<h3>Background</h3> Notwithstanding the wealth of literature on COVID-19, studies focusing on young people with autoimmune diseases (ADs) are lacking. Despite their younger age, they may have been exposed to immunosuppressants (IS) for longer than older adults, particularly if diagnosed at pediatric age. <h3>Objectives</h3> To determine early (within 7 days) and late (after 7 days) anti-SARS-CoV-2 vaccine-related adverse events (AEs), post-vaccine disease flares, COVID-19 severity and breakthrough infections (B-INFs) in young people with rheumatic diseases (RMDs) and non-rheumatic (nr)-ADs compared to healthy controls (HC). <h3>Methods</h3> The EULAR Young PARE definition was used to classify young patients (18-35 years old). Data were captured through the international COVID-19 Vaccination in AD (COVAD) 1 and 2 questionnaires (covering the years 2021 and 2022) and variables differing across groups in univariable analysis were included in multivariable analysis adjusting for baseline factors defined a priori. <h3>Results</h3> Of 20,685 complete responses, 6010 were from young people (1692 RMD, 400 nrADs, 3918 HC). RMDs and nr-ADs comprised mainly females of Caucasian, Asian and Hispanic ethnicities. Before vaccination, &lt;5% and 7% of nrAD were taking glucocorticoids (GC) or immunosuppressants (IS) other than GC vs 30% GC and &gt;80% IS in RMDs. Over 80% of total responders had received ≥2 vaccine doses. 1) AEs after 1 or 2 doses. Early mild AEs were more frequent in RMDs and nr-ADs compared to HC [RMD vs HC odds ratio (OR) (95% confidence interval (CI)) 2.4 (2.0-3.1); nr-AD vs HC 2.0 (1.4-2.9)]. Injection site pain, headache and fatigue were the most frequent mild AE in all 3 groups, but they were more frequent in nr-AD than in HC and RMD. Fever and chills were also more frequent in nr-AD compared to HC and to RMD. The frequency of late mild AEs after either of the 2 doses was &lt; 10% in all 3 groups with no differences between groups. Severe AEs were &lt; 2% in all groups, with no differences between the first and second dose. 2) AEs after 3 or 4 doses. The frequency of late mild AEs after any dose (1, 2 3 or 4) was &lt; 20% in all 3 groups with no differences between groups. Severe AEs after the third dose were &lt;3%. In the 1417 responders that received a fourth dose, only two (1 RMD and 1 HC) reported AEs (0.1%). 3) Pre-vaccine vs breakthrough infections (B-INFs). The frequency of reported SARS-CoV-2 infections was similar in all groups (RMD=28%, nr-ADs=25%, HC=28%). However, RMD patients reported only one infection more frequently than nrADs and HC, while nrADs reported ≥ 2 infections more frequently than RMD. Pre-vaccine infections were less frequent in RMD vs HC (OR=0.6, 95% CI= 0.4-0.9), but similar in nr-AD vs HC. In contrast, the frequency of B-INFs was higher in RMD vs HC (OR=2.7 95% CI 2.1-3.5), while it was similar in nr-AD vs HC. Regarding the clinical profiles of pre-vaccine infections versus B-INFs, no differences were observed among nrADs whereas in RMD a significantly lower frequency of loss of smell and loss of taste was reported for B-INFs. Less than 5% of total respondents received advanced therapies for SARS-CoV-2 infection. 4) Post-vaccination disease flares: Self-reported disease flares after the second vaccine dose were reported by 10% or RMD and 7% of nrAD patients. Of these, approximately half reported requiring a change in their medications (increased dose/addition of a new IS and/or GC). <h3>Conclusion</h3> This study provides the first detailed exploration of the SARS-CoV2 spectrum in young people with RMDs and nrADs compared to HC and highlights important similarities and differences between disease groups. In fact, despite being less exposed to GC and IS, nr-AD reported a higher number of SARS-CoV-2 infections, no difference in the clinical picture of pre-vaccine infections vs B-INFs and a more pronounced burden of post-vaccine mild AEs after earlier doses compared to RMD. These findings may highlight that in young people the type of disease rather than IS therapy may be more important to influence the vaccine safety and the features of B-INFs. <h3>REFERENCES</h3> <b>NIL</b>. <h3>Acknowledgements</h3> <b>NIL</b>. <h3>Disclosure of Interests</h3> Alessia Alunno: None declared, Francesco Carubbi: None declared, Ai Lyn Tan: None declared, Parikshit Sen: None declared, Lorenzo Cavagna: None declared, Mrudula Joshi: None declared, Jessica Day: None declared, Kshitij Jagtap: None declared, Sreoshy Saha: None declared, Carlos Enrique Toro Gutierrez: None declared, Carlo Vinicio Caballero: None declared, Oliver Distler Consultant of: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur., Speakers bureau: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur., Grant/research support from: 4P-Pharma, Abbvie, Acceleron, Alcimed, Altavant, Amgen, AnaMar, Arxx, AstraZeneca, Baecon, Blade, Bayer, Boehringer Ingelheim, Corbus, CSL Behring, Galderma, Galapagos, Glenmark, Gossamer, iQvia, Horizon, Inventiva, Janssen, Kymera, Lupin, Medscape, Merck, Miltenyi Biotec, Mitsubishi Tanabe, Novartis, Prometheus, Redxpharma, Roivant, Sanofi and Topadur., Hector Chinoy: None declared, Rohit Aggarwal Consultant of: Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Kyverna Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant, Merck, Galapagos, Actigraph, Scipher, Horizon Therapeutics, Teva, Beigene, ANI Pharmaceuticals, Biogen, Nuvig, Capella Bioscience, and CabalettaBio., Grant/research support from: Bristol Myers-Squibb, Pfizer, Genentech, Octapharma, CSL Behring, Mallinckrodt, AstraZeneca, Corbus, Kezar, Abbvie, Janssen, Kyverna Alexion, Argenx, Q32, EMD-Serono, Boehringer Ingelheim, Roivant, Merck, Galapagos, Actigraph, Scipher, Horizon Therapeutics, Teva, Beigene, ANI Pharmaceuticals, Biogen, Nuvig, Capella Bioscience, and CabalettaBio., Vikas Agarwal: None declared, Latika Gupta: None declared.