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

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.