A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys
A Replicating Adenovirus Capsid Display Recombinant Elicits Antibodies against Plasmodium falciparum Sporozoites in Aotus nancymaae Monkeys
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DOI：
10.1128/iai.02626-14
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发表时间：
2015-01-01
影响因子：
3.1
通讯作者：
Ketner, Gary
中科院分区：
文献类型：
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作者：
Karen, Kasey A.;Deal, Cailin;Ketner, Gary
活腺病毒疫苗数十年来的成功表明，复制型重组腺病毒（rAds）可以作为有效的载体，用于免疫其他病原体。为了探索抗疟疾的活rAd疫苗的潜力，我们制备了一种活的腺病毒5（Ad5）重组体，其在病毒体表面上展示来自恶性疟原虫环子孢子蛋白（CSP）的B细胞表位。重组体在小鼠中诱导恶性疟原虫子孢子中和抗体。人腺病毒不能在小鼠体内复制。因此，为了检查系统中的免疫原性，在该系统中，如在人类中，重组复制，我们在腺病毒突变体中构建了一个类似的重组体，该腺病毒突变体在猴细胞中复制并免疫四只Aotus nancymaae猴。重组体在鼻腔滴注后在猴子中复制，这是人类腺病毒在新世界猴子中复制的第一个证明。免疫引发针对疟原虫表位和Ad5载体的抗体。来自所有四只猴子的抗体识别完整寄生虫上的CSP，并且来自一只猴子的血浆在体外中和子孢子，并在被动转移至小鼠后赋予针对恶性疟原虫子孢子感染的部分保护。先前用抗原性野生型腺病毒肠道接种两只动物引发了对随后的肠道内接种的反应，这表明了优化性能的途径。目前还没有针对恶性疟原虫的疫苗，恶性疟原虫是最致命的疟疾，每年造成约100万儿童死亡。这里描述的活衣壳展示重组体可能构成急需的疟疾免疫新方法的早期步骤。
Decades of success with live adenovirus vaccines suggest that replication-competent recombinant adenoviruses (rAds) could serve as effective vectors for immunization against other pathogens. To explore the potential of a live rAd vaccine against malaria, we prepared a viable adenovirus 5 (Ad5) recombinant that displays a B-cell epitope from the circumsporozoite protein (CSP) of Plasmodium falciparum on the virion surface. The recombinant induced P. falciparum sporozoite-neutralizing antibodies in mice. Human adenoviruses do not replicate in mice. Therefore, to examine immunogenicity in a system in which, as in humans, the recombinant replicates, we constructed a similar recombinant in an adenovirus mutant that replicates in monkey cells and immunized four Aotus nancymaae monkeys. The recombinant replicated in the monkeys after intratracheal instillation, the first demonstration of replication of human adenoviruses in New World monkeys. Immunization elicited antibodies both to the Plasmodium epitope and the Ad5 vector. Antibodies from all four monkeys recognized CSP on intact parasites, and plasma from one monkey neutralized sporozoites in vitro and conferred partial protection against P. falciparum sporozoite infection after passive transfer to mice. Prior enteric inoculation of two animals with antigenically wild-type adenovirus primed a response to the subsequent intratracheal inoculation, suggesting a route to optimizing performance. A vaccine is not yet available against P. falciparum, which induces the deadliest form of malaria and kills approximately one million children each year. The live capsid display recombinant described here may constitute an early step in a critically needed novel approach to malaria immunization.