A major European research initiative launched on June 1st to develop the first antibody-based treatment that could protect against both monkeypox and smallpox. The IMPACT project brings together 11 institutions across five European countries and the Democratic Republic of Congo to create a single therapeutic molecule capable of neutralizing multiple orthopoxviruses, the viral family that includes both monkeypox and variola (smallpox) viruses.

Why Is a New Orthopoxvirus Treatment Needed Now?

The urgency behind this project stems from a critical vulnerability in global immunity. Since smallpox was eradicated in 1980, vaccination campaigns stopped worldwide. Today, an estimated 75 to 90 percent of the global population lacks immunity to variola virus and therefore remains vulnerable to infection. Meanwhile, monkeypox has demonstrated an alarming ability to adapt and spread between humans, with the Clade IIb variant spreading globally in 2022 and recurrent Clade Ib epidemics occurring in Central Africa in 2024.

Beyond natural disease threats, international health security assessments have repeatedly highlighted concerns about accidental release, deliberate misuse, or re-emergence of related zoonotic orthopoxviruses. These complex viruses employ sophisticated immune evasion strategies, making them particularly challenging to target with conventional vaccine and therapeutic approaches.

How Does the IMPACT Project Work?

The IMPACT initiative focuses on developing broadly neutralizing monoclonal antibodies, which are laboratory-engineered proteins that mimic the body's natural immune response. The project targets a conserved antigen called OPG153, recently discovered using Reverse Vaccinology 3.0, a cutting-edge approach that combines human immunology, structural biology, and artificial intelligence.

The research strategy involves several interconnected steps:

• AI-Driven Optimization: Researchers will use artificial intelligence to enhance the potency and effectiveness of monoclonal antibodies and improve protein engineering to create more powerful therapeutic candidates.
• Preclinical Testing: Selected antibody candidates will be tested in laboratory models before advancing to human trials, ensuring safety and efficacy.
• Manufacturing and Clinical Trials: The project will establish good manufacturing practice (GMP) production standards and conduct Phase I clinical trials, the first stage of human testing in a small group of volunteers.
• Immune Response Analysis: Researchers will analyze more than 1,800 human serum samples from infected and vaccinated individuals to understand immune responses and identify protective markers that support future regulatory approval.

The monoclonal antibodies being developed demonstrate dual neutralization capabilities, meaning they can target both mature viruses and extracellular virions (virus particles outside cells). Importantly, these antibodies show cross-neutralization across different monkeypox clades and related orthopoxviruses in a single molecule, offering broad protection.

Who Is Leading This European Effort?

The IMPACT consortium represents a strategic partnership combining world-class scientific expertise with European biodefense infrastructure. The project is coordinated by the Sclavo Vaccines Association, a non-profit organization based in Siena, Italy, dedicated to vaccine research and development. Many participating institutions belong to the European Vaccines Hub network, including the Fondazione Biotecnopolo di Siena, where the original monoclonal antibody was discovered.

"This project has the unique opportunity to develop a new tool to prevent and cure infections from monkeypox and other poxviruses, thus providing a safety net able to protect against natural or deliberate exposures to these dangerous viruses," said Dr. Emanuele Andreano, Head of Serology and Immunology at Fondazione Biotecnopolo di Siena and co-leader of the IMPACT project.

Dr. Emanuele Andreano, Head of Serology and Immunology, Fondazione Biotecnopolo di Siena

The Institute of Tropical Medicine (ITM) in Antwerp is contributing unique patient cohorts and cutting-edge antibody measurement expertise to the initiative. ITM provides access to groups of monkeypox patients and vaccinated individuals whose biological samples and clinical data are invaluable for understanding immune responses.

"ITM is proud to contribute to the IMPACT project by providing access to our unique cohorts of monkeypox patients and vaccinees, combined with cutting-edge antibody measurement expertise. This strategic European cross-sector partnership will play an important role in strengthening global health preparedness," stated Prof. Joachim Mariën.

Prof. Joachim Mariën, Institute of Tropical Medicine

What Makes This Approach Different?

Traditional vaccine and therapeutic development relies on conventional approaches that often struggle with the structural complexity and diversity of orthopoxviruses. The IMPACT project takes a fundamentally different path by integrating discovery science, artificial intelligence, and structural biology from the outset. By identifying and targeting OPG153, a conserved antigen shared across multiple orthopoxviruses, researchers can create a single therapeutic molecule effective against multiple threats.

The project's emphasis on analyzing immune responses in naturally infected and vaccinated individuals provides real-world data that supports regulatory pathways. This approach accelerates the translation from laboratory discovery to clinical application while building the scientific evidence base needed for approval.

"IMPACT represents a strategic effort to strengthen Europe's preparedness against emerging infectious diseases and biodefence threats. By leveraging the integrated infrastructure and expertise of the European Vaccines Hub, the project will reinforce Europe's capability to rapidly develop and deploy innovative countermeasures against future epidemic and pandemic threats," explained Prof. Rino Rappuoli, Scientific Director of Fondazione Biotecnopolo di Siena and Coordinator of the IMPACT project.

Prof. Rino Rappuoli, Scientific Director, Fondazione Biotecnopolo di Siena

The IMPACT project represents a significant step forward in global health preparedness. By developing a scalable, antibody-based countermeasure against orthopoxviruses, the initiative aims to provide both a deployable therapeutic for treating infections and a strategic biodefense tool for protecting populations against epidemic and deliberate threats. The project's integration of European scientific infrastructure, combined with funding from the European Union's Horizon Europe programme, signals a commitment to strengthening global resilience against emerging infectious disease threats.