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

• 批准号: 10376277
• 负责人: Javier Gordon Ogembo
• 金额: $ 85.8万
• 依托单位: BECKMAN RESEARCH INSTITUTE/CITY OF HOPE
• 依托单位国家: 美国
• 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/10376277
• 关键词: AIDS/HIV problem; Adult; Animal Model; Animals; Antibodies; Antibody Response; Antibody titer measurement; B-Cell Lymphomas; B-Lymphocytes; CD34 gene; Callithrix; Callithrix jacchus jacchus; Carcinogens; Cells; Child; Data; Developed Countries; Developing Countries; Development; Disease; Dose; Endothelium; Enzyme-Linked Immunosorbent Assay; Epithelial; FK506; Fibroblasts; Funding; Future; Glycoproteins; Goals; 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; Malignant Neoplasms; 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; T-Lymphocyte; Tacrolimus; Testing; Time; Transplant Recipients; United States National Institutes of Health; Vaccinated; Vaccination; Vaccines; Viral; Viral Proteins; Viremia; Virus Diseases; Virus-like particle; Wild Type Mouse; base; cancer prevention; cell type; design; early childhood; 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; vaccine candidate; vaccine development; vaccine evaluation; vector

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%.

项目总结