Vaccine Advances against Venezuelan, Eastern, and Western Equine Encephalitis Viruses

Abstract

Vaccinations are a crucial intervention in combating infectious diseases. The three neurotropic Alphaviruses, Eastern (EEEV), Venezuelan (VEEV), and Western (WEEV) equine encephalitis viruses, are pathogens of interest for animal health, public health, and biological defense. In both equines and humans, these viruses can cause febrile illness that may progress to encephalitis. Currently, there are no licensed treatments or vaccines available for these viruses in humans. Experimental vaccines have shown variable efficacy and may cause severe adverse effects. Here, we outline recent strategies used to generate vaccines against EEEV, VEEV, and WEEV with an emphasis on virus-vectored and plasmid DNA delivery. Despite candidate vaccines protecting against one of the three viruses, few studies have demonstrated an effective trivalent vaccine. We evaluated the potential of published vaccines to generate cross-reactive protective responses by comparing DNA vaccine sequences to a set of EEEV, VEEV, and WEEV genomes and determining the vaccine coverages of potential epitopes. Finally, we discuss future directions in the development of vaccines to combat EEEV, VEEV, and WEEV.

Keywords: Alphavirus; DNA vaccine; Eastern equine encephalitis virus (EEEV); Venezuelan equine encephalitis virus (VEEV); Western equine encephalitis virus (WEEV); antigens; vaccine.

Figure 1

Vaccine strategies against encephalitic Alphavirus infections. (A) Schematic overview of encephalitic the Alphavirus structure, including the genome organization of nonstructural proteins (nsps), capsid (C), assembly protein (E3), spike glycoproteins (E2 and E1), and viroporin protein (6K). (B) Viral vector delivery of encephalitic Alphavirus genes (blue). (C) Plasmid DNA containing backbone (black) and encephalitic Alphavirus DNA (blue).

Figure 2

Strain origin and gene content of Alphavirus structural, protein-based, viral-vectored, and plasmid DNA vaccines. Venezuelan equine encephalitis virus (VEEV) vaccines are indicated in purple, Western (WEEV) vaccines in blue to green, and Eastern (EEEV) vaccines in orange to red; genes not included in a particular vaccine (NA) are indicated in white.

Figure 3

Matching of potential linear epitopes (9-amino-acid fragments) in natural sequences by selected vaccine candidates. Highly similar sequences were removed from an alignment of all available VEEV-clade, WEEV-clade, and EEEV-clade sequences in GenBank in November 2019. For each vaccine, the fraction of vaccine-matched 9-mers, “9-mer coverage”, was computed for each sequence; sequences were plotted in descending rank order of coverage. For example, for the E3 protein, vaccine pVXH-6 covers ~50% of WEEV isolates at a level of 82% of 9-mers or better (those to the left of the red dot), whereas 32% of isolates (those to the right of the gold dot, x-axis value 0.68 and above) are covered at a level of 41% or less. Colors identify candidate vaccines as in Figure 2.