Background: To explore the long-term safety and dynamics of the immune response induced by the second and third doses of the BNT162b2 mRNA COVID-19 vaccine in adolescents with juvenile-onset autoimmune inflammatory rheumatic diseases (AIIRD) compared with healthy controls. Methods: This international prospective study included adolescents with AIIRD and controls vaccinated with two (AIIRD n=124; controls n=80) or three (AIIRD n=64; controls n=30) doses of the BNT162b2 vaccine, evaluated for vaccine side-effects, disease activity, COVID-19 breakthrough infection rates and severity, and anti-spike S1/S2 IgG antibody titres in a sample from both groups. Results: The vaccination safety profile was favourable, with most patients reporting mild or no side-effects. The rheumatic disease remained stable among 98% and 100% after the second and third doses, respectively. The two-dose vaccine induced comparable seropositivity rates among patients (91%) and controls (100%), (p=0.55), which declined within 6 months to 87% and 100%, respectively (p=0.3), and increased to 100% in both groups, after the third vaccine dose. The overall post-vaccination COVID-19 infection rate was comparable between patients and controls, 47.6% (n=59) and 35% (n=28), respectively; p=0.5278, with most infections occurring during the Omicron surge. In relation to the last vaccination, time-to-COVID-19 infection was similar between patients and controls, at a median of 5.5 vs. 5.2 months, respectively (log-rank p=0.1555). Conclusion: The safety profile of three doses of the BNT162b2 mRNA vaccine was excellent, with an adequate humoral response and similar efficacy among patients and controls. These results support the recommendation for vaccinating adolescents with juvenile-onset AIIRD against COVID-19.