Cytokine signatures associated with persistent antibody responses to multiple Plasmodium vivax blood-stage antigens

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Introduction Long-term humoral immunity to Plasmodium vivax remains poorly understood, particularly the mechanisms sustaining persistent antibody responses to Duffy Binding Protein region II (DBPII), a key vaccine candidate. Here, a 15-year follow-up study of Amazonian malaria-exposed individuals investigated major cytokine pathways associated with sustained IgG responses to DBPII-related antigens, including DEKnull-2, an engineered immunogen targeting conserved DBPII epitopes. Methods As a proof-of-concept, this study was designed to compare two well-defined immunological phenotypes among P. vivax- exposed individuals: (i) Persistent Responders (PR, n = 11), who developed a long-lasting strain-transcending anti-DBPII immune response, defined here as sustained antibody responses to both DBPII and DEKnull-2, together with detectable binding-inhibitory antibody activity (BIAbs), throughout the follow-up period; and (ii) Non-Responders (NR; n = 14), who showed no detectable antibody response or BIAbs activity during follow-up. Cytokine responses were measured in supernatants of PBMC cultures stimulated with DBPII or DEKnull-2 by cytometric bead array (CBA), and IgG breadth was assessed using a panel of 16 P . vivax blood-stage antigens using Bio-Plex assay. Results Regardless of the antigen used for stimulation, P. vivax -exposed individuals (NR and PR) exhibited lower IL-6 and TNF levels than malaria-naïve non-exposed controls (NE, n = 14). Notably, the PR subgroup displayed a distinct profile characterized by a coordinated increase across inflammatory and anti-inflammatory cytokines. Even without antigen-specific stimulation, the PR group showed a distinct cytokine profile compared with NE controls, suggesting that host-intrinsic factors may influence DBPII-specific immune responses. Finally, PR (but not NR) displayed broader long-lasting antibody responses to multiple P. vivax blood-stage antigens, even in the absence of frequent reinfection-induced boosting. Conclusion Overall, these findings suggest that the PR profile is associated with a distinct and balanced cytokine profile. Our hypothesis-generating findings may improve our understanding of immune responses to P. vivax blood-stage antigens and inform future vaccine development.

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