Bernard Marie-Clotilde, Barban Véronique, Pradezynski Fabrine, de Montfort Aymeric, Ryall Robert, Caillet Catherine, Londono-Hayes Patricia
Sanofi Pasteur, Research and Development, Marcy-l'Étoile, France.
Sanofi Pasteur, Research and Development, Swiftwater, Pennsylvania, United States of America.
PLoS One. 2015 Apr 2;10(4):e0121518. doi: 10.1371/journal.pone.0121518. eCollection 2015.
HSV-2 vaccine is needed to prevent genital disease, latent infection, and virus transmission. A replication-deficient mutant virus (dl5-29) has demonstrated promising efficacy in animal models of genital herpes. However, the immunogenicity, protective efficacy, and non-replicative status of the highly purified clinical vaccine candidate (HSV529) derived from dl5-29 have not been evaluated. Humoral and cellular immune responses were measured in mice and guinea pigs immunized with HSV529. Protection against acute and recurrent genital herpes, mortality, latent infection, and viral shedding after vaginal HSV-2 infection was determined in mice or in naïve and HSV-1 seropositive guinea pigs. HSV529 replication and pathogenicity were investigated in three sensitive models of virus replication: severe combined immunodeficient (SCID/Beige) mice inoculated by the intramuscular route, suckling mice inoculated by the intracranial route, and vaginally-inoculated guinea pigs. HSV529 immunization induced HSV-2-neutralizing antibody production in mice and guinea pigs. In mice, it induced production of specific HSV-2 antibodies and splenocytes secreting IFNγ or IL-5. Immunization effectively prevented HSV-2 infection in all three animal models by reducing mortality, acute genital disease severity and frequency, and viral shedding. It also reduced ganglionic viral latency and recurrent disease in naïve and HSV-1 seropositive guinea pigs. HSV529 replication/propagation was not detected in the muscles of SCID/Beige mice, in the brains of suckling mice, or in vaginal secretions of inoculated guinea pigs. These results confirm the non-replicative status, as well as its immunogenicity and efficacy in mice and guinea pigs, including HSV-1 seropositive guinea pigs. In mice, HSV529 produced Th1/Th2 characteristic immune response thought to be necessary for an effective vaccine. These results further support the clinical investigation of HSV529 in human subjects as a prophylactic vaccine.
需要单纯疱疹病毒2型（HSV-2）疫苗来预防生殖器疾病、潜伏感染和病毒传播。一种复制缺陷型突变病毒（dl5-29）在生殖器疱疹动物模型中已显示出有前景的疗效。然而，源自dl5-29的高度纯化临床候选疫苗（HSV529）的免疫原性、保护效力和非复制状态尚未得到评估。在用HSV529免疫的小鼠和豚鼠中测量了体液和细胞免疫反应。在小鼠或未感染及HSV-1血清阳性的豚鼠中，确定了阴道感染HSV-2后对急性和复发性生殖器疱疹、死亡率、潜伏感染和病毒脱落的保护作用。在三种病毒复制敏感模型中研究了HSV529的复制和致病性：经肌肉途径接种的严重联合免疫缺陷（SCID/米色）小鼠、经颅内途径接种的乳鼠以及经阴道接种的豚鼠。HSV529免疫在小鼠和豚鼠中诱导产生HSV-2中和抗体。在小鼠中，它诱导产生特异性HSV-2抗体以及分泌IFNγ或IL-5的脾细胞。免疫通过降低死亡率、急性生殖器疾病的严重程度和频率以及病毒脱落，在所有三种动物模型中有效预防了HSV-2感染。它还降低了未感染及HSV-1血清阳性豚鼠的神经节病毒潜伏和复发性疾病。在SCID/米色小鼠的肌肉、乳鼠的大脑或接种豚鼠的阴道分泌物中未检测到HSV529的复制/增殖。这些结果证实了其非复制状态以及在小鼠和豚鼠（包括HSV-1血清阳性豚鼠）中的免疫原性和效力。在小鼠中，HSV529产生了被认为是有效疫苗所必需的Th1/Th2特征性免疫反应。这些结果进一步支持将HSV529作为预防性疫苗在人类受试者中进行临床研究。
