Additionally, animal STx-17 in the 8.9F-treatment cohort ( Supplementary Table 2, STx17–20) had detectable circulating infectious virus ( Fig. 1b), but none of the three had marked clinical pathology except for fever, which was detected in STx-4. Animals STx-2–4 also had detectable viral RNA ( Supplementary Fig. and experienced clinical signs of illness consistent with LF, requiring euthanasia ( Supplementary Table 2). 1a, P < 0.0078), in which one of four in the cohort, animal STx-1, had detectable infectious virus ( Fig. One exception occurred in the STx cohort ( Supplementary Table 2, STx-1–4) that received huMab 19.7E on days 0 and 5 after LASV exposure ( Fig. Each huMab was well tolerated, and all STx-huMAb treatment regimens resulted in both 100% protection from LF and in survival to study endpoint ( Fig.
1a) as early as days 4 and 3 p.i., respectively. 1a Supplementary Table 1, bracket denotes which experiment each control is from) clinical signs consistent with LF ( Supplementary Table 1) and viremia, as measured by infectious LASV ( Fig. Untreated control animals ( n = 7) had a mean time to death of 12 d p.i. 1a) treatment was initiated at day 0 after LASV exposure, with additional treatments administered during the course of infection for all STx cohorts (19.7E, at day 0 and 5 postinfection (p.i.) ( n = 4) 37.2D, day 0, 4, and 8 p.i. Macaques were inoculated on day 0 with a target dose of 3,500 plaque-forming units (PFU), and these huMAbs were administered as a monotherapy referred to as a single-antibody treatment (STx) cohort ( Fig. Here we used the cynomolgus macaque model of lethal LASV to assess the protective efficacy of five promising LASV-GP-neutralizing huMAbs (37.2D, 12.1F, 8.9F, 19.7E, and 37.7H) on the basis of cross-reactivity to the four clades (I–IV) of LASV GP, neutralization from in vitro assays 16, and protective efficacy in guinea pigs 17. These NHP data suggested that antibodies targeting the GP of LASV might be of clinical benefit for individuals with LF, and that they thus warranted further preclinical study of antibody efficacy against LASV. These neutralizing antibodies were found to bind the LASV glycoprotein (GP), which is composed of the GP subunits GP1 and GP2, and either (i) prevent the binding of the GP1 subunit to the receptor α-dystroglycan 15 (ii) prevent fusion of the viral envelope with the host-cell membrane through GP2-subunit binding or (iii) perform a combination of both. Notably, it was shown that immune plasma protected cynomolgus monkeys if given shortly after LASV exposure and if the plasma contained neutralizing antibodies that were closely matched to the challenge strain of LASV 10. There are also a few reports of convalescent plasma being administered to individuals with LASV infection 12, 13, 14, and in one of these cases, a beneficial effect was observed when the plasma was administered early in the disease course 14. Intravenous ribavirin has been shown to reduce the mortality from 55% to 5% in individuals at high risk for the disease who present with elevated liver enzymes upon hospital admission, provided that the treatment is administered during the first 6 d of illness 11. So far, no preventive vaccines or therapeutics for LF have been approved for human use, and only a few candidate vaccines and treatments, such as ribavirin, have been assessed in preclinical studies for their potential to protect against against wild-type LASV in nonhuman primates (NHPs) 6, 7, 8, 9, 10.
Moreover, LASV is also classified by several US government agencies as a 'Category A' priority pathogen because of a concern about deliberate misuse of the virus. Previous and recent importation of LF into Europe and the US by travelers on commercial airlines 4, 5 illustrates the potential for spread outside the endemic area. Between December 2016 and June 2017, the World Health Organization reported a total of 501 suspected cases (175 laboratory confirmed) and 59 deaths among all cases, with a CFR of 33.7% 3.
Currently, a large outbreak of LF that began in August of 2015 is devastating Nigeria. The case-fatality rate (CFR) for the hemorrhagic fever Lassa fever (LF) has historically ranged from 15% to 50% in hospitalized patients, and a recent multi-year study in Sierra Leone reported a 69% CFR in admitted patients 2. Lassa virus (LASV) infects more than 300,000 individuals per year across West Africa, causing over 3,000 deaths 1.
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