Department of Mathematics, Duke University, Durham, NC 27708, USA.
J R Soc Interface. 2012 Oct 7;9(75):2603-13. doi: 10.1098/rsif.2012.0180. Epub 2012 May 9.
Antigenically evolving pathogens such as influenza viruses are difficult to control owing to their ability to evade host immunity by producing immune escape variants. Experimental studies have repeatedly demonstrated that viral immune escape variants emerge more often from immunized hosts than from naive hosts. This empirical relationship between host immune status and within-host immune escape is not fully understood theoretically, nor has its impact on antigenic evolution at the population level been evaluated. Here, we show that this relationship can be understood as a trade-off between the probability that a new antigenic variant is produced and the level of viraemia it reaches within a host. Scaling up this intra-host level trade-off to a simple population level model, we obtain a distribution for variant persistence times that is consistent with influenza A/H3N2 antigenic variant data. At the within-host level, our results show that target cell limitation, or a functional equivalent, provides a parsimonious explanation for how host immune status drives the generation of immune escape mutants. At the population level, our analysis also offers an alternative explanation for the observed tempo of antigenic evolution, namely that the production rate of immune escape variants is driven by the accumulation of herd immunity. Overall, our results suggest that disease control strategies should be further assessed by considering the impact that increased immunity--through vaccination--has on the production of new antigenic variants.
由于抗原进化的病原体（如流感病毒）能够通过产生免疫逃逸变异体来逃避宿主免疫，因此很难控制它们。实验研究反复表明，免疫逃逸变异体在免疫宿主中比在未免疫宿主中更频繁地出现。宿主免疫状态与体内免疫逃逸之间的这种经验关系在理论上尚未得到充分理解，其对群体水平抗原进化的影响也尚未得到评估。在这里，我们表明，这种关系可以理解为新抗原变异体产生的概率与宿主内达到的病毒血症水平之间的权衡。将这种宿主内的权衡扩展到一个简单的群体水平模型中，我们得到了一个与流感 A/H3N2 抗原变异体数据一致的变异体持续时间分布。在宿主内水平，我们的结果表明，靶细胞限制或功能等效物为宿主免疫状态如何驱动免疫逃逸突变体的产生提供了一个简洁的解释。在群体水平上，我们的分析还为观察到的抗原进化速度提供了另一种解释，即免疫逃逸变体的产生率是由群体免疫的积累所驱动的。总的来说，我们的结果表明，疾病控制策略应该通过考虑增加的免疫（通过接种疫苗）对新抗原变异体产生的影响来进一步评估。
