Launch of the IMPACT project to develop the first antibody-based countermeasure for orthopoxviruses

Starting on 1 June, the IMPACT project aims to develop the first antibody-based countermeasure for orthopoxviruses. The project targets both variola major virus (VARV) and monkeypox virus (MPXV) with a single antibody. With the contribution of the European Union under the Horizon Europe programme, IMPACT will strengthen Europe’s biodefence preparedness and responsiveness to epidemic and deliberate threats.

The eradication of smallpox in 1980 remains a major milestone in global health. However, the discontinuation of vaccination campaigns has led to a gradual decline in immunity to orthopoxviruses worldwide. Today, an estimated 75–90% of the global population lacks immunity to variola virus , and therefore is vulnerable.

Recent outbreaks of monkeypox virus (MPXV), including the global spread of Clade IIb in 2022 and recurrent Clade Ib epidemics in Central Africa in 2024, demonstrate the virus’s increasing ability to adapt and sustain human-to-human transmission. In addition, the threat of accidental release, deliberate misuse, or re-emergence of related zoonotic orthopoxviruses has been repeatedly highlighted in international health security assessments.

Orthopoxviruses are one of the most complex viral families characterised by diverse structures and immune evasion strategies. The high heterogeneity, understudied protein landscape and diversity of envelope-associated proteins pose significant challenges to development of therapeutic and vaccines using conventional approaches.

The IMPACT is a public-private consortium made up of 11 institutions from 5 European countries and the Democratic Republic of Congo. The project brings together leading European organizations, many belonging to the European Vaccines Hub (EVH) network, including the Fondazione Biotecnopolo di Siena where the monoclonal antibody (mAb) was discovered. The entire network has proven expertise in structural biology, computational modelling, immunology, virology, pre-clinical models, GMP manufacturing, regulatory science, and clinical trial execution. The project is coordinated by the Sclavo Vaccines Association, a non-profit organization based in Siena dedicated to advancing vaccine research and development.

The IMPACT project focuses on broadly neutralising monoclonal antibodies (mAbs) targeting OPG153, a conserved antigen recently discovered thanks to the use of the Reverse Vaccinology 3.0, a novel approach that combines human immunology, structural biology and artificial intelligence. These mAbs combine high potency, dual neutralisation of mature and extracellular virions, and cross-neutralisation across MPXV clades and related orthopoxviruses in a single molecule.

IMPACT will integrate AI-driven optimisation of monoclonal antibodies mAbs and protein engineering to enhance antibody efficacy. Selected candidates will be tested in preclinical models, followed by GMP manufacturing and evaluation in a Phase I clinical trial. In parallel, under the project more than 1,800 human sera samples from infected and vaccinated individuals will be analysed to characterise the immune responses to OPG153 and identify correlates of protection, supporting future regulatory approval.

IMPACT project will provide a scalable and globally relevant antibody-based countermeasure against orthopoxviruses, integrating discovery, preclinical validation, GMP manufacturing, and first-in-human clinical evaluation. By combining world-class science with European strategic infrastructures, IMPACT will deliver not only a deployable first-in-class therapeutic but also a decisive biodefence tool, reinforcing Europe’s leadership and resilience against epidemic and biothreat pathogens.