Therapeutic advances in Lassa fever: From ribavirin to mechanism-based antivirals and monoclonal antibody combinations

Lassa fever is a zoonotic viral haemorrhagic disease that is a public health problem in West Africa, and has become a concern for global health security. The clinical efficacy of ribavirin is still unknown, although the drug has been used for over 40 years; evidence is mainly from observational studies, and efficacy seems to be highly dependent on its early use. Recent developments in Lassa virus (LASV) biology, structural virology, and translational pharmacology have led to rapid progress in the development of mechanism-based therapeutic agents targeting different stages of the viral life cycle. This review critically reassesses the role of ribavirin as a historical comparator, the ongoing need for optimized supportive care, and the evaluation of emerging candidates, particularly favipiravir, LHF-535, and 4′-fluorouridine (4′-FlU). We also discuss the emerging data for broadly neutralizing monoclonal antibody (mAb) therapies that have shown great promise in nonhuman primate models for protection from the onset of viremia and clinical disease. Special emphasis is placed on rational combination strategies that combine both anti-viral and monoclonal antibodies to maximize antiviral activity, increase the therapeutic window, and minimize the likelihood of treatment failure. We also address frameworks for stage-specific treatment, therapeutic issues in special populations, and barriers to translation in endemic settings. Overall, current evidence suggests a shift from empirical antiviral therapy to mechanism-driven therapeutic strategies according to the stage. Success will require an adaptive clinical trial platform, strong pharmacological evaluation of new drugs within varied patient demographics, and reinforcement of a healthcare system infrastructure equipped to provide advanced therapeutics in resource-limited settings.