A chimeric Sindbis-based vaccine protects cynomolgus macaques against a lethal aerosol challenge of eastern equine encephalitis virus

Abstract

Eastern equine encephalitis virus (EEEV) is a mosquito-borne alphavirus that causes sporadic, often fatal disease outbreaks in humans and equids, and is also a biological threat agent. Two chimeric vaccine candidates were constructed using a cDNA clone with a Sindbis virus (SINV) backbone and structural protein genes from either a North (SIN/NAEEEV) or South American (SIN/SAEEEV) strain of EEEV. The vaccine candidates were tested in a nonhuman primate (NHP) model of eastern equine encephalitis (EEE). Cynomolgus macaques were either sham-vaccinated, or vaccinated with a single dose of either SIN/NAEEEV or SIN/SAEEEV. After vaccination, animals were challenged by aerosol with a virulent North American strain of EEEV (NA EEEV). The SIN/NAEEEV vaccine provided significant protection, and most vaccinated animals survived EEEV challenge (82%) with little evidence of disease, whereas most SIN/SAEEEV-vaccinated (83%) and control (100%) animals died. Protected animals exhibited minimal changes in temperature and cardiovascular rhythm, whereas unprotected animals showed profound hyperthermia and changes in heart rate post-exposure. Acute inflammation and neuronal necrosis were consistent with EEEV-induced encephalitis in unprotected animals, whereas no encephalitis-related histopathologic changes were observed in the SIN/NAEEEV-vaccinated animals. These results demonstrate that the chimeric SIN/NAEEEV vaccine candidate protects against an aerosol EEEV exposure.

Combined Alphavirus Replicon Particle Vaccine Induces Durable and Cross-Protective Immune Responses against Equine Encephalitis Viruses

“…In nonhuman primates, responses were generally stronger against VEEV-IAB than the other viruses, with the response to WEEV being the weakest, and only four of six macaques vaccinated with the WEEV VRP alone were seropositive on day 56. Neutralizing antibody titers failed to correlate with protection against EEEV in macaques vaccinated with Sindbis (SIN)/EEE virus (18). As previously mentioned, a live attenuated VEEV-IAB virus failed to generate neutralizing antibody against VEEV-IE in NHP while still protecting against aerosol challenge against VEEV-IE (15).…”

“…Chimeric VEEV and EEEV vaccines have been generated using a Sindbis (SIN) virus vector and have been shown to be safe and immunogenic in mice and to protect mice against VEEV and EEEV challenge (19,20,53). The SIN/EEE vaccine was the first to demonstrate good protection in macaques against aerosol challenge with EEEV (18). The potential for reversion makes the hurdle of safety much more difficult to achieve with approaches using live attenuated vaccines, particularly given public perception of adverse events associated with biological products and the associated risk/benefit of the product.…”

“…Live attenuated vaccines developed using modern molecular techniques provided good immunogenicity, safety, and protection in rodents and nonhuman primates although in phase I clinical trials mild fever responses were seen at very low dosages (15)(16)(17). Other approaches using live attenuated vaccines are being evaluated and have shown promise in mice and nonhuman primates (18)(19)(20). However, the public perception of the risk associated with live vaccines in general has created great resistance to their potential use.…”

Immunologic Characterization of a Rhesus Macaque H1N1 Challenge Model for Candidate Influenza Virus Vaccine Assessment

“…The animals were exposed to pH1N1 (Cal04) influenza virus using conventional methodology that was previously established for infectious mixed-particle aerosol challenge in nonhuman primate species (14). Inductive plethysmography, which measures the volume of air breathed per minute by each individual animal, was performed just before the exposure.…”

Dissecting the Role of E2 Protein Domains in Alphavirus Pathogenicity

“…Furthermore, chimeric SINV/Ross River virus constructs have been used to identify important residues in budding, nucleocapsid/envelope-protein interactions, and virus assembly (19)(20)(21)(22). Chimeric alphaviruses also have been developed as vaccine candidates, usually swapping the entire sPs from one virus into another for attenuation (23,24). Others have used chimeras to probe the role of viral proteins on important viral factors such as host tropism or infectivity.…”