Section on Immune Biology of Retroviral Infection, Vaccine Branch, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-5065.
Laboratory of Cell Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4256; and.
J Immunol. 2020 Jun 15;204(12):3315-3328. doi: 10.4049/jimmunol.2000165. Epub 2020 May 11.
Because of microbicide noncompliance and lack of a durable, highly effective vaccine, a combined approach might improve HIV prophylaxis. We tested whether a vaccine-microbicide combination would enhance protection against SIV infection in rhesus macaques. Four macaque groups included vaccine only, vaccine-microbicide, microbicide only, and controls. Vaccine groups were primed twice mucosally with replicating adenovirus type 5 host range mutant SIV env/rev, gag, and nef recombinants and boosted twice i.m. with SIV gp120 proteins in alum. Controls and the microbicide-only group received adenovirus type 5 host range mutant empty vector and alum. The microbicide was SAMT-247, a 2-mercaptobenzamide thioester that targets the viral nucleocapsid protein NCp7, causing zinc ejection and preventing RNA encapsidation. Following vaccination, macaques were challenged intravaginally with repeated weekly low doses of SIV administered 3 h after application of 0.8% SAMT-247 gel (vaccine-microbicide and microbicide groups) or placebo gel (vaccine-only and control groups). The microbicide-only group exhibited potent protection; 10 of 12 macaques remained uninfected following 15 SIV challenges. The vaccine-only group developed strong mucosal and systemic humoral and cellular immunity but did not exhibit delayed acquisition compared with adjuvant controls. However, the vaccine-microbicide group exhibited significant acquisition delay compared with both control and vaccine-only groups, indicating further exploration of the combination strategy is warranted. Impaired protection in the vaccine-microbicide group compared with the microbicide-only group was not attributed to a vaccine-induced increase in SIV target cells. Possible Ab-dependent enhancement will be further investigated. The potent protection provided by SAMT-247 encourages its movement into human clinical trials.
由于杀微生物剂的不依从性和缺乏持久、高效的疫苗，联合方法可能会改善 HIV 的预防。我们测试了疫苗-杀微生物剂联合是否会增强恒河猴对 SIV 感染的保护。四个猕猴组包括仅疫苗组、疫苗-杀微生物剂组、杀微生物剂仅组和对照组。疫苗组两次经粘膜用复制型腺病毒 5 型宿主范围突变 SIV env/rev、gag 和 nef 重组体进行初级免疫，两次经肌内用 SIV gp120 蛋白在明矾中进行加强免疫。对照组和杀微生物剂仅组接受腺病毒 5 型宿主范围突变空载体和明矾。杀微生物剂是 SAMT-247，一种 2-巯基苯甲酰胺硫酯，靶向病毒核衣壳蛋白 NCp7，导致锌释放并阻止 RNA 包裹。接种疫苗后，猕猴经阴道接受重复每周低剂量 SIV 挑战，在应用 0.8% SAMT-247 凝胶（疫苗-杀微生物剂和杀微生物剂组）或安慰剂凝胶（仅疫苗和对照组）后 3 小时进行。杀微生物剂仅组表现出强大的保护作用；在 15 次 SIV 挑战后，12 只猕猴中有 10 只未感染。仅疫苗组产生了强烈的粘膜和全身体液和细胞免疫，但与佐剂对照组相比，没有表现出延迟获得。然而，疫苗-杀微生物剂组与对照组和仅疫苗组相比，明显延迟获得，表明有必要进一步探索联合策略。与杀微生物剂仅组相比，疫苗-杀微生物剂组的保护受损并不是由于疫苗诱导的 SIV 靶细胞增加所致。可能的 Ab 依赖性增强将进一步研究。SAMT-247 提供的强大保护作用鼓励其进入人类临床试验。
