An mRNA Vaccine Encoding Rabies Virus Glycoprotein Induces Protection against Lethal Infection in Mice and Correlates of Protection in Adult and Newborn Pigs.
An mRNA Vaccine Encoding Rabies Virus Glycoprotein Induces Protection against Lethal Infection in Mice and Correlates of Protection in Adult and Newborn Pigs.
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DOI：
10.1371/journal.pntd.0004746
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发表时间：
2016-06
影响因子：
3.8
通讯作者：
Stitz L
中科院分区：
文献类型：
--
作者：
Schnee M;Vogel AB;Voss D;Petsch B;Baumhof P;Kramps T;Stitz L
狂犬病是一种人畜共患的中枢神经系统传染病。在未接种疫苗或未经治疗的受试者中，狂犬病病毒感染会导致严重的神经系统症状，并且总是致命的。尽管有效疫苗的存在由来已久，但疫苗供应仍然不足，致命感染人数很多，主要发生在发展中国家。基于核酸的疫苗已被令人信服地证明是一种新技术，用于快速开发针对新出现的病原体、不存在疫苗的疾病的疫苗或用于替代现有的疫苗。我们使用优化的非复制型狂犬病病毒糖蛋白（RABV-G）编码的信使RNA（mRNA），以诱导有效的中和抗体（VN滴度）在小鼠和家猪。在小鼠中跟踪功能性抗体滴度长达一年，所有剂量组的滴度在整个观察期内保持稳定。T细胞分析显示RABV-G mRNA诱导特异性CD 4+和CD 8 + T细胞，诱导的CD 4 + T细胞高于许可疫苗诱导的那些。值得注意的是，RABV-G mRNA接种的小鼠被保护免于致死性脑内攻击感染。通过qRT-PCR验证疫苗接种对病毒复制的抑制。此外，我们证明了CD 4 + T细胞对于中和抗体的产生至关重要。在家猪中，我们能够诱导与成年猪和新生猪的保护相关的VN滴度。这项研究证明了非复制型mRNA狂犬病疫苗在小型和大型动物中的可行性，并强调了mRNA疫苗预防传染病的前景。尽管路易·巴斯德在19世纪世纪首次成功接种了狂犬病病毒感染疫苗，但由于全球有效的低成本疫苗供应不足，每年约有50，000名患者（主要是儿童）死于狂犬病感染。本文介绍的工作描述了这种基于非复制信使RNA（mRNA）的候选疫苗的保护能力。在这里，我们强调了这种类型的疫苗在高致死性病毒感染小鼠模型中的有效性，并证明了在家猪中诱导可接受的保护相关性。这些结果扩展并加强了我们先前在基于mRNA的疫苗预防流感方面的工作。来自狂犬病和流感研究的数据，以及增加的热稳定性（手稿正在编写中）和预期的生产成本效益表明，基于非复制型mRNA的疫苗是一种有吸引力和有前途的形式，用于开发针对各种传染病的保护性疫苗。
Rabies is a zoonotic infectious disease of the central nervous system (CNS). In unvaccinated or untreated subjects, rabies virus infection causes severe neurological symptoms and is invariably fatal. Despite the long-standing existence of effective vaccines, vaccine availability remains insufficient, with high numbers of fatal infections mostly in developing countries. Nucleic acid based vaccines have proven convincingly as a new technology for the fast development of vaccines against newly emerging pathogens, diseases where no vaccine exists or for replacing already existing vaccines. We used an optimized non-replicating rabies virus glycoprotein (RABV-G) encoding messenger RNA (mRNA) to induce potent neutralizing antibodies (VN titers) in mice and domestic pigs. Functional antibody titers were followed in mice for up to one year and titers remained stable for the entire observation period in all dose groups. T cell analysis revealed the induction of both, specific CD4+ as well as CD8+ T cells by RABV-G mRNA, with the induced CD4+ T cells being higher than those induced by a licensed vaccine. Notably, RABV-G mRNA vaccinated mice were protected against lethal intracerebral challenge infection. Inhibition of viral replication by vaccination was verified by qRT-PCR. Furthermore, we demonstrate that CD4+ T cells are crucial for the generation of neutralizing antibodies. In domestic pigs we were able to induce VN titers that correlate with protection in adult and newborn pigs. This study demonstrates the feasibility of a non-replicating mRNA rabies vaccine in small and large animals and highlights the promises of mRNA vaccines for the prevention of infectious diseases. Although first successful vaccination against rabies virus infection was performed by Louis Pasteur in the 19th century, every year about 50,000 patients, predominantly children, succumb to rabies infection because of insufficient availability of effective low-cost vaccines worldwide. The work presented here describes the protective capacity of such a vaccine candidate based on a non-replicating messenger RNA (mRNA). Here we highlight the efficacy of this type of vaccine in a highly fatal viral infection mouse model and demonstrate the induction of accepted correlates of protection in domestic pigs. The results extend and strengthen our previous work on mRNA-based vaccines protecting against Influenza. The data from Rabies and Influenza studies, together with the increased thermostability (manuscript in preparation) and the conceived cost-effectiveness of production suggest that non-replicating mRNA-based vaccines are an attractive and promising format for the development of protective vaccines against a wide range of infectious diseases.