Shielding Replicating Single-cycle Vaccines against SARS-CoV-2
屏蔽针对 SARS-CoV-2 的复制单周期疫苗
基本信息
- 批准号:10884592
- 负责人:
- 金额:$ 47.06万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-08-17 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:2019-nCoVAdenovirus InfectionsAdenovirusesAffectAffinityAnimal ModelAnimalsAntibodiesAntigensBenchmarkingBindingBiologyBloodBlood Coagulation FactorBlood ProteinsBlood coagulationBody WeightCOVID-19COVID-19 vaccinationCOVID-19 vaccineCellsChemical EngineeringChemicalsComplementarity Determining RegionsComplexCryoelectron MicroscopyDNADNA biosynthesisDoseEngineeringFutureGenesGeneticGenetic EngineeringHamstersHumanImmune responseImmunizationLungMessenger RNAProductionProteinsRNA vaccineResolutionRiskSafetySerotypingStructureTestingThrombocytopeniaTransgenesTranslatingVaccinationVaccine AntigenVaccinesViral Load resultVirionVirusgene therapyin vivoneutralizing antibodyoncolytic adenoviruspathogenpermissivenesspreservationpreventrisk mitigationside effectthromboticvaccine deliveryvaccine efficacyvaccine safetyvaccine trialvector
项目摘要
Abstract
Many COVID-19 vaccines are replication-defective mRNA, DNA, or adenovirus (Ad) vaccines. In each case, the
vaccine delivers its one copy of an antigen gene and expresses "1X" of the antigens that are encoded by the
vaccine. We developed single cycle Ad (SC-Ad) vaccines that replicate vaccine antigen genes up to 10,000-fold
in every cell to amplify antigen production but do not produce infectious progeny viruses. When RD-Ad and SC-
Ad6 expressing SARS-CoV-2 are compared, SC-Ad produces 100 times more spike protein than RD-Ad and
significantly higher spike antibodies than RD-Ad-Spike. When the animals were challenged 10.5 months after
single immunization, SC-Ad reduced SARS-CoV-2 lung viral loads and damage and preserved body weights
better than RD-Ad. However, observations of vaccine-induced thrombotic thrombocytopenia (VITT) in Ad26 and
ChAdOx-1 COVID-19 vaccine trials endanger the prospects of SC-Ad and all other adenovirus vaccines. In one
hypothesis, VITT is thought to be caused by the binding of PF4 to the hexons of Ad26 and ChAdOx-1. This
complex is thought to provoke antibodies against PF4 that cause VITT. While VITT could theoretically occur with
any adenovirus, the particular serotype of each Ad may influence the risk of this side effect. Different Ad
serotypes vary in the hypervariable regions (HVRs) of their hexon proteins. These HVRs determine whether the
antibodies and other proteins like PF4 bind or do not bind each adenovirus. We hypothesize that the natural
binding of blood proteins to species C Ads may naturally shield them from PF4 binding whereas other serotypes
are at risk of PF4 binding. One can also genetically and chemically engineer Ads to proactively shield them from
interactions with antibodies and PF4. We hypothesize that genetic and chemical shielding can be used to make
safer SC-Ad and other Ads for vaccination against SARS-CoV-2 and other pathogens.
This project will test these hypotheses in three Specific Aims. In the first, we will perform high resolution cryo-
electron microscopy to examine the interactions of PF4 and other proteins on species C and species D
adenoviruses. In the second aim, we will compare the utility of genetic and chemical shielding strategies to
protect Ads from PF4 and also against neutralizing antibodies. In the third aim, we will test if different Ad
serotypes bound to PF4 can provoke VITT in animal models, whether this is different for different serotypes, and
whether genetic and chemical shielding can maintain vaccine efficacy while mitigating the risks of VITT induction.
Successful pursuit of this project will lead to better understanding of natural binding of blood clotting factors to
different serotypes and how this affects their in vivo biology and side effects. This project will also test and
optimize proactive strategy to increase adenovirus vaccine safety for SARS-CoV-2 and future pathogen targets.
This can have utility for vaccines, gene therapy, or oncolytic adenoviruses to increase efficacy and safety and
protect them from not only PF4, but also against problematic vector neutralizing antibodies.
摘要
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Michael A Barry其他文献
Michael A Barry的其他文献
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{{ truncateString('Michael A Barry', 18)}}的其他基金
Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis
埃博拉病毒介导的炎症激活机制与发病机制相关
- 批准号:
10462588 - 财政年份:2019
- 资助金额:
$ 47.06万 - 项目类别:
Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis
埃博拉病毒介导的炎症激活机制与发病机制相关
- 批准号:
10673795 - 财政年份:2019
- 资助金额:
$ 47.06万 - 项目类别:
Mechanisms of Ebola virus-mediated inflammatory activation linked to pathogenesis
埃博拉病毒介导的炎症激活机制与发病机制相关
- 批准号:
10216646 - 财政年份:2019
- 资助金额:
$ 47.06万 - 项目类别:
Immunoevasive Mucosal Vaccines Against HIV-1
针对 HIV-1 的免疫逃避粘膜疫苗
- 批准号:
8489258 - 财政年份:2012
- 资助金额:
$ 47.06万 - 项目类别:
Immunoevasive Mucosal Vaccines Against HIV-1
针对 HIV-1 的免疫逃避粘膜疫苗
- 批准号:
8849820 - 财政年份:2012
- 资助金额:
$ 47.06万 - 项目类别:
Immunoevasive Mucosal Vaccines Against HIV-1
针对 HIV-1 的免疫逃避粘膜疫苗
- 批准号:
8662690 - 财政年份:2012
- 资助金额:
$ 47.06万 - 项目类别:
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