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佐以稳定乳剂和Toll样受体9激动剂的预防性单纯疱疹病毒2型(HSV-2)疫苗可诱导强烈的HSV-2特异性细胞介导免疫反应,预防症状性疾病,并减少潜伏病毒库。

Prophylactic Herpes Simplex Virus 2 (HSV-2) Vaccines Adjuvanted with Stable Emulsion and Toll-Like Receptor 9 Agonist Induce a Robust HSV-2-Specific Cell-Mediated Immune Response, Protect against Symptomatic Disease, and Reduce the Latent Viral Reservoir.

作者信息

Hensel Michael T, Marshall Jason D, Dorwart Michael R, Heeke Darren S, Rao Eileen, Tummala Padmaja, Yu Li, Cohen Gary H, Eisenberg Roselyn J, Sloan Derek D

机构信息

Vaccine Platform Group, MedImmune, Gaithersburg, Maryland, USA

Vaccine Platform Group, MedImmune, Gaithersburg, Maryland, USA.

出版信息

J Virol. 2017 Apr 13;91(9). doi: 10.1128/JVI.02257-16. Print 2017 May 1.

Abstract

Several prophylactic vaccines targeting herpes simplex virus 2 (HSV-2) have failed in the clinic to demonstrate sustained depression of viral shedding or protection from recurrences. Although these vaccines have generated high titers of neutralizing antibodies (NAbs), their induction of robust CD8 T cells has largely been unreported, even though evidence for the importance of HSV-2 antigen-specific CD8 T cells is mounting in animal models and in translational studies involving subjects with active HSV-2-specific immune responses. We developed a subunit vaccine composed of the NAb targets gD and gB and the novel T cell antigen and tegument protein UL40, and we compared this vaccine to a whole-inactivated-virus vaccine (formaldehyde-inactivated HSV-2 [FI-HSV-2]). We evaluated different formulations in combination with several Th1-inducing Toll-like receptor (TLR) agonists In mice, the TLR9 agonist cytosine-phosphate-guanine (CpG) oligodeoxynucleotide formulated in a squalene-based oil-in-water emulsion promoted most robust, functional HSV-2 antigen-specific CD8 T cell responses and high titers of neutralizing antibodies, demonstrating its superiority to vaccines adjuvanted by monophosphoryl lipid A (MPL)-alum. We further established that FI-HSV-2 alone or in combination with adjuvants as well as adjuvanted subunit vaccines were successful in the induction of NAbs and T cell responses in guinea pigs. These immunological responses were coincident with a suppression of vaginal HSV-2 shedding, low lesion scores, and a reduction in latent HSV-2 DNA in dorsal root ganglia to undetectable levels. These data support the further preclinical and clinical development of prophylactic HSV-2 vaccines that contain appropriate antigen and adjuvant components responsible for programming elevated CD8 T cell responses. Millions of people worldwide are infected with herpes simplex virus 2 (HSV-2), and to date, an efficacious prophylactic vaccine has not met the rigors of clinical trials. Attempts to develop a vaccine have focused primarily on glycoproteins necessary for HSV-2 entry as target antigens and to which the dominant neutralizing antibody response is directed during natural infection. Individuals with asymptomatic infection have exhibited T cell responses against specific HSV-2 antigens not observed in symptomatic individuals. We describe for the first time the immunogenicity profile in animal models of UL40, a novel HSV-2 T cell antigen that has been correlated with asymptomatic HSV-2 disease. Additionally, vaccine candidates adjuvanted by a robust formulation of the CpG oligonucleotide delivered in emulsion were superior to unadjuvanted or MPL-alum-adjuvanted formulations at eliciting a robust cell-mediated immune response and blocking the establishment of a latent viral reservoir in the guinea pig challenge model of HSV-2 infection.

摘要

几种针对单纯疱疹病毒2型(HSV-2)的预防性疫苗在临床试验中未能证明能持续抑制病毒排出或预防复发。尽管这些疫苗产生了高滴度的中和抗体(NAbs),但它们诱导产生强大的CD8 T细胞的情况在很大程度上未被报道,即便在动物模型以及涉及具有活跃HSV-2特异性免疫反应受试者的转化研究中,HSV-2抗原特异性CD8 T细胞重要性的证据越来越多。我们研发了一种亚单位疫苗,其由中和抗体靶点gD和gB以及新型T细胞抗原和被膜蛋白UL40组成,并将这种疫苗与全灭活病毒疫苗(甲醛灭活的HSV-2 [FI-HSV-2])进行了比较。我们评估了不同配方与几种诱导Th1的Toll样受体(TLR)激动剂的组合。在小鼠中,以角鲨烯基水包油乳液配制的TLR9激动剂胞嘧啶 - 磷酸 - 鸟嘌呤(CpG)寡脱氧核苷酸促进了最强大、功能性的HSV-2抗原特异性CD8 T细胞反应以及高滴度的中和抗体,证明其优于单磷酰脂质A(MPL)-明矾佐剂的疫苗。我们进一步证实,单独的FI-HSV-2或与佐剂联合使用以及佐剂亚单位疫苗在豚鼠中成功诱导了中和抗体和T细胞反应。这些免疫反应与阴道HSV-2排出的抑制、低病变评分以及背根神经节中潜伏性HSV-2 DNA减少到无法检测的水平相一致。这些数据支持进一步对包含负责编程增强CD8 T细胞反应的适当抗原和佐剂成分的预防性HSV-2疫苗进行临床前和临床开发。全球数以百万计的人感染了单纯疱疹病毒2型(HSV-2),迄今为止,一种有效的预防性疫苗尚未通过临床试验的严格检验。研发疫苗的尝试主要集中在HSV-2进入所必需的糖蛋白作为靶抗原,以及在自然感染期间主导中和抗体反应所针对的抗原上。无症状感染个体表现出针对有症状个体未观察到的特定HSV-2抗原的T细胞反应。我们首次描述了UL40在动物模型中的免疫原性概况,UL40是一种与无症状HSV-2疾病相关的新型HSV-2 T细胞抗原。此外,在HSV-2感染的豚鼠攻击模型中,以乳液形式递送的强力CpG寡核苷酸佐剂的候选疫苗在引发强大的细胞介导免疫反应和阻断潜伏病毒库的建立方面优于未佐剂或MPL-明矾佐剂的配方。

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