Prophylactic protection from lethal henipavirus disease mediated by Nipah-derived defective interfering particles is influenced by challenge virus strain and viral species

Authors: WELCH, STEPHEN - Centers For Disease Control And Prevention (CDC) - United States; SPENGLER, JESSICA - Centers For Disease Control And Prevention (CDC) - United States; HARMON, JESSICA - Centers For Disease Control And Prevention (CDC) - United States; COLEMAN-MCCRAY, JOANN - Centers For Disease Control And Prevention (CDC) - United States; GENZER, SARAH - Centers For Disease Control And Prevention (CDC) - United States; DAVIES, KATHERINE - Oak Ridge Institute For Science And Education (ORISE); SORVILLO, TERESA - Centers For Disease Control And Prevention (CDC) - United States; MONTGOMER, JOEL - Centers For Disease Control And Prevention (CDC) - United States; NICHOL, STUART - Centers For Disease Control And Prevention (CDC) - United States; SPIROPOULOU, CHRISTINA - Centers For Disease Control And Prevention (CDC) - United States; SCHOLTE, FLORINE - Centers For Disease Control And Prevention (CDC) - United States; RODRIGUEZ, SERGIO - Centers For Disease Control And Prevention (CDC) - United States

Submitted to: EBioMedicine
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 8/7/2025
Publication Date: 8/25/2025
Citation: Welch, S.R., Spengler, J.R., Harmon, J.R., Coleman-Mccray, J.D., Genzer, S.C., Davies, K.A., Sorvillo, T.E., Montgomery, J.M., Nichol, S.T., Spiropoulou, C.F., Scholte, F.E., Rodriguez, S.E. 2025. Prophylactic protection from lethal henipavirus disease mediated by Nipah-derived defective interfering particles is influenced by challenge virus strain and viral species. EBioMedicine. 119. Article 105897. https://doi.org/10.1016/j.ebiom.2025.105897.
DOI: https://doi.org/10.1016/j.ebiom.2025.105897

Interpretive Summary: Henipaviruses, including the Nipah and Hendra viruses, are highly lethal pathogens causing severe respiratory and neurological disease in humans. Mortality rates range from 30% to 80%, and no approved treatments are currently available. These viruses pose a serious global health threat, particularly in regions where outbreaks occur frequently. Here, we have explored the use of defective interfering particles (DIPs), naturally occurring virus-like particles that can disrupt normal viral replication, as a potential medical countermeasure (MCM). This study demonstrated that pre-exposure treatment with Nipah-derived DIPs can significantly reduce symptoms and increase survival rates in the small animal model of henipavirus disease (Syrian hamsters). The most effective treatment was given three days before infection, providing robust protection against both Nipah virus strains. We demonstrated that protection was specific to those viruses closely related to the original strain used to develop the DIPs, meaning the treatment was less effective against more genetically distant viruses like Hendra virus. This study provides strong evidence that DIPs could be developed as a preventive treatment for Nipah virus infections, offering a novel antiviral strategy for outbreak control and pandemic preparedness. These data highlight the potential of DIPs as a safe and easily administered preventive measure, paving the way for further research into their effectiveness against different viral strains. In the future, DIPs could become a valuable tool in fighting emerging viral threats and reducing the risk of deadly outbreaks.

Technical Abstract: Henipaviruses, including Nipah and Hendra viruses, are zoonotic pathogens capable of causing severe respiratory and neurological disease with high mortality rates in humans. Given the severity of disease, high pandemic potential of these viruses, and absence of approved treatments, development of safe and effective medical countermeasures targeting henipaviruses is considered a high priority. One potential strategy involves the therapeutic use of defective interfering particles (DIPs), naturally occurring virus-like particles lacking large portions of the viral genome. Here, we demonstrate that prophylactic DIP treatment can greatly reduce incidence of clinical signs and lethality in the Syrian hamster model of Nipah virus (NiV) disease. We also demonstrated that while single or repeated pre-exposure treatment regimens starting as late as 3 days prior to challenge can offer protection, post-exposure treatment was ineffective. NiV strain Malaysia-derived DIPs performed best to protect against NiV strain Malaysia but also offered robust protection against the closely related NiV strain Bangladesh with certain treatment regimens. However, these DIPs offered minimal, if any, protection from lethality against the more distantly related Hendra virus, indicating a direct inhibition mechanism of action. These data inform future DIP development and suggest that DIPs may offer significant promise as pre-exposure treatment for henipavirus infections, providing a critical peri-exposure preventative option to complement existing preventative treatment modalities.