Second generation inactivated eastern equine encephalitis virus vaccine candidates protect mice against a lethal aerosol challenge.

Shelley P Honnold,Jeffrey W Cohen,Cathleen M Lind,Russell R Bakken,Lori T Eccleston,Pamela J Glass,Diana Fisher,Radha K Maheshwari,Kevin B Spurgers,Sang-Moo Kang

doi:10.1371/journal.pone.0104708

Abstract

Currently, there are no FDA-licensed vaccines or therapeutics for eastern equine encephalitis virus (EEEV) for human use. We recently developed several methods to inactivate CVEV1219, a chimeric live-attenuated eastern equine encephalitis virus (EEEV). Dosage and schedule studies were conducted to evaluate the immunogenicity and protective efficacy of three potential second-generation inactivated EEEV (iEEEV) vaccine candidates in mice: formalin-inactivated CVEV1219 (fCVEV1219), INA-inactivated CVEV1219 (iCVEV1219) and gamma-irradiated CVEV1219 (gCVEV1219). Both fCVEV1219 and gCVEV1219 provided partial to complete protection against an aerosol challenge when administered by different routes and schedules at various doses, while iCVEV1219 was unable to provide substantial protection against an aerosol challenge by any route, dose, or schedule tested. When evaluating antibody responses, neutralizing antibody, not virus specific IgG or IgA, was the best correlate of protection. The results of these studies suggest that both fCVEV1219 and gCVEV1219 should be evaluated further and considered for advancement as potential second-generation inactivated vaccine candidates for EEEV.

Highlights

Eastern equine encephalitis virus (EEEV), an arbovirus, is an important human and veterinary pathogen belonging to one of seven antigenic complexes in the genus Alphavirus, family Togaviridae
There are four antigenic subtypes of EEEV, one that circulates in North America and the Caribbean (NA EEEV), and three that circulate in Central and South America (SA EEEV)
We optimized processes to inactivate a genetically modified strain of EEEV using formalin, INA, and gammairradiation, since all three of these methods were successful in inactivating V3526 and most induced significant immune responses and were at least partially protective against a subcutaneous or aerosol challenge [11,12,13,14]

Summary

Introduction

Eastern equine encephalitis virus (EEEV), an arbovirus, is an important human and veterinary pathogen belonging to one of seven antigenic complexes in the genus Alphavirus, family Togaviridae. EEEV is considered the most deadly of the mosquito-borne alphaviruses due to the high case fatality rate associated with clinical infections, reaching as high as 75% in humans and 90% in horses [1]. In a recent outbreak in Panama, 8 patients were hospitalized with eastern equine encephalitis (EEE) as a result of SA EEEV infection [4]. NA EEEV is listed as a category B agent by the National Institute of Allergy and Infectious Diseases (NIAID) due to its virulence, its potential use as a biological weapon, and the lack of a licensed vaccine or effective antiviral treatment for human infections

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