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 幼儿 SARS-CoV-2 的疫苗接种策略尚未完全融入其独特的策略 免疫学特征，以确保有效和持久的保护。儿童通常患有较轻的 SARS-CoV- 2 种疾病比成人多，但仍面临急性 COVID-19 和多系统炎症综合征的风险 儿童（MIS-C）。在较年轻的年龄组中，SARS-CoV-2 疫苗接种的推出明显延迟，因此 许多幼儿在接种疫苗之前就已感染 SARS-CoV-2。目前未知是否 既往感染过 SARS-CoV-2 的幼儿对 SARS-CoV-2 疫苗接种有不同的反应 与未接触过 SARS-CoV-2 的儿童相比，是否存在最佳时间间隔来提高 保护。从子宫内到幼儿期再到成年期，免疫反应逐渐发生变化 耐受性至免疫原性。与婴儿相比，婴儿对某些疫苗的 T 细胞和 B 细胞反应减弱 成人，通常需要多剂初级疫苗系列。我们将利用高度详细的群体 6 个月至 4 岁的幼儿接受幼儿期 SARS-CoV-2 免疫接种。我们将使用 高维抗体分析和流式细胞术对 SARS-CoV-2 进行详细表征 幼儿的疫苗特异性免疫反应。我们假设幼儿曾患有 SARS-CoV-2 感染将对 SARS-CoV-2 产生更强大和持久的 SARS-CoV-2 特异性细胞和抗体反应 与之前未感染的相比，接种了 CoV-2 疫苗。在生命的第一年，母源 抗体 (MatAb) 存在于婴儿体内，并在此期间提供针对病原体的部分保护 免疫脆弱性。然而，婴儿免疫接种时 MatAb 的存在 已被证明可以抑制疫苗反应，无论疫苗接种类型或平台如何。多种机制 已提出通过 MatAb 进行这种抑制，包括中和疫苗抗原、表位掩蔽 免疫原性表位，或差异 Fc 功能和抑制性受体的参与。虽然它是 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 MatAb 曲目将优先包含具有 SARS-CoV-2 表位特异性持久性的中和抗体 能够掩盖婴儿 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所需的见解，以优化初次免疫的时机 疫苗接种系列，包括 SARS-CoV-2 感染后和幼儿的潜在加强疫苗接种。此外， 对 SARS-CoV-2 MatAbs 库的特征和持久性的详细研究将允许新的 深入了解婴儿早期针对 SARS-CoV-2 的保护机制以及潜在的抑制作用 疫苗反应。