Intradermal but not intramuscular MVA immunizations protect against intravaginal tier2 SHIV challenges in macaques

Route of immunization can markedly influence the quality of immune response. Here, we show that intradermal (ID) but not intramuscular (IM) modified vaccinia Ankara (MVA) vaccinations provide protection from acquisition of intravaginal tier2 SHIV challenges in female macaques. Both routes of vaccination induced comparable levels of serum IgG with neutralizing and non-neutralizing activities. The protection in MVA-ID group correlated positively with serum neutralizing and antibody-dependent phagocytic activities, and envelope-specific vaginal IgA; while the limited protection in MVA-IM group correlated only with serum neutralizing activity. MVA-ID immunizations induced greater germinal center Tfh and B cell responses, reduced the ratio of Th1 to Tfh cells in blood and showed lower activation of intermediate monocytes and inflammasome compared to MVA-IM immunizations. This lower innate activation correlated negatively with induction of Tfh responses. These data demonstrate that the MVA-ID vaccinations protect against intravaginal SHIV challenges by modulating the innate and T helper responses. Overall design: We vaccinated two groups of rhesus macaques with 10 animals per group using the DNA/MVA/Protein vaccine regimen. Animals in both groups were primed with DNA/SHIV-BG505-CD40L via the ID route and electroporation at weeks 0 and 8. At weeks 16 and 24, all animals were boosted with MVA/SHIV-BG505 delivered through either ID or IM routes.

免疫接种途径可显著调控免疫应答的质量。本研究证实，皮内（intradermal, ID）而非肌内（intramuscular, IM）接种改良痘苗安卡拉株（modified vaccinia Ankara, MVA），可使雌性猕猴免受阴道内2型SHIV（Simian-Human Immunodeficiency Virus, SHIV）攻毒感染。两种接种途径均可诱导水平相当的兼具中和与非中和活性的血清IgG。MVA-ID组的保护效果与血清中和活性、抗体依赖性吞噬活性及包膜特异性阴道IgA水平呈正相关；而MVA-IM组仅表现出有限的保护效果，且仅与血清中和活性相关。与MVA-IM免疫相比，MVA-ID免疫可诱导更强的生发中心滤泡辅助T细胞（germinal center T follicular helper, Tfh）与B细胞应答，降低血液中辅助性T细胞1（T helper 1, Th1）与Tfh细胞的比值，同时可减弱中间型单核细胞的活化及炎症小体的激活。这种更低的先天免疫活化水平与Tfh应答的诱导呈负相关。本研究数据表明，MVA-ID免疫可通过调控先天免疫与辅助性T细胞应答，抵御阴道内SHIV攻毒。

实验总体设计：本研究采用DNA/MVA/蛋白联合免疫方案，对两组共20只恒河猴进行免疫（每组10只）。两组动物均于第0周和第8周，通过皮内途径结合电穿孔法，以DNA/SHIV-BG505-CD40L进行初次免疫。于第16周和第24周，所有动物分别通过皮内或肌内途径接种MVA/SHIV-BG505进行加强免疫。