Rossi Shannan L, Russell-Lodrigue Kasi E, Plante Kenneth S, Bergren Nicholas A, Gorchakov Rodion, Roy Chad J, Weaver Scott C
Department of Pathology and Microbiology and Immunology, Institute for Human Infection and Immunity, University of Texas Medical Branch, Galveston, TX 77555, USA.
Tulane National Primate Research Center, Covington, LA 70433, USA.
Vaccines (Basel). 2020 Sep 2;8(3):497. doi: 10.3390/vaccines8030497.
Venezuelan equine encephalitis virus (VEEV) is a re-emerging virus of human, agriculture, and bioweapon threat importance. No FDA-approved treatment is available to combat Venezuelan equine encephalitis in humans, prompting the need to create a vaccine that is safe, efficacious, and cannot be replicated in the mosquito vector. Here we describe the use of a serotype ID VEEV (ZPC-738) vaccine with an internal ribosome entry site (IRES) to alter gene expression patterns. This ZPC/IRES vaccine was genetically engineered in two ways based on the position of the IRES insertion to create a vaccine that is safe and efficacious. After a single dose, both versions of the ZPC/IRES vaccine elicited neutralizing antibody responses in mice and non-human primates after a single dose, with more robust responses produced by version 2. Further, all mice and primates were protected from viremia following VEEV challenge. These vaccines were also safer in neonatal mice than the current investigational new drug vaccine, TC-83. These results show that IRES-based attenuation of alphavirus genomes consistently produce promising vaccine candidates, with VEEV/IRES version 2 showing promise for further development.
委内瑞拉马脑炎病毒（VEEV）是一种再度出现的病毒，对人类、农业和生物武器构成威胁。目前尚无美国食品药品监督管理局（FDA）批准的治疗人类委内瑞拉马脑炎的药物，因此需要研发一种安全、有效且无法在蚊媒中复制的疫苗。在此，我们描述了使用一种带有内部核糖体进入位点（IRES）的血清型ID VEEV（ZPC - 738）疫苗来改变基因表达模式。基于IRES插入位置，通过两种方式对这种ZPC/IRES疫苗进行基因工程改造，以创制出安全有效的疫苗。单次给药后，两种版本的ZPC/IRES疫苗在小鼠和非人类灵长类动物中均引发了中和抗体反应，其中版本2产生的反应更强。此外，所有小鼠和灵长类动物在受到VEEV攻击后均免受病毒血症影响。这些疫苗在新生小鼠中也比目前的研究性新药疫苗TC - 83更安全。这些结果表明，基于IRES对甲病毒基因组进行减毒处理能够持续产生有前景的疫苗候选物，VEEV/IRES版本2显示出进一步开发的潜力。
