Masking the GH-loop: model for human Rhinovirus vaccine

针对病毒、细菌和寄生虫的新疫苗开发最具挑战性的方面之一是克服与抗原变异相关的问题。在小核糖核酸病毒家族中，抗原变异是通过遗传不稳定性和衣壳结构中免疫优势的高度变异表位的进化来促进的。对这些表位的免疫反应导致分离株、菌株或血清型特异性抗体，并似乎抑制对邻近的、更保守的表位的反应。这项建议的长期目标是测试免疫抑制作为一种策略的可行性，将免疫反应的重点从免疫优势、非保护性或血清型限制性表位转移到更广泛的保护性表位，这些表位以前在抗原性上较弱或沉默。口蹄疫病毒(FMDV)是研究人鼻病毒感染的一种概念验证模型，目前尚无实用的人鼻病毒感染动物模型。口蹄疫病毒和人类鼻病毒在免疫反应方面有许多相似之处。遗传组织和结构特征。在这项拟议的研究中，口蹄疫病毒VP1 GH环将通过各种方法进行免疫抑制，并在细菌或昆虫细胞系统中以70年代自组装的空衣壳多聚蛋白的形式表达。将对一系列VP1修饰的口蹄疫病毒抗原进行佐剂和免疫原性以及同源和异种病毒中和试验。此外，急性期血清将用于精细绘制免疫反应图。免疫抑制技术提供了一种绕过抗原变异问题的新方法，并可能导致创建更广泛的保护性疫苗，以对抗人和动物的各种细菌、病毒和寄生虫病。拟议的商业应用：这项技术的商业应用可能会开发一种有效的口蹄疫疫苗，在全球范围内用于牛、羊和猪。由于这种病毒剂被列为对美国安全的高度威胁，口蹄疫疫苗将在美国储存，作为应对农业生物恐怖主义的措施。此外，使用这种方法可以制造针对人类和动物中各种病毒、细菌和寄生虫的疫苗，目前还没有针对这些病毒、细菌和寄生虫的疫苗。

One of the most challenging aspects of new vaccine development for viruses, bacteria and parasites is overcoming problems associated with antigenic variation. In the picornavirus family, antigenic variation is promoted through genetic instability and the evolution of immunodominant, highly variant epitopes within the capsid structure. Immune responses to these epitopes result in isolate-, strain- or serotype-specific antibody and appear to inhibit responses to neighboring, more conserved epitopes. The long-term objective of this proposal is to test the feasibility of immune dampening as a strategy to refocus the immune responses away from immunodominant, non- protective or serotype-restricted epitopes and towards more broadly protective epitopes which were previously antigenically weak or silent. Foot and Mouth Disease Virus (FMDV) is to be used as a proof of concept model for studying human rhinovirus infection as there is no useful animal model for human Rhinovirus infection. FMDV and human rhinoviruses share many similarities in immune responses. genetic organization, and structural characteristics. In the proposed study, the FMDV VP1 GH-loop will be immune-dampened by various approaches and expressed in bacterial or insect cell systems within the context of the 70S self-assembling empty capsid polyprotein. A series of the VP1 modified FMDV antigens will be adjuvented and tested for immunogenicity and for homologous and heterologous virus neutralization. In addition, acute phase sera will be used to fine map immune responses. Immune dampening technology offers a new approach to circumvent the issues of antigenic variation and could lead to the creation of more broadly protective vaccines against a variety of bacterial, viral and parasitic diseases of man and animals. PROPOSED COMMERCIAL APPLICATIONS: The commercial application of this technology may allow for the development of an effective FMDV vaccine for worldwide use in cattle, sheep and swine. As this viral agent is listed as a high threat to U.S. security, a FMDV vaccine would be stockpiled in the United States as a counter measure for agriculture bioterrorism. In addition, vaccines against a wide variety of viruses, bacteria and parasites in both humans and animals for which no vaccines exist to date could be made using this approach.