Genome-wide sieve analysis and immunological validation to identify targets of protective efficacy in field trials of a whole-organism malaria vaccine

全基因组筛选分析和免疫学验证，以确定全有机体疟疾疫苗现场试验中的保护功效目标

• 批准号: 10553145
• 负责人: Joana Carneiro da Silva
• 金额: $ 67.16万
• 依托单位: UNIVERSITY OF MARYLAND BALTIMORE
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-01-15 至 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10553145
• 关键词: Acceleration; Address; Affect; Africa; Alleles; Antibody Response; Antigen Targeting; Antigens; Area; Attenuated; Central Africa; Clinical; Data; Development; Disease; Enrollment; Equatorial Guinea; Erythrocytes; Exhibits; Exposure to; Falciparum Malaria; Frequencies; Funding; Future; Gabon; Gene Frequency; Genes; Genetic Variation; Genome; Genomic approach; Genomics; Genotype; Geographic Locations; Geography; Human; Immune Targeting; Immune response; Immune system; Immunity; Immunization; Immunologics; Infection; Infection Control; Kenya; Knowledge; Lead; Malaria; Malaria Vaccines; Metabolic; Outcome; Parasites; Parasitic Diseases; Participant; Peptides; Persons; Plasmodium falciparum; Plasmodium falciparum genome; Plasmodium falciparum vaccine; Population; Proteins; Radiation; Research; Sampling; Single Nucleotide Polymorphism; Specimen; Sporozoites; Subunit Vaccines; T-Lymphocyte Epitopes; Testing; Vaccinee; Vaccines; Validation; Variant; Whole Organism; arm; burden of illness; comparative; comparison control; design; dosage; efficacy trial; experience; fighting; follow-up; genome sequencing; genome-wide; improved; insertion/deletion mutation; malaria infection; protective effect; protective efficacy; reference genome; response; vaccine efficacy; vaccine response; vaccine trial; vaccine-induced antibodies; vaccine-induced immunity; whole genome

Abstract PfSPZ Vaccine, a radiation-attenuated, whole-organism vaccine against P. falciparum (Pf) malaria, based on the Pf NF54 strain, has consistently shown durable, high (>85%) protective efficacy against a homologous parasite strain after controlled human malaria infection (CHMI). This result represents a major milestone in the fight against a disease that kills >400,000 people annually. At current dosages, PfSPZ Vaccine has been shown to have significant but still incomplete protective efficacy against naturally acquired malaria infection, as well as against CHMI with a heterologous strain. The most expedited, informed path to broaden the efficacy of this vaccine relies on the knowledge of the parasite proteins against which the immune system mounts a protective response following immunization with PfSPZ Vaccine. Here, we propose to use parasites, specimen samples and clinical outcomes from the three largest efficacy field trials of PfSPZ Vaccine, to identify and validate parasite protein targets of the vaccine-induced protective immune response. We will generate whole genome sequence (WGS) data from ~400 Pf infections from controls and vaccinees in three field efficacy trials conducted, under separate funding, in Kenya, East Africa, and in Gabon, Central Africa. In AIM 1 we will develop new Pf genome reference assemblies from recently collected strains for East and West Africa, to increase the quality and quantity of sequence variants (SNPs and indels) identified in these clinical samples. In AIM 2, we will use the genome-wide genotype calls in these 400 samples to compare infections in vaccinees vs. controls, in order to identify parasite antigens targeted by PfSPZ Vaccine-induced protective immunity (“target loci”), under the assumption that, in these target loci, allele frequency distributions will differ in malaria infections in the vaccine vs. control arms of field efficacy trials, including a lower frequency of NF54-like alleles in vaccinees than in controls. We will use similar samples from control and vaccine arms of a new PfSPZ Vaccine field trial, to start in Equatorial Guinea in 2018, to validate these results. Finally, in AIM 3, we will conduct a high-throughput immunologic validation of Pf targets of PfSPZ Vaccine-induced protection that will determine whether or not allele-specific efficacy is indeed a phenomenon that impacts whole organism-based vaccines. These results will be used to inform the choice of additional P. falciparum strains with which to design multivalent vaccines with broader efficacy, and hopefully lead to a decrease in disease burden and improve the prospects of malaria eradication. By defining the targets of the immune response to a malaria parasite, this research may also expand our understanding of host immune responses to whole- organism vaccines against parasitic diseases, and accelerate future developments in this field.

