Clinical Insights Into T-Cell Immunity After Pediatric COVID-19 mRNA Vaccination

In one of the first detailed investigations into cell-mediated immune responses to COVID-19 vaccination in children, the KidCOVE trial has shown compelling evidence suggesting that the mRNA-1273 vaccine elicits robust and durable T-cell responses in pediatric populations.

While prior focus has been on humoral immunity, this new analysis published in The Journal of Infectious Diseases emphasizes the vaccine’s capacity to activate a Th1-skewed CD4+ T-cell response, which may serve as a critical defense against evolving SARS-CoV-2 variants.

A Closer Look at T-Cell Immunity

The study evaluated a subset of 68 participants aged six months to 11 years from the phase 2/3 KidCOVE trial who received two doses of mRNA-1273 (25 μg for children six months to five years and 50 μg for those six to 11 years) or placebo. T-cell responses were assessed using intracellular cytokine staining and polyfunctionality assays at days 43 (14 days after the second dose) and 209 (180 days after second dose).

Key findings include:

• Th1-dominant CD4+ T-cell responses were detected in 92 to 100 percent of vaccine recipients by day 43 across all age groups, compared to 0 percent after placebo, and remaining detectable in 75-91 percent at day 209. These responses were marked by expression of IFN-γ and IL-2.
• Th2 CD4+ T-cell responses, which could indicate a more allergic or humoral bias, were detected in 50 percent (six to 23 months), 8 percent (two to five years), and 33 percent (six to 11 years) of participants. This response was lower in magnitude and prevalence, supporting Th1-skewing of the vaccine’s immune activation.
• CD8+ T-cell responses were notably age-dependent—undetectable in children under two, 15 percent in ages two to five years, and 44 percent in ages six to 11 years at day 43. This aligns with known developmental immunology, where CD8+ populations expand with age.

Additionally, the COMPASS model revealed that CD4+ T cells elicited by mRNA-1273 were highly polyfunctional and capable of co-expressing multiple cytokines (IFN-γ, IL-2, TNF, and CD40L) at day 43. These polyfunctional responses persisted through six months post-vaccination. By contrast, CD8+ T-cell polyfunctionality was more limited and confined to older children.

Notably, there was also a moderate to strong correlation (Pearson r = 0.748) between neutralizing antibody titers and CD4+ Th1 cell frequencies among vaccine recipients, suggesting a synergistic relationship between humoral and cellular immunity in the pediatric response to mRNA-1273.

Implications in the Age of Variants

These results carry particular weight given the emergence of immune-evasive variants like Omicron sublineages JN.1 and KP.3. Unlike antibodies, which target mutable surface epitopes on the spike protein, T-cells recognize conserved internal peptide fragments presented via MHC molecules. This makes them more resilient to viral escape mutations.

The presence of long-lived, polyfunctional Th1 memory T cells in vaccinated children may provide cross-variant protection, even in the face of waning antibody levels or variant-specific neutralization gaps. The findings bolster support for mRNA vaccination strategies that include young children, especially as updated variant-targeting formulations are deployed globally.

While promising, the study is exploratory in nature and limited by its small sample size and the inclusion of participants with intercurrent infections. Moreover, the cellular responses reported pertain to the ancestral SARS-CoV-2 strain, not the newer bivalent or variant-adapted vaccines currently in use. Still, the data represent a crucial step toward a more comprehensive understanding of pediatric vaccine immunology.

Reference
Rostad CA, Campbell JD, Paulsen GC, et al. Evaluation of cellular immune responses after mRNA-1273 vaccination in children 6 months to 11 years of age. J Infect Dis. 2025;231(5):e945-e955.