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.

抽象的 PfSPZ 疫苗是一种针对恶性疟原虫 (Pf) 疟疾的辐射减毒全生物体疫苗，基于 Pf NF54 菌株始终表现出针对同源病毒的持久、高 (>85%) 保护功效 受控人类疟疾感染（CHMI）后的寄生虫菌株是该研究的一个重要里程碑。 以目前的剂量，PfSPZ 疫苗已用于对抗每年导致超过 40 万人死亡的疾病。 已显示对自然获得性疟疾感染具有显着但仍不完全的保护功效，如 以及用异源菌株对抗 CHMI 扩大疗效的最快捷、最明智的途径。 这种疫苗依赖于免疫系统针对寄生虫蛋白的了解 使用 PfSPZ 疫苗免疫后的保护性反应在这里，我们建议使用寄生虫， 来自 PfSPZ 疫苗三个最大的功效现场试验的标本样本和临床结果， 识别和验证疫苗诱导的保护性免疫反应的寄生虫蛋白靶标。 我们将从来自对照和疫苗的约 400 个 Pf 感染中生成全基因组序列 (WGS) 数据 在单独资助的情况下，在东非肯尼亚和中部加蓬进行了三项实地功效试验 在 AIM 1 中，我们将从最近收集的东部菌株中开发新的 Pf 基因组参考组件。 和西非，以提高这些地区发现的序列变异（SNP 和插入缺失）的质量和数量 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进行比较。 疫苗感染与对照感染，以确定 PfSPZ 疫苗诱导的寄生虫抗原 保护性免疫（“目标位点”），假设在这些目标位点中，等位基因频率分布 现场疗效试验中疫苗与对照组的疟疾感染情况会有所不同，包括频率较低 我们将使用来自对照组和疫苗组的相似样本。 一项新的 PfSPZ 疫苗现场试验将于 2018 年在赤道几内亚开始，以验证这些结果。 3、我们将对PfSPZ疫苗诱导保护的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 这些结果将用于指导选择其他恶性疟原虫菌株。 以此设计具有更广泛功效的多价疫苗，并有望减少疾病 通过确定针对疟疾的免疫反应目标，减轻负担并改善根除疟疾的前景。 疟疾寄生虫，这项研究还可能扩大我们对宿主免疫反应的理解 寄生虫病生物疫苗，并加速该领域的未来发展。

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.