Optimization of a mucosal RSV vaccine

粘膜 RSV 疫苗的优化

基本信息

  • 批准号:
    9305833
  • 负责人:
  • 金额:
    $ 22.78万
  • 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:
    2016-07-01 至 2020-06-30
  • 项目状态:
    已结题

项目摘要

Abstract Human respiratory syncytial virus (RSV) is a highly infectious member of the paramyxovirus family causing upper and lower respiratory tract infections. RSV is the leading cause of pulmonary disease of the lower respiratory tract (bronchiolitis, pneumonia and respiratory failure) in infants due to virus-induced airway damage and complex inflammatory processes and responsible for an estimated 160,000 deaths annually worldwide. RSV also causes morbidity/mortality to immunocompromised and elderly populations. In the USA, treatment of RSV pneumonia and bronchiolitis annual health care costs exceed $400 million. Because of either low immunogenicity and/or for safety reasons, previous attempts to formulate a vaccine to prevent RSV- mediated disease have not been successful. The formalin-inactivated vaccine candidate (FI-RSV) induced severe disease upon subsequent natural infection with RSV wherein vaccinated children were found to suffer from enhanced disease severity and even death. Severe lung inflammatory responses characterized by a skewed CD4+ T-cell response (in the absence of neutralizing antibodies) and an influx of eosinophils in the lung were detected. Because of the unmet need of a safe and effective RSV vaccine, novel approaches are in high demand. Since it is important for an RSV vaccine to protect the upper and lower respiratory tracts from subsequent RSV infection, the ideal RSV vaccine candidate should elicit a durable mucosal response and protection as the first line of defense in the host. Vaccines that are able to induce durable RSV-specific mucosal IgA responses in the respiratory tract may be more protective than those that generate a systemic antibody response alone. Fortunately, one of the most exciting advances in RSV research was made by a co-investigator on this grant. Specifically, a newly discovered antigenic site (Ø) was identified on stabilize the pre-fusion F (pre-F) protein and this pre-F, with all four neutralizing antigen sites (Ø, I, II, and IV), was proven to be a far more immunogenic antigen than the post-fusion F (post-F) with three neutralizing antigen sites (I, II, and IV) that have been previously employed in vaccination approaches. To develop a safe and effective mucosal RSV vaccine, in this proposal we plan to combine the merits of this novel antigen and our patented mucosal vaccination platform, and optimize the best vaccination conditions in mice and cotton rats. This platform has already demonstrated potent immune responses and significant protection against two different, mucosally challenged viruses such as HSV-2 and RSV. This powerful vaccine regimen can generate a Th1 biased, broad and potent humoral, mucosal and T cell responses including substantial mucosal IgA and CTL. The uniqueness of our patented immunization regimen are:1) both mucosal (especially mucosal neutralizing antibodies), systemic immune responses and complete mucosal protection were raised without using any virus vectors and/or toxic adjuvants; 2) no immunopathology or vaccine-enhanced diseases have been detected in virus challenged animals. Therefore, this mucosal vaccine platform is an ideal candidate for developing a mucosal vaccine that protects against pathogens which enter at mucosal surfaces, as is the case for RSV. Using this patented mucosal immunization strategy, we will build on a safe and effective mucosal RSV vaccine that was developed in a previously funded SBIR grant and further optimize by extensively testing and comparing the pre-F and the post-F antigens in mice and cotton rats. A very strong scientific team including four collaborating Institutes: Biomedical Research Models, Inc., Dartmouth College, University of Iowa and Sigmovir Biosystem, Inc. will: 1) prepare and optimize vaccine formulations to be tested in both BALB/c mice and cotton rats, 2) optimize the best immunization dose and schedule for comparing pre-F vs. post F in eliciting the immune responses and protection in mice, 3) Optimize the best conditions for immunization of cotton rats with pre-F and post F, test and compare the durability of immune responses, protection, and safety (pulmonary histopathology) provided by the RSV vaccine candidates in cotton rats. At the completion of the grant, we expect: 1) complete or significant protection of animals from virus replication in both lung and nasal passage; 2) no vaccine-enhanced pulmonary diseases; 3) durable mucosal and protective immunity. The best antigen, optimal formulation/dose, and immunization schedule will be identified for further development. This study is a critical step before we can advance with phase II studies, which will require key partners for cGMP manufacturing the best vaccine antigen formulation, performing toxicology studies, and testing of the mucosal RSV vaccine in the African Green Monkey model and eventually filing the IND for clinical trials.
摘要

项目成果

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Kejian Yang其他文献

Kejian Yang的其他文献

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{{ truncateString('Kejian Yang', 18)}}的其他基金

A Mucosal RSV Vaccine
粘膜 RSV 疫苗
  • 批准号:
    8511504
  • 财政年份:
    2012
  • 资助金额:
    $ 22.78万
  • 项目类别:
A Mucosal RSV Vaccine
粘膜 RSV 疫苗
  • 批准号:
    8392826
  • 财政年份:
    2012
  • 资助金额:
    $ 22.78万
  • 项目类别:
A Mucosal Vaccine for HSV-2
HSV-2 粘膜疫苗
  • 批准号:
    8034318
  • 财政年份:
    2006
  • 资助金额:
    $ 22.78万
  • 项目类别:
Advancing a Mucosal HSV-2 Vaccine Towards Clinical Trials
推进粘膜 HSV-2 疫苗的临床试验
  • 批准号:
    8784739
  • 财政年份:
    2006
  • 资助金额:
    $ 22.78万
  • 项目类别:

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