ST-246 treatment of smallpox vaccine-related adverse events in murine models

ST-246 治疗小鼠模型中天花疫苗相关不良事件

• 批准号: 7475285
• 负责人: Douglas W. Grosenbach
• 金额: $ 32.13万
• 依托单位: SIGA TECHNOLOGIES, INC.
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-08-01 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7475285
• 关键词: Adverse event; Animal Model; Animals; Antiviral Agents; Atopic Dermatitis; B-Lymphocytes; Brain; Dermal; Dermatitis; Disease; Dose; Goals; Health; Human; Humoral Immunities; Immune; Immune response; Immune system; Immunity; Immunocompetent; Immunocompromised Host; Immunologic Deficiency Syndromes; In Vitro; Infection; Knock-out; Knockout Mice; Modeling; Monitor; Monkeypox; Mus; Onset of illness; Organ; Pathology; Pharmaceutical Preparations; Pilot Projects; Population; Poxviridae; Poxviridae Infections; Principal Investigator; Progressive Disease; Relative (related person); Research; Research Design; Risk; Safety; Site; Skin; Smallpox; Smallpox Vaccine; Standards of Weights and Measures; Systemic infection; T-Cell Immunodeficiency; T-Lymphocyte; Therapeutic; Treatment Efficacy; Treatment Protocols; Upper arm; Vaccinated; Vaccination; Vaccines; Vaccinia; Viral; Virulent; Virus; Visceral; antimicrobial peptide; improved; mouse model; prevent; programs; prophylactic; response

DESCRIPTION (provided by applicant): The renewed threat of smallpox as a bioweapon and the emerging zoonotic threat of monkeypox highlight the need for effective poxvirus countermeasures. Use of the smallpox vaccine poses a serious health risk, especially for the immunocompromised, or those with eczema/atopic dermatitis. It is our long-term goal to establish a safe and effective vaccine regimen that includes the use of the currently approved, efficacious smallpox vaccine and an antiviral drug to prevent or treat adverse events particularly in the aforementioned high-risk populations. We hypothesize that co-administration of the smallpox vaccine and ST-246, an antiviral drug, to inhibit viral dissemination from the original site of inoculation, will significantly reduce vaccine-related pathologies in immunodeficient and eczematous hosts without compromising protective immunity elicited by the vaccine. Our hypothesis extends from previous observations: First, lethal poxvirus infections in humans and in animal models results from dissemination from the original site of inoculation and wide-spread systemic infection. Second, treatment of a normally lethal poxvirus infection, with ST-246, a drug that specifically blocks viral dissemination, is fully protective in numerous animal models. Third, we have completed pilot studies performed in immunocompetent mice, demonstrating that protective immunity elicited by the Dryvax(r) smallpox vaccine is in no way compromised by ST-246 and may in fact be enhanced. It remains to be seen whether ST-246 actually reduces the occurrence of vaccine-related adverse events. To evaluate whether ST-246 may improve the safety of the smallpox vaccine without compromising protective immunity, we propose to utilize murine models for immunodeficiency and eczema/atopic dermatitis as hosts for poxvirus challenge and ST-246 treatment. Toward this end, the following specific aims are proposed: 1. Evaluate the prophylactic and therapeutic efficacy of ST-246 in vaccinia-challenged murine models of B and T cell immunodeficiency. 2. Evaluate the prophylactic and therapeutic efficacy of ST-246 in vaccinia-challenged murine models of eczema/atopic dermatitis. 3. Analyze protective immune responses elicited by vaccination in combination with ST- 246 in immunodeficient and eczematous mice.

描述（由申请人提供）：天花作为生物武器的重新威胁，而新兴的人畜共患病威胁强调了需要有效的痘病毒对策。天花疫苗的使用会带来严重的健康风险，尤其是对于免疫功能低下或患有湿疹/特应性皮炎的人。我们的长期目标是建立一种安全有效的疫苗方案，其中包括使用当前批准的有效天花疫苗和一种抗病毒药，以预防或治疗不良事件，尤其是在上述高危人群中。我们假设天花疫苗和ST-246（一种抗病毒药物）共同给药，以抑制与原始接种部位的病毒传播，将显着降低免疫缺陷型疫苗相关的病理，而无需损害免疫免疫的免疫免疫宿主，而无需通过疫苗促进疫苗。我们的假设从以前的观察结果延伸：首先是人类中的致命痘病毒感染以及动物模型中的，这是由于接种原始部位传播和广泛的全身感染而引起的。其次，在众多动物模型中，对正常致命的痘病毒感染的治疗是一种特异性阻断病毒传播的药物（一种专门阻止病毒传播）的药物。第三，我们完成了在免疫能力小鼠中进行的试点研究，表明由Dryvax（R）天花疫苗引起的保护性免疫绝不会受到ST-246的损害，实际上可能会增强。 ST-246是否实际减少了与疫苗相关的不良事件的发生还有待观察。为了评估ST-246是否可以在不损害保护性免疫力的情况下改善天花疫苗的安全性，我们建议利用鼠模型来实现免疫缺陷和湿疹/特应性皮炎作为鼠疫挑战和ST-246治疗的宿主。为此，提出了以下特定目标： 1。评估ST-246在疫苗和T细胞免疫缺陷的接线鼠模型中的预防性和治疗功效。 2。评估ST-246在湿疹/特应性皮炎的疫苗挑战的鼠模型中的预防性和治疗功效。 3。分析免疫缺陷和昏迷小鼠中通过疫苗与ST-246结合进行疫苗接种引起的保护性免疫反应。