Abstract
Lassa virus (LASV), a highly prevalent mammalian arenavirus endemic in West Africa, can cause Lassa fever (LF), which is responsible for thousands of deaths annually. LASV is transmitted to humans from naturally infected rodents. At present, there is not an effective vaccine nor treatment. The genetic diversity of LASV is the greatest challenge for vaccine development. The reassortant ML29 carrying the L segment from the nonpathogenic Mopeia virus (MOPV) and the S segment from LASV is a vaccine candidate under current development. ML29 demonstrated complete protection in validated animal models against a Nigerian strain from clade II, which was responsible for the worst outbreak on record in 2018. This study demonstrated that ML29 was more attenuated than MOPV in STAT1-/- mice, a small animal model of human LF and its sequelae. ML29 infection of these mice resulted in more than a thousand-fold reduction in viremia and viral load in tissues and strong LASV-specific adaptive T cell responses compared to MOPV-infected mice. Persistent infection of Vero cells with ML29 resulted in generation of interfering particles (IPs), which strongly interfered with the replication of LASV, MOPV and LCMV, the prototype of the Arenaviridae. ML29 IPs induced potent cell-mediated immunity and were fully attenuated in STAT1-/- mice. Formulation of ML29 with IPs will improve the breadth of the host’s immune responses and further contribute to development of a pan-LASV vaccine with full coverage meeting the WHO requirements.
Highlights
Lassa virus (LASV) is a highly prevalent arenavirus in West Africa, where it infects several hundred thousand individuals annually
Arenavirus interfering particles (IPs) can be generated at high multiplicity of infection (MOI) by serial infection of fresh tissue cultures with undiluted culture medium harvested from previous passages
The protocol previously applied for the generation of LASV IPs in cell cultures was used to establish ML29 persistent infection of Vero cells
Summary
Lassa virus (LASV) is a highly prevalent arenavirus in West Africa, where it infects several hundred thousand individuals annually. This results in a large number of Lassa fever (LF) cases associated with high morbidity and mortality rates [1,2]. The area where LASV is endemic covers large regions of West Africa [3], putting a population of up to 200 million people at risk for infection [4]. There is evidence that LASV-endemic regions are expanding [5]. The high degree of LASV genetic diversity [6,7] likely contributes to underestimates of its prevalence [8]. With the exception of dengue fever, LF has the greatest estimated global burden among all viral hemorrhagic fevers (HFs) [9]
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