This study screened plasma from 51 P. vivax-infected adults in Thailand to identify inhibitory B cell epitopes on P. vivax circumsporozoite protein (PvCSP), then isolated monoclonal antibody GRAM-4 targeting the newly identified PvCSP-B/NAGG epitope and tested its ability to block sporozoite traversal, hepatocyte invasion, and liver-stage development (schizonts and hypnozoites) in vitro using Thai field isolates.
Two non-repeat neutralizing epitopes were identified: PvCSP-A (N-terminal, residues 50–68) and PvCSP-B/NAGG (residues 247–265). Monoclonal antibody GRAM-4, targeting PvCSP-B/NAGG, potently inhibited hepatocyte traversal and invasion at 0.53 mg/mL—reducing both schizonts and hypnozoites per well at a level statistically indistinguishable from the established repeat-targeting antibody 2F2—and induced CSP shedding (the CSP reaction) from sporozoite surfaces. A 2.65 Å crystal structure (PDB: 9YE2) revealed that GRAM-4 recognizes a minimal linear GNAG core motif.
All functional inhibition data are from in vitro assays only, with no in vivo P. vivax challenge validation; only a single murine monoclonal antibody was characterized per PvCSP domain due to limited field-isolate availability; and the peptide array format detects only linear epitopes, likely missing conformational targets.
No approved P. vivax vaccine exists; these findings identify PvCSP-B/NAGG as a validated, structurally defined neutralization target outside the central repeat region, providing a concrete blueprint for next-generation P. vivax vaccine immunogen design. Clinicians should be aware this work is preclinical—human antibody and in vivo confirmation are still needed before clinical translation.
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