Novel vaccine to enhance breadth of influenza immunity by skin vaccination

 描述(申请人提供)：流感是一个世界性的公共卫生问题。目前的季节性疫苗在预防由紧密匹配的病毒引起的疾病方面是有效的。然而，由于点突变的不断积累，不同亚型之间的基因重组，以及非人类流感病毒对人类的适应，疫苗与流通病毒之间的不匹配损害了现有疫苗的效力，并导致接种对象的易感性增加。能够通过季节性疫苗加强对异源病毒的保护的新疫苗战略将对公众健康产生重要影响。我们最近报道了含有M2e串联重复序列和细菌鞭毛蛋白Toll样受体(TLR)5配体(4.M2e-tFliC)的融合蛋白(4.M2e-tFliC)的微针皮肤疫苗对异型病毒具有有效的保护作用。我们将调查在常规疫苗接种后用溶解的聚合物微针贴片将重新设计的4.M2e-tFliC递送到皮肤的加强免疫，或者共同递送常规疫苗和4.M2e-tFliC的微针贴片是否会迅速扩大当前季节性疫苗对新出现的漂移变异甚至潜在的大流行毒株的保护效力。我们将追求两个具体目标：具体目标1。评估增强对漂移病毒和潜在大流行病毒株的免疫保护。我们将测试在常规免疫后通过溶解微针将4.M2e-tFliC输送到皮肤的加强免疫，或者微针联合输送裂解疫苗和4.M2e-tFliC，是否会导致对新出现的漂移或潜在的大流行变异的加强保护。特定目的2.对豚鼠加强保护的测定。作为为人类皮肤接种和预防流感传播获得概念验证数据的更相关动物模型，我们将确定：1)常规接种后使用4.M2e-tFliC包裹的溶解微针加强免疫，或联合向皮肤输送裂解疫苗和4.M2e-tFliC的微针，是否会在豚鼠身上诱导增强的免疫反应，从而对异源病毒产生保护；以及2)拟议的疫苗策略是否会防止受感染的豚鼠作为捐赠者模拟自然感染而进行接触和气雾剂传播。总体而言，我们的方法是创新的，将溶解微针贴片中封装的4.M2e-tFliC与传统流感疫苗相结合，并将提供一种有前景的新方法，在新的漂移或大流行毒株出现时为疫苗提供额外保护。

 DESCRIPTION (provided by applicant): Influenza is a worldwide public health problem. The present seasonal vaccines are effective in prevention of disease induced by closely matched viruses. However, because of the continuous accumulation of point mutations, genetic reassortment between different subtypes, and non-human influenza virus adaption to humans, mismatch between vaccines and circulating viruses compromises the efficacy of current vaccines and results in increased susceptibility of vaccinated subjects. New vaccine strategies capable to provide enhanced protection by seasonal vaccines against heterologous viruses will have an important impact on public health. We recently reported that microneedle-based skin vaccination with a fusion protein including M2e tandem repeats and the Toll-like receptor (TLR) 5 ligand from bacterial flagellin (4.M2e-tFliC) elicited effective protection against heterosubtypi viruses. We will investigate whether a boost immunization with dissolving polymer microneedles patch delivering redesigned 4.M2e-tFliC to skin after the conventional vaccination, or a microneedle patch co- delivering conventional vaccines and 4.M2e-tFliC, will rapidly broaden the protective efficacy of current seasonal vaccines against an emerging drift variant or even a potential pandemic strain. We will pursue two specific aims: Specific Aim 1. Evaluation of enhanced immune protection against drifted viruses as well as potential pandemic strains in mice. We will test whether a boost immunization with dissolving microneedles delivering 4.M2e-tFliC to skin after conventional immunization, or microneedle co-delivery of split vaccines and 4.M2e-tFliC, will elicit enhanced protection against an emerging drift or potential pandemic variant. Specific Aim 2. Determination of enhanced protection in guinea pigs. As a more relevant animal model to obtain proof-of-concept data for human skin vaccination and prevention of influenza transmission, we will determine: 1) whether a boost immunization with 4.M2e-tFliC-encapsulated dissolving microneedles after conventional vaccination, or microneedles co-delivering split vaccines plus 4.M2e-tFliC to skin, will induce enhanced immune responses conferring protection against heterologous viruses in guinea pigs; and 2) whether the proposed vaccine strategies will prevent contact and aerosol transmission from infected guinea pigs as a donor to mimic natural infection. Overall, our approach is innovative in combining 4.M2e-tFliC encapsulated in dissolving microneedle patches with conventional influenza vaccines, and will provide a promising novel approach to provide additional protection to vaccines when a new drift or pandemic strain is emerging.