Department of Medicine, Boston Children's Hospital, Boston, MA, United States.
Department of Pediatrics, Harvard Medical School, Boston, MA, United States.
Front Immunol. 2021 Jun 21;12:702705. doi: 10.3389/fimmu.2021.702705. eCollection 2021.
We modified a Sabin Oral Poliovirus Vaccine (OPV) vector to permit secretion of the antigens of interest with the goal of improving anti-HIV Env humoral responses in a SHIV mucosal immunization composed of DNA and recombinant OPVs. We evaluated stimulation of systemic and mucosal cell-mediated and humoral immunity in Rhesus macaques by two regimens, both involving a prime with a SHIVDNA construct producing non-infectious particles formulated in lipid nanoparticles, administered in the oral cavity, and two different viral vector boostings, administered in the oral cavity and intestinally.Group 1 was boosted with rMVA-SHIVBG505, expressing SIV Gag/Pol and HIV Env. Group 2 was boosted with a SHIV-OPV vaccine including a non-secreting SIVCA-p6-OPV, expressing Gag CA, NC and p6 proteins, and a HIVC1-V2-OPV, secreting the C1-V2 fragment of HIV Env, recognized by the broadly neutralizing antibody PG16. A time course analysis of anti-SHIV Gag and Env CD4+ and CD8+ T-cell responses in PBMC and in lymph node, rectal, and vaginal MNC was carried out. Both regimens stimulated significant cell-mediated responses in all compartments, with SHIV-OPV immunization stimulating more significant levels of responses than rMVA- SHIV. Boolean analysis of these responses revealed predominantly monofunctional responses with multifunctional responses also present in all tissues. Stimulation of antibody responses was disappointing in both groups with negative anti-SHIV IgG in plasma, and IgA in salivary, rectal and vaginal secretions being restricted to a few animals. After repeated rectal challenge with SHIV, two Group 1 animals remained uninfected at challenge termination. No significant differences were observed in post-infection viral loads between groups. After the acute phase decline, CD4+ T cell percentages returned to normal levels in vaccinated as well as control animals. However, when compared to controls, vaccinate groups had more significant preservation of PBMC and rectal MNC Th17/Treg ratios, considered the strongest surrogate marker of progression to AIDS. We conclude that the vaccine platforms used in this study are insufficient to stimulate significant humoral immunity at the tested doses and schedule but sufficient to stimulate significant mucosal and systemic cell-mediated immunity, impacting the preservation of key Th17 CD4+ T cells in blood and rectal mucosa.
我们修改了沙宾口服脊髓灰质炎疫苗（OPV）载体，使其能够分泌感兴趣的抗原，目的是提高由 DNA 和重组 OPV 组成的 SHIV 黏膜免疫中抗 HIV Env 的体液反应。我们通过两种方案评估了恒河猴的全身性和黏膜细胞介导和体液免疫刺激，两种方案均涉及用产生非感染性颗粒的 SHIVDNA 构建体进行初免，该构建体在脂质纳米颗粒中配制，经口腔给药，并用两种不同的病毒载体进行加强免疫，经口腔和肠道给药。第 1 组用表达 SIV Gag/Pol 和 HIV Env 的 rMVA-SHIVBG505 进行加强免疫。第 2 组用 SHIV-OPV 疫苗进行加强免疫，该疫苗包括不分泌 SIVCA-p6-OPV，表达 Gag CA、NC 和 p6 蛋白，以及 HIVC1-V2-OPV，分泌 HIV Env 的 C1-V2 片段，被广泛中和抗体 PG16 识别。对 PBMC 和淋巴结、直肠和阴道 MNC 中抗 SHIV Gag 和 Env CD4+和 CD8+T 细胞反应进行了时间过程分析。两种方案均在所有部位刺激了显著的细胞介导反应，SHIV-OPV 免疫刺激的反应水平高于 rMVA-SHIV。对这些反应进行布尔分析显示，大多数为单功能反应，所有组织中也存在多功能反应。两组的抗体反应均令人失望，血浆中抗 SHIV IgG 为阴性，唾液、直肠和阴道分泌物中的 IgA 仅限于少数动物。在接受 SHIV 多次直肠攻击后，第 1 组的 2 只动物在攻击结束时仍未感染。两组之间在感染后的病毒载量方面没有观察到显著差异。急性阶段下降后，接种疫苗和对照动物的 CD4+T 细胞百分比恢复正常水平。然而，与对照组相比，接种组在 PBMC 和直肠 MNC Th17/Treg 比值方面有更显著的保留，被认为是向 AIDS 进展的最强替代标志物。我们得出结论，在测试剂量和方案下，该研究中使用的疫苗平台不足以刺激显著的体液免疫，但足以刺激显著的黏膜和全身细胞介导免疫，影响血液和直肠黏膜中关键 Th17 CD4+T 细胞的保存。
