Therapeutic administration of a recombinant human monoclonal antibody reduces the severity of chikungunya virus disease in rhesus macaques

<div><p>Chikungunya virus (CHIKV) is a mosquito-borne virus that causes a febrile syndrome in humans associated with acute and chronic debilitating joint and muscle pain. Currently no licensed vaccines or therapeutics are available to prevent or treat CHIKV infections. We recently isolated a panel of potently neutralizing human monoclonal antibodies (mAbs), one (4N12) of which exhibited prophylactic and post-exposure therapeutic activity against CHIKV in immunocompromised mice. Here, we describe the development of an engineered CHIKV mAb, designated SVIR001, that has similar antigen binding and neutralization profiles to its parent, 4N12. Because therapeutic administration of SVIR001 in immunocompetent mice significantly reduced viral load in joint tissues, we evaluated its efficacy in a rhesus macaque model of CHIKV infection. Rhesus macaques that were treated after infection with SVIR001 showed rapid elimination of viremia and less severe joint infiltration and disease compared to animals treated with SVIR002, an isotype control mAb. SVIR001 reduced viral burden at the site of infection and at distant sites and also diminished the numbers of activated innate immune cells and levels of pro-inflammatory cytokines and chemokines. SVIR001 therapy; however, did not substantively reduce the induction of CHIKV-specific B or T cell responses. Collectively, these results show promising therapeutic activity of a human anti-CHIKV mAb in rhesus macaques and provide proof-of-principle for its possible use in humans to treat active CHIKV infections.</p></div

CHIKV mAb treatment did not cause significant changes in CD4⁺ or CD8⁺ T cell proliferation.

<p>Rhesus macaques were inoculated with CHIKV and treated with control antibody SVIR002 or CHIKV mAb SVIR001. Blood was drawn daily 0–7 dpi, and PBMCs were examined for proliferative responses of different <b>(A-C)</b> CD4⁺ and <b>(D-F)</b> CD8⁺ T cell subsets. T cell subsets were defined in <b><a href="http://www.plosntds.org/article/info:doi/10.1371/journal.pntd.0005637#pntd.0005637.s002" target="_blank">S2 Fig</a></b> as Naïve (NV), Central Memory (CM), and Effector Memory (EM). The Ki67⁺ proliferative status was plotted as a percentage of the total population. <b>(G)</b> IFNγ ELISpot analysis was performed on PBMCs from rhesus macaques at 7 dpi. PBMCs from animals treated with SVIR001 (5 mg/kg or 15 mg/kg) or SVIR002 (15 mg/kg) were stimulated with CHIKV peptide pools (10 μg/well), inactivated CHIKV (iCHIKV) (10 μg/well), or PMA/Ionomycin as a positive control. DMSO was used as a negative control to establish the baseline number of IFNγ-producing T cells for each animal. Spots were quantified on an AID ELISpot plate reader (n = 4/group).</p

Tissue viral load following CHIKV mAb therapy.

<p>Animals were euthanized at day 7 post-infection, and viral RNA was isolated from tissues and quantified by qRT-PCR. The viral load in <b>(A)</b> arm joints and muscles, <b>(B)</b> leg joints and muscles, and <b>(C)</b> lymphoid tissues, heart and kidney are reported. Statistical significance was determined on the log-transformed data using Dunnett’s multiple comparison test, and multiplicity-adjusted <i>P</i> values are reported (n = 4; ** <i>P</i> < 0.005, * <i>P</i> < 0.05).</p