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Nigeria continues to experience ever increasing annual outbreaks of Lassa fever (LF). The World Health Organization has recently declared Lassa virus (LASV) as a priority pathogen for accelerated research leading to a renewed international effort to develop relevant animal models of disease and effective countermeasures to reduce LF morbidity and mortality in endemic West African countries. A limiting factor in evaluating medical countermeasures against LF is a lack of well characterized animal models outside of those based on infection with LASV strain Josiah originating form Sierra Leone, circa 1976. Here we genetically characterize five recent LASV isolates collected from the 2018 outbreak in Nigeria. Three isolates were further evaluated in vivo and despite being closely related and from the same spatial / geographic region of Nigeria, only one of the three isolates proved lethal in strain 13 guinea pigs and non-human primates (NHP). Additionally, this isolate exhibited atypical pathogenesis characteristics in the NHP model, most notably respiratory failure, not commonly described in hemorrhagic cases of LF. These results suggest that there is considerable phenotypic heterogeneity in LASV infections in Nigeria, which leads to a multitude of pathogenesis characteristics that could account for differences between subclinical and lethal LF infections. Most importantly, the development of disease models using currently circulating LASV strains in West Africa are critical for the evaluation of potential vaccines and medical countermeasures. Author summary: Lassa fever is a severe viral hemorrhagic fever of humans caused by infection with Lassa virus, which is endemic in many countries in West Africa. Annually, an estimated 300,000–500,000 people are infected with Lassa virus, making it one of the most prominent agents responsible for hemorrhagic disease in humans. Despite this significant burden of disease, to date, no approved therapeutic or prophylactic vaccine exists for Lassa fever, due in part to a lack of characterized animal models for studying the disease. Here, we describe guinea pig and non-human primate models for Lassa fever using recently isolated viruses from a 2018 outbreak of Lassa fever in Nigeria. Despite similar collection locations and dates, the isolates obtained from human infections demonstrated a high degree of genotypic heterogeneity and phenotypic characteristics in animal models resulting in both lethal and non-lethal infections. Of interest, one isolate resulted in significant respiratory manifestations, an under-reported disease manifestation in humans. These models will provide comparative models to those already characterized and aid in elucidating disease characteristics of Lassa fever. In addition, they will serve the immediate purpose of evaluating known and novel medical countermeasures to treat and prevent disease in West Africa. [ABSTRACT FROM AUTHOR]