Could infants’ robust immune responses reshape future vaccination strategies?

In a recent study published in the journal Cell, researchers employed a range of next-generation sequencing techniques, including the assay for transposase-accessible chromatin with sequencing (ATAC-seq) and single-cell RNA sequencing (scRNA-seq) to elucidate the system-wide immune responses of children in their first few weeks of life to infections. Their findings reveal that the immune responses of this unique cohort of individuals starkly contrast those of adults and, surprisingly, even those of young children aged five years and above.

While the former groups show a combination of both innate and acquired immune activation, infants present a solely innate immune response. These findings could help inform future child vaccination research and equip pediatricians with the knowledge to effectively manage infection in newborns.

Study: Multi-omics analysis of mucosal and systemic immunity to SARS-CoV-2 after birth. Image Credit: Phonlamai Photo / Shutterstock

Immunity and childhood infection

Immune responses are of two broad types – innate and acquired. The innate immune system is the body’s first line of defense against pathogens. This genetics-derived immunity responds in the same way to all germs and foreign substances, which is why it is sometimes referred to as the “nonspecific” immune system. In contrast, acquired immunity is also called “specific immunity” because it tailors its response to a specific antigen previously encountered. Its hallmarks are its ability to learn, adapt, and remember.

While innate immunity remains largely unchanged from birth through life, acquired immune response varies from individual to individual given specific antigen exposure, either through direct environmental exposure or vaccination. Antigen exposure, in turn, results in the priming of the immune system via antibody production. The type and abundance of these antibodies contribute to an adult’s ability to fight subsequent exposure to the same or highly similar antigens.

Prior research has revealed that immunity in adults and children performs significantly differently in both composition and function. The first few weeks of life are known to have a profound maturation effect on the subsequent immunity of a child through adulthood. While scientists have explored this maturation in children aged five and above, and recent work has attempted the same in healthy infants, no studies thus far have investigated the direct responses of newborns’ innate immunity to infections within the critical maturation period.

This distinction is essential to investigate given that children aged five have already developed a relatively mature immune system and thus may potentially respond very differently to infants without any immune system maturity.

About the study

In the present study, researchers used severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) data from infants to answer three primary questions – (1.) Since newborns only have nascent immune systems available to counter environmental infection, how do their T and B cells respond to and develop memory in the face of a pathogen? (2.) Pediatric coronavirus disease 2019 (COVID-19) has been observed to be much more symptomatically mild compared to adults’ disease response. Given this observation, what are the hallmarks of infants’ immune response that bring about these patterns?; (3.) Studies in adults and children have elucidated long-lasting epigenetic changes and autoimmune antibody generation. Are these patterns replicated in newborns?

To answer these questions, researchers employed a next-generation multi-omics approach to analyze and profile SARS-CoV-2 and its resultant immune activation in infants in their first few weeks and months of life. Blood (125 samples) from both infants and young children enrolled in the IMPRINT study cohort from the Cincinnati Children’s Hospital Medical Center were collected and screened weekly for COVID-19. These samples revealed 54 infection cases (case-cohort) and 27 uninfected controls. Blood analyses revealed that 32 infants were infected with pre-Omicron COVID-19 variants, while the remaining presented Omicron (or its variants).

To compare infant findings against those of adults, 62 blood samples representing 48 adult COVID-19 cases and 10 healthy controls were collected from the Hope Clinic at Emory University in Atlanta, and 47 blood samples representing 41 infected mothers and 3 healthy controls from the Stanford University Medical Centre.

Anti-Spike electrochemiluminescence (ECL) binding enzyme-linked immunosorbent assay (ELISA) was used to investigate antibody titers (both binding and neutralizing) against pre- and Omicron COVID-19 variants. Autoantibody response was subsequently measured using a custom ELISA against IFNa2 analysis of plasma samples. To further elucidate the adaptive immune responses in infants, the kinetics of COVID-19-specific memory T and B cells were investigated.

Since severe COVID-19 infection has been previously shown to follow dysregulations in innate immune responses (in adults), researchers measured the kinetics of plasma cytokine responses using principal-component analysis (PCA) of cytokines separated by type and abundance. To elucidate the cellular dynamics of immune responses, mass cytometry was employed to analyze peripheral blood leukocytes. This analysis was followed up by single-cell RNA sequencing (scRNA-seq) to further insights into the activation state of various immune cells. Herein, gene expression and chromatin accessibility profiles of adults before, during, and after were compared with those of infants displaying mild infection.

The assay for transposase-accessible chromatin with sequencing (ATAC-seq) was used to reveal system-wide modifications in chromatic accessibility during COVID-19. Finally, nasal swab samples were analyzed through PCA to determine the differences between newborns’ and young children’s mucosal immune responses.

Study findings

This multi-omics study revealed that while antibodies against COVID-19 rapidly decay in adults (allowing for repeat infection from the same COVID-19 variant), memory T and B cells in infants depict robust and long-lasting responses against SARS-CoV-2. While adult antibodies are known to almost completely decay in 120 days following COVID-19 infection, infants’ antibodies showed almost no change in ELISA titers over the 300-day duration of this study. This data is confounded by the differences in results from pre-Omicron and Omicron SARS-CoV-2 variants of concern (VOCs).

While antibodies against the former did not decay over time, B cells against the latter did. Additionally, T cells, known to mutate and evolve at a slow rate, did not change on infection by an Omicron variant following pre-Omicron infection, suggesting that while infants’ innate immunity far outperforms that of adults in the COVID-19 context (none of the infants under study ever presented severe COVID-19 symptoms), they immune systems may potentially be overwhelmed on repeated COVID-19 exposure comprising different VOCs.

This study revealed three key findings regarding infant innate immune response – (1.) Infants and young children (median age 5 years) depict very different mucosal and systemic immune responses. While children and adults present high levels of TNF-a, (interleukin) IL-6, OSM, EN-RAGE, and other inflammatory mediators in the nasal mucosa, infants depict high levels of type I and II interferons (IFNs), inflammatory cytokines (IL-6, IL-8, TNF-a, and IL-17C), and various chemokines.

(2.) Infants and children presented musical immune responses characterized by chemokines and cytokines associated with the Th17 response type. When combined with high observed neutrophil densities in processed blood samples, these findings suggest crosstalk between Th 17 cells and neutrophils, which may play a crucial role in both the innate and adaptive immunity of infants against subsequent COVID-19 infection. (3.) Innate immunity in infants was rapidly activated in both mucosal and systemic systems, contrasting patterns of slow recruitment and defective plasmacytoid dendritic- and myeloid cells during initial SARS-CoV-2 exposure.

“Taken together, these findings suggest that the rapid induction of mucosal immunity in the nasal tract might contribute to the mild course of disease in infants and young children by containing viral replication in the nose.”

Conclusions

In the present study, the research employed a multi-omics approach to investigate infant immune response to COVID-19 infection for the first time. Results highlight a stark contrast between the immune responses of infants and adults, both innate (wherein infants’ immune systems are recruited far more rapidly and effectively than those of adults) and acquired (wherein memory cell decay in infants is much slower than that observed in adults). This implies that against highly virulent pathogens, including COVID-19, the immune systems of infants during their first year of life far outperform that of adults and, surprisingly, even the more mature immune systems of children five years their senior.

“This raises the prospect of devising vaccine adjuvants that target such non-canonical pathways of innate activation to stimulate persistent antibody responses, without the collateral immunopathology that often results from unwanted inflammation.”