Abstract Introduction Seasonal influenza A (H3N2) virus is an important cause of morbidity and mortality in the last 50 years in population that is greater than the impact of H1N1. Data assessing immunogenicity and safety of this virus component in juvenile systemic lupus erythematosus (JSLE) is lacking in the literature. Objective To evaluate short-term immunogenicity and safety of influenza A/Singapore (H3N2) vaccine in JSLE. Methods 24 consecutive JSLE patients and 29 healthy controls (HC) were vaccinated with influenza A/Singapore/ INFIMH-16-0019/2016(H3N2)-like virus. Influenza A (H3N2) seroprotection (SP), seroconversion (SC), geometric mean titers (GMT), factor increase in GMT (FI-GMT) titers were assessed before and 4 weeks post-vaccination. Disease activity, therapies and adverse events (AE) were also evaluated. Results JSLE patients and controls were comparable in current age [14.5 (10.1–18.3) vs. 14 (9–18.4) years, p = 0.448] and female sex [21 (87.5%) vs. 19 (65.5%), p = 0.108]. Before vaccination, JSLE and HC had comparable SP rates [22 (91.7%) vs. 25 (86.2%), p = 0.678] and GMT titers [102.3 (95% CI 75.0–139.4) vs. 109.6 (95% CI 68.2–176.2), p = 0.231]. At D30, JSLE and HC had similar immune response, since no differences were observed in SP [24 (100%) vs. 28 (96.6%), p = 1.000)], SC [4 (16.7%) vs. 9 (31.0%), p = 0.338), GMT [162.3 (132.9–198.3) vs. 208.1 (150.5–287.8), p = 0.143] and factor increase in GMT [1.6 (1.2–2.1) vs. 1.9 (1.4–2.5), p = 0.574]. SLEDAI-2K scores [2 (0–17) vs. 2 (0–17), p = 0.765] and therapies remained stable throughout the study. Further analysis of possible factors influencing vaccine immune response among JSLE patients demonstrated similar GMT between patients with SLEDAI < 4 compared to SLEDAI ≥ 4 ( p = 0.713), as well as between patients with and without current use of prednisone ( p = 0.420), azathioprine ( p = 1.0), mycophenolate mofetil ( p = 0.185), and methotrexate ( p = 0.095). No serious AE were reported in both groups and most of them were asymptomatic (58.3% vs. 44.8%, p = 0.958). Local and systemic AE were alike in both groups ( p > 0.05). Conclusion This is the first study that identified adequate immune protection against H3N2-influenza strain with additional vaccine-induced increment of immune response and an adequate safety profile in JSLE. ( www.clinicaltrials.gov , NCT03540823). H3N2 HN H N (H3N2 5 H1N1 (JSLE literature shortterm short term ASingapore Singapore (HC INFIMH160019/2016H3N2like INFIMH1600192016H3N2like INFIMHHNlike INFIMH 16 0019/2016 like 0019 2016 SP, (SP) SC, (SC) GMT, (GMT) FIGMT FI (FI-GMT postvaccination. postvaccination post vaccination. vaccination post-vaccination activity (AE evaluated 14.5 145 [14. 