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%.

项目摘要 Kaposi肉瘤相关的疱疹病毒（KSHV）已被国际归类为直接致癌癌症研究机构，因为它能够引起Kaposi肉瘤（KS）和两种罕见类型的 B细胞淋巴瘤。 KS经常发生在医源性或HIV/AIDS诱导的免疫抑制个体中。迄今为止，还没有持牌的KSHV疫苗可以防止原发性感染和随后的恶性肿瘤。我们在此应用程序中的目标是优化关键KSHV糖蛋白（GPS）的包含参与上皮，内皮，成纤维细胞和B细胞进入，以多价亚基疫苗候选可以刺激中和抗体（NAB）免疫反应以防止或限制KSHV感染和KSHV+ 体内癌症。该应用程序建立在我最近完成的NCI K01 CA184388-05研究基于KSHV的研究进入机制和疫苗开发。最近，我们表明在体外，KSHV糖蛋白GH是上皮，内皮和成纤维细胞的病毒感染至关重要，而不是B细胞。值得注意的是，我们和其他还表明，单克隆和多克隆ABS均与KSHV糖蛋白K8.1，GB和GH/GL CAN一起在体外中和各种允许的人类细胞的KSHV感染。在这一成功的基础上，我们有产生的四价病毒样颗粒（KSHV-LPS）掺入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性化的小鼠和常见 Marmoset（Callithrix jacchus）模型，以测试直接传递的KSHV-LPS或通过修改的离甲卡拉载体（MVA-KSHV-LPS）通过免疫接种，将引起强大的保护性NAB 对KSHV感染及其相关的恶性肿瘤的反应。我们提案的前提是建立在强大的基础上证据表明1）在童年时期不会发生KSHV感染，而其他人则是典型的疱疹病毒，打开疫苗接种的机会之窗，2）腹肌对抗KSHV糖蛋白 K8.1，GB和GH/GL可以中和KSHV感染。此外，人性化小鼠的允许和 KSHV感染的Marmosets提供了测试候选疫苗的理想平台。因此，多价疫苗诱导预防性中和的ABS反应不仅将是宝贵的候选疫苗防止KSHV感染，但在预防KSHV相关疾病方面也非常重要。我们将根据三种临床前动物模型，提供了我们候选人KSHV疫苗安全的证据 I阶段临床试验的IND应用程序的先决条件数据。从长远来看，我们的方法的成功将向市场引入一种新疫苗，有可能降低KSHV+的全球发病率恶性肿瘤（> 44,000例），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从KSHV血清阳性率<10％的发达国家中消除它们。