Therapeutic monoclonal antibody treatment protects nonhuman primates from severe Venezuelan equine encephalitis virus disease after aerosol exposure

Abstract

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.

Exposing cryptic epitopes on the Venezuelan equine encephalitis virus E1 glycoprotein prior to treatment with alphavirus cross-reactive monoclonal antibody allows blockage of replication early in infection

“…There are no approved vaccines or virus-specific treatment options available ( Stromberg et al, 2020 ). Most passive antibody approaches developed for prophylactic and therapeutic treatment to alphaviruses target highly neutralizing virus type-specific epitopes ( Burke et al, 2019 ; Hunt et al, 1991 , 2011 ; Hunt and Roehrig, 1995 ; Phillpotts, 2006 ). Cross-reactive antibodies with broad-protective capacity present a more appealing technology for use as an early therapy before specific viral diagnosis is made.…”

The Immune Response to Eastern Equine Encephalitis Virus Acquired Through Organ Transplantation

“…Evidence from non-human primate and mouse models suggest that antibodies play a role in both protection against disease and clearance of neuroinvasive alphavirus infections, such as EEEV and VEEV in non-human primates and Sindbis virus (SINV) in mice. Passive antibody transfer and monoclonal antibody studies demonstrate protection against infection or development of severe disease when given prior to exposure or up to 48 h post-challenge ( Goodchild et al, 2011 ; Hunt et al, 2011 ; Phillips et al, 2014 ; Gardner et al, 2017 ; Burke et al, 2019 ; Kim et al, 2019 ; Ko et al, 2019 ) and treatment with hyperimmune serum mediates clearance of SINV from neurons in vitro and in vivo in SINV-infected mice with severe combined immunodeficiency ( Levine et al, 1991 ; Yun et al, 2009 ; Griffin, 2010 ). Although the central nervous system is considered an immunoprivileged site, antibody-secreting B cells and virus-specific antibody can be detected in mice with SINV infection ( Metcalf and Griffin, 2011 ; Metcalf et al, 2013 ).…”

Requirement of Fc-Fc Gamma Receptor Interaction for Antibody-Based Protection against Emerging Virus Infections

“…Although these experiments were not repeated in FcγR-deficient mice to confirm Fc-mediated enhanced disease, this phenotype should be considered when evaluating efficacy of mAbs targeting alphaviruses. Neutralizing and non-neutralizing mAbs against EEEV, VEEV, and WEEV have been isolated, characterized, and shown to be protective against aerosol and subcutaneous challenge in mice and non-human primates [117][118][119][120][121]. Some of the most protective mAbs in vivo were either mouse IgG2a/c or human IgG1 and/or non-neutralizing, which suggests that Fc effector functions may be at least partially involved [117,118,121].…”