Children's first exposures to SARS-CoV-2, whether through infection or vaccination, might shape the specificity of their immune responses to SARS-CoV-2 variants for the rest of their lives. Previous studies on influenza virus infections may inform how childhood SARS-CoV-2 infections affect long-lived immunity. Thomas Francis Jr. coined the phrase "original antigenic sin" in 1960 to describe the observation that antibody responses elicited by childhood influenza virus infections can be recalled later in life upon exposure to antigenically distinct influenza viruses (48). This recall can lead to different patterns of antibody specificity among individuals exposed to the same influenza virus strain. But it remains uncertain whether de novo immune responses to new antigens are diminished by these previous exposures and recalled immune memory. The specificity of antibody responses to influenza virus arises from targeting different epitopes. Often, these responses target epitopes that are conserved between contemporary and childhood viral strains. This bias can be beneficial when antibodies are neutralizing, but potentially detrimental when these epitopes change in the virus, leading to a loss of antibody recognition and greater risk of infection (49). Evidence suggests that variation in risk of medically attended influenza virus infection and vaccine effectiveness between influenza seasons and age groups arises partly from these idiosyncratic interactions with immune memory (50-54).
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