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Multisystem inflammatory syndrome in children (MIS-C) is a severe SARS-CoV-2-associated condition that shares clinical features with Kawasaki disease (KD), characterised by a distinct polyclonal expansion of Vβ21.3+ T cells. We report five patients diagnosed with breakthrough MIS-C despite COVID-19 immunisation, all within a limited time period at the beginning of the Omicron wave, to assess whether breakthrough MIS-C cases share the same TCR Vβ21.3 skewing seen in non-vaccinated MIS-C cases. We retrospectively reviewed five MIS-C patients hospitalised between December 2021 and April 2022 despite previous immunisation against SARS-CoV-2 (BNT162b2, an mRNA vaccine against S-protein). Immunophenotyping, including TCR Vβ subset distribution, was performed in four patients.Patients (100% male, 12.2–17.2 years) had a natural breakthrough SARS-CoV-2 infection following prior immunisation (between August 2021 and February 2022). Recent infection was proven by positive SARS-CoV-2 PCR and/or IgG antibodies against the nucleocapsid protein. Blood samples of four patients were available. All presented with Vβ21.3+ T cell expansion, similar to MIS-C patients and in contrast to vaccinated historical KD patients (n=10). The two patients with the earliest sampling post-illness displayed frequencies of Vβ21.3+ T cells exceeding the reference mean value+10×SD. These Vβ21.3+ T cells showed increased surface expression of activation (HLA-DR, CD38) and exhaustion (PD-1, TIM-3) markers.In conclusion, breakthrough MIS-C patients presented with features consistent with unvaccinated MIS-C patients, including the hallmark Vβ21.3+ T cell expansion, indicating that prior immunisation with an mRNA vaccine targeting the Wuhan strain did not fully protect against MIS-C at the wave of a novel emerging variant early 2022. Trial registration number: NL41023.018.12.