Early for a complete scenario of MPXV Tecovirimat-resistance individual mutations and multi-mutations (mutants), representative studies of the 2022 outbreak mapped the most important F13L amino acid mutations emerging on Tecovirimat-treated 26 patients (Figure , Table ). This previous work may constitute the largest number and best characterized Tecovirimat-resistant MPXV isolates from humans reported to date . All those 2022 MPXV isolates belonged to the clade IIb lineage B.1, which codes for the F13L E353K mutation (unrelated to Tecovirimat resistance), compared to the reference MPXV strain isolated in 2003 or with the still partially characterized clade I of the most recent 2024 outbreak . Together with other sources of possible Tecovirimat-resistant mutations and because it is not yet clear which of the individual-or multi-mutation mutant isolates could be the main responsible of the Tecovirimat-resistance or alternatively be required for poxviral survival, the models studied here included the most abundant mutations reported from several sources (Figure , green and red circles), including: i) earliest reported poxvirus F13L mutations generated by in vitro selection , ii) mutations found at F13L by screening healthy patients and iii) mutations isolated from Tecovirimat-treated patients (Table ).