{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,17]],"date-time":"2026-10-17T03:13:18Z","timestamp":1792206798070,"version":"4.4.0"},"reference-count":25,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T00:00:00Z","timestamp":1764201600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100008807","name":"Ministry of Science, Technology and Environment","doi-asserted-by":"crossref","award":["2020\u201320"],"award-info":[{"award-number":["2020\u201320"]}],"id":[{"id":"10.13039\/501100008807","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background: With the emergence of SARS-CoV-2 Omicron sub-variants exhibiting increased 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 scheme consisting of two doses of SOBERANA\u00ae 02 followed by a third dose of SOBERANA\u00ae Plus, which are recombinant protein subunit vaccines constructed from the ancestral RBD, has proven safety, immunogenicity, and effectiveness in pediatric populations as primary series. This study evaluated the safety and immunogenicity of a SOBERANA\u00ae Plus booster dose administered six months after primary vaccination in individuals aged 3\u201318 years. Methods: In this follow-up analysis of a phase I\/II trial, 244 participants received the booster. Safety was monitored via active surveillance at 1 h, 24 h, and over 28 days post-vaccination. Humoral responses were assessed 28 days post-booster. Antibody responses to the SARS-CoV-2 nucleocapsid (N) protein were assessed in all collected serum samples. Results: Adverse events occurred in 18% of participants, predominantly local (85.2%) versus systemic (14.8%); no serious or severe adverse events were reported. All humoral response parameters increased significantly post-booster, including neutralizing antibodies against D614G (24.7-fold increase) and Omicron BA.1 (55.9-fold increase), with similar responses 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\u00ae Plus booster is safe and significantly enhances cross-neutralizing immunity against evolving Omicron sub-variants in children and adolescents. These results highlight the potential of first-generation RBD-based vaccines to maintain broad immunity despite viral evolution.<\/jats:p>","DOI":"10.3390\/vaccines13121198","type":"journal-article","created":{"date-parts":[[2025,11,27]],"date-time":"2025-11-27T10:25:16Z","timestamp":1764239116000},"page":"1198","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Safety and Cross-Neutralizing Immunity Against SARS-CoV-2 Omicron Sub-Variant After a Booster Dose with SOBERANA\u00ae Plus in Children and Adolescents"],"prefix":"10.3390","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-2099-1791","authenticated-orcid":false,"given":"Dagmar","family":"Garc\u00eda-Rivera","sequence":"first","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Meiby","family":"Rodr\u00edguez-Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Beatriz","family":"Paredes-Moreno","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rinaldo","family":"Puga-Gomez","sequence":"additional","affiliation":[{"name":"Pediatric Hospital \u201cJuan Manuel M\u00e1rquez\u201d, Havana 11500, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yariset","family":"Ricardo-Delgado","sequence":"additional","affiliation":[{"name":"Pediatric Hospital \u201cJuan Manuel M\u00e1rquez\u201d, Havana 11500, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carmen Valenzuela","family":"Silva","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5329-5971","authenticated-orcid":false,"given":"Sonsire","family":"Fern\u00e1ndez-Castillo","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1657-6130","authenticated-orcid":false,"given":"Rocmira","family":"P\u00e9rez-Nicado","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laura","family":"Rodr\u00edguez-Noda","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Darielys","family":"Santana-Mederos","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yanet","family":"Climent-Ruiz","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Enrique","family":"Noa-Romero","sequence":"additional","affiliation":[{"name":"National Civil Defense Research Laboratory, San Jos\u00e9 de las Lajas 32700, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Otto","family":"Cruz-Sui","sequence":"additional","affiliation":[{"name":"National Civil Defense Research Laboratory, San Jos\u00e9 de las Lajas 32700, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Belinda","family":"S\u00e1nchez-Ram\u00edrez","sequence":"additional","affiliation":[{"name":"Center for Molecular Immunology, 15th Ave. and 216 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tays","family":"Hern\u00e1ndez-Garc\u00eda","sequence":"additional","affiliation":[{"name":"Center