With the ongoing presence of SARS-CoV-2, understanding the dynamics of neutralizing antibody responses in children is of paramount importance, particularly considering emerging variants and the unique challenges posed by this age group. This study measured neutralizing antibodies against prevalent SARS-CoV-2 VOC in plasma samples from children aged 5–12 years, with the objective of elucidating antibody responses within distinct cohorts and against emerging variants. Our data suggest that a significant percentage of children do not demonstrate neutralizing antibodies against the Omicron variant.
A major advantage of this study was the use of ICES data, which accurately linked SARS-CoV-2 infections and vaccinations with all participants. According to our data, 31% of children had a SARS-CoV-2 infection and 46% were vaccinated. Children who were both naturally infected and vaccinated constituted 11% of the population. Of those vaccinated, 27% of children received one vaccination and 19% received two doses. Over a 5-month period, the study observed a general upward trend in neutralizing antibody responses across all VOC. Omicron antibody responses were lower than those of WT and other VOC, both in relation to the percentage of positive cases and over time. While two chronic conditions, asthma and diabetes, did not alter antibody responses, active immunotherapy and leukopenia resulted in blunted responses to some VOC. Taken together, these findings emphasize the need for continued surveillance and vaccine optimization.
Multiple pediatric studies have measured plasma antibodies to the spike and NCP antibodies8,9,10, but they did not examine the neutralizing ability of circulating antibodies to specific VOCs. High throughput mapping of antibody sequence to antigen specificity has been used in a pediatric population, but this study relied on patient self-reporting for infection and vaccination data, and they examined only a limited number of pooled samples25. Our study examined a large cohort of children with accurate SARS-CoV-2 testing and vaccination data, together with individual antibody studies to elucidate responses with higher fidelity.
Vaccination plays a crucial role in generating a neutralizing immune response against SARS-CoV-226. The safety and effectiveness of the Pfizer-BioNTech COVID-19 vaccination in children aged 5–11 years have been demonstrated, with no serious adverse events reported27. Children with SARS-CoV-2 infection (symptomatic or asymptomatic) developed neutralizing antibodies lasting longer than adults28. However, these antibodies gradually diminished in concentration over time, along with decreases in the levels of broad IgG antibodies. Notably, the levels of neutralizing antibodies post-infection were lower than those observed after vaccination. Among children aged 5–11 years, the mRNA vaccine demonstrated moderate effectiveness in protecting against infections caused by Omicron29. However, these vaccines were likely to be highly protective against severe COVID-19 cases requiring hospitalization. Pediatric and adult SARS-CoV-2 patients have also demonstrated alignment in protective neutralizing antibody responses30. There was an increase in symptomatic COVID-19 infections among non-hospitalized children over the past two years, particularly with the emergence of VOC31. Neutralizing antibodies in children remained strong for up to 16 months after infection, with no differences based on gender or symptoms. Children under 5 years old showed a quicker rise in antibody levels during infection and less decline over time compared to older individuals, suggesting a lower risk of SARS-CoV-2 reinfection and milder clinical disease in this age group11. However, it has also been suggested that children exhibit comparable antibody levels in response to SARS-CoV-2, irrespective of their age12. These findings emphasize the need for further research to better understand pediatric responses to emerging variants.
Numerous studies have reported elevated rates of symptomatic infection as a result of Omicron’s heightened transmissibility and decreased vaccine efficacy32,33. Omicron, while more transmissible and capable of evading some vaccine-induced immunity, still allows first-generation vaccines to be effective against severe disease and death. Recent studies have shown that COVID-19 vaccines can still exhibit neutralizing potency against Omicron34. Immunized individuals have also demonstrated the ability to generate neutralizing antibodies against variants35. However, over time, vaccine effectiveness against Omicron decreases36. In comparison, infection with the Omicron BA.2.38 variant induced the production of antibodies that responded not only to Omicron BA.2.38 but also to other Omicron variants (Omicron BA.1-BA.5)37. Both children and adults infected with the ancestral strain of SARS-CoV-2 developed robust serological and T-cell memory responses persisting for at least 12 months38, suggesting an enduring immunological memory and partial cross-reactivity against the Omicron BA.1 variant.
The majority of people develop anti-SARS-CoV-2 antibodies through vaccination or infection39. However, less than half of people exhibited neutralizing activity against the currently circulating Omicron BA.5 subvariant. Notably, hybrid immunity obtained through booster vaccination and prior infection provided the highest level of neutralization capacity, even against Omicron. Neutralizing activity against Delta and Omicron variants was significantly lower compared to the WT strain, and did not improve even after a third vaccine dose40. In contrast, infection with SARS-CoV-2 provided higher levels of neutralization against these variants. These findings collectively emphasize the potential challenges of mounting an effective immune response against the Omicron variant.
Recent research has shed light on various aspects of pediatric immune responses to SARS-CoV-2. For instance, vaccination of children with inflammatory bowel disease was both immunogenic and safe41. However, the study also raised concerns about vaccine efficacy against Omicron42. This aligns with our findings of variations in antibody positivity between groups, emphasizing the importance of vaccination to bolster immunity in vulnerable populations. Additionally, when children with SARS-CoV-2 infection and neuroinflammatory diseases received CD20 monoclonal antibodies compared to other treatments, SARS-CoV-2 antibodies decreased43. The serologic responses to SARS-CoV-2 vaccination in children with a history of multisystem inflammatory syndrome revealed significant reductions in neutralizing titres to Omicron44.
This study adds to the growing body of research on the immune response in children to SARS-CoV-2 infection and vaccination. Together with previous research, our findings underscore the importance of continued surveillance, vaccination strategies, and tailored medical interventions to address the evolving landscape of SARS-CoV-2 variants in children. These insights are critical for public health decision-making and safeguarding children’s well-being in the face of this global health challenge. Specifically, our study questions the efficacy of current vaccines against Omicron in pediatric populations; booster shots and variant-specific vaccines may become essential tools in protecting children from this highly transmissible variant.
While this study offers valuable insights into the immune response of children aged 5–12 years to SARS-CoV-2 variants of concern (VOCs), we acknowledge several limitations. First, our focus on known variants up to a specific point in time limits our ability to assess responses to newer emerging variants that may have arisen after the study period. Second, the reliance on plasma samples collected from specific pediatric populations in a single geographical location may restrict the generalizability of our findings to other regions or demographic groups. Third, the design of our surveillance study did not allow for the evaluation of the immune response timeline following acute infection, reporting primarily prevalence rates. Additionally, we utilized two different antigen expression systems based on availability; however, both Hek- and Cho-expressed proteins demonstrated equivalent in vitro biological activity, and both WT Hek and WT Cho proteins exhibited similar antibody profiles. Fourth, while we focused on measuring neutralizing antibodies—an essential component of immunity—other aspects of the immune response, such as cellular immunity, were not explored. Finally, while this study provides important data on antibody prevalence, it does not directly assess clinical outcomes such as cross-reactivity or immune protection against VOCs. Despite these limitations, our findings have important implications for public health interventions and surveillance strategies, highlighting the need for additional vaccination doses in immunocompromised populations.
