Intranasal Administration of a Therapeutic HIV Vaccine (Vacc-4x) Induces Dose-Dependent Systemic and Mucosal Immune Responses in a Randomized Controlled Trial

Background
Vacc-4x, a Gag p24-based therapeutic HIV vaccine, has been shown to reduce viral load set-points after intradermal administration. In this randomized controlled pilot study we investigate intranasal administration of Vacc-4x with Endocine as adjuvant.
Methods
Safety and immunogenicity were tested in patients on effective ART. They were randomized to low, medium or high dose Vacc-4x or adjuvant alone, administered four times at weekly intervals with no booster. Vacc-4x-specific T cell responses were measured in vitro by proliferation and in vivo by a single DTH skin test at the end of study. Nasal and rectal mucosal secretions were analyzed for Vacc-4x-specific antibodies by ELISA. Immune regulation induced by Vacc-4x was assessed by functional blockade of the regulatory cytokines IL-10 and TGF-β.
Results
Vacc-4x proliferative T cell responses increased only among the vaccinated (p≤0.031). The low dose group showed the greatest increase in Vacc-4x CD8+T cell responses (p = 0.037) and developed larger DTH (p = 0.005) than the adjuvant group. Rectal (distal) Vacc-4x IgA and IgG antibodies also increased (p = 0.043) in this group. In contrast, the high dose generated higher nasal (local) Vacc-4x IgA (p = 0.028) and serum IgG (p = 0.030) antibodies than the adjuvant. Irrespective of dose, increased Vacc-4x CD4+T cell responses were associated with low proliferation (r = −0.82, p<0.001) and high regulation (r = 0.61, p = 0.010) at baseline.
Conclusion
Intranasal administration of Vacc-4x with Endocine was safe and induced dose-dependent vaccine-specific T cell responses and both mucosal and systemic humoral responses. The clinical significance of dose, immune regulation and mucosal immunity warrants further investigation.
Trial Registration
ClinicalTrials.gov NCT01473810

背景

以Gag p24为基础的治疗性HIV疫苗Vacc-4x，经皮内给药后可降低病毒载量设定值。本随机对照先导研究旨在考察以Endocine为佐剂的Vacc-4x经鼻内给药的效果。

方法

本研究在接受有效抗逆转录病毒治疗（antiretroviral therapy, ART）的患者中评估疫苗的安全性与免疫原性。将受试者随机分为低剂量、中剂量、高剂量Vacc-4x组以及单纯佐剂组，共给药4次，每周1次，无需加强免疫。采用体外增殖实验与研究结束时的单次迟发型超敏反应（delayed-type hypersensitivity, DTH）皮肤试验，分别检测Vacc-4x特异性T细胞应答。通过酶联免疫吸附试验（enzyme-linked immunosorbent assay, ELISA）分析鼻腔与直肠黏膜分泌物中的Vacc-4x特异性抗体。通过对调节性细胞因子白细胞介素10（interleukin-10, IL-10）与转化生长因子β（transforming growth factor-β, TGF-β）进行功能阻断实验，评估Vacc-4x诱导的免疫调节作用。

结果

仅疫苗接种组出现Vacc-4x特异性T细胞增殖应答升高（p≤0.031）。低剂量组的Vacc-4x特异性CD8+T细胞应答增幅最为显著（p=0.037），且迟发型超敏反应皮肤试验硬结面积大于单纯佐剂组（p=0.005）。该组直肠（远端）黏膜的Vacc-4x特异性IgA与IgG抗体水平亦有所升高（p=0.043）。与之相反，高剂量组的鼻腔（局部）黏膜Vacc-4x特异性IgA（p=0.028）与血清IgG（p=0.030）抗体水平高于单纯佐剂组。无论剂量高低，基线状态下Vacc-4x特异性CD4+T细胞应答升高均与低增殖活性（r=-0.82, p<0.001）及高免疫调节活性（r=0.61, p=0.010）相关。

结论

以Endocine为佐剂的Vacc-4x经鼻内给药具有安全性，可诱导剂量依赖性的疫苗特异性T细胞应答，以及黏膜与全身性体液免疫应答。剂量、免疫调节与黏膜免疫的临床意义尚需进一步研究。

试验注册

ClinicalTrials.gov NCT01473810