Antibodies elicited in humans upon chimeric hemagglutinin-based influenza virus vaccination confer FcγR-dependent protection in vivo.
Antibodies elicited in humans upon chimeric hemagglutinin-based influenza virus vaccination confer FcγR-dependent protection in vivo.
复制标题
基于嵌合血凝素的流感病毒疫苗接种在人体中引发的抗体赋予 FcγR 依赖性体内保护。
DOI：
10.1073/pnas.2314905120
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发表时间：
2023
影响因子：
11.1
通讯作者：
Bournazos,Stylianos
中科院分区：
文献类型：
--
作者：
Edgar,JuliaE;Trezise,Stephanie;Anthony,RobertM;Krammer,Florian;Palese,Peter;Ravetch,JeffreyV;Bournazos,Stylianos
针对流感病毒血凝素（HA）茎域上的高度保守表位的抗体应答赋予广泛的保护;然而，这种应答是有限的。为了有效地诱导针对保守HA表位的茎特异性免疫，已经开发了基于嵌合HA（cHA）构建体的顺序免疫策略，所述嵌合HA构建体具有不同的头部结构域但具有相同的茎区。在小动物模型以及人类中的免疫原性研究表明，cHA免疫原引发茎特异性IgG应答，对异源流感病毒株具有广泛的特异性。然而，这些抗体赋予体内保护的机制及其Fc效应子功能的贡献仍不清楚。为了表征Fc-FcγR（Fcγ受体）相互作用对cHA候选疫苗I期试验参与者中引发的IgG抗体体内保护活性的作用，我们在所有类别Fcγ R人源化小鼠以及Fcγ R缺陷小鼠中进行了疫苗引发的IgG抗体的被动转移研究。cHA疫苗接种后引发的IgG抗体完全保护FcγR人源化小鼠免受致死性流感病毒攻击，而Fcγ R缺陷小鼠中无明显保护作用，表明FcγR途径在疫苗引发的IgG抗体的保护功能中发挥主要作用。这些发现对流感疫苗开发具有重要意义，指导设计具有引发具有最佳Fc效应器功能的IgG应答的能力的疫苗接种方法。
Antibody responses against highly conserved epitopes on the stalk domain of influenza virus hemagglutinin (HA) confer broad protection; however, such responses are limited. To effectively induce stalk-specific immunity against conserved HA epitopes, sequential immunization strategies have been developed based on chimeric HA (cHA) constructs featuring different head domains but the same stalk regions. Immunogenicity studies in small animal models, as well as in humans, revealed that cHA immunogens elicit stalk-specific IgG responses with broad specificity against heterologous influenza virus strains. However, the mechanisms by which these antibodies confer in vivo protection and the contribution of their Fc effector function remain unclear. To characterize the role of Fc-FcγR (Fcγ receptor) interactions to the in vivo protective activity of IgG antibodies elicited in participants in a phase I trial of a cHA vaccine candidate, we performed passive transfer studies of vaccine-elicited IgG antibodies in mice humanized for all classes of FcγRs, as well as in mice deficient for FcγRs. IgG antibodies elicited upon cHA vaccination completely protected FcγR humanized mice against lethal influenza virus challenge, while no protection was evident in FcγR-deficient mice, suggesting a major role for FcγR pathways in the protective function of vaccine-elicited IgG antibodies. These findings have important implications for influenza vaccine development, guiding the design of vaccination approaches with the capacity to elicit IgG responses with optimal Fc effector function.