Novel vaccine to enhance breadth of influenza immunity by skin vaccination

 描述（由申请人提供）：流感是一个全球性的公共卫生问题。目前的季节性疫苗可以有效预防由密切匹配的病毒引起的疾病。然而，由于点突变的持续积累、不同亚型之间的基因重配以及非人流感病毒对人类的适应，疫苗和流行病毒之间的错配损害了当前疫苗的效力并导致接种受试者的易感性增加。能够通过季节性疫苗提供针对异源病毒的增强保护的新疫苗策略将对公共卫生产生重要影响。我们最近报道了用融合蛋白（包括M2 e串联重复序列和来自细菌鞭毛蛋白的Toll样受体（TLR）5配体（4. M2 e-tFliC））进行的基于微针的皮肤疫苗接种引起针对异亚型病毒的有效保护。我们将研究在常规疫苗接种后使用将重新设计的4. M2 e-tFliC递送至皮肤的溶解性聚合物微针贴片或共同递送常规疫苗和4. M2 e-tFliC的微针贴片的加强免疫是否将迅速扩大当前季节性疫苗针对新出现的漂移变体或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。评估小鼠对漂移病毒以及潜在大流行毒株的增强免疫保护。我们将测试在常规免疫后用溶解微针向皮肤递送4. M2 e-tFliC的加强免疫，或裂解疫苗和4. M2 e-tFliC的微针共递送，是否会引起针对新出现的漂移或潜在的大流行性变体的增强保护。具体目标2。豚鼠中增强保护的测定。作为获得人类皮肤接种和预防流感传播的概念验证数据的更相关的动物模型，我们将确定：1）在常规接种后用4. M2 e-tFliC包封的溶解微针或将裂解疫苗加4. M2 e-tFliC共递送至皮肤的微针进行加强免疫是否将在豚鼠中诱导增强的免疫应答，从而赋予针对异源病毒的保护;以及2）拟议的疫苗策略是否将防止受感染的豚鼠作为模仿自然感染的供体的接触和气溶胶传播。 总的来说，我们的方法是创新的，将封装在溶解微针贴片中的4. M2 e-tFliC与常规流感疫苗相结合，并且将提供一种有前途的新方法，当新的漂移或大流行毒株出现时，为疫苗提供额外的保护。

 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.