摘要 PfSPZ疫苗是一种针对恶性疟原虫（Pf）疟疾的放射减毒全生物疫苗，基于 Pf NF 54菌株始终表现出针对同源病毒的持久、高（>85%）保护功效 控制人类疟疾感染（CHMI）后的寄生虫株。这一结果是一个重要的里程碑， 与每年导致超过40万人死亡的疾病作斗争。在目前的剂量下，PfSPZ疫苗已经 显示出对自然获得的疟疾感染具有显著但仍不完全的保护功效， 以及用异源菌株对抗CHMI。最快速，知情的途径，以扩大疗效 这种疫苗依赖于免疫系统对寄生虫蛋白的了解， PfSPZ疫苗免疫后的保护性应答。在这里，我们建议使用寄生虫， PfSPZ疫苗三项最大有效性田间试验的样本和临床结果， 以鉴定和验证疫苗诱导的保护性免疫应答的寄生虫蛋白靶。 我们将从来自对照组和疫苗接种者的约400例Pf感染中生成全基因组序列（WGS）数据， 在东非肯尼亚和中非加蓬进行了三项田间药效试验， 非洲在AIM 1中，我们将从最近收集的菌株中开发新的Pf基因组参考组件， 和西非，以提高在这些地区发现的序列变异（SNP和indels）的质量和数量。 临床样本。在AIM 2中，我们将使用这400个样本中的全基因组基因型调用来比较 疫苗接种者与对照的感染，以鉴定PfSPZ疫苗诱导的 保护性免疫（“靶基因座”），假设在这些靶基因座中，等位基因频率分布 在田间有效性试验的疫苗组与对照组中， NF 54样等位基因在疫苗接种者中的比例高于对照组。我们将使用来自对照组和疫苗组的类似样本， 一项新的PfSPZ疫苗田间试验将于2018年在赤道几内亚开始，以验证这些结果。最后，在AIM 3、对PfSPZ疫苗诱导保护作用的Pf靶点进行高通量免疫学验证 这将决定等位基因特异性功效是否确实是一种影响整体的现象， 生物疫苗。这些结果将被用来告知其他恶性疟原虫菌株的选择 用它来设计具有更广泛功效的多价疫苗，并有望减少疾病 减轻疟疾负担并改善根除疟疾的前景。通过定义免疫反应的靶点， 疟疾寄生虫，这项研究也可能扩大我们对宿主免疫反应的理解， 生物体疫苗对抗寄生虫病，并加速在这一领域的未来发展。

项目成果

The Hypervariable Tpr Multigene Family of Theileria Parasites, Defined by a Conserved, Membrane-Associated, C-Terminal Domain, Includes Several Copies with Defined Orthology Between Species.

• DOI: 10.1007/s00239-023-10142-z
• 发表时间: 2023-12
• 期刊: Journal of molecular evolution
• 影响因子: 3.9

Malaria in Angola: recent progress, challenges and future opportunities using parasite demography studies.

• DOI: 10.1186/s12936-022-04424-y
• 发表时间: 2022-12-28
• 期刊: MALARIA JOURNAL
• 影响因子: 3
• 作者: Tavares, Wilson;Morais, Joana;Martins, Jose F.;Scalsky, Ryan J.;Stabler, Thomas C.;Medeiros, Marcia M.;Fortes, Filomeno J.;Arez, Ana Paula;Silva, Joana C.
• 通讯作者: Silva, Joana C.