The immune system in early-life is shaped by both intrinsic trajectories and environmental influences, reflecting a dynamic balance between genetic regulation and epigenetic plasticity. These developmental trajectories remain poorly understood, limiting our ability to distinguish patterns of healthy immune development from those predisposed to disease. A deeper understanding of immune ontogeny is essential to guide the design of immunomodulatory strategies, including vaccines, that are optimally tailored to protect infants during this vulnerable window of life.

Cytokines and chemokines are soluble molecules acting on both the innate and adaptive immune system [1]. Those key proteins regulate inflammation as well as various cellular processes including immune signaling, growth, and differentiation [[1], [2], [3]]. With pro- and anti-inflammatory properties, as well as T-helper cell (Th)-polarizing activities, they play a critical role in inducing and controlling inflammation following infection [[4], [5], [6]]. In humans, cytokines and chemokines are highly dynamic and change in response to multiple factors including age, sex, microbial exposures, vaccination, disease status, body weight, and seasonality [[7], [8], [9], [10], [11], [12], [13], [14], [15]]. Several studies have identified immune signatures in early life [[16], [17], [18]]. After birth, plasma concentrations of cytokines and chemokines, including IFNγ, IL-2, IL-4, IL-12p70 and TNF, increase with age [[19], [20], [21], [22], [23], [24]], while CXCL8, IL-10, and TGFα levels decrease [25,26].

While efforts are being done to characterize trajectories of plasma cytokines and chemokines, more remains to be learned. Characterizing the immune development in healthy term infants is essential for defining the immunological baseline and identifying immune modulation associated with diseases and interventions. Additionally, longitudinal quantification of plasma cytokine and chemokine concentrations in pediatric cohorts provides valuable insights, by following the same participants over time, however collation of these cohorts poses several challenges, including participant retention and limited sample volumes. Investigating immune ontogeny in distinct populations that vary by genetics and/or environmental exposures allows for a broader understanding of immune development in early life, ultimately improving standards of care globally.

In this study, plasma cytokine and chemokine concentrations were measured across the first four months of life in a longitudinal infant cohort in Papua New Guinea (PNG), Oceania. We assessed whether the observed ontogenetic patterns were associated with demographic factors such as maternal age, gestational age, sex, and season of birth. Here, we demonstrated that clusters of plasma cytokines and chemokines showed dynamic patterns of trajectories across the first four months of life in the PNG cohort. Plasma concentrations of cytokines and chemokines such as CCL2, CXCL8, IL-6, and TGFα decreased, while other cytokines and chemokines such as CXCL10, IL-2, IL-12p70, and IFNγ increased from day of life (DOL)-0 to −128 (∼ 4 months of age). Ontogenetic trajectories had a greater impact on plasma cytokine and chemokine concentrations than demographic factors. These findings provide a deeper understanding of plasma cytokine and chemokine trajectories in early life, providing insight into healthy development in this distinct and vulnerable population.