Department of Chemistry and Chemical Biology, Harvard University, Cambridge, MA, United States.
Laboratoire de Chimie Biophysique, ISIS, Université de Strasbourg, Strasbourg, France.
Front Immunol. 2022 Mar 18;13:816634. doi: 10.3389/fimmu.2022.816634. eCollection 2022.
The elicitation of broadly neutralizing antibodies (bnAbs) is a major goal in the design of vaccines against rapidly-mutating viruses. In the case of influenza, many bnAbs that target conserved epitopes on the stem of the hemagglutinin protein (HA) have been discovered. However, these antibodies are rare, are not boosted well upon reinfection, and often have low neutralization potency, compared to strain-specific antibodies directed to the HA head. Different hypotheses have been proposed to explain this phenomenon. We use a coarse-grained computational model of the germinal center reaction to investigate how B-cell receptor binding valency affects the growth and affinity maturation of competing B-cells. We find that receptors that are unable to bind antigen bivalently, and also those that do not bind antigen cooperatively, have significantly slower rates of growth, memory B-cell production, and, under certain conditions, rates of affinity maturation. The corresponding B-cells are predicted to be outcompeted by B-cells that bind bivalently and cooperatively. We use the model to explore strategies for a universal influenza vaccine, , how to boost the concentrations of the slower growing cross-reactive antibodies directed to the stem. The results suggest that, upon natural reinfections subsequent to vaccination, the protectiveness of such vaccines would erode, possibly requiring regular boosts. Collectively, our results strongly support the importance of bivalent antibody binding in immunodominance, and suggest guidelines for developing a universal influenza vaccine.
诱导广谱中和抗体 (bnAbs) 是设计针对快速突变病毒疫苗的主要目标。在流感的情况下，已经发现了许多针对血凝素蛋白 (HA) 茎部保守表位的 bnAbs。然而，与针对 HA 头部的针对特定菌株的抗体相比，这些抗体数量稀少，再次感染时不能很好地增强，并且通常中和效力较低。已经提出了不同的假说来解释这种现象。我们使用生发中心反应的粗粒计算模型来研究 B 细胞受体结合价如何影响竞争 B 细胞的生长和亲和力成熟。我们发现，不能以二价结合抗原的受体，以及那些不能协同结合抗原的受体，其生长、记忆 B 细胞产生的速度以及在某些条件下亲和力成熟的速度明显较慢。相应的 B 细胞预计会被以二价和协同方式结合抗原的 B 细胞所竞争。我们使用该模型探讨了通用流感疫苗的策略，即如何提高针对茎部的交叉反应性较慢生长抗体的浓度。结果表明，在接种后的自然再感染后，此类疫苗的保护作用可能会减弱，可能需要定期加强。总的来说，我们的结果强烈支持二价抗体结合在免疫优势中的重要性，并为开发通用流感疫苗提供了指导方针。