for Molecular Immunology, 15th Ave. and 216 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ariel","family":"Palenzuela-Diaz","sequence":"additional","affiliation":[{"name":"Center of Immunoassays, 134 and 25 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yury","family":"Vald\u00e9s-Balb\u00edn","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Vicente G.","family":"V\u00e9rez-Bencomo","sequence":"additional","affiliation":[{"name":"Finlay Vaccine Institute, 200 and 21 Street, Havana 11600, Cuba"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,11,27]]},"reference":[{"key":"ref_1","unstructured":"WHO (2025, March 14). COVID-19 Weekly Epidemiological Update-12 March 2025. Available online: https:\/\/www.who.int\/publications\/m\/item\/covid-19-epidemiological-update-edition-177."},{"key":"ref_2","unstructured":"WHO (2025, March 14). COVID-19 Advice for the Public: Getting Vaccinated. Available online: https:\/\/www.who.int\/emergencies\/diseases\/novel-coronavirus-2019\/covid-19-vaccines\/advice."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1151","DOI":"10.1001\/jamapediatrics.2021.2770","article-title":"Association of age and pediatric household transmission of SARS-CoV-2 infection","volume":"175","author":"Paul","year":"2021","journal-title":"JAMA Pediatr."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"666","DOI":"10.1016\/S1473-3099(24)00157-9","article-title":"The era of SARS-CoV-2 variants calls for an urgent strategy for COVID-19 vaccination in children","volume":"24","author":"Li","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"760","DOI":"10.1016\/j.medj.2022.08.001","article-title":"Safety and immunogenicity of anti-SARS-CoV-2 heterologous scheme with SOBERANA 02 and SOBERANA Plus vaccines: Phase IIb clinical trial in adults","volume":"3","year":"2022","journal-title":"Med"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"e2310302","DOI":"10.1001\/jamanetworkopen.2023.10302","article-title":"Efficacy and Safety of a protein-based SARS-CoV-2 vaccine. A randomized clinical trial","volume":"6","author":"Mostafavi","year":"2023","journal-title":"JAMA Netw. Open"},{"key":"ref_7","first-page":"100423","article-title":"Safety and efficacy of the two doses conjugated protein-based SOBERANA-02 COVID-19 vaccine and of a heterologous three-dose combination with SOBERANA PLUS: Double-blind, randomized, placebo-controlled phase 3 clinical trial","volume":"18","author":"Romero","year":"2023","journal-title":"Lancet Reg. Health\u2014Am."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"164","DOI":"10.1016\/j.ijid.2022.11.016","article-title":"Open label phase I\/II clinical trial of SARS-CoV-2 receptor binding domain-tetanus toxoid conjugate vaccine (FINLAY-FR-2) in combination with receptor binding domain-protein vaccine (FINLAY-FR-1A) in children","volume":"126","year":"2023","journal-title":"Int. J. Infect. Dis."},{"key":"ref_9","doi-asserted-by":"crossref","unstructured":"P\u00e9rez-Nicado, R., Massa, C., Rodr\u00edguez-Noda, L.M., M\u00fcller, A., Puga-G\u00f3mez, R., Ricardo-Delgado, Y., Paredes-Moreno, B., Rodr\u00edguez-Gonz\u00e1lez, M., Garc\u00eda-Ferrer, M., and Palmero-\u00c1lvarez, I. (2023). Comparative Immune Response after Vaccination with SOBERANA\u00ae 02 and SOBERANA\u00ae plus Heterologous Scheme and Natural Infection in Young Children. Vaccines, 11.","DOI":"10.20944\/preprints202309.0564.v1"},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"100595","DOI":"10.1016\/j.jvacx.2024.100595","article-title":"Safety and durability of the immune response after vaccination with the heterologous schedule of anti-COVID-19 vaccines SOBERANA\u00ae02 and SOBERANA\u00ae Plus in children 3\u201318 years old","volume":"22","author":"Silva","year":"2025","journal-title":"Vaccine X"},{"key":"ref_11","first-page":"100750","article-title":"Real-world effectiveness of the heterologous SOBERANA-02 and SOBERANA-Plus vaccine scheme in 2\u201311 years-old children during the SARS-CoV-2 Omicron wave in Cuba: A longitudinal case-population study","volume":"34","year":"2024","journal-title":"Lancet Reg. Health\u2014Am."},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"77","DOI":"10.15585\/mmwr.mm7304a2","article-title":"Early estimates of updated 2023\u20132024 (monovalent XBB.1.5) COVID-19 vaccine effectiveness against symptomatic SARS-CoV-2 infection attributable to co-circulating Omicron variants among immunocompetent adults\u2014Increasing Community Access to Testing Program, United States, September 2023\u2013January 2024","volume":"73","author":"Ciesla","year":"2024","journal-title":"MMWR Morb. Mortal. Wkly. Rep."