Establishing ferret models to optimize new influenza vaccines that replace original antigenic sin with initial blessings of induced immunity

早在1960年，小托马斯弗朗西斯就开始了他的研究。首先注意到对幼儿流感病毒的抗体反应 在以后的生活中，当暴露于抗原性不同的病毒株时，感染优先被回忆起来。他创造 用“原始抗原单”来描述这种现象。我们最近证明了人类抗体 对H1N1和H3 N2的反应通常集中在与H1N1和H3 N2的反应不同的抗原表位上， 病毒株和在个体童年时期传播的病毒株。重要的是，我们发现雪貂 相继感染了较老和现代流感病毒株的人， 与人类接触相同病毒株的特异性相同。因此，雪貂是很好的动物模型 用于研究先前的流感暴露如何影响针对以下疾病引起的抗体应答的特异性： 抗原性新的流感病毒株。我们还没有探索先前的暴露如何影响抗体， 针对包括来自H1N1、H3 N2和B型流感抗原的季节性流感疫苗的应答 病毒。这是一个重要的考虑因素，因为每种流感疫苗成分的有效性不同 在不同年龄段有不同免疫史的个体中。我们假设季节性流感 疫苗引起的抗体反应偏向于个体遇到的第一个病毒亚型 在儿童早期，针对这些抗原的抗体应答的优先加强发生在 产生强有力的从头反应的代价。在目标1中，我们将通过定义罚款来解决这个问题- 从接种疫苗的雪貂和不同病毒暴露的人中分离的血清抗体的特异性 历史在目标2中，我们将开发和应用新技术来表征之前雪貂的B细胞反应。 以及季节性流感疫苗接种后。最后，在目标3中，我们将确定一种新的基于mRNA的疫苗是否 与最初通过单一免疫途径接触流感病毒相比， 病毒感染和灭活疫苗。总之，这些研究将提高我们对先前如何的理解。 流感病毒暴露影响对季节性流感疫苗的抗体应答 并将测试一种新的流感疫苗，这种疫苗有可能引起广泛的无偏见的免疫反应。

As early as 1960, Thomas Francis Jr. first noted that antibody responses to early childhood influenza virus infections are preferentially recalled later in life upon exposure to antigenically distinct viral strains. He coined the phrase ‘original antigenic sin’ to describe this phenomena. We recently demonstrated that human antibody responses to H1N1 and H3N2 are typically focused on epitopes that are conserved between contemporary viral strains and viral strains that circulated during an individual’s childhood. Importantly, we found that ferrets sequentially infected with older and contemporary influenza virus strains possess antibodies that have the same specificity as humans that were exposed to the same viral strains. Thus, ferrets are good animal models for studying how prior influenza exposures affect the specificity of antibody responses elicited against antigenically novel influenza virus strains. We have not yet explored how prior exposures influence antibody responses against seasonal influenza vaccines that include antigens from H1N1, H3N2, and influenza B viruses. This is an important consideration since the effectiveness of each influenza vaccine component differs among different aged individuals with distinct immune histories. We hypothesize that seasonal influenza vaccines elicit antibody responses that are biased towards the first viral subtype that an individual encounters early in childhood, and that preferential boosting of antibody responses against these antigens occurs at the expense of generating robust de novo responses. In Aim 1, we will address this question by defining the fine- specificities of serum antibodies isolated from vaccinated ferrets and humans with different viral exposure histories. In Aim 2, we will develop and apply new techniques to characterize B cell responses in ferrets before and after seasonal influenza vaccination. Finally, in Aim 3 we will determine if a novel mRNA-based vaccine establishes broader immunological memory compared to initial influenza virus encounters that occur via single viral infections and inactivated vaccines. Together, these studies will improve our understanding of how prior influenza virus exposures influence the generation of antibody responses against seasonal influenza vaccines and will test a new influenza vaccine that has the potential to elicit broad unbiased immune responses.