Chikungunya Virus Vaccine Candidates with Decreased Mutational Robustness Are Attenuated In Vivo and Have Compromised Transmissibility
Chikungunya Virus Vaccine Candidates with Decreased Mutational Robustness Are Attenuated In Vivo and Have Compromised Transmissibility
复制标题
DOI：
10.1128/jvi.00775-19
复制
发表时间：
2019-09-01
影响因子：
5.4
通讯作者：
Vignuzzi, Marco
中科院分区：
文献类型：
--
作者：
Carrau, Lucia;Rezelj, Veronica V.;Vignuzzi, Marco
基孔肯雅病毒（Chikungunya virus，CHIKV）是披膜病毒科（Togaviridae）的一种虫媒病毒。它通过主要是伊蚊科的蚊子媒介和哺乳动物宿主传播。CHIKV引起基孔肯雅热，一种以关节痛为特征的轻度至重度疾病，描述了一些致命的结果。在过去几年中，已报告了几次暴发，主要是由于病毒对媒介的适应性增强以及受感染的蚊子种群与人类宿主之间的接触控制不力。疫苗是控制包括CHIKV在内的虫媒病毒的最佳解决方案，但通常无法获得。我们通过应用基于同义密码子的多次替换的合理基因组设计来设计活的减毒CHIKV。在这样做时，病毒突变鲁棒性（尽管向基因型引入突变但维持表型的能力）降低，从而将病毒群体推向有害的进化轨迹。当候选病毒在昆虫和哺乳动物宿主中进行测试时，我们观察到两者的总体强减毒和大大减少的疾病体征。此外，我们发现候选疫苗在单剂量后引起与中和抗体产生相关的保护性免疫。在蚊子和未感染过的小鼠之间的实验性传播周期中，候选疫苗可通过蚊子叮咬传播，导致小鼠无症状感染，传播受损。使用深度测序技术，我们观察到有害（终止）密码子的增加，这证实了这种基因组设计的有效性。由于这种方法涉及数百种对基因组的同义修饰，逆转风险大大降低，使病毒成为有希望的候选疫苗。重要性基孔肯雅热是一种使人衰弱的疾病，会导致关节剧烈疼痛，影响患者数月的生活方式，甚至在某些严重病例中导致死亡。病原体是基孔肯雅病毒，一种通过蚊子叮咬传播的甲病毒。目前，还没有批准的疫苗或治疗方法来对抗这种疾病。在我们的研究中，我们通过应用创新的基因组设计开发了针对基孔肯雅病毒的新型减毒活疫苗候选物。当在昆虫和哺乳动物宿主中进行测试时，候选疫苗不会引起疾病，引起对进一步感染的强烈保护，并且具有低致病性表型逆转的风险。
Chikungunya virus (CHIKV) is a reemerged arbovirus, a member of the Togaviridae family. It circulates through mosquito vectors mainly of the Aedes family and a mammalian host. CHIKV causes chikungunya fever, a mild to severe disease characterized by arthralgia, with some fatal outcomes described. In the past years, several outbreaks mainly caused by enhanced adaptation of the virus to the vector and ineffective control of the contacts between infected mosquito populations and the human host have been reported. Vaccines represent the best solution for the control of insect-borne viruses, including CHIKV, but are often unavailable. We designed live attenuated CHIKVs by applying a rational genomic design based on multiple replacements of synonymous codons. In doing so, the virus mutational robustness (capacity to maintain phenotype despite introduction of mutations to genotype) is decreased, driving the viral population toward deleterious evolutionary trajectories. When the candidate viruses were tested in the insect and mammalian hosts, we observed overall strong attenuation in both and greatly diminished signs of disease. Moreover, we found that the vaccine candidates elicited protective immunity related to the production of neutralizing antibodies after a single dose. During an experimental transmission cycle between mosquitoes and naive mice, vaccine candidates could be transmitted by mosquito bite, leading to asymptomatic infection in mice with compromised dissemination. Using deep-sequencing technology, we observed an increase in detrimental (stop) codons, which confirmed the effectiveness of this genomic design. Because the approach involves hundreds of synonymous modifications to the genome, the reversion risk is significantly reduced, rendering the viruses promising vaccine candidates.IMPORTANCE Chikungunya fever is a debilitating disease that causes severe pain to the joints, which can compromise the patient's lifestyle for several months and even in some grave cases lead to death. The etiological agent is chikungunya virus, an alphavirus transmitted by mosquito bite. Currently, there are no approved vaccines or treatments against the disease. In our research, we developed novel live attenuated vaccine candidates against chikungunya virus by applying an innovative genomic design. When tested in the insect and mammalian host, the vaccine candidates did not cause disease, elicited strong protection against further infection, and had low risk of reversion to pathogenic phenotypes.