Awasthi Sita, Mahairas Gregory G, Shaw Carolyn E, Huang Meei-Li, Koelle David M, Posavad Christine, Corey Lawrence, Friedman Harvey M
Infectious Disease Division, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, USA
Department of Laboratory Medicine, School of Medicine, University of Washington, Seattle, Washington, USA.
J Virol. 2015 Aug;89(16):8497-509. doi: 10.1128/JVI.01089-15. Epub 2015 Jun 3.
We evaluated a genital herpes prophylactic vaccine containing herpes simplex virus 2 (HSV-2) glycoproteins C (gC2) and D (gD2) to stimulate humoral immunity and UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) as T cell immunogens. The HSV-2 gC2 and gD2 proteins were expressed in baculovirus, while the UL19 and UL47 genes were expressed from replication-defective adenovirus vectors. Adenovirus vectors containing UL19 and UL47 stimulated human and murine CD4(+) and CD8(+) T cell responses. Guinea pigs were either (i) mock immunized; (ii) immunized with gC2/gD2, with CpG and alum as adjuvants; (iii) immunized with the UL19/UL47 adenovirus vectors; or (iv) immunized with the combination of gC2/gD2-CpG/alum and the UL19/UL47 adenovirus vectors. Immunization with gC2/gD2 produced potent neutralizing antibodies, while UL19 and UL47 also stimulated antibody responses. After intravaginal HSV-2 challenge, the mock and UL19/UL47 adenovirus groups developed severe acute disease, while 2/8 animals in the gC2/gD2-only group and none in the combined group developed acute disease. No animals in the gC2/gD2 or combined group developed recurrent disease; however, 5/8 animals in each group had subclinical shedding of HSV-2 DNA, on 15/168 days for the gC2/gD2 group and 13/168 days for the combined group. Lumbosacral dorsal root ganglia were positive for HSV-2 DNA and latency-associated transcripts for 5/8 animals in the gC2/gD2 group and 2/8 animals in the combined group. None of the differences comparing the gC2/gD2-only group and the combined group were statistically significant. Therefore, adding the T cell immunogens UL19 and UL47 to the gC2/gD2 vaccine did not significantly reduce genital disease and vaginal HSV-2 DNA shedding compared with the excellent protection provided by gC2/gD2 in the guinea pig model.
HSV-2 infection is a common cause of genital ulcer disease and a significant public health concern. Genital herpes increases the risk of transmission and acquisition of HIV-1 infection 3- to 4-fold. A herpes vaccine that prevents genital lesions and asymptomatic genital shedding will have a substantial impact on two epidemics, i.e., both the HSV-2 and HIV-1 epidemics. We previously reported that a vaccine containing HSV-2 glycoprotein C (gC2) and glycoprotein D (gD2) reduced genital lesions and asymptomatic HSV-2 genital shedding in guinea pigs, yet the protection was not complete. We evaluated whether adding the T cell immunogens UL19 (capsid protein VP5) and UL47 (tegument protein VP13/14) would enhance the protection provided by the gC2/gD2 vaccine, which produces potent antibody responses. Here we report the efficacy of a combination vaccine containing gC2/gD2 and UL19/UL47 for prevention of genital disease, vaginal shedding of HSV-2 DNA, and latent infection of dorsal root ganglia in guinea pigs.
我们评估了一种生殖器疱疹预防性疫苗，其包含单纯疱疹病毒2型（HSV-2）糖蛋白C（gC2）和D（gD2）以刺激体液免疫，以及UL19（衣壳蛋白VP5）和UL47（包膜蛋白VP13/14）作为T细胞免疫原。HSV-2 gC2和gD2蛋白在杆状病毒中表达，而UL19和UL47基因从复制缺陷型腺病毒载体表达。含有UL19和UL47的腺病毒载体刺激人和小鼠的CD4(+)和CD8(+) T细胞反应。豚鼠被分为以下几组：（i）假免疫；（ii）用gC2/gD2免疫，并使用CpG和明矾作为佐剂；（iii）用UL19/UL47腺病毒载体免疫；或（iv）用gC2/gD2-CpG/明矾和UL19/UL47腺病毒载体的组合免疫。用gC2/gD2免疫产生了强效中和抗体，而UL19和UL47也刺激了抗体反应。经阴道HSV-2攻击后，假免疫组和UL19/UL47腺病毒组发生了严重的急性疾病，而仅gC2/gD2组的8只动物中有2只未发生急性疾病，联合组则无动物发生急性疾病。gC2/gD2组或联合组中没有动物发生复发性疾病；然而，gC2/gD2组的8只动物中有5只在168天中的15天出现HSV-2 DNA的亚临床脱落，联合组则是在168天中的13天出现。gC2/gD2组的8只动物中有5只、联合组的8只动物中有2只的腰骶部背根神经节的HSV-2 DNA和潜伏相关转录本呈阳性。比较仅gC2/gD2组和联合组的差异均无统计学意义。因此，与gC2/gD2在豚鼠模型中提供的优异保护相比，在gC2/gD2疫苗中添加T细胞免疫原UL19和UL47并未显著降低生殖器疾病和阴道HSV-2 DNA脱落。
HSV-2感染是生殖器溃疡疾病的常见病因，也是一个重大的公共卫生问题。生殖器疱疹使HIV-1感染的传播和感染风险增加3至4倍。一种能预防生殖器病变和无症状生殖器脱落的疱疹疫苗将对两种流行病，即HSV-2和HIV-1流行病产生重大影响。我们之前报道过，一种含有HSV-2糖蛋白C（gC2）和糖蛋白D（gD2）的疫苗可减少豚鼠的生殖器病变和无症状HSV-2生殖器脱落，但保护并不完全。我们评估了添加T细胞免疫原UL19（衣壳蛋白VP5）和UL47（包膜蛋白VP13/14）是否会增强gC2/gD2疫苗提供的保护，该疫苗可产生强效抗体反应。在此我们报告了一种包含gC2/gD2和UL19/UL47的联合疫苗在预防豚鼠生殖器疾病、阴道HSV-2 DNA脱落和背根神经节潜伏感染方面的疗效。
