Immunogenicity and safety of CoronaVac vaccine in children and adolescents (Immunita-002, Brazil): A phase IV six-month follow up

Abstract

Vaccines are essential for the prevention and control of several diseases, and monitoring the immune response generated by vaccines is crucial. The immune response generated by vaccination against SARS-CoV-2 in children and adolescents is not well defined in terms of the intensity and medium to long-term duration of protective immunity, which may indicate the need for booster doses and could support decisions in public health. The study aims to evaluate the immunogenicity and safety of an inactivated SARS-CoV-2 vaccine (CoronaVac) in a two-dose primary protocol in children and adolescents aged 3 to 17 years old in Brazil. Participants were invited to the research at two public healthcare centers located in Serrana (São Paulo) and Belo Horizonte (Minas Gerais), Brazil. They underwent medical interviews to gather their medical history, including COVID-19 history and medical records. Physical exams were conducted, which included measurements of weight, blood pressure, temperature, and pulse rate. Blood samples were obtained from the participants before vaccination, 1 month after the first dose, and at 1, 3, and 6 months after the second dose. These samples were followed up using a virtual platform to monitor post-vaccination reactions and symptoms of COVID-19. The SARS-CoV-2 genome from swab samples of COVID-19 positive individuals was sequenced using NGS. Total antibodies were measured by ELISA, and neutralizing antibodies to the B.1 lineage and Omicron variant (BA.1) were quantified by PRNT and VNT assays. The cellular immune response was evaluated by flow cytometry through the quantification of systemic soluble immune mediators. The follow-up of 640 participants showed that CoronaVac was able to significantly induce the production of total IgG antibodies to SARS-CoV-2 and the production of neutralizing antibodies to the B.1 lineage and Omicron variant. Additionally, a robust cellular immune response was observed, characterized by a wide release of pro-inflammatory and regulatory mediators in the early post-immunization moments. Adverse events recorded so far have been mild and transient, except for seven serious adverse events reported on VigiMed. The results indicate a robust and sustained immune response induced by CoronaVac in children and adolescents for up to six months, providing evidence to support the safety and immunogenicity of this effective immunizer.

Keywords: Antibodies kinetics; COVID-19; Cellular markers; CoronaVac; Neutralizing antibodies; SARS-CoV-2; Vaccine.

Fig. 1

Schematic representation of the Immunita-002 study design.

Fig. 2

Kinetics of SARS-CoV-2 anti-S IgG (A) and anti-N IgG (B) levels at pre-vaccination, 1 month after the first dose, and 1, 3, and 6 months after receiving the second dose of CoronaVac. The cutoff of 0.1508 in (A) and 0.1460 in (B) is represented by dashed lines. The black dots represent individual data points of optical density (450 nm) for each vaccinated participant. The geometric mean titers (GMT) of IgG antibodies against S and N proteins is represented by blue and green bars, respectively. Statistical differences defined by Kruskal–Wallis and Mann–Whitney methods are represented for comparisons over time.

Fig. 3

Kinetics of total IgG anti-S (A) and anti-N (B) antibody levels to SARS-CoV-2 at pre-vaccination, 1 month after the first dose, and 1, 3, and 6 months after receiving the second dose of CoronaVac separately for age groups (3–11 and 12–17 years old). The detection limit of 0.1508 in (A) and 0.1460 in (B) is represented by dashed lines. The colored dots represent the geometric mean of optical density (450 nm) for each vaccinated age group.

Fig. 4

(A) Neutralizing antibodies detected by PRNT against the B.1 lineage of SARS-CoV-2 in children and adolescents vaccinated with CoronaVac. (B) Neutralizing antibodies detected by VNT50 against the Omicron variant (BA.1) of SARS-CoV-2 in children and adolescents vaccinated with CoronaVac. The cutoff for seropositivity, defined as 20, is represented by dashed lines. The geometric mean antibody titer is represented by bars. The colored points represent the individual results of each participant at different follow-up times in the study. Statistical differences, defined by Mann–Whitney tests, are presented for comparisons over time.