},{"key":"ref_13","unstructured":"Schmidt, C. (2025, March 14). Why COVID Vaccines for Young Children Have Been Hard to Get. Available online: https:\/\/www.scientificamerican.com\/article\/why-covid-vaccines-for-young-children-have-been-hard-to-get\/."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"313","DOI":"10.1016\/j.medj.2021.01.005","article-title":"Stable neutralizing antibody levels 6 months after mild and severe COVID-19 episodes","volume":"2","author":"Pradenas","year":"2021","journal-title":"Med"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Fadlyana, E., Rusmil, K., Dwi Putra, M.G., Fulendry, F.P., Somantri, N.K., Putri, A.D., Sari, R.M., Puspita, M., and Dewi, G.P. (2024). Immunogenicity and Safety of SARS-CoV-2 Protein Subunit Recombinant Vaccine (IndoVacR) as a Heterologous Booster Dose against COVID-19 in Indonesian Adolescents. Vaccines, 12.","DOI":"10.3390\/vaccines12080938"},{"key":"ref_16","unstructured":"European Medicines Agency (EMA) (2025, March 14). Summary of Product Characteristics. Nuvaxovid. Available online: https:\/\/www.ema.europa.eu\/en\/documents\/product-information\/nuvaxovid-epar-product-information_en.pdf."},{"key":"ref_17","unstructured":"(2022). COVID-19 Update. Booster Dose of the Pfizer Vaccine for Children 5-11 Years Old. Med. Lett. Drugs Ther., 64, 94."},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"6952","DOI":"10.1038\/s41467-022-34280-y","article-title":"Safety and immunogenicity following a homologous booster dose of CoronaVac in children and adolescents","volume":"13","author":"Wang","year":"2022","journal-title":"Nat. Commun."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"100642","DOI":"10.1016\/j.lansea.2025.100642","article-title":"Safety and immunogenicity of booster doses of an XBB.1.5 RBD subunit COVID-19 vaccine among individuals aged 5\u201380 years in India: A phase 3, single-blind, randomised controlled trial","volume":"4","author":"Thuluva","year":"2025","journal-title":"Lancet Reg. Health\u2014Southeast Asia"},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"2254","DOI":"10.1038\/s41467-024-46490-7","article-title":"Distinct evolution of SARSCoV-2 Omicron XBB and BA.2.86\/JN.1 lineages combining increased fitness and antibody evasion","volume":"15","author":"Planas","year":"2024","journal-title":"Nat. Commun."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"344","DOI":"10.1038\/s41591-022-02162-x","article-title":"Low neutralization of SARS-CoV-2 Omicron BA.2.75.2, BQ.1.1 and XBB.1 by parental mRNA vaccine or a BA.5 bivalent booster","volume":"29","author":"Kurhade","year":"2023","journal-title":"Nat. Med."},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"107060","DOI":"10.1016\/j.ijid.2024.107060","article-title":"The contributions of vaccination and natural infection to the production of neutralizing antibodies against the SARS-CoV-2 prototype strain and variants","volume":"144","author":"Xie","year":"2024","journal-title":"Int. J. Infect. Dis."},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Ramezani, A., Sorouri, R., Maghsoudi, S.H., Dahmardeh, S., Doroud, D., Larijani, M.S., Eybpoosh, S., Mostafavi, E., Olyaeemanesh, A., and Salehi-Vaziri, M. (2023). Pasto-Covac and PastoCovac Plus as protein subunit COVID-19 vaccines led to great humoral immune responses in BBIP-CorV immunized individuals. Sci. Rep., 13.","DOI":"10.1038\/s41598-023-35147-y"},{"key":"ref_24","unstructured":"WHO (2025, October 16). WHO SAGE Roadmap on Uses of COVID-19 Vaccines in the Context of Omicron and High Population Immunity. Available online: https:\/\/www.who.int\/publications\/i\/item\/WHO-2019-nCoV-Vaccines-SAGE-Prioritization-2023.1."},{"key":"ref_25","unstructured":"International Register Clinical Trials (2025, March 14). Identifier RPCEC00000374. Phase I\u2013II Study, Sequential During Phase I, Open-Label, Adaptive and Multicenter to Evaluate the Safety, Reactogenicity and Immunogenicity of a Heterologous Two-Dose Schedule of the Prophylactic Anti-SARS-CoV-2 Vaccine Candidate, FINLAY-FR-2 and a Dose of FINLAY-FR-1A. Available online: https:\/\/rpcec.sld.cu\/trials\/RPCEC00000374-En."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/12\/1198\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,11,29]],"date-time":"2025-11-29T05:17:21Z","timestamp":1764393441000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/12\/1198"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,11,27]]},"references-count":25,"journal-issue":{"issue":"12","published-online":{"date-parts":[[2025,12]]}},"alternative-id":["vaccines13121198"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13121198","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,11,27]]}}}