Data pertaining to immunogenicity, as assessed through total antibody levels by anti-SARS-CoV-2 ELISA, revealed that most children and adolescents exhibited seropositivity for anti-S IgG prior to vaccination, while 46% displayed seropositivity for anti-N IgG, indicating prior exposure to SARS-CoV-2 before immunization.
Epidemiological data published during the period of this study demonstrated peaks of COVID-19 transmission in Brazil, particularly in the southeastern region of the country, where there was a prevalence of 58.4% of SARS-CoV-2 infections among severe acute respiratory syndrome (SARS) cases, according to data published at InfoGripe23. Furthermore, a study assessing the circulation of SARS-CoV-2 in children in Brazil from April 2020 to July 2022 reported a higher risk of infection in children from symptomatic family adults, usually the mother, reinforcing the importance of vaccination across all age groups24.
A comprehensive statistical analysis of the collective data indicated a significant rise in titers of anti-S IgG antibodies and anti-N IgG antibodies, as well as in seropositivity rates, one month after completing the primary immunization course with two doses of CoronaVac. Similar findings were reported by Fernandes et al.25, wherein all children in the study exhibited a substantial increase in antibody titers induced one month after vaccination, underscoring a robust serological response to a single dose in a pediatric population up to five years old, with no reports of severe adverse effects.
Despite a reduction in the overall mean antibody titers observed at three months post-vaccination in our study, these averages remained consistently high (above the detection limit of the reference assay) throughout the study period, demonstrating the durability and persistence of the total antibody response. The seropositivity rate reached 90% for anti-S IgG in the third month and 95% after six months of follow-up. Similarly, seropositivity rates reached 93% and 99% for anti-N IgG in the third- and sixth-months post-vaccination. Evaluation of the geometric mean titers of anti-S and anti-N IgG antibodies among participants grouped by age revealed a consistent pattern of seropositivity, confirming a substantial increase in total antibodies against SARS-CoV-2 within the first month after vaccination, followed by a stable immune response over the course of the six-month study.
These outcomes align with those reported by Rosa et al.26, indicating that 97% of adolescents aged 11 to 17 displayed anti-S IgG antibodies against SARS-CoV-2 after receiving two doses of CoronaVac. Moreover, the same adolescents were assessed for anti-N IgG as secondary immunogenicity markers, revealing a high seropositivity rate of 98%. Additionally, in accordance with findings from the Immunita-02 study, previously published data indicated that over 96% of children and adolescents aged 3 to 17 years exhibited specific antibodies to SARS-CoV-2 after 28 days of receiving two doses of CoronaVac27.
Virus neutralization assays showed that a significant percentage of children and adolescents displayed seropositivity to the B.1 lineage prior to vaccination. This percentage increased after the first dose and continued to rise following the second dose. Regarding neutralizing antibodies to the Omicron variant, most of the children and adolescents being monitored showed seropositivity before their first dose, indicating previous infection. After vaccination, they maintained significant seropositivity over time, indicating a sustained neutralizing response to the Omicron variant across different age groups. Good neutralizing antibody responses were also noted following the administration of CoronaVac in previously published phase 1 and 2 studies, which reported the vaccine’s good tolerability and safety, along with satisfactory humoral responses in children and adolescents aged 3 to 17 years. Additionally, it was observed that the neutralizing antibody titers induced by the 3.0 μg dose exceeded those of the 1.5 μg dose. These findings support the use of the 3.0 μg dose in a two-dose immunization regimen for further investigations in the same age group27.
We chose to use individuals without a history of prior infection for the VNT assays. However, our data show that a significant portion of them already had neutralizing antibodies before vaccination, both for the Omicron variant and the ancestral B lineage, indicating previous, likely asymptomatic exposure. A meta-analysis study published in the Journal of Medical Virology compiled data on asymptomatic infections, revealing that during waves of Omicron variant infections, children and adolescents had a high proportion of asymptomatic cases (82%), while in the elderly (already widely vaccinated at that time), this proportion was lower (62%)28. These data reinforce the importance of vaccination among children and adolescents, as they may contribute to the ongoing circulation of SARS-CoV-228.
Regarding the cellular response data demonstrated in this study, in general, a similar profile was observed among the age groups, with occasional differences in pro-inflammatory cytokines when comparing the profiles of children to adolescents from the third to the sixth month of follow-up. An initial inflammation observed triggered by vaccination is a premise for the development of a robust cellular response. It is noticeable that there was an increasing release of soluble pro-inflammatory and regulatory mediators in the first three months post-vaccination, with the maintenance of the response at six months of post-vaccination follow-up. Hence, it is evident that a robust and enduring cellular immune response, characterized by a combination of pro-inflammatory and regulatory elements, persists for up to six months after the administration of two doses of the CoronaVac in the children and adolescents observed within the scope of this study.
