Natural infections and vaccination with a pathogen typically stimulate the production of potent antibodies specific for the pathogen through a Darwinian evolutionary process known as affinity maturation. Such antibodies provide protection against reinfection by the same strain of a pathogen. A highly mutable virus, like HIV or influenza, evades recognition by these strain-specific antibodies via the emergence of new mutant strains. A vaccine that elicits antibodies that can bind to many diverse strains of the virus—known as broadly neutralizing antibodies (bnAbs)—could protect against highly mutable pathogens. Despite much work, the mechanisms by which bnAbs emerge remain uncertain. Using a computational model of affinity maturation, we studied a wide variety of vaccination strategies. Our results suggest that an effective strategy to maximize bnAb evolution is through a sequential immunization protocol, wherein each new immunization optimally increases the pressure on the immune system to target conserved antigenic sites, thus conferring breadth. We describe the mechanisms underlying why sequentially driving the immune system increasingly further from steady state, in an optimal fashion, is effective. The optimal protocol allows many evolving B cells to become bnAbs via diverse evolutionary paths.

自然感染和病原体疫苗接种通常会通过称为亲和力成熟的达尔文进化过程来刺激针对病原体的有效抗体的产生。这样的抗体提供针对相同病原体菌株的再感染的保护。高度易变的病毒（如HIV或流感）通过出现新的突变株而逃避了这些菌株特异性抗体的识别。一种能够引发与多种不同病毒株结合的抗体的疫苗（称为广泛中和抗体（bnAbs））可以预防高度易变的病原体。尽管做了很多工作，但bnAb出现的机制仍不确定。使用亲和力成熟的计算模型，我们研究了各种各样的疫苗接种策略。我们的结果表明，最大的bnAb进化的有效策略是通过顺序免疫方案，其中每次新的免疫最佳地增加了免疫系统对保守抗原位点的压力，因此具有广度。我们描述了为什么以最佳方式从稳定状态逐步驱动免疫系统越来越有效的根本机制。最佳方案允许许多进化的B细胞通过不同的进化途径变成bnAb。以最佳方式有效。最佳方案允许许多进化的B细胞通过不同的进化途径变成bnAb。以最佳方式有效。最佳方案允许许多进化的B细胞通过不同的进化途径变成bnAb。