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Background: Increased pediatric COVID-19 occurrence due to the SARS-CoV-2 Omicron variant has raised concerns about the effectiveness of existing vaccines. The protection provided by the SOBERANA-02-Plus vaccination scheme against this variant has not yet been studied. We aimed to evaluate the scheme's effectiveness against symptomatic Omicron infection and severe disease in children., Methods: In September 2021, Cuba implemented a mass pediatric immunization with the heterologous SOBERANA-02-Plus scheme: 2 doses of conjugated SOBERANA-02 followed by a heterologous SOBERANA-Plus dose. By December, before the Omicron outbreak, 95.4% of 2-18 years-old had been fully immunized. During the entire Omicron wave, we conducted a nationwide longitudinal post-vaccination case-population study to evaluate the real-world effectiveness of the SOBERANA-02-Plus scheme against symptomatic infection and severe disease in children without previous SARS-CoV-2 infection. The identification of COVID-19 cases relied on surveillance through first line services, which refer clinical suspects to pediatric hospitals where they are diagnosed based on a positive RT-PCR test. We defined the Incidence Rate ratio (IRR) as IRvaccinated age group/IRunvaccinated 1-year-old and calculated vaccine effectiveness as VE = (1-IRR)∗100%. 24 months of age being the 'eligible for vaccination' cut-off, we used a regression discontinuity approach to estimate effectiveness by contrasting incidence in all unvaccinated 1-year-old versus vaccinated 2-years-old. Estimates in the vaccinated 3-11 years-old are reported from a descriptive perspective., Findings: We included 1,098,817 fully vaccinated 2-11 years-old and 98,342 not vaccinated 1-year-old children. During the 24-week Omicron wave, there were 7003/26,241,176 person-weeks symptomatic COVID-19 infections in the vaccinated group (38.2 per 10 5 person-weeks in 2-years-old and 25.5 per 10 5 person-weeks in 3-11 years-old) against 3577/2,312,273 (154.7 per 10 5 person-weeks) in the unvaccinated group. The observed overall vaccine effectiveness against symptomatic infection was 75.3% (95% CI, 73.5-77.0%) in 2-years-old children, and 83.5% (95% CI, 82.8-84.2%) in 3-11 years-old. It was somewhat lower during Omicron BA.1 then during Omicron BA.2 variant circulation, which took place 1-3 and 4-6 months after the end of the vaccination campaign. The effectiveness against severe symptomatic disease was 100.0% (95% CI not estimated) and 94.6% (95% CI, 82.0-98.6%) in the respective age groups. No child death from COVID-19 was observed., Interpretation: Immunization of 2-11 years-old with the SOBERANA-02-Plus scheme provided strong protection against symptomatic and severe disease caused by the Omicron variant, which was sustained during the six months post-vaccination follow-up. Our results contrast with the observations in previous real-world vaccine effectiveness studies in children, which might be explained by the type of immunity a conjugated protein-based vaccine induces and the vaccination strategy used., Funding: National Fund for Science and Technology (FONCI-CITMA-Cuba)., Competing Interests: MCRG, MMC, SFC, YCR, DSM, YVB, DGR and VVB are employees of the Finlay Vaccine Institute that developed and manufactures the SOBERANA vaccines. VVB, YVB, DGR, YCR, SFC and DSM are authors of two patent applications related with the vaccines. The other authors have no potential conflict of interest., (© 2024 The Author(s).)

