Summary: Infants hospitalized with severe COVID-19 mount an immune response that is strikingly different from that of adults and older children. Researchers observed simultaneous elevation of interferon-driven antiviral responses and pro-inflammatory signals—an unusual combination not previously seen with other viral infections in infants.
T and B cells in these infants remained largely naïve yet showed high levels of activation, and some infants even generated their own strong antibody responses despite their young age. These results indicate that infant immunity follows distinct patterns and may require age-specific approaches for treatment, prevention and clinical care.
Key Facts:
- Concurrent interferon and inflammation: Infants demonstrated high interferon activity alongside elevated inflammatory cytokines—an uncommon combination in viral disease.
- Naïve but activated lymphocytes: CD4 and CD8 T cells and B cells were largely antigen‑naïve but displayed clear activation signatures.
- Independent antibody production: Several infants produced robust SARS‑CoV‑2–specific antibodies early in life, even when maternal antibodies were present.
Source: St. Jude Children’s Research Hospital
Infants hospitalized with severe COVID-19 show distinct immune profiles compared with older children and adults.
A collaborative team from St. Jude Children’s Research Hospital, The Jackson Laboratory for Genomic Medicine, Weill Cornell Medicine, Nationwide Children’s Hospital, Icahn School of Medicine at Mount Sinai and Yale University analyzed immune cells from infants with mild, moderate and severe COVID-19 to identify age‑specific immune responses and features that could inform prevention and treatment strategies.
The peer‑reviewed study was published in Nature Communications.
“This study provides one of the first high‑resolution characterizations of the immune response in very young infants hospitalized with severe COVID‑19,” said co‑corresponding author Octavio Ramilo, MD, chair of the St. Jude Department of Infectious Diseases. “We discovered that the infant immune response to SARS‑CoV‑2 is fundamentally different from responses at other ages, underscoring the importance of studying infants specifically to prevent severe infections.”
The researchers examined immune cells from infants aged a few weeks to 16 months who were hospitalized with varying disease severity, comparing them to healthy infant controls and to published data from adults hospitalized with COVID‑19.
While monocytes (a type of white blood cell) in infected infants shared some similarities with adult monocytes in COVID‑19, T and B cells differed markedly. Hospitalized infants showed increased numbers of CD4 T cells, and both T and B cell populations displayed activation signatures despite being predominantly naïve—indicating activation without prior antigen experience.
Importantly, many infant immune cells exhibited strong expression of interferon‑stimulated genes (ISGs). The interferon signature in infant T and B cells was markedly higher than that seen in older children or adults, suggesting a unique antiviral activation state in early life.
Conflicting immune signals in infants
Nearly all immune cell types in infected infants showed elevated ISG expression. At the same time, blood measurements revealed high levels of inflammatory cytokines. This concurrent upregulation of antiviral interferon responses and inflammatory mediators contrasts with the more typical pattern in which one pathway is balanced against the other.
“We usually expect interferon responses and inflammation to be balanced—if one rises, the other declines,” said co‑first author M. Asunción Mejías, MD, PhD, of St. Jude’s Department of Infectious Diseases. “In these infants both systems were upregulated in the same cells, especially monocytes, which we have not observed in other respiratory viral infections.”
The team used single‑cell RNA sequencing (scRNA‑seq) of peripheral blood mononuclear cells to identify these patterns. This method profiles gene expression in individual cells, allowing precise identification of cell states and how they vary with disease severity. The researchers observed that greater disease severity correlated with higher interferon and ISG expression, and with increased inflammatory cytokine levels.
“We do not yet know whether these strong interferon and inflammatory signals help protect infants or contribute to severe illness,” Ramilo cautioned. “What is clear is that they play a critical role and warrant focused study.”
Infant antibody responses develop early and independently
B cells generate antibodies tailored to specific viruses. Infants typically benefit from maternal antibodies for the first months of life, but this study found that hospitalized infants often produced their own potent SARS‑CoV‑2 antibody responses. Preexisting maternal antibodies against common seasonal coronaviruses did not prevent infection.
“We were surprised that some infants, including those only weeks old, mounted strong new antibody responses to SARS‑CoV‑2,” said Mejías. “This contrasts with other respiratory viruses, where infants usually take longer to produce their own antibodies.”
The children studied did not have anti‑interferon autoantibodies—immune factors linked to severe COVID‑19 in some adults—highlighting that mechanisms driving severe disease in infants can differ from those in adults.
“As COVID‑19 becomes endemic, understanding the distinct features of infant immunity is essential to protect babies during their vulnerable first months,” Ramilo said.
Authors and funding
The study’s first authors include M. Asunción Mejías and Djamel Nehar‑Belaid (The Jackson Laboratory for Genomic Medicine). Co‑corresponding authors are Octavio Ramilo (St. Jude), Jacques Banchereau (The Jackson Laboratory for Genomic Medicine) and Virginia Pascual (Weill Cornell Medicine). Additional contributors came from St. Jude, The Jackson Laboratory for Genomic Medicine, Nationwide Children’s Hospital, Yale University and the Icahn School of Medicine at Mount Sinai.
Funding: The research was supported by grants from the U.S. National Institutes of Health, start‑up funds from The Jackson Laboratory, CRIPT (Center for Research on Influenza Pathogenesis and Transmission), the National Institute of Allergy and Infectious Diseases (Center of Excellence for Influenza Research and Response), and ALSAC, the fundraising and awareness organization of St. Jude.
About this COVID-19 and neurodevelopment research news
Author: Michael Sheffield
Source: St. Jude Children’s Research Hospital
Contact: Michael Sheffield – St. Jude Children’s Research Hospital
Image: The image is credited to Neuroscience News
Original Research: Open access.
“Immune perturbations induced by SARS‑CoV‑2 in infants vary with disease severity and differ from adults’ responses” by Octavio Ramilo et al., Nature Communications
Abstract
Immune perturbations induced by SARS‑CoV‑2 in infants vary with disease severity and differ from adults’ responses
Previous work has described immune differences between children and adults with COVID‑19, but systematic studies focusing on infants hospitalized with severe disease were lacking. Using a multidimensional approach, the authors profiled immune responses in SARS‑CoV‑2‑infected infants (n = 26; 10 subacute, 11 moderate and 5 severe; median age 1.6 months) and matched healthy controls (n = 14; median age 2 months).
Single‑cell RNA sequencing of peripheral blood mononuclear cells revealed broad shifts in cell composition and activation in infected infants. Most cell types shifted into an interferon‑stimulated gene (ISG‑high) state, including CD14+ monocytes co‑expressing ISGs and inflammasome‑related molecules, ISG‑high naive CD4+ T cells, proliferating cytotoxic CD8+ T cells with ISG signatures, and ISG‑high naive and transitional B cells.
The study detected increased serum levels of both interferons and inflammatory cytokines in infected infants. Antibody responses to SARS‑CoV‑2 were consistently observed in the absence of anti‑interferon autoantibodies. Compared with infected adults, infants displayed a similar ISG signature in monocytes but a markedly stronger ISG signature in T and B cells.
These results shed light on distinct immune responses to SARS‑CoV‑2 during the first year of life and emphasize the need to further define the unique features of early life immunity to guide clinical care and public health strategies.