Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes
Nucleoside-modified mRNA encoding HSV-2 glycoproteins C, D, and E prevents clinical and subclinical genital herpes
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DOI：
10.1126/sciimmunol.aaw7083
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发表时间：
2019-09-01
影响因子：
24.8
通讯作者：
Friedman, Harvey M.
中科院分区：
文献类型：
--
作者：
Awasthi, Sita;Hook, Lauren M.;Friedman, Harvey M.
生殖器疱疹疫苗的目标是预防疼痛性生殖器病变，减少或消除有可能传播给伴侣和新生儿的亚临床感染。我们评估了一种含有单纯疱疹病毒2型（HSV-2）进入分子糖蛋白D （gD2）和两个免疫逃避分子的三价糖蛋白疫苗：糖蛋白C （gC2）结合补体C3b，糖蛋白E （gE2）阻断免疫球蛋白G (IgG) Fc活性。三价疫苗是用含有CpG和明矾的杆状病毒蛋白给药，或者用核苷修饰的mRNA在脂质纳米颗粒（LNPs）中表达相同的氨基酸。这两种配方完全防止了小鼠和豚鼠的生殖器损伤。在评估亚临床感染时出现了差异。三价蛋白疫苗可预防背根神经节感染，30只小鼠中有23只（73%）阴道培养第2天和第4天阴性，而mRNA组64只小鼠中有63只（98%）阴道培养阴性（P = 0.0012）。在豚鼠中，三价亚单位蛋白组10只动物中有5只（50%）在210天中的19天（9%）发生HSV-2 DNA阴道脱落，而mRNA组10只动物中有2只（20%）在210天中的5天（2%）发生HSV-2 DNA阴道脱落（P = 0.0052）。三价mRNA疫苗在刺激ELISA IgG抗体、中和抗体、结合参与进入和细胞间扩散的关键gD2表位的抗体、CD4(+) T细胞应答、T滤泡辅助和生发中心B细胞应答方面优于三价蛋白。三价核苷修饰mRNA-LNP疫苗是一种很有希望用于人体试验的候选疫苗。
The goals of a genital herpes vaccine are to prevent painful genital lesions and reduce or eliminate subclinical infection that risks transmission to partners and newborns. We evaluated a trivalent glycoprotein vaccine containing herpes simplex virus type 2 (HSV-2) entry molecule glycoprotein D (gD2) and two immune evasion molecules: glycoprotein C (gC2), which binds complement C3b, and glycoprotein E (gE2), which blocks immunoglobulin G (IgG) Fc activities. The trivalent vaccine was administered as baculovirus proteins with CpG and alum, or the identical amino acids were expressed using nucleoside-modified mRNA in lipid nanoparticles (LNPs). Both formulations completely prevented genital lesions in mice and guinea pigs. Differences emerged when evaluating subclinical infection. The trivalent protein vaccine prevented dorsal root ganglia infection, and day 2 and 4 vaginal cultures were negative in 23 of 30 (73%) mice compared with 63 of 64 (98%) in the mRNA group (P = 0.0012). In guinea pigs, 5 of 10 (50%) animals in the trivalent subunit protein group had vaginal shedding of HSV-2 DNA on 19 of 210 (9%) days compared with 2 of 10 (20%) animals in the mRNA group that shed HSV-2 DNA on 5 of 210 (2%) days (P = 0.0052). The trivalent mRNA vaccine was superior to trivalent proteins in stimulating ELISA IgG antibodies, neutralizing antibodies, antibodies that bind to crucial gD2 epitopes involved in entry and cell-to-cell spread, CD4(+) T cell responses, and T follicular helper and germinal center B cell responses. The trivalent nucleoside-modified mRNA-LNP vaccine is a promising candidate for human trials.