A virus-like particle vaccine prevents equine encephalitis virus infection in nonhuman primates

Abstract

Western, Eastern, and Venezuelan equine encephalitis viruses (WEEV, EEEV, and VEEV, respectively) are important mosquito-borne agents that pose public health and bioterrorism threats. Despite considerable advances in understanding alphavirus replication, there are currently no available effective vaccines or antiviral treatments against these highly lethal pathogens. To develop a potential countermeasure for viral encephalitis, we generated a trivalent, or three-component, EEV vaccine composed of virus-like particles (VLPs). Monovalent VLPs elicited neutralizing antibody responses and protected mice and nonhuman primates (NHPs) against homologous challenges, but they were not cross-protective. In contrast, NHPs immunized with trivalent VLPs were completely protected against aerosol challenge by each of these three EEVs. Passive transfer of IgG from immunized NHPs protected mice against aerosolized EEV challenge, demonstrating that the mechanism of protection was humoral. Because they are replication incompetent, these trivalent VLPs represent a potentially safe and effective vaccine that can protect against diverse encephalitis viruses.

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

“…particle representing a single alphavirus, neutralizing antibodies developed only to the corresponding virus with no cross-reactive neutralization observed (Ko et al, 2019). Both the E1 and E2 envelope protein sequences of EEEV differ significantly from the other encephalitic alphaviruses with only 49% and 58% sequence homology in the E1 protein, and 44% and 46% sequence homology in the E2 protein compared to WEEV and VEEV, respectively (Hahn et al, 1988).…”

Human-Like Neutralizing Antibodies Protect Mice from Aerosol Exposure with Western Equine Encephalitis Virus

“…Anti-WEEV immune serum from rabbits [ 23 ], mice [ 14 ] and NHPs [ 25 ] passively administered to mice can protect against lethal WEE disease. However, to date, no neutralizing or protective murine, human or human-like anti-WEEV monoclonal antibodies have been identified [ 26 ].…”

“…In vaccination studies delivering WEEV, EEEV and VEEV antigen concomitantly, WEEV antigens appear to be less immunogenic in comparison to VEEV and EEEV antigens. This is evidenced by lower neutralizing and binding antibody titers to WEEV vaccine components when similar protein concentrations are delivered in a trivalent formulation [ 25 , 31 ]. Alternatively, the reduced immunogenicity of WEEV antigen in these studies may be a result of immunologic interference similar to what was observed in humans after sequential alphavirus vaccine administration [ 32 , 33 ].…”

“…Neither antibody provided 100% protection from lethality after WEEV aerosol exposure even at the 200 µg dose. Studies with passive administration of immune serum from NHPs [ 25 , 34 ] and transchromosomic bovine IgG [ 35 ] into mice have found that a single administration was not 100% protective against a high dose aerosol exposure of VEEV [ 35 ], EEEV or WEEV [ 25 , 34 ]; however, delivery of a second administration resulted in 90–100% survival. This would suggest that a second administration of ToR69-3A2 or ToR68-2C3 may result in enhanced survival.…”

Complete Coding Sequence of Western Equine Encephalitis Virus Strain Fleming, Isolated from a Human Case

“…The last recorded human cases of WEEV were in 2009 in Uruguay (10), and virus is rarely detected in mosquito pools (11). A trivalent alphavirus virus-like particle vaccine was recently developed (12) and is undergoing human safety testing. Due to the rarity of WEEV cases, the McMillan strain (GenBank accession number GQ287640) is the only complete human isolate sequence available.…”