Using defective antiviruses to fight flu pandemics

Scientists at the Max Planck Institute in Magdeburg are paving the way for new antiviral treatments

A new type of antiviral drug could offer more effective prevention and treatment of viral infections like influenza: so-called defective interfering particles (DIPs). Scientists of the Max Planck Institute in Magdeburg have discovered a novel, highly effective class of DIPs and have set the stage for the development of such drugs by implementing initial steps to realise an industrial-scale production process. A contribution to the Yearbook 2025/2026 of the Max Planck Society.

Influenza A viruses (IAV) cause significant strain on medical systems worldwide. Year after year, epi-
demics lead to high rates of illness and death, while newly emerging strains carry the potential to trigger 
severe pandemics. Although vaccination remains the most effective preventive measure, adapting vaccines to seasonal strains and producing them in sufficient quantities is a time-consuming process.

Furthermore, the human adaptive immune response requires several weeks to build up robust pro-
tection. Antiviral drugs (“antivirals”) play a vital role in closing this gap. Clinically established antivirals, such as oseltamivir and zanamivir, are fast-acting, low-molecular-weight substances. However, influenza viruses frequently mutate during replication, allowing them to easily develop resistance. This limits the effectiveness of current treatments and creates a need for new antiviral agents that are broadly effective, rapidly deployable, and highly resilient to viral mutation.

 

Defective interfering particles as potential universal antivirals

The use of defective interfering particles (DIPs) represents a promising new approach. These faulty viruses are created naturally through errors that occur during viral replication. Due to their partially deleted genetic material, DIPs are unable to reproduce independently and therefore cannot cause disease. They can, however, interfere with the replication of infectious “wild-type” viruses if they infect a host simultaneously with the pathogen.

Though incapable of reproducing, they still claim cellular and viral resources, as cells continue to produce proteins based on the faulty blueprints of the DIPs. Yet no new viruses are created from these defective or incomplete virus building blocks. In this way, they suppress or hinder the formation of infectious virus particles. Additionally, they stimulate the interferon system, a cellular alarm system that inhibits virus multiplication and activates antiviral genes. This creates a broadly effective antiviral state in infected cells.

DIPs of the influenza A virus are effective not only against epidemic and pandemic IAV, but also against other respiratory viruses, including the influenza B virus, SARS-CoV-2 and the respiratory syncytial virus (RSV). Particularly in situations where vaccines or other antiviral drugs are not yet available, DIPs could represent a valuable addition to the pandemic preparedness toolbox. It is considered very unlikely that resistance to DIPs could develop. To date, no IAV strain has been described that has developed resistance to DIP-mediated inhibition.

Ideally, they would be used preventatively as a nasal spray, but they also have a therapeutic effect during the onset of an infection, helping to prevent severe illness. Administration via a nasal spray has the advantage of being aligned with the natural infection process and such delivery methods are already established for human vaccines. This would allow for direct treatment at the primary site of infection.

Due to the defect in virus replication, the administration of DIPs is considered very safe and well-tolerated. Animal experiments using DIPs of various virus types showed no toxic effects, such as inflammation, pathological changes in lung tissue or clinical symptoms of disease.

OP7: a novel, particularly effective DIP

In our basic research, we discovered a novel type of DIP called OP7. It is the first known DIP whose defect consists of point mutations – the exchange of individual letters in the genetic blueprint – rather than completely deleted genes. Previously, such point mutations had not been taken into account in DIP research. In preclinical studies, OP7 demonstrated a stronger antiviral effect than conventional influenza virus DIPs.

To produce OP7 as a medicine, we developed production methods in bioreactors using animal cell cultures. Due to their replication defect, DIPs cannot easily multiply in standard animal cells. We therefore modified the cell lines to provide the missing viral functions. This allows us to produce OP7 without creating any infectious material – a key requirement for safe clinical usage.

We tested the purified OP7 particles, produced in the bioreactor, in mice in collaboration with the Helmholtz Centre for Infection Research in Braunschweig. We observed a remarkable antiviral effect: following the intranasal application of OP7, all animals survived an otherwise fatal IAV infection. These investigations are supported by extensive systems virology studies on the co-infection of IAV and OP7 in cell models. Thanks 
to these mathematical simulations, we not only understand the mechanisms of action of OP7 better, but can also predict optimal dosage regimes, thereby supporting future clinical trials.

From lab to clinical use

To prepare the transition to clinical testing, we have initiated key steps to establish a production process that meets the 'Good Manufacturing Practice' (GMP) standards of the pharmaceutical industry. This includes the production of qualified cell and virus banks, created in collaboration with the Fraunhofer Institute for Toxicology and Experimental Medicine in Braunschweig. Our aim is to establish the foundation for toxicological investigations and initial clinical studies.

Through our extensive preliminary work on the efficacy, toxicity and production of OP7, protected by 
two patents, we have significantly reduced the development risk for potential industrial partners. Overall, we are demonstrating a realistic path to attract pharmaceutical companies early on to produce this novel class of antivirals, enabling them to take over further clinical development.

Full text and all illustrations in the Yearbook Highlights of the Max Planck Society (PDF)
https://www.mpg.de/26813955/yearbook-highlights-2025.pdf