Innate and adaptive immune responses to SARS-CoV-2 in convalescent children and adults

In a recent study posted to the bioRxiv* preprint server, researchers explored the systemic immune responses during the acute and convalescent phases of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in children and adults with the same disease severity.

Ever since the emergence of SARS-CoV-2 in 2019, several research works have attempted to understand the human immune response to SARS-CoV-2 and immunopathogenesis of coronavirus disease 2019 (COVID-19) with life-threatening severity. Crucial information has been obtained by incorporating advanced tissue sampling methods and single-cell technologies to determine systemic and local immune responses.

However, most of the initial studies focused on the SARS-CoV-2-associated immune responses in adults, and only recently have studies begun to focus on the immune responses in children towards SARS-CoV-2. Hence the impact of rapid SARS-CoV-2 clearance of children on adaptive immunity is still unclear.

About the study 

In the present longitudinal multimodal study, the researchers analyzed the acute and convalescent immune responses of seven children and five adults from the same family with asymptomatic or mild COVID-19, respectively. SARS-CoV-2 infection was confirmed by reverse transcription-polymerase chain reaction (RT-PCR). Further, two unrelated adults with life-threatening, severe COVID-19 under ventilator support in the intensive care unit (ICU) were also included in the study.

The researchers evaluated the cellular phenotype, cytokine profile, and serum antibody response to SARS-CoV-2 of the acute and convalescent blood samples. Furthermore, they determined ex vivo the memory T cell responses to recombinant SARS-CoV-2 spike (S) and receptor-binding domains (RBD) proteins and concurrently evaluated single-cell transcriptome and B cell receptor (BCR), and T cell receptor (TCR) repertoire sequencing of 433,301 single cells acquired from the blood samples. 

Study Findings

The results indicated that diverse polyclonal SARS-CoV-2-specific naïve T cells were observed in SARS-CoV-2-infected children, whereas clonally expanded and exhausted SARS-CoV-2-specific memory T cells were found in adults.

High dimensional flow cytometry and RNA sequencing (scRNAseq) demonstrated age-specific variations in the cellular composition of the B, NK, and T cell compartments.

During acute SARS-CoV-2 infection in adults, the upregulation of interferon (IFN)-activated genes was observed in both the innate and acquired immune system. In contrast, this was limited to nonspecific immunity in children.

The IFN-induced naïve CD4+ and CD8+ T cells expanded during the acute SARS-CoV-2 infection in children and adults and gradually decreased during the SARS-CoV-2 recovery phase of children. In adults compared to children, memory T cells were the more naïve IFN-induced CD4+ T cells. Moreover, SARS-CoV-2 recovery was based on the robust CD4+ memory T cell responses in adults and not in children, according to the OX40 assay. 

SARS-CoV-2-specific T cell compartment of children had naïve T cells with a large diversity of TCR repertoires capable of cross-reacting with multiple T cell epitopes, including the conserved components of the replication-transcription complex (RTC) of SARS-CoV-2. By contrast, fewer SARS-CoV-2-specific T cells were observed in adults with high clonally expanded memory T cells and antigenic experience with cross-recognition to diverse T cell epitopes, including the conserved RTC of SARS-CoV-2.  

SARS-CoV-2-infected adults had higher circulating activated CD38+ HLA-DR+ T cells than children. Further, the ICU-admitted adults with higher CD38+ HLA-DR+ T cells also demonstrated high serum interleukin (IL)-6 levels. T cell exhaustion was the least in children, followed by non-ICU adults, and the highest in adults admitted in ICU.

Conclusions

The study findings indicated that SARS-CoV-2 convalescent children are at a higher risk of reinfection due to the rapid clearance of the virus in children that compromises their immunity. The present longitudinal study was free from any confounding effects which may arise from analyzing heterogenous subjects with different disease severity as it followed adults and children with the same COVID-19 severity.

Previous studies indicate that pre-existing cross-reactive memory T cells were associated with severe COVID-19 in older patients, whereas it is associated with less severe disease in adults most likely via boosting existing immunity. 

The current multimodal investigation demonstrated that the acquired immunity in adults exhibited stronger immunological memory after the SARS-CoV-2 infection compared to children. The small immunological footprint left by COVID-19, which was further limited to innate immunity in children, was supported by the observed early production of IFN in children in contrast to the late IFN production in adults.

Although similar antibody responses against SARS-CoV-2 S were observed in children and adults, the higher circulating CD38 and HLA-DR T cells in adults were the classical markers of viral infection. Moreover, adults exhibited more SARS-CoV-2-specific activated and terminally differentiated T cells than children despite the same COVID-19 severity. Thus, the number of SARS-CoV-2-specific memory CD4+ T cells positively correlated with age.

Overall, the study suggested that strong nonspecific immunity impairs acquired immune response against SARS-CoV-2, thus highlighting the significance of COVID-19 vaccination in children to reduce their risk of reinfection and build strong immunity against SARS-CoV-2.

*Important notice

bioRxiv publishes preliminary scientific reports that are not peer-reviewed and, therefore, should not be regarded as conclusive, guide clinical practice/health-related behavior, or treated as established information.

Written by

Shanet Susan Alex

Shanet Susan Alex, a medical writer, based in Kerala, India, is a Doctor of Pharmacy graduate from Kerala University of Health Sciences. Her academic background is in clinical pharmacy and research, and she is passionate about medical writing. Shanet has published papers in the International Journal of Medical Science and Current Research (IJMSCR), the International Journal of Pharmacy (IJP), and the International Journal of Medical Science and Applied Research (IJMSAR). Apart from work, she enjoys listening to music and watching movies.