Highly mutated Omicron sub-lineages JN.1 and NB.1.8.1 harbor extensive spike changes, but their impact in preterm infants is poorly documented. We report a preterm male infant with three hospitalizations in seven weeks: severe SARS-CoV-2 ARDS at 40 days of life (DOL 40) requiring ventilation caused by JN.1.16, HCoV-OC43 infection at DOL 65, and a mild SARS-CoV-2 reinfection at DOL 87 due to NB.1.8.1, the first detection of this variant in Tunisia. Spike analysis showed a shared JN.1 backbone but distinct N-terminal and receptor-binding domain changes, supporting intra-Omicron reinfection driven by antigenic divergence and immature immunity and underscoring the value of pediatric genomic surveillance, including phylogenetic placement of case genomes within local Omicron diversity.