The efficacy of COVID-19 vaccines appears to depend in complex ways on the vaccine dosage and the interval between the prime and boost doses. Unexpectedly, lower dose prime and longer prime-boost intervals have yielded higher efficacies in clinical trials. To elucidate the origins of these effects, we developed a stochastic simulation model of the germinal centre (GC) reaction and predicted the antibody responses elicited by different vaccination protocols. The simulations predicted that a lower dose prime could increase the selection stringency in GCs due to reduced antigen availability, resulting in the selection of GC B cells with higher affinities for the target antigen. The boost could relax this selection stringency and allow the expansion of the higher affinity GC B cells selected, improving the overall response. With a longer dosing interval, the decay in the antigen with time following the prime could further increase the selection stringency, amplifying this effect. The effect remained in our simulations even when new GCs following the boost had to be seeded by memory B cells formed following the prime. These predictions offer a plausible explanation of the observed paradoxical effects of dosage and dosing interval on vaccine efficacy. Tuning the selection stringency in the GCs using prime-boost dosages and dosing intervals as handles may help improve vaccine efficacies.

中文翻译：

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低剂量初免和延迟加强可以通过增加生发中心的 B 细胞选择严格性来提高 COVID-19 疫苗的效力

COVID-19 疫苗的功效似乎以复杂的方式取决于疫苗剂量以及初始剂量和加强剂量之间的间隔。出乎意料的是，较低的初始剂量和较长的初始-加强间隔在临床试验中产生了更高的疗效。为了阐明这些影响的起源，我们开发了生发中心 (GC) 反应的随机模拟模型，并预测了由不同疫苗接种方案引起的抗体反应。模拟预测，由于抗原可用性降低，较低剂量的初免会增加 GC 中的选择严格性，从而导致选择对目标抗原具有更高亲和力的 GC B 细胞。增强可以放松这种选择严格性，并允许扩增选择的更高亲和力的 GC B 细胞，从而改善整体反应。随着给药间隔的延长，抗原随着时间的推移随着时间的推移而衰减，可以进一步增加选择严格性，放大这种效果。即使在增强后的新 GC 必须由初始后形成的记忆 B 细胞播种时，我们的模拟中仍然存在这种影响。这些预测为观察到的剂量和给药间隔对疫苗效力的矛盾影响提供了合理的解释。使用初始-加强剂量和给药间隔作为手柄调整 GC 中的选择严格性可能有助于提高疫苗效力。这些预测为观察到的剂量和给药间隔对疫苗效力的矛盾影响提供了合理的解释。使用初始-加强剂量和给药间隔作为手柄调整 GC 中的选择严格性可能有助于提高疫苗效力。这些预测为观察到的剂量和给药间隔对疫苗效力的矛盾影响提供了合理的解释。使用初始-加强剂量和给药间隔作为手柄调整 GC 中的选择严格性可能有助于提高疫苗效力。