Comparative humoral profiles in mpox cases, survivors, and vaccinated individuals reveal correlates of protection against MPXV.

Mpox is regarded as the most important orthopoxvirus infection since the eradication of smallpox, yet the determinants of protective antibody responses remain poorly defined. Here, we investigate factors shaping humoral protection against MPXV and observe a moderate correlation between orthopoxvirus antibody levels and age among vaccinia virus (VACV)-vaccinated individuals. No correlation is found between orthopoxvirus-binding antibodies and gender. Pre-existing humoral immunity does not impair the induction of MPXV-specific antibody responses in mpox cases. Despite a high seropositivity rate for neutralizing antibodies in both mpox cases and vaccinated individuals, the overall titers remain modest. Quantitative analyses identify MPXV antigens A29, E8, and M1 on intracellular mature virion (IMV), together with A35 and B6 on extracellular enveloped virion (EEV), as the principal targets of neutralizing antibodies elicited during both MPXV infection and vaccination. Passive transfer of plasma from mpox patients and convalescents significantly reduces viral replication in vivo. These findings provide critical insights into the correlates of protection against MPXV.