10.1–18.3 101183 10 1 18 3 (10.1–18.3 vs 9–18.4 9184 (9–18.4 0.448 0448 0 448 21 87.5% 875 87 (87.5% 65.5%, 655 65.5% 65 (65.5%) 0.108. 0108 0.108 . 108 0.108] 22 91.7% 917 91 7 (91.7% 86.2%, 862 86.2% 86 (86.2%) 0.678 0678 678 102.3 1023 102 [102. 95% 95 (95 75.0–139.4 7501394 75 139 1096 109 6 109. 68.2–176.2, 6821762 68.2–176.2 68 176 68.2–176.2) 0.231. 0231 0.231 231 0.231] D30 D 100% 100 (100% 96.6%, 966 96.6% 96 (96.6%) 1.000, 1000 1.000 000 1.000)] [ 16.7% 167 (16.7% 31.0%, 310 31.0% 31 (31.0%) 0.338, 0338 0.338 338 0.338) 162.3 1623 162 [162. 132.9–198.3 13291983 132 198 (132.9–198.3 2081 208 208. 150.5–287.8, 15052878 150.5–287.8 150 287 8 (150.5–287.8) 0.143 0143 143 1.6 [1. 1.2–2.1 1221 (1.2–2.1 1. 1.4–2.5, 1425 1.4–2.5 (1.4–2.5) 0.574. 0574 0.574 574 0.574] SLEDAI2K SLEDAIK 2K K 0–17 017 17 (0–17 0–17, 0.765 0765 765 0.713, 0713 0.713 713 0.713) 0.420, 0420 0.420 420 0.420) 1.0, 1.0 1.0) 0.185, 0185 0.185 185 0.185) 0.095. 0095 0.095 095 0.095) 58.3% 583 58 (58.3 44 44.8% 0.958. 0958 0.958 958 0.958) 0.05. 005 0.05 05 0.05) H3N2influenza HNinfluenza vaccineinduced induced wwwclinicaltrialsgov www clinicaltrials gov NCT03540823. NCT03540823 NCT NCT03540823) H3N (H3N H1N INFIMH160019 2016H3N2like 00192016 0019/201 001 201 (SP (SC (GMT 14. [14 10.1–18. 10118 (10.1–18. 9–18. 918 (9–18. 0.44 044 87.5 (87.5 65.5 (65.5% 010 0.10 91.7 (91.7 86.2 (86.2% 0.67 067 67 102. [102 (9 75.0–139. 750139 13 682176 68.2–176. 023 0.23 23 D3 (100 96.6 (96.6% 1.00 00 1.000) 16.7 (16.7 31.0 (31.0% 033 0.33 33 162. [162 132.9–198. 1329198 (132.9–198. 20 1505287 150.5–287. 15 (150.5–287.8 0.14 014 [1 1.2–2. 122 (1.2–2. 142 1.4–2. (1.4–2.5 057 0.57 57 0–1 01 (0–1 0.76 076 76 071 0.71 71 042 0.42 42 018 0.18 009 0.09 09 58.3 (58. 44.8 0.95 0.0 NCT0354082 INFIMH16001 HNlike 0019201 0019/20 10.1–18 1011 (10.1–18 9–18 (9–18 0.4 04 87. (87. 65. (65.5 0.1 91. (91. 86. (86.2 0.6 06 [10 75.0–139 75013 68217 68.2–176 02 0.2 (10 96. (96.6 16. (16. 31. (31.0 03 0.3 [16 132.9–198 132919 (132.9–198 150528 150.5–287 (150.5–287. 1.2–2 12 (1.2–2 1.4–2 (1.4–2. 0.5 0– (0– 0.7 07 58. (58 44. 0.9 0. NCT035408 INFIMH1600 001920 0019/2 10.1–1 101 (10.1–1 9–1 (9–1 (87 (65. (91 (86. 75.0–13 7501 6821 68.2–17 (1 (96. (16 (31. 132.9–19 13291 (132.9–19 15052 150.5–28 (150.5–287 1.2– (1.2– 1.4– (1.4–2 (0 (5 NCT03540 INFIMH160 00192 0019/ 10.1– (10.1– 9– (9– (8 (65 (86 75.0–1 750 682 68.2–1 (96 (31 132.9–1 1329 (132.9–1 1505 150.5–2 (150.5–28 1.2 (1.2 1.4 (1.4– NCT0354 INFIMH16 10.1 (10.1 (6 75.0– 68.2– (3 132.9– (132.9– 150.5– (150.5–2 (1. (1.4 NCT035 INFIMH1 10. (10. 75.0 68.2 132.9 (132.9 150.5 (150.5– NCT03 75. 68. 132. (132. 150. (150.5 NCT0 (132 (150. (13 (150 (15