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

摘要 SARS-CoV-2在幼儿中的疫苗接种策略尚未完全纳入其独特的 免疫特征，以确保有效和持久的保护。儿童通常会出现较轻的SARS-CoV， 2疾病比成人，但仍然存在急性COVID-19和多系统炎症综合征的风险， 儿童（MIS-C）。SARS-CoV-2疫苗的推出在年轻群体中明显延迟，因此， 许多幼儿在接种疫苗之前就已经感染了SARS-CoV-2。目前尚不清楚， 有SARS-CoV-2感染史的幼儿对SARS-CoV-2疫苗接种的反应不同 与SARS-CoV-2初治儿童相比，如果存在最佳时间间隔， 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， 致耐受性到免疫原性。婴儿对某些疫苗的T和B细胞反应比 成年人，往往需要多剂量的主要疫苗系列。我们将利用高度详细的队列， 6个月至4岁的幼儿接受SARS-CoV-2免疫接种。我们将使用 高维抗体谱分析和流式细胞术，以进行SARS-CoV-2的详细表征 疫苗特异性免疫反应。我们假设患有SARS-CoV-2的幼儿 感染将对SARS产生更强大和持久的SARS-CoV-2特异性细胞和抗体反应， CoV-2疫苗接种与以前未感染相比。在出生后的第一年， 婴儿体内存在MatAbs抗体，在此期间可提供部分保护以对抗病原体 免疫脆弱性。然而，在婴儿免疫时MatAb的存在， 已经显示出抑制疫苗应答，无论疫苗接种类型或平台如何。众多机制 已经提出了MatAb的这种抑制作用，包括中和疫苗抗原，表位掩蔽， 免疫原性表位，或不同的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是否影响婴儿免疫应答。我们假设MatAb 抗体库将优先包含具有SARS-CoV-2表位特异性持久性的中和抗体 这些抗体将掩盖婴儿对SARS-CoV-2疫苗的特异性反应。这些研究将 提供对SARS-CoV-2疫苗特异性和混合免疫的必要了解，以优化初次免疫的时间 疫苗接种系列，包括SARS-CoV-2感染后和幼儿的潜在加强。此外，本发明还 对SARS-CoV-2 MatAb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SARS-CoV-2的保护机制和潜在的抑制 疫苗反应。

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.