Current research for a vaccine against Lassa hemorrhagic fever virus

Warner, Bryce M; Safronetz, David; Stein, Derek R

Nigeria is currently struggling with a severe reoccurrence of Lassa fever (LF), with confirmed cases in over half of the country (18 States). 1 The World Health Organization (WHO) is currently reporting thousands of suspected cases with 317 confirmed cases, over 72 deaths, and a probable case fatality rate of 22%. In addition, 14 health care workers have been infected with a case fatality rate of 30%. LASV was first discovered in 1969 when two missionary nurses died in Nigeria. 2 Lassa virus (LASV), the causative agent of LF, belongs to the family Arenaviridae, and is endemic over most of West Africa ( Figure 1 ). It is transmitted by the multimammate rat, Mastomys natalensis, 3 and has an enveloped, negative-sense, RNA genome. The genome is ambisense and consists of two segments, a small (S) segment and a large (L) segment. The S segment encodes the glycoprotein precursor (GPC), which is expressed on the envelope of the virus in a trimeric state. 4 The S segment also encodes the nucleoprotein (NP) in the opposite direction, which encapsulates the viral genome. The L segment encodes the viral matrix protein (Z) and the viral RNA-dependent RNA polymerase (L). When transmitted to humans, LASV presents in most cases (80%) as a mild non-descript disease; however, 20% of infections result in severe hemorrhagic fever with multi-organ failure. 5 The incubation period of LF is typically 1-3 weeks with accompanying headache, fever, muscle/joint pain, diarrhea, vomiting, elevated liver enzymes (AST and ALT), and hematocrit. The signs of pathogenesis can vary depending on the animal model used in various vaccine studies; however, the gold standard that best recapitulates the human condition are non-human primates (NHPs) (Figure 2A) . A poor prognosis is also indicated with accompanying edema of the face and neck, abdominal and retrosternal pain, enlarged lymph nodes, and/or hemorrhage in the conjunctiva or mucosal surfaces. It is estimated that there are over 300,000 infections on an annual basis in West Africa, making LASV a primary cause of hemorrhagic fever worldwide. Currently, there are no approved vaccines or therapeutics for the treatment or prevention of LASV with the questionable exception of the off-label use of ribavirin. 6 Additionally, historical imported cases of LASV infection and human-to-human transmission warrant strong development of vaccine and treatment modalities. 5, 7, 8 Recently, the Bill and Melinda Gates Foundation along with its collaborating partners founded the Coalition for Epidemic Preparedness Innovations (CEPI) with the sole purpose of advancing three priority pathogens with promising preclinical candidates to Phase III clinical trials in the event of future outbreaks. CEPI, along with the WHO, has initially named LASV, Middle East Respiratory Syndrome Coronavirus, and Nipah virus as the top pathogens of priority for their first round of applications. Despite the high disease burden and lack of preventative measures for LASV, significant progress has been made in the identification of promising preclinical candidates. In this review, we discuss the current understanding of LASV immunobiology, the correlates of protection, and the most promising vaccine candidates for the prevention of LF.