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

摘要 针对幼儿的SARS-CoV-2疫苗接种策略尚未完全纳入他们独特的 免疫档案，以确保有效和持久的保护。儿童通常携带较轻微的SARS-CoV- 2疾病比成年人更多，但仍有患急性新冠肺炎和多系统炎症综合征的风险 儿童(管理信息系统C)。因此，在年轻群体中推出SARS-CoV-2疫苗的时间明显推迟 许多幼儿在接种疫苗之前就感染了SARS-CoV-2。目前尚不清楚是否 既往感染SARS-CoV-2的幼儿对接种SARS-CoV-2疫苗的反应不同 与SARS-CoV-2幼稚的儿童相比，如果有一个最佳的时间间隔来增加耐久性 保护。从子宫内到儿童早期到成年，免疫反应逐渐转变为 从耐受性到免疫性。婴儿对某些疫苗的T和B细胞反应减弱 成人，经常需要多剂初级疫苗系列。我们将利用一组高度详细的 6个月至4岁的幼儿接受儿童早期SARS-CoV-2免疫。我们将使用 高维抗体图谱和流式细胞术对SARS-CoV-2进行详细表征 幼儿的疫苗特异性免疫反应。我们假设患有SARS-CoV-2病毒的儿童 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- 接种CoV-2疫苗与以前未感染的比较。在生命的第一年，母亲衍生的 抗体(MatAbbs)存在于婴儿体内，并在此期间对病原体提供部分保护 免疫易损性。然而，在婴儿免疫时存在的MatAbs具有 经证明，无论接种类型或接种平台如何，都会抑制疫苗反应。无数的机制 已经提出了通过MatAbs来抑制这种作用，包括中和疫苗抗原、表位掩蔽 免疫原性表位的差异，或Fc功能的差异和抑制性受体的结合。尽管它是 目前尚不清楚SARS-CoV-2 MatAbbs是否会影响婴儿的免疫反应。我们假设MatAbbs 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 将在婴儿中掩盖SARS-CoV-2疫苗特异性反应的抗体。这些研究将结合在一起 对SARS-CoV-2疫苗的特异性和混合免疫提供必要的见解，以优化初选时间 疫苗接种系列，包括SARS-CoV-2感染后的疫苗接种和对幼儿的潜在强化接种。另外， 对SARS-CoV-2MatAbs特征和持久性的详细研究将允许新的 对婴儿早期对SARS-CoV-2潜在保护机制的洞察和潜在的抑制 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.