A novel VLP vaccine to prevent EBV infection and EBV - associated malignancies
A novel VLP vaccine to prevent EBV infection and EBV - associated malignancies
批准号:
9302981
负责人:
Javier Gordon Ogembo
金额:
$23.5万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-05-01 至 2019-04-30
关键词:
AdultAfricaAfrica South of the SaharaAfricanAgeAnimal ModelAntibodiesAntibody ResponseAntigensAntiviral ResponseB-LymphocytesBurkitt LymphomaCD8-Positive T-LymphocytesCellsCellular ImmunityChildChinese Hamster Ovary CellCitiesClinicalClinical ResearchClinical TrialsComplexDiagnosisDiseaseEBV-associated diseaseEBV-associated malignancyEpstein-Barr Virus InfectionsEpstein-Barr Virus Nuclear AntigensGlycoproteinsGoalsGrowthHumanHuman Herpesvirus 4Immune systemImmunizeIn VitroInbred BALB C MiceIncidenceIndividualLeftLegal patentLifeMalignant Childhood NeoplasmMalignant NeoplasmsMeasuresMediatingMembrane GlycoproteinsMembrane ProteinsMusNuclear AntigensOncogenicParticipantPatientsPediatric NeoplasmPeripheral Blood Mononuclear CellPhasePhysiologic pulsePolyvalent VaccinePopulationPreventive vaccinePrimary InfectionProductionPropertyProteinsPublic HealthRecurrent diseaseResearchSafetySecond Primary CancersSubunit VaccinesSurfaceSurvivorsT cell responseT-LymphocyteT-Lymphocyte SubsetsTestingTherapeuticUnited States Food and Drug AdministrationUnited States National Institutes of HealthVaccine AntigenVaccinesViralViral AntigensViral GenomeViral ProteinsViral Structural ProteinsVirusVirus DiseasesVirus-like particleWild Type Mousearmbasecell immortalizationcell mediated immune responsechemotherapyhumanized mouseimmortalized cellimmunogenicimmunogenicityimmunological statusin vitro Modelin vivomeetingsmouse modelneutralizing antibodynovel viruspre-clinicalpreclinical studypreventprophylacticprotective efficacyprotein complexsuccesstherapeutic vaccinetreatment responsetumorvaccine candidatevaccine developmentvaccine evaluationvirus envelope
中文摘要
项目总结
英文摘要
PROJECT SUMMARY
Burkitt lymphoma (BL) is the most common childhood cancer in sub-Saharan Africa, outnumbering all
other forms of pediatric tumors combined. BL is lethal if left untreated; however, the current treatment
(intensive chemotherapy) is only 50% effective and difficult to implement in sub-Saharan Africa. To date, the
vast majority of African cases of BL are associated with Epstein-Barr virus (EBV) infection. Thus, there is a
critical need for a safe and effective vaccine to prevent and treat EBV and its associated diseases.
The objective of the proposed study is to develop, characterize, and validate gp42-gH/gL-EBNA1-LMP2
virus-like particles (VLPs) in pre-clinical studies as a candidate vaccine against EBV. Previous approaches to
EBV vaccine development have been limited due in part to the oncogenic potential of the virus genome and
lack of animal models to test vaccine candidates. This proposal will examine a new strategy to develop a safe
and effective vaccine against EBV, using VLPs that can present properly folded EBV proteins. To target both
arms of the immune system—antibody-mediated and T-cell mediated—the vaccine will incorporate multiple
EBV surface and intracellular antigens. The EBV protein complex gp42-gH/gL and tumor-associated Epstein-
Barr nuclear antigen 1 (EBNA1) and latent membrane protein (LMP2) are prime candidates for use in EBV
vaccine development. There is strong evidence that antibodies to the EBV protein complex gp42-gH/gL can
neutralize EBV infection. EBNA1 and LMP2 are consistently expressed in B cells of all EBV+ BL patients and
are recognized by CD4+ and CD8+ T cells. Thus, we hypothesize that gp42-gH/gL-EBNA1-LMP2 VLPs will
generate robust EBV-neutralizing antibody responses and EBV-specific T-cell responses in vitro and in a
humanized mouse model. The VLPs will be generated, characterized, and validated using wild-type mice (Aim
1), an in vitro model of BL (Aim 2), and humanized mice (Aim 2)
A polyvalent vaccine that induces both prophylactic neutralizing antibodies and elicits therapeutic human
T-cell responses will not only be an invaluable candidate vaccine in preventing EBV infection, but also of
utmost importance in preventing and/or treating EBV-associated disease. If the vaccine is immunogenic,
following completion of the proposal, we will utilize the current good manufacturing practice facility available at
City of Hope to mass-produce clinical grade gp42-gH/gL-EBNA1-LMP2 VLPs and begin a phase 1 clinical
study in 10-15 healthy adults to establish safety profiles and determine the protective efficacy of the candidate
vaccine. In the long term, if successful, our approach will introduce a new prophylactic/therapeutic vaccine to
the market with a potential for preventing or treating over 200,000 annual cancer cases associated with EBV,
including 24,000 cases of BL in African children.
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会议论文
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海外基金