Fig. 5

(A) Neutralizing antibodies to B.1 lineage of SARS-CoV-2 (detected by PRNT) in children aged 3 to 11 years vaccinated with CoronaVac. (B) Neutralizing antibodies detected by PRNT to B.1 lineage of SARS-CoV-2 in adolescents aged 12 to 17 years vaccinated with CoronaVac. (C) Neutralizing antibodies to Omicron variant (BA.1) (detected by VNT50) in children aging from 3 to 11 years vaccinated with CoronaVac. (D) Neutralizing antibodies to Omicron variant (BA.1) (detected by VNT50) in adolescents aging from 12 to 17 years vaccinated with CoronaVac. The cutoff for seropositivity, defined as 20, is represented by dashed lines. The geometric mean antibody titer is represented by bars. The colored points represent the individual results of each participant at different follow-up times in the study. Statistical differences, defined by Mann–Whitney tests, are presented for comparisons over time.

Fig. 6

Kinetics of serum soluble mediators at one month (1 M), three months (3 M), and six months (6 M) after receiving two doses of CoronaVac in children and adolescents (3–17 years old) compared to the pre-vaccination period (Not Vaccinated—NV). The biomarkers were individually presented for chemokines (CXCL8, CCL11, CCL3, CCL4, CCL2, CCL5, and CXCL10); pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-12, IFN-γ, IL-15, and IL-17); regulatory cytokines (IL-1Ra, IL-4, IL-5, IL-9, IL-10, and IL-13); and growth factors (FGF-basic, PDGF, VEGF, G-CSF, GM-CSF, IL-7, and IL-2). Statistical differences by Mann–Whitney and ANOVA with significance levels of p < 0.05 are denoted by (*) between groups.

Fig. 7

Kinetics of serum soluble mediators at one month (1 M), three months (3 M), and six months (6 M) after receiving two doses of CoronaVac in children (3–11 years old) compared to the pre-vaccination period (Not Vaccinated—NV). The biomarkers were individually presented for chemokines (CXCL8, CCL11, CCL3, CCL4, CCL2, CCL5, and CXCL10); pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-12, IFN-γ, IL-15, IL-17); regulatory cytokines (IL-1Ra, IL-4, IL-5, IL-9, IL-10, and IL-13); and growth factors (FGF-basic, PDGF, VEGF, G-CSF, GM-CSF, IL-7, and IL-2). Statistical differences by Mann–Whitney and ANOVA with significance levels of p < 0.05 are denoted by (*) between groups.

Fig. 8

Kinetics of serum soluble mediators at one month (1 M), three months (3 M), and six months (6 M) after receiving two doses of CoronaVac in adolescents (12–17 years old) compared to the pre-vaccination period (Not Vaccinated—NV). The biomarkers were individually presented for chemokines (CXCL8, CCL11, CCL3, CCL4, CCL2, CCL5, and CXCL10); pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-12, IFN-γ, IL-15, IL-17); regulatory cytokines (IL-1Ra, IL-4, IL-5, IL-9, IL-10, and IL-13); and growth factors (FGF-basic, PDGF, VEGF, G-CSF, GM-CSF, IL-7, and IL-2). Statistical differences by Mann–Whitney and ANOVA with significance levels of p < 0.05 are denoted by (*) between groups.

Fig. 9

Differences in the kinetics of serum soluble mediators between children (3–11 years old) and adolescents (12–17 years old) at one month (1 M), three months (3 M), and six months (6 M) after receiving two doses of CoronaVac compared to the pre-vaccination period (Not Vaccinated—NV) are presented. The biomarkers were individually analyzed for chemokines (CXCL8, CCL11, CCL3, CCL4, CCL2, CCL5, and CXCL10); pro-inflammatory cytokines (IL-1β, IL-6, TNF-α, IL-12, IFN-γ, IL-15, IL-17); regulatory cytokines (IL-1Ra, IL-4, IL-5, IL-9, IL-10, and IL-13); and growth factors (FGF-basic, PDGF, VEGF, G-CSF, GM-CSF, IL-7, and IL-2). Statistical differences between groups were assessed using Mann–Whitney and ANOVA tests, with significance levels of p < 0.05 denoted by (*).