Cytokine signatures associated with persistent antibody responses to multiple Plasmodium vivax blood-stage antigens
- Author(s)
- Moreira-Nascimento, SL; Nascimento, MFA; Fernandes, GM; Afonso, SL; Gunderman, VHG; Rodrigues, BA; Lopes, SCP; Fabbri, C; Lacerda, MVG; Almeida, GG; Longley, RJ; Mueller, I; Antonelli, Lrdv; Ntumngia, FB; Adams, JH; Teixeira-Carvalho, A; Carvalho, LH; Kano, FS;
- Journal Title
- Frontiers in Immunology
- Abstract
- 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.
- Publisher
- Frontiers
- Keywords
- Humans; *Plasmodium vivax/immunology; *Antigens, Protozoan/immunology; *Cytokines/immunology/metabolism; *Malaria, Vivax/immunology/parasitology/blood; *Antibodies, Protozoan/immunology/blood; Male; Female; Immunoglobulin G/immunology/blood; Adult; *Protozoan Proteins/immunology; *Antibody Formation/immunology; Young Adult; Receptors, Cell Surface/immunology; Follow-Up Studies; Malaria Vaccines/immunology; Immunity, Humoral; Duffy binding protein II; Plasmodium vivax; blood-stage antigens; cytokines; long-term humoral immunity; malaria vaccine
- Research Division(s)
- Infection and Global Health
- PubMed ID
- 42741167
- Publisher's Version
- https://doi.org/10.3389/fimmu.2026.1899417
- Open Access at Publisher's Site
https://doi.org/10.3389/fimmu.2026.1899417- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2026-10-02 08:18:58
Last Modified: 2026-10-02 08:19:08