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Strains used in whole organism Plasmodium falciparum vaccine trials differ in genome structure, sequence, and immunogenic potential.
Genome Medicine ( IF 12.3 ) Pub Date : 2020-01-08 , DOI: 10.1186/s13073-019-0708-9
Kara A Moser 1, 2 , Elliott F Drábek 1 , Ankit Dwivedi 1 , Emily M Stucke 3 , Jonathan Crabtree 1 , Antoine Dara 3 , Zalak Shah 3 , Matthew Adams 3 , Tao Li 4 , Priscila T Rodrigues 5 , Sergey Koren 6 , Adam M Phillippy 6 , James B Munro 1 , Amed Ouattara 3 , Benjamin C Sparklin 1 , Julie C Dunning Hotopp 1 , Kirsten E Lyke 3 , Lisa Sadzewicz 1 , Luke J Tallon 1 , Michele D Spring 7 , Krisada Jongsakul 7 , Chanthap Lon 7 , David L Saunders 7, 8 , Marcelo U Ferreira 5 , Myaing M Nyunt 3, 9 , Miriam K Laufer 3 , Mark A Travassos 3 , Robert W Sauerwein 10 , Shannon Takala-Harrison 3 , Claire M Fraser 1 , B Kim Lee Sim 4 , Stephen L Hoffman 4 , Christopher V Plowe 3, 9 , Joana C Silva 1, 11
Affiliation  

BACKGROUND Plasmodium falciparum (Pf) whole-organism sporozoite vaccines have been shown to provide significant protection against controlled human malaria infection (CHMI) in clinical trials. Initial CHMI studies showed significantly higher durable protection against homologous than heterologous strains, suggesting the presence of strain-specific vaccine-induced protection. However, interpretation of these results and understanding of their relevance to vaccine efficacy have been hampered by the lack of knowledge on genetic differences between vaccine and CHMI strains, and how these strains are related to parasites in malaria endemic regions. METHODS Whole genome sequencing using long-read (Pacific Biosciences) and short-read (Illumina) sequencing platforms was conducted to generate de novo genome assemblies for the vaccine strain, NF54, and for strains used in heterologous CHMI (7G8 from Brazil, NF166.C8 from Guinea, and NF135.C10 from Cambodia). The assemblies were used to characterize sequences in each strain relative to the reference 3D7 (a clone of NF54) genome. Strains were compared to each other and to a collection of clinical isolates (sequenced as part of this study or from public repositories) from South America, sub-Saharan Africa, and Southeast Asia. RESULTS While few variants were detected between 3D7 and NF54, we identified tens of thousands of variants between NF54 and the three heterologous strains. These variants include SNPs, indels, and small structural variants that fall in regulatory and immunologically important regions, including transcription factors (such as PfAP2-L and PfAP2-G) and pre-erythrocytic antigens that may be key for sporozoite vaccine-induced protection. Additionally, these variants directly contributed to diversity in immunologically important regions of the genomes as detected through in silico CD8+ T cell epitope predictions. Of all heterologous strains, NF135.C10 had the highest number of unique predicted epitope sequences when compared to NF54. Comparison to global clinical isolates revealed that these four strains are representative of their geographic origin despite long-term culture adaptation; of note, NF135.C10 is from an admixed population, and not part of recently formed subpopulations resistant to artemisinin-based therapies present in the Greater Mekong Sub-region. CONCLUSIONS These results will assist in the interpretation of vaccine efficacy of whole-organism vaccines against homologous and heterologous CHMI.

中文翻译:

用于整个有机体恶性疟原虫疫苗试验的菌株在基因组结构、序列和免疫原性潜力方面有所不同。

背景技术在临床试验中,恶性疟原虫(Pf)全有机体子孢子疫苗已被证明可以针对受控人类疟疾感染(CHMI)提供显着的保护。最初的 CHMI 研究显示,针对同源菌株的持久保护明显高于异源菌株,这表明存在菌株特异性疫苗诱导的保护。然而,由于缺乏对疫苗和 CHMI 毒株之间遗传差异以及这些毒株与疟疾流行地区寄生虫的关系的了解,对这些结果的解释以及对其与疫苗功效的相关性的理解受到了阻碍。方法 使用长读长 (Pacific Biosciences) 和短读长 (Illumina) 测序平台进行全基因组测序,为疫苗株 NF54 和异源 CHMI 中使用的菌株(来自巴西的 7G8、NF166.来自几内亚的 C8,以及来自柬埔寨的 NF135.C10)。这些组件用于表征每个菌株中相对于参考 3D7(NF54 的克隆)基因组的序列。对菌株进行了相互比较,并与来自南美洲、撒哈拉以南非洲和东南亚的临床分离株(作为本研究的一部分或来自公共储存库进行测序)进行了比较。结果 虽然 3D7 和 NF54 之间检测到的变异很少,但我们在 NF54 和三个异源菌株之间发现了数万个变异。这些变异包括 SNP、插入缺失和位于调节和免疫学重要区域的小结构变异,包括转录因子(如 PfAP2-L 和 PfAP2-G)和前红细胞抗原,它们可能是子孢子疫苗诱导保护的关键。此外,通过计算机 CD8+ T 细胞表位预测检测到,这些变异直接促进了基因组免疫学重要区域的多样性。在所有异源菌株中,与 NF54 相比,NF135.C10 具有最多数量的独特预测表位序列。与全球临床分离株的比较表明,尽管经过长期的培养适应,这四种菌株仍能代表其地理起源;值得注意的是,NF135.C10 来自混合群体,而不是大湄公河次区域最近形成的对青蒿素疗法耐药的亚群体的一部分。结论 这些结果将有助于解释针对同源和异源 CHMI 的全生物体疫苗的疫苗功效。
更新日期:2020-04-22
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