OPX-IMMUNE

This research program aims to define the quality and breadth of human immune responses to orthopoxviruses, with a particular focus on mpox virus (MPXV) and emerging related viruses. Despite the historical success of smallpox vaccination, the extent to which vaccine- or infection-induced immunity confers cross-protection against antigenically distinct orthopoxviruses remains poorly understood.

To address this, we established multicountry human cohorts including individuals vaccinated with first-generation (Dryvax) and third-generation (MVA-BN/Jynneos) smallpox vaccines, as well as individuals recovering from mpox infection. Using these cohorts, we systematically evaluate antibody binding, neutralization capacity, and cellular immune responses, including antigen-specific CD4⁺ and CD8⁺ T cell responses, across multiple orthopoxviruses, including vaccinia virus (VACV), MPXV clades Ia, Ib, and IIb, and emerging related viruses.

Our work integrates whole-virus serological assays with antigen-specific analyses, monoclonal antibody characterization, and B cell profiling to define memory B cell populations and clonal expansion patterns associated with vaccination and infection. Recent findings from our group demonstrate that, although cross-reactive antibody binding across orthopoxviruses is common, neutralizing activity is often limited in magnitude and breadth, particularly against antigenically divergent viruses. In parallel, cellular immune analyses indicate the presence of durable and cross-reactive T cell responses, highlighting complementary layers of immune protection beyond neutralizing antibodies.

In parallel, we leverage structural and sequence-based analyses to map antigenic differences across orthopoxvirus surface proteins and assess how these differences impact antibody recognition and B cell clonal selection. This integrated approach enables us to link population-level immune responses with molecular determinants of immune escape and immune memory.