Determinants of Early Childhood Immune Responses to SARS-CoV-2 Vaccination

幼儿期 SARS-CoV-2 疫苗免疫反应的决定因素

• 批准号: 10715485
• 负责人: Mary Prahl
• 金额: $ 67.05万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-09-20 至 2028-06-30
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10715485
• 关键词: 2019-nCoV; 4 year old; Acute; Adult; Age; Age Months; Antibodies; Antibody Repertoire; Antibody Response; Attenuated; B-Lymphocytes; Birth; Blood specimen; COVID-19; COVID-19 vaccination; COVID-19 vaccine; Characteristics; Child; Clinical Data; Data; Disease; Disease model; Dose; Ensure; Epitope Mapping; Epitopes; Fetus; Flow Cytometry; Future; Hybrids; Immune response; Immunity; Immunization; Immunoglobulin G; Immunologic Memory; Immunologics; Infant; Infection; Length; Life; Masks; Maternal antibody; Memory; Memory B-Lymphocyte; Monoclonal Antibody Therapy; Multisystem Inflammatory Syndrome in Children; Natural Immunity; Passive Transfer of Immunity; Phenotype; Pregnancy; Recommendation; Risk; SARS-CoV-2 antibody; SARS-CoV-2 infection; SARS-CoV-2 inhibitor; Series; Seroprevalences; T cell response; T-Lymphocyte; T-Lymphocyte Subsets; Time; Vaccination; Vaccine Antigen; Vaccinee; Vaccines; age group; age related; aged; antigen-specific T cells; cohort; early childhood; glycosylation; high dimensionality; high risk; immunogenic; in utero; infancy; inhibiting antibody; insight; neutralizing antibody; neutralizing vaccine; pathogen; placental transfer; post SARS-CoV-2 infection; receptor; response; severe COVID-19; time interval; vaccination strategy; vaccine response

Abstract Vaccination strategies for SARS-CoV-2 in young children have not yet fully incorporated their unique immunologic profiles to ensure effective and durable protection. Children often present with milder SARS-CoV- 2 disease than adults but remain at risk for acute COVID-19 and multisystem inflammatory syndrome in children (MIS-C). Roll out of SARS-CoV-2 vaccination was markedly delayed in younger age groups, therefore many young children have been infected with SARS-CoV-2 prior to vaccination. It is currently unknown if young children with prior SARS-CoV-2 infection have differential responses to SARS-CoV-2 vaccination compared to SARS-CoV-2 naïve children and if there is an optimal timing interval to increase durability of protection. From in utero to early childhood to adulthood there is a gradual shift in immune responses from tolerogenic to immunogenic. Infants have attenuated T and B cell responses to some vaccines compared to adults, and often need multiple doses of primary vaccine series. We will leverage a highly-detailed cohort of young children aged 6 months to 4 years old receiving early childhood SARS-CoV-2 immunization. We will use high-dimensional antibody profiling and flow cytometry to perform a detailed characterization of SARS-CoV-2 vaccine-specific immune responses in young children. We hypothesize young children with prior SARS-CoV-2 infection will have more robust and durable SARS-CoV-2 specific cellular and antibody responses to SARS- CoV-2 vaccination compared to previously uninfected. During the first year of life, maternally-derived antibodies (MatAbs) are present in infants and provide partial protection against pathogens during this period of immunologic vulnerability. However, the presence of MatAbs at the time of immunization in infants have been shown to inhibit vaccine responses regardless of vaccination type or platform. Numerous mechanisms have been proposed for this inhibition by MatAbs, including neutralization of vaccine antigen, epitope masking of immunogenic epitopes, or differential Fc function and engagement of inhibitory receptors. Though it is currently unknown if SARS-CoV-2 MatAbs impact infant immune responses. We hypothesize that the MatAbs repertoire will preferentially contain neutralizing antibodies with persistence of SARS-CoV-2 epitope-specific antibodies that will mask SARS-CoV-2 vaccine-specific responses in infants. Together these studies will provide needed insight on SARS-CoV-2 vaccine-specific and hybrid immunity to optimize timing of primary vaccination series including after SARS-CoV-2 infection and potential boosting for young children. Additionally, detailed studies of the characterization and persistence of SARS-CoV-2 MatAbs repertoires will allow new insights into mechanisms underlying protection against SARS-CoV-2 in early infancy and potential inhibition of vaccine responses.

抽象的 SARS-COV-2在幼儿中的疫苗接种策略尚未完全纳入其独特 免疫概况，以确保有效耐用的保护。孩子们经常出现米勒·萨尔斯·托克（Miller Sars-Cov） 2比成人疾病，但仍有急性共卷-19和多系统炎症综合征的风险 儿童（MIS-C）。在年轻年龄段中，SARS-COV-2疫苗接种明显延迟，因此 在接种疫苗之前，许多幼儿已经感染了SARS-COV-2。目前未知是否 患有先前SARS-COV-2感染的幼儿对SARS-COV-2疫苗接种有不同的反应 与SARS-COV-2幼稚儿童相比，如果有最佳的时机间隔以提高耐用性 保护。从子宫到童年到成年，免疫反应的年级转变 对免疫原性的耐受性。婴儿减弱了T和B细胞对某些疫苗的反应 成人，通常需要多剂剂量的原发性疫苗系列。我们将利用高度确定的队列 6个月至4岁的幼儿接受幼儿时期SARS-COV-2免疫。我们将使用 高维抗体分析和流式细胞术，以执行SARS-COV-2的详细表征 幼儿中的疫苗特异性免疫复发。我们假设患有先前SARS-COV-2的幼儿 感染将具有更坚固耐用的SARS-COV-2特异性细胞和对SARS-的抗体反应 与先前未感染的COV-2疫苗接种相比。在生命的第一年，主要衍生 抗体（MATAB）存在于婴儿中，并在此期间对病原体提供部分保护 免疫脆弱性。但是，婴儿免疫时的MATAB存在已有 被证明可以抑制疫苗反应，而与疫苗类型或平台无关。许多机制 已通过MATABS提出了这种抑制作用，包括疫苗抗原的中和表位掩盖 免疫原性表位，或抑制受体的差异FC功能。虽然是 目前尚不清楚SARS-COV-2 MATAB是否会影响婴儿免疫反应。我们假设MATABS 曲目优选包含具有SARS-COV-2特异性持续性的中和抗体 将掩盖婴儿中SARS-COV-2疫苗特异性反应的抗体。这些研究将共同 提供有关SARS-COV-2疫苗特异性和混合免疫学的所需见解，以优化主要的时间 疫苗接种系列包括SARS-COV-2感染后的疫苗和幼儿潜在增强。此外， SARS-COV-2 MATABS曲目的表征和持久性的详细研究将允许新 洞悉婴儿早期对SARS-COV-2保护的机制，并潜在抑制 疫苗反应。