Safety and durability of the immune response after vaccination with the heterologous schedule of anti-COVID-19 vaccines SOBERANA®02 and SOBERANA® Plus in children 3-18 years old

Abstract

Background: The heterologous three-dose schedule of the protein subunit anti-COVID-19 SOBERANA®02 and SOBERANA® Plus vaccines has proved its safety, immunogenicity and efficacy in pediatric population, but durability of immunogenicity is not yet dilucidated. This study reports the safety and durability of the humoral and cellular responses in children and adolescents 5-7 months after receiving the heterologous vaccine schedule of SOBERANA® 02 and SOBERANA® Plus.

Methods: Children participating in a phase I/II clinical trial were followed-up for 5-7 months after the last dose. They were clinically examined by medical doctors, and their parents were interviewed searching for long-term adverse events. Blood samples were collected to evaluate the duration of humoral and cellular immune responses. Sera were tested for the presence of SARS-CoV-2 nucleocapsid (N) protein.

Results: There were no reports of severe adverse events such as coagulation disorders, myocarditis, or pericarditis. None of the participants who withdrew from the trial during the follow-up period did so due to post-vaccination adverse events. The humoral response waned in time for N-negative children, but levels of specific and neutralizing antibodies remained similar to those attained after the second dose of SOBERANA® 02 in the heterologous schedule. Neutralizing antibodies against SARS-CoV-2 D614G and omicron BA.1 were detected 5-7 months post-vaccination. RBD-specific IFN-γ secreting cells showed no significant change compared to levels following primary immunization, in both N-negative and N-positive children.

Conclusions: The vaccination regimen was safe over time, and both humoral and cellular immunity persisted in the vaccinated population aged 3-18 years, 5-7 months after receiving the heterologous SOBERANA® 02 and SOBERANA® Plus vaccine schedule.Trial registry: https://rpcec.sld.cu/trials/RPCEC00000374-En.

Keywords: COVID-19 vaccine; Cellular response; Conjugate vaccine; Pediatric vaccine; RBD; SARS-CoV-2; Subunit vaccine.

Fig. 1

Flow chart. Stage 1: Phase I/II clinical trial: recruitment, inclusion and vaccination with the heterologous schedule of two doses of SOBERANA®02 and a heterologous third dose of SOBERANA® Plus 28 days apart of children aged 3–18 years old. Stage 2: follow-up for safety and durability of the immune response 5–7 months after the third dose.

Fig. 2

Kinetics of IgG anti-RBD in N-Negative (A) and N-Positive (B) children. Children received two doses of SOBERANA® Plus (T0 and T28) and a third dose with SOBERANA®Plus. Anti-RBD IgG was measured on T0 (before immunization), T42 (14 days after second immunization), T70 (14 days after third immunization) and between 5 and 7 months after the last dose (represented as T210 in the graph). The Wilcoxon signed-Rank Test was used for before-after statistical comparison.

Fig. 3

RBD-specific Interferon-γ (INF-γ) and interleukin-4 (IL-4) secreting cells in peripheral blood mononuclear cells (PBMCs) in 14 randomly selected subjects aged 3–18 y/o. PBMC were obtained fourteen days after the third dose of the heterologous schedule with SOBERANA®02 and SOBERANA® Plus vaccines (T70) and 6 months after schedule conclusion (paired samples). At the follow-up period, samples were classified as N-positive (N+) or N-negative (N-) according to SARS-CoV-2 nucleocapsid protein ELISA assay. All samples were N-negative at T70. Wilcoxon signed-rank test was used for before-after statistical comparison and Mann-Whitney U test for N+ vs N- comparison.