Division of Biology and Biological Engineering, California Institute of Technology, Pasadena, CA 91125.
Laboratory of Virology and Infectious Disease, The Rockefeller University, New York, NY 10065.
Proc Natl Acad Sci U S A. 2020 May 5;117(18):9865-9875. doi: 10.1073/pnas.1919269117. Epub 2020 Apr 22.
Recent epidemics demonstrate the global threat of Zika virus (ZIKV), a flavivirus transmitted by mosquitoes. Although infection is usually asymptomatic or mild, newborns of infected mothers can display severe symptoms, including neurodevelopmental abnormalities and microcephaly. Given the large-scale spread, symptom severity, and lack of treatment or prophylaxis, a safe and effective ZIKV vaccine is urgently needed. However, vaccine design is complicated by concern that elicited antibodies (Abs) may cross-react with other flaviviruses that share a similar envelope protein, such as dengue virus, West Nile virus, and yellow fever virus. This cross-reactivity may worsen symptoms of a subsequent infection through Ab-dependent enhancement. To better understand the neutralizing Ab response and risk of Ab-dependent enhancement, further information on germline Ab binding to ZIKV and the maturation process that gives rise to potently neutralizing Abs is needed. Here we use binding and structural studies to compare mature and inferred-germline Ab binding to envelope protein domain III of ZIKV and other flaviviruses. We show that affinity maturation of the light-chain variable domain is important for strong binding of the recurrent VH3-23/VK1-5 neutralizing Abs to ZIKV envelope protein domain III, and identify interacting residues that contribute to weak, cross-reactive binding to West Nile virus. These findings provide insight into the affinity maturation process and potential cross-reactivity of VH3-23/VK1-5 neutralizing Abs, informing precautions for protein-based vaccines designed to elicit germline versions of neutralizing Abs.
最近的几次流行病表明，寨卡病毒（ZIKV）对全球构成了威胁，这是一种由蚊子传播的黄病毒。尽管感染通常无症状或症状轻微，但受感染母亲所生的新生儿可能会出现严重症状，包括神经发育异常和小头畸形。鉴于其大规模传播、症状严重程度以及缺乏治疗或预防措施，急需一种安全有效的 ZIKV 疫苗。然而，由于人们担心所诱导的抗体（Abs）可能会与其他具有相似包膜蛋白的黄病毒（如登革热病毒、西尼罗河病毒和黄热病病毒）发生交叉反应，因此疫苗设计变得复杂。这种交叉反应可能会通过抗体依赖性增强作用使随后的感染症状恶化。为了更好地了解中和抗体反应和抗体依赖性增强的风险，需要进一步了解针对 ZIKV 包膜蛋白结构域 III 的原始 Abs 结合以及产生具有强大中和作用的 Abs 的成熟过程。在这里，我们使用结合和结构研究来比较 ZIKV 和其他黄病毒的成熟和推断的原始 Abs 对包膜蛋白结构域 III 的结合。我们表明，轻链可变结构域的亲和力成熟对于反复出现的 VH3-23/VK1-5 中和 Abs 与 ZIKV 包膜蛋白结构域 III 的强结合非常重要，并确定了与西尼罗河病毒的弱交叉反应结合有关的相互作用残基。这些发现为 VH3-23/VK1-5 中和 Abs 的亲和力成熟过程和潜在的交叉反应提供了深入的了解，为设计旨在诱导中和 Abs 的原始版本的基于蛋白质的疫苗提供了预防措施。
