Malaria vaccine evaluation in a novel infant NHP challenge model

新型婴儿 NHP 攻击模型中的疟疾疫苗评估

• 批准号: 10592678
• 负责人: Melanie Janet Shears
• 金额: $ 35.3万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-11-04 至 2024-10-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10592678
• 关键词: Acceleration; Adjuvant; Adult; Age; Animals; Antibodies; Antibody titer measurement; Attenuated; Autopsy; B-Lymphocytes; Blood; Cell physiology; Cells; Cessation of life; Characteristics; Child; Childhood; Clinical Trials; Clinical assessments; Communicable Diseases; Cytotoxic T-Lymphocytes; Data; Development; Disease; Dose; Enrollment; Human; Immune; Immune Tolerance; Immune response; Immune system; Immunity; Immunization; Immunological Models; Immunologics; Individual; Infant; Infection; Intravenous; Licensing; Liver; Longevity; Macaca mulatta; Malaria; Malaria Vaccines; Modeling; Morbidity - disease rate; Nature; Parasites; Peripheral; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phenotype; Plasma; Plasmodium; Plasmodium falciparum vaccine; Plasmodium knowlesi; Population; Research; Research Design; Reverse Transcriptase Polymerase Chain Reaction; Rhesus; Ribosomal RNA; Route; Sampling; Schedule; Shapes; Sporozoite vaccine; Sporozoites; Subunit Vaccines; Symptoms; System; Systems Development; T cell response; T-Lymphocyte; Target Populations; Testing; Tissues; Vaccination; Vaccine Clinical Trial; Vaccines; age effect; age group; age related; cell killing; cohort; diagnostic assay; human model; immunogenicity; infant infection; liver biopsy; malaria infection; malaria transmission; mature animal; mortality; nonhuman primate; novel; peripheral blood; preclinical study; response; transmission process; trend; vaccination outcome; vaccine candidate; vaccine development; vaccine efficacy; vaccine evaluation; vaccine immunogenicity; vaccine response; vaccine strategy; vaccine trial; young adult

PROJECT SUMMARY The objective of this proposal is to develop a novel infant rhesus malaria challenge model and use this model to determine how age impacts immune responses to malaria vaccination and protection at challenge. Malaria, caused by Plasmodium parasites, is responsible for 225 million infections and 400,000 deaths per year. Malaria burden is unevenly distributed by age, with infants and children suffering most. There is currently no licensed malaria vaccine that can provide high level efficacy and reduce transmission in these populations. The most advanced vaccine candidates target the malaria sporozoite and liver stages, which precede the symptomatic blood stage of infection. These include the subunit vaccines RTS,S, R21, and ME-TRAP, and the live-attenuated sporozoite vaccine PfSPZ. These vaccines confer protection by inducing anti-sporozoite antibodies or cytotoxic T cells that kill infected cells in the liver. While these candidates have shown promising vaccine efficacy in adults, age de-escalation trials have revealed vaccine immunogenicity and efficacy vary with age, with a trend for poorer vaccine efficacy in younger infants. This has been attributed to the inherently tolerogenic nature of the infant immune system, which gradually changes as the individual ages and becomes more immunologically mature. Non-human primates (NHPs) are excellent models of the human immune system and pre-clinical studies in adult rhesus macaques have directly informed malaria vaccine clinical trials. For vaccines that induce liver-specific T cell responses, NHPs have been particularly valuable for identifying tissue correlates of protection since the liver is typically inaccessible in vaccine clinical trials. Yet, despite infants and children being the target population for malaria vaccines, there is currently no infant NHP challenge model for malaria vaccine evaluation. This proposal will address this critical gap by establishing a novel infant rhesus malaria challenge model and using it to define the effect of age on immune responses to malaria vaccination and protection at challenge. This model will use the NHP-adapted Plasmodium knowlesi (Pk) malaria parasite and the well-characterized PkSPZ live-attenuated sporozoite vaccine, which is equivalent to the PfSPZ vaccine recently tested in human infants. This vaccine strategy is ideal as it is known to induce antibodies and T cell responses in both the periphery and liver and confer substantial protection in adult rhesus macaques. The study design will age de-escalate and enroll one cohort young adult animals and another of 5-12 month old infants. The hypothesis is that age-dependent differences in peripheral and liver-specific immune responses to vaccination will result in decreased vaccine efficacy in the infants. As it is infeasible to study vaccine-induced T cell responses in the liver of human infants, this study will be the first to assess how the inherent characteristics of the developing infant immune system impact liver T cell responses in a translationally relevant model. These studies aim to launch this novel infant NHP research model and accelerate the development of a highly effective malaria vaccine for human infants.

项目总结