PDF(Pubmed)
Abstract：
Inactivated influenza vaccines induce greater antibody responses in females than males among both humans and mice. To test the breadth of protection, we used recombinant mouse-adapted A/California/2009 (maA/Cal/09) H1N1 viruses containing mutations at one (1M), two (2M), or three (3M) antigenic sites, in addition to a virus containing the 1M mutation and a substitution of the Ca2 antigenic site (Sub) with one derived from an H5 hemagglutinin (HA) to challenge mice of both sexes. Following maA/Cal/09 vaccination, females produced greater virus-specific, class-switched total IgG and IgG2c antibodies against the vaccine and all mutant viruses, and antibodies from females recognized a greater number of unique, linear HA epitopes than did antibodies from males. While females had greater neutralizing antibody titers against the vaccine virus, both sexes showed a lower neutralization capacity against mutant viruses. After virus challenge, vaccinated females had lower pulmonary virus titers and reduced morbidity than males for the 1M and 2M viruses, but not the Sub virus. Females generated greater numbers of germinal center (GC) B cells containing superior somatic hypermutation (SHM) frequencies than vaccinated males. Deletion of activation-induced cytidine deaminase (Aicda) eliminated female-biased immunity and protection against the 2M virus. Harnessing methods to improve GC B cell responses and frequencies of SHM, especially in males, should be considered in the development of universal influenza vaccines. IMPORTANCE Adult females develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection would be dependent on the extent of virus diversity as well as molecular mechanisms in B cells which constrain the breadth of epitope recognition. We developed a panel of mouse-adapted (ma) A/Cal/09 viruses that had mutations in the immunodominant hemagglutinin. Following vaccination against maA/Cal/09, females were better able to neutralize maA/Cal/09 than males, but neutralization of mutant maA/Cal/09 viruses was equally poor in both sexes, despite vaccinated females being better protected against these viruses. Vaccinated females benefited from the greater production of class-switched, somatically hypermutated antibodies generated in germinal center B cells, which increased recognition of more diverse maA/Cal/09 hemagglutinin antigen epitopes. Female-biased protection against influenza infection and disease after vaccination is driven by differential mechanisms in males versus females and should be considered in the design of novel vaccine platforms.
摘要：
在人类和小鼠中,灭活的流感疫苗在女性中诱导比男性更大的抗体应答。为了测试保护的广度，我们使用重组小鼠适应的A/California/2009（maA/Cal/09）H1N1病毒，两个（2M），或三个（3M）抗原位点，除了含有1M突变和Ca2抗原位点（Sub）被来自H5血凝素（HA）的病毒取代以攻击两种性别的小鼠之外。MAA/Cal/09疫苗接种后，女性产生了更高的病毒特异性，针对疫苗和所有突变病毒的类别转换总IgG和IgG2c抗体，来自女性的抗体识别出更多的独特，线性HA表位比男性抗体。虽然女性对疫苗病毒有更高的中和抗体滴度，两种性别对突变病毒的中和能力均较低。病毒挑战后，对于1M和2M病毒，接种疫苗的女性比男性具有更低的肺部病毒滴度和降低的发病率。但不是亚病毒.与接种疫苗的男性相比，女性产生的生发中心（GC）B细胞数量更多，其体细胞超突变（SHM）频率更高。激活诱导的胞苷脱氨酶（Aicda）的缺失消除了女性偏向的免疫力和对2M病毒的保护。利用方法改善GCB细胞反应和SHM频率，尤其是男性，应该在通用流感疫苗的开发中考虑。重要性成年女性比男性对流感疫苗产生更大的抗体反应。我们假设女性偏向的免疫和保护将取决于病毒多样性的程度以及B细胞中限制表位识别广度的分子机制。我们开发了一组小鼠适应的（ma）A/Cal/09病毒，其在免疫显性血凝素中具有突变。在接种maA/Cal/09疫苗后，女性比男性更能够中和maA/Cal/09，但是突变的maA/Cal/09病毒的中和在两性中同样差，尽管接种疫苗的女性可以更好地抵御这些病毒。接种疫苗的女性受益于更多的阶级转换生产，生发中心B细胞中产生的体细胞超突变抗体，这增加了对更多样化的maA/Cal/09血凝素抗原表位的识别。疫苗接种后，女性偏向的针对流感感染和疾病的保护是由男性与女性的不同机制驱动的，在设计新型疫苗平台时应予以考虑。