(1) Background: In children, SARS-CoV-2 infection is mostly accompanied by mild COVID-19 symptoms. However, multisystem inflammatory syndrome (MIS-C) and long-term sequelae are often severe complications. Therefore, the protection of the pediatric population against SARS-CoV-2 with effective vaccines is particularly important. Here, we compare the humoral and cellular immune responses elicited in children ( n = 15, aged 5-11 years) vaccinated with the RBD-based vaccines SOBERANA ® 02 and SOBERANA ® Plus combined in a heterologous scheme with those from children ( n = 10, aged 4-11 years) who recovered from mild symptomatic COVID-19. (2) Methods: Blood samples were taken 14 days after the last dose for vaccinated children and 45-60 days after the infection diagnosis for COVID-19 recovered children. Anti-RBD IgG and ACE2-RBD inhibition were assessed by ELISA; IgA, cytokines, and cytotoxic-related proteins were determined by multiplex assays. Total B and T cell subpopulations and IFN-γ release were measured by multiparametric flow cytometry using a large panel of antibodies after in vitro stimulation with S1 peptides. (3) Results: Significant higher levels of specific anti-RBD IgG and IgA and ACE2-RBD inhibition capacity were found in vaccinated children in comparison to COVID-19 recovered children. Th1-like and Th2-like CD4 + T cells were also significantly higher in vaccinated subjects. IFN-γ secretion was higher in central memory CD4 + T cells of COVID-19 recovered children, but no differences between both groups were found in the CD4 + and CD8 + T cell effector, terminal effector, and naïve T cell subpopulations. In contrast to low levels of IL-4, high levels of IL-2, IL-6, IFN-γ, and IL-10 suggest a predominant Th1 cell polarization. Cytotoxic-related proteins granzyme A and B, perforin, and granulin were also found in the supernatant after S1 stimulation in both vaccinated and recovered children. (4) Conclusions: Vaccination with the heterologous scheme of SOBERANA ® 02/SOBERANA ® Plus induces a stronger antibody and cellular immune response compared to natural infections in young children.

Objectives: To evaluate a heterologous vaccination scheme in children 3-18 years old (y/o) combining two SARS-CoV-2r- receptor binding domain (RBD)protein vaccines., Methods: A phase I/II open-label, adaptive, and multicenter trial evaluated the safety and immunogenicity of two doses of FINLAY-FR-2 (subsequently called SOBERANA 02) and the third heterologous dose of FINLAY-FR-1A (subsequently called SOBERANA Plus) in 350 children 3-18 y/o in Havana Cuba. Primary outcomes were safety (phase I) and safety/immunogenicity (phase II) measured by anti-RBD immunoglobulin (Ig)G enzyme-linked immunoassay (ELISA), molecular and live-virus neutralization titers, and specific T-cells response. A comparison with adult immunogenicity and predictions of efficacy were made based on immunological results., Results: Local pain was the unique adverse event with frequency >10%, and none was serious neither severe. Two doses of FINLAY-FR-2 elicited a humoral immune response similar to natural infection; the third dose with FINLAY-FR-1A increased the response in all children, similar to that achieved in vaccinated young adults. The geometric mean (GMT) neutralizing titer was 173.8 (95% confidence interval [CI] 131.7; 229.5) vs Alpha, 142 (95% CI 101.3; 198.9) vs Delta, 24.8 (95% CI 16.8; 36.6) vs Beta and 99.2 (95% CI 67.8; 145.4) vs Omicron., Conclusion: The heterologous scheme was safe and immunogenic in children 3-18 y/o., Trial Registry: https://rpcec.sld.cu/trials/RPCEC00000374., Competing Interests: Declaration of competing interest The authors RPG, YRD, CRI, LCH, MPB, DVM, NPP, CVS, APD, EGO, YCE, JCFP, MSM, MDE, JMEP, YIH, and METR declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. The authors BPM, MRG, BSR, LMRN, RPN, RGM, THG, TFB, ICQ, SFC, YCR, DSM, YGV, YVB, DGR, and VVB work at Finlay Vaccine Institute or the Centre of Molecular Immunology, institutions that develop and manufacture the vaccine candidates but have not received an honorarium for this paper. BSR, SFC, YCR, LRN, DSM, YVB, DGR, and VVB have filed patent applications related to the vaccine FINLAY-FR-2. DD and AB work at Pasteur Institute of Iran and are co-developer of the vaccines., (Copyright © 2022 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Background: As a first step towards a vaccine protecting COVID-19 convalescents from