Rapid development of replication-controlled vaccinia virus vectors for vaccines and therapeutics with single or double safety features
快速开发复制控制的痘苗病毒载体,用于具有单一或双重安全特征的疫苗和疗法
基本信息
- 批准号:9230098
- 负责人:
- 金额:$ 21.93万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-12-09 至 2018-11-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdverse reactionsAnimalsAntibiotic TherapyAntibioticsAtopic DermatitisAttenuatedAttenuated VaccinesBody Weight decreasedCancer VaccinesCell Culture TechniquesCommunicable DiseasesDataDevelopmentDiseaseDoxycyclineElementsEssential GenesGenesGoalsGrowthHeart DiseasesHumanImmunosuppressionImmunotherapyIn VitroIndividualInterferon Type IIInterferonsInternal Ribosome Entry SiteKineticsLesionLinkMethodsModified Vaccinia Virus AnkaraMusMutationOncolyticOperonPoxviridaeProcessResearchResolutionSCID MiceSafetySmallpoxSmallpox VaccineSmallpox VirusesSystemTetanus Helper PeptideTetracyclinesTherapeuticVaccinationVaccinesVaccinia virusViral GenomeVirusZika Virusattenuationbasecancer therapygenetic elementimmunogenicimmunogenicityin vivomouse modeloncolytic virotherapypreclinical studypreventpromotersafety testingvaccine developmentvaccine safetyvaccinia virus vectorvectorvector vaccineviral vector development
项目摘要
PROJECT SUMMARY
This application is responsive to PA-15-313, Research to Advance Vaccine Safety (R21). Vaccinia virus
(VACV) was used as a live vaccine for smallpox, a disease caused by variola virus. VACV has also been
successfully used as a live viral vector for the development of effective human and animal vaccines, as well as
immunotherapies and oncolytic virotherapies. However, VACV can cause complications in individuals with
conditions such as atopic dermatitis, cardiac disease, and immunosuppression. Consequently, individuals with
such conditions or with contacts that have these conditions are contraindicated for vaccination with replicating
VACV vectors. We recently generated VACV vectors with a built-in safety mechanism that replicate only in the
presence of tetracycline (TC) antibiotics (replication-inducible VACVs). In this system, a VACV gene essential
for replication (eg, D6R) is inducibly expressed by TCs using elements of the tet operon. When administered
as a vaccine (in the absence of antibiotics), the vector does not replicate but retains its immunogenicity, and
therefore is safer for human use. Conveniently, the vector can be propagated in cell culture at high titers in the
presence of TCs, unlike other replication-defective VACV-based vectors such as MVA. We also developed
VACV vectors that replicate normally in the absence of antibiotics, but are replication-defective in the presence
of TCs (replication-repressible VACVs). When administered as a vaccine (in the absence of antibiotics), the
vector is replication competent like traditional VACV vectors (and therefore highly immunogenic), and
treatment of any adverse reactions would be as simple as TC antibiotic therapy. We can further enhance the
safety of our vectors by a fail-safe feature that links expression of the essential gene (D6R) with interferon-γ
(IFN-γ), via an internal ribosome entry site (IRES). We showed that expression of IFN-γ by VACV, either
constitutively or inducibly, leads to complete attenuation of VACV in vivo, even when expressed at very low
levels. Surprisingly, the virus is still able to grow to wild-type levels in vitro. Thus, both strategies can be
combined to develop replication-defective VACVs inducibly or repressibly expressing D6R (under its natural
promoter) and IFN-γ (under a small murine IRES). The resulting vectors should be able to grow to high titers in
vitro (thus allowing propagation) in the presence of TCs (inducible vectors) or absence of TCs (repressible
vectors). Since expression of D6R will be linked to IFN-γ expression, any potential replication-competent
VACV that may originate during in vitro propagation or in vivo administration would be replication-incompetent
in vivo due to concomitant expression of IFN-γ. In Aim 1 we will determine the safety of replication-inducible
and replication-repressible VACV vectors in vivo using immunodeficient SCID mice. In Aim 2, we will develop,
characterize, and determine the safety of replication-defective VACV vectors with a fail-safe feature. We plan
to use this VACV vaccine platform for rapid development of safe vaccines for infectious diseases such as Zika
virus, immunotherapies (eg, personalized cancer vaccines), and oncolytic virotherapies.
项目总结
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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PAULO H VERARDI其他文献
PAULO H VERARDI的其他文献
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{{ truncateString('PAULO H VERARDI', 18)}}的其他基金
Vaccines for Prevention of RG3 and RG4 Emerging Tickborne Viral Deseases
用于预防 RG3 和 RG4 新出现蜱传病毒性疾病的疫苗
- 批准号:
9990349 - 财政年份:2021
- 资助金额:
$ 21.93万 - 项目类别:
Vaccines for Prevention of RG3 and RG4 Emerging Tickborne Viral Diseases
用于预防 RG3 和 RG4 新出现蜱传病毒性疾病的疫苗
- 批准号:
10472452 - 财政年份:2021
- 资助金额:
$ 21.93万 - 项目类别:
Vaccines for Prevention of RG3 and RG4 Emerging Tickborne Viral Diseases
用于预防 RG3 和 RG4 新出现蜱传病毒性疾病的疫苗
- 批准号:
10673195 - 财政年份:2021
- 资助金额:
$ 21.93万 - 项目类别:
Rapid development and testing of Zika virus vaccine candidates
寨卡病毒候选疫苗的快速开发和测试
- 批准号:
9330079 - 财政年份:2016
- 资助金额:
$ 21.93万 - 项目类别:
SMART Virus Vectors with a Built-in Safety Mechanism
具有内置安全机制的 SMART 病毒载体
- 批准号:
6874942 - 财政年份:2004
- 资助金额:
$ 21.93万 - 项目类别:
SMART Virus Vectors with a Built-in Safety Mechanism
具有内置安全机制的 SMART 病毒载体
- 批准号:
6761381 - 财政年份:2004
- 资助金额:
$ 21.93万 - 项目类别:
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