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.