reinfection, we evaluated FINLAY-FR-1A vaccine in a clinical trial., Methods: Thirty COVID-19 convalescents aged 22-57 years were studied: convalescents of mild COVID-19, asymptomatic convalescents, both with PCR-positive at the moment of diagnosis; and individuals with subclinical infection detected by viral-specific IgG. They received a single intramuscular injection of the FINLAY-FR-1A vaccine (50 µg of the recombinant dimeric receptor binding domain). The primary outcomes were safety and reactogenicity, assessed over 28 days after vaccination. The secondary outcome was vaccine immunogenicity. Humoral response at baseline and following vaccination was evaluated by ELISA and live-virus neutralization test. The effector T cellular response was also assessed. Cuban Public Registry of Clinical Trials, WHO-ICTRP: https://rpcec.sld.cu/en/trials/RPCEC00000349-En., Findings: No serious adverse events were reported. Minor adverse events were found, the most common, local pain: 3 (10%) and redness: 2 (6·7%). The vaccine elicited a >21 fold increase in IgG anti-RBD antibodies 28 days after vaccination. The median of inhibitory antibody titres (94·0%) was three times greater than that of the COVID-19 convalescent panel. Virus neutralization titres higher than 1:160 were found in 24 (80%) participants. There was also an increase in RBD-specific T cells producing IFN-γ and TNF-α., Interpretation: A single dose of the FINLAY-FR-1A vaccine against SARS-CoV-2 was an efficient booster of pre-existing natural immunity, with excellent safety profile., Funding: Partial funding for this study was received from the Project-2020-20, Fondo de Ciencia e Innovación (FONCI), Ministry of Science, Technology and the Environment, Cuba.    RESUMEN ., Antecedentes: Como un primer paso hacia una vacuna que proteja a los convalecientes de COVID-19 de la reinfección, evaluamos la vacuna FINLAY-FR-1A en un ensayo clínico., Métodos: Se estudiaron treinta convalecientes de COVID-19 de 22 a 57 años: convalecientes de COVID-19 leve y convalecientes asintomáticos, ambos con prueba PCR positiva al momento del diagnóstico; e individuos con infección subclínica detectada por IgG específica viral. Los participantes recibieron una dosis única por vía intramuscular de la vacuna FINLAY-FR-1A (50 µg del dominio de unión al receptor recombinante dimérico del SARS CoV-2). Las variables de medida primarias fueron la seguridad y la reactogenicidad, evaluadas durante 28 días después de la vacunación. La variable secundaria, la inmunogenicidad. La respuesta humoral, al inicio del estudio y después de la vacunación, se evaluó por ELISA y mediante la prueba de neutralización del virus vivo. También se evaluó la respuesta de células T efectoras. Registro Público Cubano de Ensayos Clínicos, WHO-ICTRP: https://rpcec.sld.cu/en/trials/RPCEC00000349-En., Resultados: No se reportaron eventos adversos graves. Se encontraron eventos adversos leves, los más comunes, dolor local: 3 (10%) y enrojecimiento: 2 (6·7%). La vacuna estimuló un incremento >21 veces de los anticuerpos IgG anti-RBD 28 días después de la vacunación. La mediana de los títulos de anticuerpos inhibidores (94·0%) fue aproximadamente tres veces mayor que la del panel de convalecientes de COVID-19. Se encontraron títulos de neutralización viral superiores a 1:160 en 24 (80%) de los participantes. También hubo un aumento en las células T específicas de RBD que producen IFN-γ y TNF-α., Interpretación: Una sola dosis de la vacuna FINLAY-FR-1A contra el SARS-CoV-2 reforzó eficazmente la inmunidad natural preexistente, con un excelente perfil de seguridad., Financiamiento: Se recibió un financiamiento parcial del Proyecto-2020-20, Fondo de Ciencia e Innovación (FONCI), Ministerio de Ciencia, Tecnología y Medio Ambiente, Cuba., Competing Interests: The Finlay Vaccine Institute and the Centre of Molecular Immunology have filed patent applications related to the vaccine's use in individuals with pre-existing SARS-CoV-2 immunity. ROA, YVB, DGR, and VVB are researchers of Finlay Vaccine Institute, and BSR is a researcher of the Centre of Molecular Immunology, the institutions that manufacture the vaccine. Partial funding for this study was received from the Fondo de Ciencia e Innovación (FONCI) of Cuba's Ministry of Science, Technology and the Environment (Project-2020-20). The other authors declare no competing interests. No authors received an honorarium for this paper., (© 2021 The Author(s).)