Blood taken from a small group of children before the COVID-19 pandemic contains memory B cells that bind SARS-CoV-2 and weakly cross-react with other coronaviruses, a new study finds, while adult blood and tissue showed few such cells. "Further study of the role of cross-reactive memory B cell populations... will be important for ongoing improvement of vaccines to SARS-CoV-2, its viral variants, and other pathogens," the authors say. As the COVID-19 pandemic has continued, children have often exhibited faster viral clearance and lower viral antigen loads than adults; whether B cell repertoires against SARS-CoV-2 (and other pathogens) differ between children and adults, contributing to differential responses, remains unknown. More broadly, it is still unclear how B cell memory to different antigens distributes in human tissues and changes during an individual's lifespan. To study this, Fan Yang et al. analyzed blood samples taken from pre-pandemic children and pre-pandemic adults. They also studied blood and tissue samples from deceased organ donors. The authors analyzed B cell receptor (BCR) repertoires - which reveal the antigen a B cell targets - specific to six common pathogens as well as two viruses the participants had not encountered before: Ebola virus and SARS-CoV-2. In comparison to adults, pre-pandemic children not only had higher frequencies of convergent (shared) B cell clones in their blood for pathogens they have encountered, but also higher frequencies of class-switched convergent B cell clones against SARS-CoV-2 and its viral variants. Adult blood and tissues showed few such clones. Notably, neither children nor adults had many BCRs for Ebola virus, highlighting the contrast to SARS-CoV-2 and other human coronaviruses commonly encountered prior to the current pandemic. "We hypothesize that previous [coronavirus] exposures may stimulate cross-reactive memory, and that such clonal responses may have their highest frequencies in childhood," the authors say. The results highlight the prominence of early childhood B cell clonal expansions and cross-reactivity for future responses to novel pathogens.