A Vaccine Platform against Arenaviruses Based on a Recombinant Hyperattenuated Mopeia Virus Expressing Heterologous Glycoproteins
A Vaccine Platform against Arenaviruses Based on a Recombinant Hyperattenuated Mopeia Virus Expressing Heterologous Glycoproteins
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DOI：
10.1128/jvi.02230-17
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发表时间：
2018-06-01
影响因子：
5.4
通讯作者：
Baize, Sylvain
中科院分区：
文献类型：
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作者：
Carnec, Xavier;Mateo, Mathieu;Baize, Sylvain
几种旧大陆和新大陆沙粒病毒引起严重的地方性和流行性出血热，而沙粒病毒科的其他成员是非致病性的。到目前为止，除了朱宁病毒外，还没有批准的疫苗、抗病毒药或特定的治疗方法。然而，通过在用拉沙热病毒（LASV）攻击之前接种密切相关但非致病性的莫佩亚病毒（MOPV），可以保护非人灵长类动物免受拉沙热病毒（LASV）的侵害。我们推断，这种通过反向遗传学修饰的病毒将代表产生针对LASV和其他致病性沙粒病毒的疫苗平台的基础。在显示MOPV NP中的核糖核酸外切酶（ExoN）活性的证据后，我们发现这种活性对于抗原呈递细胞中的增殖是必需的。在MOPV NP的ExoN位点中引入多个突变产生了超减毒株（MOPVExoN6b），其（i）在传代过程中遗传稳定，（ii）与MOPV相比具有增加的免疫原性，和（iii）仍然促进强的I型干扰素（IFN）应答。进一步修饰MOPVExoN6b以携带异源致病性沙粒病毒（如LASV或Lujo、Machupo、Guanarito、Chapare或Sabia病毒）的包膜糖蛋白，以拓宽特异性抗原性，同时保留亲本菌株的超减毒特征。我们基于MOPV的LASV候选疫苗MOPEVAC（LASV）用于非人灵长类动物的一次性免疫试验，并完全保护它们免受LASV的致命攻击。因此，我们的超减毒株的MOPV构成了一个有前途的新的减毒活疫苗平台，免疫对几个，如果不是所有的，致病性沙粒病毒。重要性沙粒病毒是新兴的病原体传播给人类的啮齿动物和负责地方性和流行性出血热的全球关注。与感染开始相关的非特异性症状使得这些病毒难以与其他地方病病原体区分。此外，现场快速诊断的不可用性延迟了病毒的识别和早期治疗护理，并有利于传播。对接触人群进行疫苗接种将大大有助于减少发病率和人与人之间的传播。使用反向遗传学，我们基于非致病性Mopeia病毒的改良和超减毒株生成了致病性沙粒病毒的疫苗平台，并表明拉沙病毒候选物完全保护非人灵长类动物免受致命挑战。这些结果表明，合理设计的重组MOPV疫苗在非人灵长类动物中是安全的、免疫原性的和有效的。
Several Old World and New World arenaviruses are responsible for severe endemic and epidemic hemorrhagic fevers, whereas other members of the Arenaviridae family are nonpathogenic. To date, no approved vaccines, antivirals, or specific treatments are available, except for Junin virus. However, protection of non-human primates against Lassa fever virus (LASV) is possible through the inoculation of the closely related but nonpathogenic Mopeia virus ( MOPV) before challenge with LASV. We reasoned that this virus, modified by using reverse genetics, would represent the basis for the generation of a vaccine platform against LASV and other pathogenic arenaviruses. After showing evidence of exoribonuclease (ExoN) activity in NP of MOPV, we found that this activity was essential for multiplication in antigen-presenting cells. The introduction of multiple mutations in the ExoN site of MOPV NP generated a hyperattenuated strain (MOPVExoN6b) that is (i) genetically stable over passages, (ii) has increased immunogenic properties compared to those of MOPV, and (iii) still promotes a strong type I interferon (IFN) response. MOPVExoN6b was further modified to harbor the envelope glycoproteins of heterologous pathogenic arenaviruses, such as LASV or Lujo, Machupo, Guanarito, Chapare, or Sabia virus in order to broaden specific antigenicity while preserving the hyperattenuated characteristics of the parental strain. Our MOPV-based vaccine candidate for LASV, MOPEVAC(LASV), was used in a one-shot immunization assay in nonhuman primates and fully protected them from a lethal challenge with LASV. Thus, our hyperattenuated strain of MOPV constitutes a promising new live-attenuated vaccine platform to immunize against several, if not all, pathogenic arenaviruses.IMPORTANCE Arenaviruses are emerging pathogens transmitted to humans by rodents and responsible for endemic and epidemic hemorrhagic fevers of global concern. Nonspecific symptoms associated with the onset of infection make these viruses difficult to distinguish from other endemic pathogens. Moreover, the unavailability of rapid diagnosis in the field delays the identification of the virus and early care for treatment and favors spreading. The vaccination of exposed populations would be of great help to decrease morbidity and human-to-human transmission. Using reverse genetics, we generated a vaccine platform for pathogenic arenaviruses based on a modified and hyperattenuated strain of the nonpathogenic Mopeia virus and showed that the Lassa virus candidate fully protected nonhuman primates from a lethal challenge. These results showed that a rationally designed recombinant MOPV-based vaccine is safe, immunogenic, and efficacious in nonhuman primates.