Human-monoclonal-antibody therapy protects nonhuman primates against advanced Lassa fever

Abstract

There are no approved treatments for Lassa fever, which is endemic to the same regions of West Africa that were recently devastated by Ebola. Here we show that a combination of human monoclonal antibodies that cross-react with the glycoproteins of all four clades of Lassa virus is able to rescue 100% of cynomolgus macaques when treatment is initiated at advanced stages of disease, including up to 8 d after challenge.

Figure 1

Protective efficacy profile of LASV GP huMAb monotherapy in a cynomolgus macaque model of lethal LF. (a) Kaplan–Meier survival curve for each cohort treated with a single anti-LASV GP huMAb (STx), beginning on day of LASV challenge. *Day of LASV challenge; huMAb symbols depicting the days of treatment post LASV challenge: blue square, 37.2D, days 0, 4, and 8; green triangle, 12.1F, days 0, 4, and 8; orange circle, 8.9F, days 0, 4, and 8; teal square, 19.7E, days 0 and 5; gray diamond, 37.7H, days 0, 4, and 8; and open squares, untreated controls. **P < 0.0078, ****P < 0.0001. (star designation determined by GraphPad Prism 7.0 software); error bars are ± s.d. from mean values, as determined by Mantel–Cox test. For b,c, and d: circulating infectious-virus load for each cohort, as measured by PFU/ml with the lower limit of detection of 15 PFU/ml. C, control. STx, monotherapy huMAb treatment group. Error bars are ± s.d. from mean values. Limit of detection is depicted as dashed line on graphs.

Figure 2

Protective-efficacy profile of LASV-GP huMAb combination therapy in a cynomolgus- macaque model of LF. (a) Kaplan–Meier survival curve for each cohort treated with a cocktail of anti-LASV-GP huMAb (CTx) after LASV challenge. (37.2D + 19.7E) or day 3 (+3), day 6 (+6), or day 8 (+8) post LASV challenge. *Day of LASV challenge; huMAb symbols depict the days of antibody-cocktail treatment post LASV challenge: blue square, +3 8.9F/12.F/37.2D cohort, days 3, 6, and 9; orange triangle, +6 8.9F/12.F/37.2D cohort, days 6, 9, and 12; open triangle, +8 8.9F/12.F/37.2D cohort, days 8, 11, and 14; and open squares, untreated controls. ****P < 0.0001; as determined by Mantel–Cox test. In b and c: circulating infectious-virus load for each cohort, as measured by PFU/ml with the lower limit of detection of 15 PFU/ml. C, control. CTx, cocktail-huMAb treatment group. Error bars are ± s.d. from mean values. Limit of detection depicted as dashed line on graphs.