Promising results regarding the cellular immune response in children and adolescents who received CoronaVac have also been reported, as described by Soto and collaborators28. Their findings highlighted a significant increase in CD4 + AIM + T-cells in response to the structural proteins of the virus. In the 12 to 17-year-old group, there was a notable expansion in the activation of CD4 + T-cells in response to all the structural proteins of SARS-CoV-2, indicating that CoronaVac, as an inactivated virus vaccine, stimulates cellular immunity not only against the Spike (S) protein but also against the membrane (M) and nucleocapsid (N) proteins. Furthermore, an increase in IL-2 secretion in response to the S and N proteins was observed in both age groups, with this increase being particularly pronounced in individuals aged 12 to 17 years in relation to the M protein29. The vaccine also promoted a pro-inflammatory profile, with an increase in IFN-γ and no increase in IL-4, in both the 3 to 11-year-old group and the 12 to 17-year-old group. Additionally, an increase in the frequency of memory CD4 + AIM + T-cells in response to the SARS-CoV-2 proteins was noted, with a slight intensification observed in individuals aged 12 to 17 years, suggesting that the vaccine may induce long-lasting CD4 + T-cell responses29.
Among the 640 children and adolescents monitored, one third presented suspected cases of COVID-19. After conducting RT-qPCR tests, 56 cases of SARS-CoV-2 infections were confirmed, with no instances of moderate or severe COVID-19 necessitating hospitalization among the pediatric population. Of the swab samples collected from COVID-19 positive participants, 11 met the criteria for NGS sequencing, all of which were identified as belonging to the Omicron variant sub-lineages, including BA.2 and BA.5.
After vaccination, mostly mild and transient adverse effects were reported, with pain at the injection site being the most common issue. The few serious adverse events observed were unrelated to the vaccine and included conditions like acute gastroenteritis, cellulitis, fractures, and asthmatic bronchiolitis. Similar outcomes were observed in phase 1 and 2 studies described by Han and collaborators27, where most post-vaccination adverse reactions were mild and transient, with pain at the injection site being the most frequently reported event (73.1% of 550 participants). Furthermore, in a phase 3 study conducted in Chile, the primary adverse event reported after the first and second doses was also pain at the injection site. This study also concluded that CoronaVac was safe and immunogenic in individuals aged 3 to 17 years, inducing the production of neutralizing antibodies and activation of CD4 + T-cells to SARS-CoV-2 variants29.
Recently published data on the effectiveness of the CoronaVac against COVID-19 in Brazilian children (aged 6 to 11 years), during a period of high Omicron variant (B.1.1.529 lineage) circulation (January 21, 2022, to April 15, 2022), indicated an estimated vaccine effectiveness of 39.8% (95% CI 33.7–45.4) against symptomatic infection at ≥ 14 days post-second dose30. For hospitalization, vaccine effectiveness was 59.2% (95% CI 11.3–84.5) at ≥ 14 days30. Conversely, noteworthy results emerged from the evaluation of CoronaVac effectiveness in Chile, involving a large national prospective cohort of approximately two million children and adolescents aged 6 to 16 years. The estimated effectiveness stood at 74.5% (95% CI, 73.8–75.2), 91.0% (95% CI, 87.8–93.4), and 93.8% (95% CI, 87.8–93.4) for the prevention of COVID-19, hospitalization, and ICU admission, respectively31. For children aged 6 to 11 years, vaccine effectiveness was 75.8% (95% CI, 74.7–76.8) against COVID-19 and 77.9% (95% CI, 61.5–87.3) against hospitalization31.
Another study assessing CoronaVac effectiveness in children aged 3 to 5 years, conducted during the Omicron (B.1.1.529 lineage) outbreak in Chile, revealed estimated effectiveness of 38.2% (95% CI, 36.5–39.9) against symptomatic COVID-19, 64.6% (95% CI, 49.6–75.2) against hospitalization, and 69.0% (95% CI, 18.6–88.2) against ICU admission31. The study concluded that despite the modest effectiveness against symptomatic COVID-19, CoronaVac vaccination provided robust protection against severe COVID-19 in this age group32.
This study adopted a prospective observational design, which provided valuable insights into the immune response and effectiveness of CoronaVac in children and adolescents. However, it is important to note that the study results are based on a sample recruited from two locations in southeastern Brazil. Therefore, it is important to consider that sociodemographic and health characteristics of these regions may differ significantly from other parts of the country. While the study included a valuable cohort, a larger sample size would provide greater statistical power and more robust conclusions. Although this study followed participants for a period of six months after the second dose of CoronaVac, the long-term impact of vaccination should be assessed. Hence, further studies are needed to evaluate the persistence of immune response and safety over longer durations in this age group. Additionally, to complement the immunogenicity data of this study, it is recommended to conduct broader assessments such as specific T and B cell responses to SARS-CoV-2, to obtain more comprehensive insights into the immune response following vaccination.
