Safety and Cross‐Reactive Immunity Against SARS‐CoV‐2 Omicron Sub‐Variant After a Booster Dose with SOBERANA ® Plus in Children and Adolescents

Background: With the emergence of SARS-CoV-2 Omicron sub-variants exhibiting in-creased transmissibility and immune escape, booster immunization is recommended. Ideally, vaccination across all age groups, including children and adolescents, is critical to control viral spread and reduce variant emergence. The heterologous three-dose regimen of SOBERANA® 02 and SOBERANA® Plus—protein subunit vaccines based on the orig-inal RBD—has proven safe, immunogenic, and effective in pediatric populations as a primary series. This study evaluated the safety and immunogenicity of a SOBERANA® Plus booster dose administered six months after primary vaccination in individuals aged 3–18 years. Methods: In this follow-up analysis of a phase I/II trial, 244 participants re-ceived the SOBERANA® Plus booster. Safety was monitored via active surveillance at 1 hour, 24 hours, and over 28 days post-vaccination. Humoral responses were assessed 28 days post-booster. All serum samples were tested for antibodies against the SARS-CoV-2 nucleocapsid (N) protein. Results: Adverse events occurred in 18% of participants, pre-dominantly local (85.2%) versus systemic (14.8%); no serious or severe adverse events were reported. All humoral response parameters increased significantly post-booster, in-cluding neutralizing antibodies against D614G and Omicron BA.1, with similar respons-es in N-negative and N-positive individuals. Importantly, cross-neutralizing activity against recent Omicron sub-variants (XBB.1.5 and EG.5.1) was also detected. Conclusions: A SOBERANA® Plus booster is safe and significantly enhances cross-reactive neutraliz-ing immunity against evolving Omicron sub-variants in children and adolescents. These results highlight the potential of first-generation RBD-based vaccines to sustain broad immune protection despite viral evolution.