In a recent study that was published in the journal Cell, scientists used a variety of next-generation sequencing methods, such as single-cell RNA sequencing (scRNA-seq) and the assay for transposase-accessible chromatin with sequencing (ATAC-seq), to clarify the immune responses of infants in their first few weeks of life to infections on a systemic level. Their results show that this particular group of people’s immune responses differ significantly from those of adults and, shockingly, even young children five years of age and older.
In contrast to the previous groups, which exhibit a mix of innate and acquired immune activation, infants only display an innate immune response. These results may contribute to the direction of future studies on childhood immunizations and provide pediatricians with the tools they need to treat newborn infections.
Immunity and childhood infection
There are two main categories of immune responses: acquired and innate. The body’s first line of defense against pathogens is the innate immune system. This genetically derived immunity is sometimes called the “nonspecific” immune system because it reacts to all pathogens and foreign substances in the same way. On the other hand, because acquired immunity customizes its response to a particular antigen that it has already encountered, it is also referred to as “specific immunity.” Its capacity for memory, adaptation, and learning are its defining traits.
Innate immunity does not change much from birth to adulthood, but acquired immunity differs from person to person depending on whether they are vaccinated or have been exposed directly to a particular antigen. The immune system is then primed through the production of antibodies as a result of antigen exposure. The kind and quantity of these antibodies affect an adult’s capacity to fend off reexposure to the same or very similar antigens in the future.
Previous studies have demonstrated that the composition and function of immunity varies significantly between adults and children. The early weeks of life are known to have a significant maturation impact on a child’s immunity throughout their adult life. No research has yet looked into how newborns’ innate immunity reacts to infections during the crucial maturation period, despite the fact that scientists have studied this maturation in children five years of age and older and in healthy infants.
Given that five-year-olds have already developed a relatively mature immune system and may react very differently from infants without any immune system maturity, this distinction needs to be further investigated.
About the study
Three main questions were addressed in this study by using data from infants with severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). – 1.) How do newborns’ T and B cells react to and form memory in the face of a pathogen, given that their immune systems are still developing and cannot fight off environmental infections? 2. The symptomatology of pediatric coronavirus disease 2019 (COVID-19) has been found to be significantly milder than that of adult patients. In light of this finding, what immune response characteristics unique to infants give rise to these patterns? (3.) Research on both adults and children has clarified the generation of autoimmune antibodies and long-lasting epigenetic modifications. Do babies follow these same patterns?
In order to investigate these questions, scientists profiled and analyzed SARS-CoV-2 and the ensuing immune activation in infants during their first few weeks and months of life using a next-generation multi-omics technique. Every week, 125 samples of blood were drawn from infants and young children who were part of the Cincinnati Children’s Hospital Medical Center’s IMPRINT study cohort. The samples were then checked for COVID-19. 54 infection cases (case-cohort) and 27 uninfected controls were found in these samples. According to blood analyses, 32 infants had COVID-19 variants other than Omicron, while the other infants had Omicron (or its variants).
In order to compare results for infants and adults, blood samples were taken from two locations: the Stanford University Medical Center (47 blood samples representing 41 infected mothers and 3 healthy controls) and the Hope Clinic at Emory University in Atlanta (62 blood samples representing 48 adult COVID-19 cases and 10 healthy controls).
An investigation into antibody titers (both binding and neutralizing) against pre- and Omicron COVID-19 variants was conducted using the Anti-Spike electrochemiluminescence (ECL) binding enzyme-linked immunosorbent assay (ELISA). After that, autoantibody response was assessed using a customized ELISA against plasma sample IFNa2 analysis. In order to gain more insight into the adaptive immune responses in newborns, the kinetics of memory T and B cells specific to COVID-19 were examined.
Researchers used principal-component analysis (PCA) of cytokines divided by type and abundance to measure the kinetics of plasma cytokine responses because severe COVID-19 infection has been previously shown to follow dysregulations in innate immune responses (in adults). Peripheral blood leukocytes were analyzed using mass cytometry to shed light on the cellular dynamics of immune responses. Single-cell RNA sequencing (scRNA-seq) was performed in order to gain additional understanding of the activation state of different immune cells. Here, the chromatin accessibility and gene expression profiles of adults pre-, during, and post-infection were compared to those of infants with mild infection.
The system-wide changes in chromatic accessibility during COVID-19 were discovered using the assay for transposase-accessible chromatin with sequencing (ATAC-seq). Ultimately, PCA was used to examine nasal swab samples in order to identify the variations in mucosal immune responses between newborns and early children.
Study findings
This multi-omics study found that infants’ memory T and B cells exhibit strong and enduring responses against SARS-CoV-2, whereas adults’ COVID-19 antibodies rapidly deteriorate, allowing for re-infection with the same COVID-19 variant. Infants’ antibodies showed virtually no change in ELISA titers over the 300-day study period, in contrast to adult antibodies, which are known to almost entirely deteriorate in 120 days after COVID-19 infection. The disparities between the pre-Omicron and Omicron SARS-CoV-2 variants of concern (VOCs) results confuse this data.
B cells against the latter degraded over time, but antibodies against the former did not. Furthermore, T cells, which are known to mutate and evolve slowly, did not alter upon infection by an Omicron variant subsequent to pre-Omicron infection. This suggests that although infants’ innate immunity far surpasses adults’ in the COVID-19 context (none of the studied infants ever exhibited severe COVID-19 symptoms), their immune systems may be overwhelmed upon repeated exposure to COVID-19 that includes various VOCs.
Three important conclusions about the innate immune response in infants were made by this study: 1. Mucosal and systemic immune responses differ significantly between infants and young children (median age 5 years). Infants exhibit high levels of type I and II interferons (IFNs), inflammatory cytokines (IL-6, IL-8, TNF-a, and IL-17C), and different chemokines in the nasal mucosa, whereas children and adults show high levels of TNF-a, (interleukin) IL-6, OSM, EN-RAGE, and other inflammatory mediators.
(2.) Th17 response-related chemokines and cytokines were observed in the musical immune responses displayed by infants and kids. These results imply a role for Th 17 cells and neutrophils in the innate and adaptive immunity of infants against subsequent COVID-19 infection, especially when paired with high neutrophil densities observed in processed blood samples. 3. Upon first exposure to SARS-CoV-2, infants’ innate immunity was quickly triggered in both the mucosal and systemic systems, in contrast to patterns of delayed recruitment and compromised plasmacytoid dendritic and myeloid cell activation.
When considered collectively, these results imply that, by limiting viral replication in the nose, the quick development of mucosal immunity in the nasal tract may help to explain the disease’s mild course in newborns and early children.
Conclusions
For the first time, a multi-omics approach was used in the current study to examine the infant immune response to COVID-19 infection. The findings show a clear difference between infants’ and adults’ immune responses, both innate (i.e., infants’ immune systems are recruited far more quickly and effectively than adults’) and acquired (i.e., infants’ memory cell decay is significantly slower than adults’). This suggests that the immune systems of infants during their first year of life far outperform those of adults and, surprisingly, even the more mature immune systems of children five years older against highly virulent pathogens, including COVID-19.
“This opens up the possibility of developing adjuvants for vaccines that specifically target these non-canonical pathways of innate activation to elicit long-lasting antibody responses, without the immunopathology that frequently ensues from unintentional inflammation.”
