Center for Virology, Medical University of Vienna, Vienna, Austria.
Bundeswehr Institute of Microbiology, Munich, Germany; Center of Infection Research (DZIF) Partner, Munich, Germany.
PLoS Negl Trop Dis. 2020 Feb 4;14(2):e0008034. doi: 10.1371/journal.pntd.0008034. eCollection 2020 Feb.
Zika virus has recently spread to South- and Central America, causing congenital birth defects and neurological complications. Many people at risk are flavivirus pre-immune due to prior infections with other flaviviruses (e.g. dengue virus) or flavivirus vaccinations. Since pre-existing cross-reactive immunity can potentially modulate antibody responses to Zika virus infection and may affect the outcome of disease, we analyzed fine-specificity as well as virus-neutralizing and infection-enhancing activities of antibodies induced by a primary Zika virus infection in flavivirus-naïve as well as yellow fever- and/or tick-borne encephalitis-vaccinated individuals.
Antibodies in sera from convalescent Zika patients with and without vaccine-induced immunity were assessed by ELISA with respect to Zika virus-specificity and flavivirus cross-reactivity. Functional analyses included virus neutralization and infection-enhancement. The contribution of IgM and cross-reactive antibodies to these properties was determined by depletion experiments.
Pre-existing flavivirus immunity had a strong influence on the antibody response in primary Zika virus infections, resulting in higher titers of broadly flavivirus cross-reactive antibodies and slightly lower levels of Zika virus-specific IgM. Antibody-dependent enhancement (ADE) of Zika virus was mediated by sub-neutralizing concentrations of specific IgG but not by cross-reactive antibodies. This effect was potently counteracted by the presence of neutralizing IgM. Broadly cross-reactive antibodies were able to both neutralize and enhance infection of dengue virus but not Zika virus, indicating a different exposure of conserved sequence elements in the two viruses.
Our data point to an important role of flavivirus-specific IgM during the transient early stages of infection, by contributing substantially to neutralization and by counteracting ADE. In addition, our results highlight structural differences between strains of Zika and dengue viruses that are used for analyzing infection-enhancement by cross-reactive antibodies. These findings underscore the possible impact of specific antibody patterns on flavivirus disease and vaccination efficacy.
寨卡病毒最近已传播至南美洲和中美洲，导致先天出生缺陷和神经并发症。由于先前感染过其他黄病毒（如登革热病毒）或接种过黄病毒疫苗，许多处于感染风险中的人对黄病毒无预先免疫。由于预先存在的交叉反应性免疫可能会调节对寨卡病毒感染的抗体反应，并可能影响疾病的结局，因此我们分析了在无黄病毒感染史以及黄热病和/或蜱传脑炎疫苗接种者中，初次寨卡病毒感染诱导的抗体的精细特异性、中和以及感染增强活性。
采用 ELISA 法，评估来自寨卡康复患者血清中的抗体，以评估寨卡病毒特异性和黄病毒交叉反应性。功能分析包括病毒中和和感染增强。通过耗尽实验确定 IgM 和交叉反应性抗体对这些特性的贡献。
先前的黄病毒免疫对原发性寨卡病毒感染中的抗体反应有很强的影响，导致广泛的黄病毒交叉反应性抗体滴度更高，而寨卡病毒特异性 IgM 水平略低。抗体依赖性增强（ADE）由亚中和浓度的特异性 IgG 介导，但不由交叉反应性抗体介导。中和性 IgM 的存在可强力拮抗此效应。广泛的交叉反应性抗体既能中和又能增强登革热病毒的感染，但不能增强寨卡病毒的感染，这表明这两种病毒中保守序列元件的暴露情况不同。
我们的数据表明，在感染的短暂早期阶段，黄病毒特异性 IgM 发挥重要作用，通过大量中和以及中和 ADE 来发挥作用。此外，我们的结果突出了用于分析交叉反应性抗体感染增强的寨卡病毒和登革热病毒株之间的结构差异。这些发现强调了特定抗体模式对黄病毒病和疫苗效力的可能影响。
