Discussion
This is one of the first studies to characterize SARS-CoV-2-specific humoral and cellular immunity in children recovered from COVID-19. There was an acquired immunity established in children with either symptomatic or asymptomatic infections. Both SARS-CoV-2-specific humoral and cellular immunity were detectable at different time points during the recovery period. Detection of SARS-CoV-2 RBD IgG and reactive CD4+ and CD8+ T cells against the various peptide pools suggests both humoral and cellular immunity are present that can counter re-infections.
Our study showed that there were both CD4+ and CD8+ T cell responses to SARS-CoV-2 S, N, and M proteins. SARS-CoV-2-specific T cells were found to respond to stimulation by all peptide pools. The detection of intracellular levels of IFN-γ suggests the protective cellular immunity towards SARS-CoV-2 was similar between children and adults, in that both groups developed T cell memory.[26, 30, 39] A larger-scale study will be needed to confirm our observations.
The persistence of humoral and cellular responses against the SARS-CoV-2 virus is key to understanding the risk of re-infections. [40, 41] We observed a decline in humoral immunity associated with recovery time. The SARS-CoV-2 RBD IgG antibody level lasted on average 7.9 months with a half-life of 121.6 days, which is similar to other studies across different age groups.[42-47]. There have only been a few studies demonstrating the longevity of SARS-CoV-2 T cell response in recovered pediatrics patients. Dan et al., demonstrated that approximately 92% and 50% of recovered patients had specific CD4+ and CD8+ responses, respectively, up to 8 months after the primary infection.[30] Based on our finding and the above study, the humoral immunity against SARS-CoV-2 in recovered pediatrics patients can last up to 7-8 months after the primary infection, which is likely much longer than for cellular immunity. To prolong the humoral responses, we recommend recovered pediatrics patients to receive a booster dose of a COVID-19 vaccine approximately 6 months after the primary infection, which is in line with the current adult guidelines.[48]
Ding et al., demonstrated an age-specific variation in childhood CD4+ and CD8+ T cell subsets in healthy Chinese, suggesting differences in immune composition across pediatric age groups.[49] Along with this finding, our data demonstrated that the age of the pediatric patients is an important factor influencing the level of SARS-CoV-2 RBD IgG and the magnitude of the T cell response to SARS-CoV-2. Convalescent children younger than 12 years had higher SARS-CoV-2 RBD IgG levels, whereas convalescent adolescents aged 12 years and older had stronger SARS-CoV-2 CD8+ T cell response. Other viruses, such as the cytomegalovirus (CMV), have contrasting immune responses, with the intact CMV inducing specific CD8+ T cell response, but deficient CD4+ T cell response, in young children and toddlers.[34, 50] There was also age-dependent CD4+ T cell activity in the production of the RBD IgG antibody. Based on our data, only younger children presented with stronger SARS-CoV-2 S CD4+ T cells response and linked with higher level of anti-RBD IgG ratio. Our novel findings on the immune responses in convalescent pediatrics patients in younger age group outlined the importance of SARS-CoV-2 S specific CD4+ dependent humoral response in relations to the level of anti-RBD IgG against reinfections, which warrant further larger-scale studies to confirm the observations.
The study findings need to be interpreted with the following caveats. First, the number of patients and controls was relatively small. However, all the controls demonstrated negative immune memory responses with undetectable SARS-CoV-2 anti-RBD antibody titer, indicating immune protection against SARS-CoV-2 in unvaccinated and uninfected children was minimal. Second, the quantity of blood that can be obtained from younger children is limited, hence, other subsets of T cell responses to SARS-CoV-2 peptide pools were not evaluated in this study. Future investigations should include other T cell subsets such as regulatory T cells and T follicular helper cells (Tfh) to draw a more comprehensive picture of the T cell response against SARS-CoV-2 in children.