Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans
Induction of broadly cross-reactive antibody responses to the influenza HA stem region following H5N1 vaccination in humans
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DOI：
10.1073/pnas.1414070111
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发表时间：
2014-09-09
影响因子：
11.1
通讯作者：
Ahmed, Rafi
中科院分区：
文献类型：
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作者：
Ellebedy, Ali H.;Krammer, Florian;Ahmed, Rafi
大流行性流感病毒的出现构成了重大的公共卫生威胁。因此，需要一种疫苗，其可以诱导广泛的交叉反应性抗体，以保护免受季节性以及大流行性流感毒株的侵害。针对流感病毒HA茎区中高度保守表位的人广谱中和抗体最近已被表征。然而，针对这些保守表位的抗体和记忆B细胞的基线水平仍然未知。更重要的是，还不知道在季节性流感疫苗接种后，抗HA干B细胞反应在人体中得到了多大程度的增强。在本研究中，我们解决了这两个悬而未决的问题。我们的数据显示：（i）针对保守HA干区的抗体和记忆B细胞在人类中普遍存在，但它们的水平远低于针对HA头部中可变表位的B细胞应答;（ii）目前的季节性流感疫苗在诱导针对可变HA头部区的B细胞应答方面是有效的，但它们不能增强针对保守HA干区的应答;和（iii）与此形成鲜明对比的是，用禽流感病毒H5N1免疫人类诱导了广泛交叉反应的HA茎特异性抗体。综上所述，我们的研究结果提供了一种潜在的疫苗接种策略，其中异源流感免疫可用于增加广泛中和抗体的水平，并使人群能够快速应对新出现的大流行性流感威胁。
The emergence of pandemic influenza viruses poses a major public health threat. Therefore, there is a need for a vaccine that can induce broadly cross-reactive antibodies that protect against seasonal as well as pandemic influenza strains. Human broadly neutralizing antibodies directed against highly conserved epitopes in the stem region of influenza virus HA have been recently characterized. However, it remains unknown what the baseline levels are of antibodies and memory B cells that are directed against these conserved epitopes. More importantly, it is also not known to what extent anti-HA stem B-cell responses get boosted in humans after seasonal influenza vaccination. In this study, we have addressed these two outstanding questions. Our data show that: (i) antibodies and memory B cells directed against the conserved HA stem region are prevalent in humans, but their levels are much lower than B-cell responses directed to variable epitopes in the HA head; (ii) current seasonal influenza vaccines are efficient in inducing B-cell responses to the variable HA head region but they fail to boost responses to the conserved HA stem region; and (iii) in striking contrast, immunization of humans with the avian influenza virus H5N1 induced broadly cross-reactive HA stem-specific antibodies. Taken together, our findings provide a potential vaccination strategy where heterologous influenza immunization could be used for increasing the levels of broadly neutralizing antibodies and for priming the human population to respond quickly to emerging pandemic influenza threats.