Comparative Immunogenicity of HIV-1 gp140 Vaccine Delivered by Parenteral, and Mucosal Routes in Female Volunteers; MUCOVAC2, A Randomized Two Centre Study

BackgroundDefining optimal routes for induction of mucosal immunity represents an important research priority for the HIV-1 vaccine field. In particular, it remains unclear whether mucosal routes of immunization can improve mucosal immune responses.MethodsIn this randomized two center phase I clinical trial we evaluated the systemic and mucosal immune response to a candidate HIV-1 Clade C CN54gp140 envelope glycoprotein vaccine administered by intramuscular (IM), intranasal (IN) and intravaginal (IVAG) routes of administration in HIV negative female volunteers. IM immunizations were co-administered with Glucopyranosyl Lipid Adjuvant (GLA), IN immunizations with 0.5% chitosan and IVAG immunizations were administered in an aqueous gel.ResultsThree IM immunizations of CN54 gp140 at either 20 or 100 μg elicited significantly greater systemic and mucosal antibodies than either IN or IVAG immunizations. Following additional intramuscular boosting we observed an anamnestic antibody response in nasally primed subjects. Modest neutralizing responses were detected against closely matched tier 1 clade C virus in the IM groups. Interestingly, the strongest CD4 T-cell responses were detected after IN and not IM immunization.ConclusionsThese data show that parenteral immunization elicits systemic and mucosal antibodies in women. Interestingly IN immunization was an effective prime for IM boost, while IVAG administration had no detectable impact on systemic or mucosal responses despite IM priming.Clinical Trials RegistrationEudraCT 2010-019103-27 and the UK Clinical Research Network (UKCRN) Number 11679

背景
明确诱导黏膜免疫的最佳途径，是HIV-1疫苗研发领域的重要研究方向。目前尚不明确黏膜免疫途径是否能够增强黏膜免疫应答。

方法
本项随机双中心I期临床试验，针对HIV阴性女性志愿者，评估了分别经肌内注射（intramuscular, IM）、鼻内注射（intranasal, IN）及阴道内注射（intravaginal, IVAG）途径接种候选HIV-1 C亚型CN54gp140包膜糖蛋白疫苗后的全身及黏膜免疫应答。其中肌内注射组联合葡萄糖基脂质佐剂（Glucopyranosyl Lipid Adjuvant, GLA）接种，鼻内注射组辅以0.5%壳聚糖，阴道内注射组则采用水性凝胶载体给药。

结果
分别接种20或100微克CN54gp140的三次肌内免疫组，其诱导的全身及黏膜抗体水平均显著高于鼻内或阴道内免疫组。在追加肌内加强免疫后，鼻内初免的受试者出现了回忆性抗体应答。肌内免疫组可检测到针对与疫苗匹配度较高的1级C亚型病毒株的轻度中和应答。值得注意的是，最强的CD4阳性T细胞应答出现在鼻内免疫组，而非肌内免疫组。

结论
本研究数据表明，肠外免疫可在女性体内诱导产生全身及黏膜抗体。值得关注的是，鼻内免疫可作为肌内加强免疫的有效初免方案；而即便预先接受肌内初免，阴道内接种未对全身或黏膜免疫应答产生可检测到的影响。

临床试验注册
欧盟临床试验注册库（EudraCT）编号：2010-019103-27；英国临床研究网络（UKCRN）编号：11679