Lack of ancestral SARS-CoV-2 imprinting promotes Omicron sublineage BA.3.2.2 infection in children

The ongoing SARS-CoV-2 evolution is constrained by population-level immune imprinting. Recent genomic surveillance revealed an unexpected demographic shift with the Omicron sublineage BA.3.2.2 being predominant in paediatric populations globally. Here we show that this paediatric susceptibility arises from the absence of immune imprinting against ancestral SARS-CoV-2 Wuhan strain. Serological analyses reveal a failure to neutralize BA.3.2.2 in young children with no ancestral strain exposure. Single-B-cell sequencing analyses demonstrate that BA.3.2.2 evades Omicron-specific Class 1/4 neutralizing antibodies that target the ACE2-binding site, encoded by immunoglobulin heavy-chain variable (IGHV) germline genes IGHV2-5 and IGHV5-51, which dominate in weakly imprinted individuals. BA.3.2.2 remains susceptible to broadly cross-reactive Class 1 antibodies, encoded by IGHV3-53/66, typically enriched in adults with strong Wuhan-strain imprinting, such as mRNA vaccine recipients. Together, these findings show that classic immune imprinting provides superior protection against a highly divergent variant, explaining the age-biased transmission of BA.3.2.2, and informing future paediatric vaccination strategies. Predominance of the Omicron sublineage BA.3.2.2 in paediatric cohorts results from the absence of vaccine-induced immune imprinting to the ancestral SARS-CoV-2 Wuhan strain, resulting in distinct patterns of immunoglobulin heavy-chain variable region usage in children and adults.