Multi-epitope Models Explain How Pre-existing Antibodies Affect the Generation of Broadly Protective Responses to Influenza.
Multi-epitope Models Explain How Pre-existing Antibodies Affect the Generation of Broadly Protective Responses to Influenza.
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DOI：
10.1371/journal.ppat.1005692
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发表时间：
2016-06
期刊：
影响因子：
6.7
通讯作者：
Antia R
中科院分区：
文献类型：
--
作者：
Zarnitsyna VI;Lavine J;Ellebedy A;Ahmed R;Antia R
开发下一代流感疫苗，激发对季节性和大流行病毒的株系超越免疫，是一个关键的公共卫生目标。以流感主要表面分子血凝素的茎上进化保守的表位为靶点是一个吸引人的前景，新型疫苗配方在动物模型系统中显示出良好的结果。然而，在人类中的研究表明，自然感染和疫苗接种导致对HA茎的抗体产生有限的增强，并且所激发的茎特异性抗体水平不足以提供广泛的菌株超越性免疫。在这里，我们使用体液免疫反应的数学模型来探索先前存在的免疫如何影响疫苗增强针对人类HA头部和茎的抗体的能力，特别是它如何导致明显缺乏针对茎表位的广泛交叉反应的抗体的增强。我们考虑的假设是抗体与表位的结合：(I)导致抗原更快地清除；(Ii)通过Fcγ受体介导的机制导致抗原-抗体复合体的形成，从而抑制B细胞的激活；以及(Iii)掩盖表位并阻止特定B细胞的刺激和增殖。我们发现，只有表位掩蔽而不是前两种机制是重述数据模式的关键。我们讨论了我们的发现对开发针对季节性流感和大流行流感的疫苗的影响。目前的流感疫苗需要经常更新，以防止病毒从一年到下一年的微小变化，以及与从人畜共患病宿主中出现新的流感毒株而导致大流行有关的较大变化。人们对开发“通用”疫苗非常感兴趣，这种疫苗将增强对病毒保守区域的免疫反应，特别是对主要病毒表面分子血凝素(HA)的茎区域的免疫反应。然而，最近的数据显示，接种疫苗对HA干抗体的增强作用非常有限。我们使用数学模型来探索不同的假设，这些假设可能解释为什么疫苗接种不能增强对病毒保守部分的抗体。通过将我们的模型与人类疫苗试验的数据进行对峙，我们发现，阻止对HA茎的有效增强反应的关键机制是用先前感染和疫苗接种期间产生的预先存在的抗体掩盖茎。我们讨论了如何在“通用”流感疫苗中克服这种掩饰效应。
The development of next-generation influenza vaccines that elicit strain-transcendent immunity against both seasonal and pandemic viruses is a key public health goal. Targeting the evolutionarily conserved epitopes on the stem of influenza’s major surface molecule, hemagglutinin, is an appealing prospect, and novel vaccine formulations show promising results in animal model systems. However, studies in humans indicate that natural infection and vaccination result in limited boosting of antibodies to the stem of HA, and the level of stem-specific antibody elicited is insufficient to provide broad strain-transcendent immunity. Here, we use mathematical models of the humoral immune response to explore how pre-existing immunity affects the ability of vaccines to boost antibodies to the head and stem of HA in humans, and, in particular, how it leads to the apparent lack of boosting of broadly cross-reactive antibodies to the stem epitopes. We consider hypotheses where binding of antibody to an epitope: (i) results in more rapid clearance of the antigen; (ii) leads to the formation of antigen-antibody complexes which inhibit B cell activation through Fcγ receptor-mediated mechanism; and (iii) masks the epitope and prevents the stimulation and proliferation of specific B cells. We find that only epitope masking but not the former two mechanisms to be key in recapitulating patterns in data. We discuss the ramifications of our findings for the development of vaccines against both seasonal and pandemic influenza. The current influenza vaccine requires frequent updating in order to protect against small changes in the virus from one year to the next as well as larger changes associated with the emergence of new influenza strains from zoonotic reservoirs that cause pandemics. There is a considerable interest in developing “universal” vaccines that will boost immune responses to the conserved regions of the virus, in particular, to the stem region of the major virus surface molecule hemagglutinin (HA). However, recent data reveals that vaccination results in very limited boosting of antibodies to the stem of HA. We use mathematical models to explore different hypotheses that may explain why vaccination does not boost antibodies to the conserved parts of the virus. By confronting our models with the data from the human vaccination trials we found that the key mechanism preventing effective boosting of the responses to the stem of HA is masking of the stem by pre-existing antibodies developed during previous infections and vaccinations. We discuss how this masking effect could be overcome in a “universal” influenza vaccine.