DNA vaccine-derived human IgG produced in transchromosomal bovines protect in lethal models of hantavirus pulmonary syndrome
DNA vaccine-derived human IgG produced in transchromosomal bovines protect in lethal models of hantavirus pulmonary syndrome
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DOI：
10.1126/scitranslmed.3010082
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发表时间：
2014-11-26
影响因子：
17.1
通讯作者：
Sullivan, Eddie J.
中科院分区：
文献类型：
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作者：
Hooper, Jay W.;Brocato, Rebecca L.;Sullivan, Eddie J.
一个多世纪以来，基于多克隆免疫球蛋白的医疗产品已成功用于治疗病毒引起的疾病。我们证明了使用DNA疫苗技术和转染色体牛（TcBs），以产生完全人的多克隆免疫球蛋白（IgG）具有强大的抗病毒中和活性。具体地，两种汉坦病毒DNA疫苗[安第斯山脉病毒（ANDV）DNA疫苗和辛诺布尔病毒（SNV）DNA疫苗]用于产生用于预防和治疗汉坦病毒肺综合征（HPS）的候选免疫球蛋白产物。使用无针喷射注射装置接种TcB，在1个月内产生针对两种病毒的高滴度中和抗体（滴度>1000）。在第四次接种后第10天收集的血浆用于产生纯化的a-HPS TcB人IgG。在用ANDV攻击后5天开始用20，000中和抗体单位（NAU）/kg处理保护了8只动物中的7只，而用相同剂量的正常TcB人IgG处理的8只动物中没有动物存活。同样，在用SNV攻击后5天开始用20，000 NAU/kg处理保护免疫受损仓鼠免于致死HPS，保护了8只动物中的5只。我们发现，当暴露后给药时，α-HPS TcB人IgG能够在致死性HPS动物模型中提供保护，这一发现提供了概念证明，即该方法可用于开发候选的下一代基于多克隆免疫球蛋白的医疗产品，而无需人供体、去种方案或灭活/减毒疫苗抗原。
Polyclonal immunoglobulin-based medical products have been used successfully to treat diseases caused by viruses for more than a century. We demonstrate the use of DNA vaccine technology and transchromosomal bovines (TcBs) to produce fully human polyclonal immunoglobulins (IgG) with potent antiviral neutralizing activity. Specifically, two hantavirus DNA vaccines [Andes virus (ANDV) DNA vaccine and Sin Nombre virus (SNV) DNA vaccine] were used to produce a candidate immunoglobulin product for the prevention and treatment of hantavirus pulmonary syndrome (HPS). A needle-free jet injection device was used to vaccinate TcB, and high-titer neutralizing antibodies (titers >1000) against both viruses were produced within 1 month. Plasma collected at day 10 after the fourth vaccination was used to produce purified alpha-HPS TcB human IgG. Treatment with 20,000 neutralizing antibody units (NAU)/kg starting 5 days after challenge with ANDV protected seven of eight animals, whereas zero of eight animals treated with the same dose of normal TcB human IgG survived. Likewise, treatment with 20,000 NAU/kg starting 5 days after challenge with SNV protected immunocompromised hamsters from lethal HPS, protecting five of eight animals. Our findings that the alpha-HPS TcB human IgG is capable of protecting in animal models of lethal HPS when administered after exposure provides proof of concept that this approach can be used to develop candidate next-generation polyclonal immunoglobulin-based medical products without the need for human donors, despeciation protocols, or inactivated/attenuated vaccine antigen.