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

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)
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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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    9576448
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