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OPEN ACCESS / PEER-REVIEWED / RESEARCH ARTICLE
Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure
Crystal W. Burke, Jeffery W. Froude, Franco Rossi, Charles E. White, Crystal L. Moyer, Jane Ennis, M. Louise Pitt, Stephen Streatfield, R. Mark Jones, Konstantin Musiychuk, Jukka Kervinen, Larry Zeitlin, Vidadi Yusibov, Pamela J. Glass
Published: December 2, 2019 / DOI: https://doi.org/10.1371/journal.ppat.1008157 / This is an uncorrected proof.
There are no FDA licensed vaccines or therapeutics for Venezuelan equine encephalitis virus (VEEV) which causes a debilitating acute febrile illness in humans that can progress to encephalitis. Previous studies demonstrated that murine and macaque monoclonal antibodies (mAbs) provide prophylactic and therapeutic efficacy against VEEV peripheral and aerosol challenge in mice. Additionally, humanized versions of two neutralizing mAbs specific for the E2 glycoprotein, 1A3B-7 and 1A4A-1, administered singly protected mice against aerosolized VEEV. However, no studies have demonstrated protection in nonhuman primate (NHP) models of VEEV infection. Here, we evaluated a chimeric antibody 1A3B-7 (c1A3B-7) containing mouse variable regions on a human IgG framework and a humanized antibody 1A4A-1 containing a serum half-life extension modification (Hu-1A4A-1-YTE) for their post-exposure efficacy in NHPs exposed to aerosolized VEEV. Approximately 24 hours after exposure, NHPs were administered a single bolus intravenous mAb. Control NHPs had typical biomarkers of VEEV infection including measurable viremia, fever, and lymphopenia. In contrast, c1A3B-7 treated NHPs had significant reductions in viremia and lymphopenia and on average approximately 50% reduction in fever. Although not statistically significant, Hu-1A4A-1-YTE administration did result in reductions in viremia and fever duration. Delay of treatment with c1A3B-7 to 48 hours post-exposure still provided NHPs protection from severe VEE disease through reductions in viremia and fever. These results demonstrate that post-exposure administration of c1A3B-7 protected macaques from development of severe VEE disease even when administered 48 hours following aerosol exposure and describe the first evaluations of VEEV-specific mAbs for post-exposure prophylactic use in NHPs. Viral mutations were identified in one NHP after c1A3B-7 treatment administered 24 hrs after virus exposure. This suggests that a cocktail-based therapy, or an alternative mAb against an epitope that cannot mutate without resulting in loss of viral fitness may be necessary for a highly effective therapeutic.
Endemic in the Americas, Venezuelan equine encephalitis virus (VEEV) can be transmitted to humans, horses, and other animals through the bite of a mosquito. Beyond its natural prevalence, VEEV was previously developed as a biological weapon making the development of vaccines and therapeutics of the upmost importance. Despite over 60 years of research to identify effective therapeutics for VEEV disease, to-date no anti-VEEV therapeutics have progressed beyond pre-clinical testing in a mouse model. Here, we present the first evaluation of an anti-VEEV therapeutic in a nonhuman primate (NHP). We found that a monoclonal antibody given either one or two days after an aerosol exposure to VEEV protected from severe VEE disease. We also found the level of in vitro virus neutralization by a given antibody did not predict efficacy in NHPs. Importantly, we identified viral escape mutations in one NHP after treatment, highlighting the need for development of novel antibodies for inclusion in cocktail-based therapy against VEEV.
Citation: Burke CW, Froude JW, Rossi F, White CE, Moyer CL, Ennis J, et al. (2019) Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure. PLoS Pathog 15(12): e1008157. https://doi.org/10.1371/journal.ppat.1008157
Editor: Mehul Suthar, Emory University, UNITED STATES
Received: July 31, 2019; Accepted: October 23, 2019; Published: December 2, 2019
This is an open access article, free of all copyright, and may be freely reproduced, distributed, transmitted, modified, built upon, or otherwise used by anyone for any lawful purpose. The work is made available under the Creative Commons CC0 public domain dedication.
Data Availability: All relevant data are within the manuscript and its supporting information files.
Funding: This was supported by the Joint Science and Technology Office for Chemical and Biological Defense Program CB3957 to PJG and Contract HDTRA1-14-C-0115 to LZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Competing interests: JWF, MLP, KM, JK, YV, and PJG have filled a patent application on c1A3B-7. CLM and JE are employees of Mapp Biopharmaceutical. LZ is an employee and co-owner of Mapp. This does not alter our adherence to all PLOS Pathogens policies on sharing data and materials.
Keywords: Venezuelan Equine Encephalitis; Monoclonal antibodies; Animal models.