Abstract
Chikungunya virus (CHIKV) is a mosquito-transmitted alphavirus that causes global epidemics of a debilitating polyarthritis in humans. As there is a pressing need for the development of therapeutic agents, we screened 230 new mouse anti-CHIKV monoclonal antibodies (MAbs) for their ability to inhibit infection of all three CHIKV genotypes. Four of 36 neutralizing MAbs (CHK-102, CHK-152, CHK-166, and CHK-263) provided complete protection against lethality as prophylaxis in highly susceptible immunocompromised mice lacking the type I IFN receptor (Ifnar(-/-)) and mapped to distinct epitopes on the E1 and E2 structural proteins. CHK-152, the most protective MAb, was humanized, shown to block viral fusion, and require Fc effector function for optimal activity in vivo. In post-exposure therapeutic trials, administration of a single dose of a combination of two neutralizing MAbs (CHK-102+CHK-152 or CHK-166+CHK-152) limited the development of resistance and protected immunocompromised mice against disease when given 24 to 36 hours before CHIKV-induced death. Selected pairs of highly neutralizing MAbs may be a promising treatment option for CHIKV in humans.
Original language | English |
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Article number | e1003312 |
Number of pages | 16 |
Journal | PLoS Pathogens |
Volume | 9 |
Issue number | 4 |
DOIs | |
Publication status | Published - 18-Apr-2013 |
Keywords
- SEMLIKI-FOREST-VIRUS
- WEST-NILE-VIRUS
- SINDBIS VIRUS
- E2 GLYCOPROTEIN
- ESCAPE MUTANTS
- ANTIGENIC SITE
- MOUSE MODEL
- INFECTION
- FUSION
- MICE