A simplified antigen-based serological algorithm accurately classifies MPXV exposure and vaccination status

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ABSTRACT Reliable serological tools are needed to measure mpox virus (MPXV) exposure, evaluate vaccine-induced immunity, and support population-level surveillance. Using a previously established six-antigen serological reference framework, in which seropositivity was defined as reactivity to ≥4 of 6 MPXV antigens, we evaluated the diagnostic performance of individual antigens and all 15 pairwise combinations. B6R demonstrated the highest overall individual discriminatory performance, whereas A35R showed maximal sensitivity and M1R the highest specificity. The A35R+B6R combination most closely approximated the full multiplex assay (AUC 0.93), supporting simplified, scalable MPXV serological assays for surveillance and vaccine evaluation.

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