunize Immunocompetent Immunocompromised Host Immunoglobulin G Immunosuppression In Vitro Incidence Individual Infection International Agency for Research on Cancer Kaposi Sarcoma Licensing Malignant Neoplasms Marketing Measures Mediating Membrane Glycoproteins Modeling Modified Vaccinia Virus Ankara Monkeys Mus Myeloid Cells Oncogenic Oryctolagus cuniculus Outcome Pattern Persons Phase I Clinical Trials Polyvalent Vaccine Population Preventive vaccine Primary Infection Property Regimen Research Route Safety Saliva Seroprevalences Subunit Vaccines Tacrolimus Testing Time Transplant Recipients United States National Institutes of Health Vaccination Vaccines Viral Viral Proteins Viremia Virus Diseases Virus-like particle Wild Type Mouse cancer prevention cell type design early childhood efficacy evaluation humanized mouse immunogenic immunogenicity immunological status immunosuppressed in vivo innovation neutralizing antibody nonhuman primate novel vaccines permissiveness placebo group pre-clinical prevent primary effusion lymphoma prophylactic response success unvaccinated vaccine candidate vaccine development vaccine evaluation vector

项目摘要

PROJECT SUMMARY Kaposi sarcoma-associated herpesvirus (KSHV) has been classified as a direct carcinogen by the International Agency for Research on Cancer because of its ability to cause Kaposi sarcoma (KS) and two rare types of B-cell lymphoma. KS frequently occurs among iatrogenic or HIV/AIDS-induced immunosuppressed individuals. To date, there is no licensed KSHV vaccine that can prevent primary infection and subsequent malignancies. Our objective in this application is to optimize the inclusion of key KSHV glycoproteins (gps), which are involved in epithelial, endothelial, fibroblast and B-cell entry, into multivalent subunit vaccine candidates that can stimulate neutralizing antibody (nAb) immune responses to prevent or limit KSHV infection and KSHV+ cancers in vivo. This application builds on my recently completed NCI K01 CA184388-05 research on KSHV entry mechanisms and vaccine development. Recently, we showed that in vitro, the KSHV glycoprotein gH is essential for viral infection of epithelial, endothelial, and fibroblasts cells, but not B cells. Notably, we and other have also shown that both monoclonal and polyclonal Abs to KSHV glycoproteins K8.1, gB, and gH/gL can neutralize KSHV infection of diverse permissive human cells in vitro. Building on this success, we have generated quadrivalent virus-like particles (KSHV-LPs) incorporating the four glycoproteins critical for viral entry (K8.1, gB and gH/gL). In this application we will use wild-type and humanized mice and common marmoset (Callithrix jacchus) models to test the hypothesis that purified KSHV-LPs delivered directly or through immunization with a modified vaccinia Ankara vector (MVA-KSHV-LPs) will elicit robust protective nAb responses to KSHV infection and its associated malignancies. The premise of our proposal is built on strong evidence that 1) infection with KSHV does not occur during early childhood, as is typical for other herpesviruses, opening a window of opportunity for vaccination and 2) Abs against the KSHV glycoproteins K8.1, gB, and gH/gL can neutralize KSHV infection. Furthermore, the permissiveness of humanized mice and marmosets to KSHV infection offers an ideal platform to test candidate vaccines. Thus, a polyvalent vaccine that induces prophylactic neutralizing Abs responses will not only be an invaluable candidate vaccine in preventing KSHV infection, but also of utmost importance in preventing KSHV-associated diseases. We will provide evidence for the safety of our candidate KSHV vaccine based on three pre-clinical animal models as prerequisite data for an IND application for a phase I clinical trial. In the long term, the success of our approach will introduce a new vaccine to the market with a potential for reducing global incidence of KSHV+ malignancies (>44,000 cases/year), and the possibility of limiting KSHV infection and associated malignancies in developing countries or eradicating them from developed countries where KSHV seroprevalence is <10%.

项目概要卡波西肉瘤相关疱疹病毒（KSHV）已被国际组织列为直接致癌物癌症研究机构因其能够引起卡波西肉瘤 (KS) 和两种罕见类型 B 细胞淋巴瘤。 KS 经常发生在医源性或 HIV/AIDS 引起的免疫抑制个体中。迄今为止，还没有获得许可的 KSHV 疫苗可以预防原发感染和随后的恶性肿瘤。我们在此应用中的目标是优化关键 KSHV 糖蛋白 (gps) 的包含，这些糖蛋白是参与上皮细胞、内皮细胞、成纤维细胞和 B 细胞进入，形成多价亚单位候选疫苗可以刺激中和抗体 (nAb) 免疫反应，以预防或限制 KSHV 感染和 KSHV+ 体内癌症。该应用程序基于我最近完成的 NCI K01 CA184388-05 KSHV 研究进入机制和疫苗开发。最近，我们在体外证明，KSHV 糖蛋白 gH 是对于病毒感染上皮细胞、内皮细胞和成纤维细胞（但不是 B 细胞）至关重要。值得注意的是，我们和其他还表明，针对 KSHV 糖蛋白 K8.1、gB 和 gH/gL 的单克隆和多克隆抗体都可以在体外中和多种允许的人类细胞的 KSHV 感染。在此成功的基础上，我们生成了四价病毒样颗粒（KSHV-LP），其中包含对病毒至关重要的四种糖蛋白条目（K8.1、gB 和 gH/gL）。在此应用中，我们将使用野生型和人源化小鼠以及常见的狨猴 (Callithrix jacchus) 模型，用于检验纯化的 KSHV-LP 直接传递或传递的假设通过使用改良的痘苗安卡拉载体 (MVA-KSHV-LPs) 进行免疫接种将产生强大的保护性 nAb 对 KSHV 感染及其相关恶性肿瘤的反应。我们建议的前提是建立在强有力的有证据表明 1) KSHV 感染不会像其他儿童那样发生在幼儿期疱疹病毒，打开疫苗接种机会之窗和 2) 针对 KSHV 糖蛋白的抗体 K8.1、gB 和 gH/gL 可以中和 KSHV 感染。此外，人性化小鼠的宽容和狨猴为 KSHV 感染提供了一个理想的平台来测试候选疫苗。因此，多价疫苗诱导预防性中和抗体反应不仅是一种无价的候选疫苗预防 KSHV 感染，但对于预防 KSHV 相关疾病也至关重要。我们将基于三种临床前动物模型，为我们的候选 KSHV 疫苗的安全性提供证据： I 期临床试验 IND 申请的必备数据。从长远来看，我们的方法是成功的将向市场推出一种新疫苗，有可能降低全球 KSHV+ 发病率恶性肿瘤（>44,000 例/年），以及限制 KSHV 感染和相关恶性肿瘤的可能性在发展中国家或在 KSHV 血清流行率 <10% 的发达国家根除它们。