Petro Christopher D, Weinrick Brian, Khajoueinejad Nazanin, Burn Clare, Sellers Rani, Jacobs William R, Herold Betsy C
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA; Department of Pediatrics, Albert Einstein College of Medicine, Bronx, New York, USA.
Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, New York, USA; Howard Hughes Medical Institute, Albert Einstein College of Medicine, Bronx, New York, USA.
JCI Insight. 2016 Aug 4;1(12). doi: 10.1172/jci.insight.88529.
A single-cycle herpes simplex virus (HSV) deleted in glycoprotein D (ΔgD-2) elicited high titer HSV-specific antibodies (Abs) that (i) were rapidly transported into the vaginal mucosa; (ii) elicited antibody-dependent cell-mediated cytotoxicity but little neutralization; (iii) provided complete protection against lethal intravaginal challenge; and (iv) prevented establishment of latency in mice. However, clinical isolates may differ antigenically and impact vaccine efficacy. To determine the breadth and further define mechanisms of protection of this vaccine candidate, we tested ΔgD-2 against a panel of clinical isolates in a murine skin challenge model. The isolates were genetically diverse, as evidenced by genomic sequencing and in vivo virulence. Prime and boost immunization (s.c.) with live but not heat- or UV-inactivated ΔgD-2 completely protected mice from challenge with the most virulent HSV-1 and HSV-2 isolates. Furthermore, mice were completely protected against 100 times the lethal dose that typically kills 90% of animals (LD90) of a South African isolate (SD90), and no latent virus was detected in dorsal root ganglia. Immunization was associated with rapid recruitment of HSV-specific FcγRIII- and FcγRIV-activating IgG2 Abs into the skin, resolution of local cytokine and cellular inflammatory responses, and viral clearance by day 5 after challenge. Rapid clearance and the absence of latent virus suggest that ΔgD-2 elicits sterilizing immunity.
一种缺失糖蛋白D（ΔgD-2）的单周期单纯疱疹病毒（HSV）可引发高滴度的HSV特异性抗体（Abs），这些抗体：（i）能迅速转运至阴道黏膜；（ii）引发抗体依赖性细胞介导的细胞毒性，但中和作用较弱；（iii）提供针对致死性阴道内攻击的完全保护；（iv）防止小鼠建立潜伏感染。然而，临床分离株在抗原性上可能存在差异并影响疫苗效力。为了确定这种候选疫苗的保护广度并进一步明确其保护机制，我们在小鼠皮肤攻击模型中用一组临床分离株测试了ΔgD-2。这些分离株在基因上具有多样性，基因组测序和体内毒力证明了这一点。用活的而非热灭活或紫外线灭活的ΔgD-2进行初次和加强免疫（皮下注射）可使小鼠完全免受最具毒力的HSV-1和HSV-2分离株的攻击。此外，小鼠完全受到保护，可抵御比通常杀死90%动物的致死剂量（LD90）高100倍的南非分离株（SD90），且在背根神经节中未检测到潜伏病毒。免疫与HSV特异性FcγRIII和FcγRIV激活型IgG2抗体迅速募集到皮肤中、局部细胞因子和细胞炎症反应的消退以及攻击后第5天病毒清除有关。快速清除和无潜伏病毒表明ΔgD-2可引发无菌免疫。
