Treatment paradigms for measles-like immune amnesia and exacerbated disease after virus co-infection in ferrets

After years of COVID-19 pandemic, over 40 million children worldwide are at risk of measles due to halted vaccination and temporary SARS-CoV-2 viral dominance. Acute measles has a case-fatality rate of ~1%, but most morbidity and mortality arises post-measles due to destruction of pre-existing immune memory by lymphotropic measles virus (MeV), a paramyxovirus of the Morbillivirus genus. Post-exposure measles vaccination is ineffective and little is known about the effect of unrelated respiratory virus disease history on measles severity. Using a lethal canine distemper virus (CDV)-ferret model as a surrogate for human morbillivirus disease and the orally efficacious broad-spectrum paramyxovirus polymerase inhibitor GHP-88309, we established in this study measles treatment paradigms. Having engineered a receptor tropism-intact low-lethal CDV recombinant (recCDV), we confirmed the morbillivirus immune amnesia hypothesis in an animal model and mapped a 7-day advantage over therapeutic vaccination to preserve preexisting immune memory through treatment. Infection of ferrets with non-lethal influenza A virus (IAV) A/CA/07/2009 (H1N1) or respiratory syncytial virus (RSV) four weeks before infection with recCDV caused exacerbated CDV disease rapidly advancing to fatal hemorrhagic pneumonia due to lung colonization with commensal bacteria. RNAseq of BALF samples and lung tissue identified upregulated trefoil factor family (TFF1/2/3) expression in animals infected with CDV versus those pre-infected with IAV followed by CDV, highlighting immune priming by unrelated respiratory viruses as determinant for altered response to morbillivirus infection. Non-invasive monitoring through pulmonary ferret MRI revealed that late-onset oral GHP-88309 reverses outcome even when treatment is initiated after peak CDV clinical signs. This study validates the morbillivirus immune amnesia hypothesis, defines treatment paradigms for measles, identifies prior disease history as risk factor for exacerbated morbillivirus disease, and establishes precedent for therapeutic benefit from a direct-acting oral antiviral administered after the window for mitigation of primary morbillivirus clinical signs has closed.