Identity of virus-specific and cross-reactive T cell memory to mpox

The unprecedented spread of mpox (previously known as monkeypox) in several countries worldwide has led the WHO to declare the mpox outbreak a global health emergency in 2022. T cell responses are likely to play a central role in the resolution of the mpox infection. However, the prevalence and phenotype of mpox-specific T cells have not been investigated in detail, and the extent of cross-reactive immunological memory following previous smallpox vaccination is not known. Here, we assessed T cell responses to mpox infection in n=22 convalescent patients and n=53 healthy blood donors of different age groups, using CD4- and CD8-targeted peptide pools and optimal peptides through activation-induced marker (AIM), functional, and tetramer assays. We observed considerable CD4 and CD8 T cell activation among mpox patients in response to the peptide pools. Surprisingly, we did not detect differences between age groups of non-infected donors, despite previous exposure of older individuals to smallpox vaccination. Investigation of n=3 mpox-cross-reactive immunodominant vaccinia epitopes revealed that memory cells, although present, were maintained at comparable frequencies to naïve T cell precursors in older individuals. CD8+ T cells specific for the cross-reactive epitopes were significantly expanded and acquired an effector memory phenotype of elevated T-bet and Granzyme-B levels after mpox infection. Our data demonstrate low magnitudes of cross-reactive T cells against mpox across different age groups, whereas mpox infection leads to robust induction of effector memory T cells with strong recall potential. Supported by SNF Post-doc mobility grant (P500PB_211069)