Immunization with HIV Gag targeted to dendritic cells followed by recombinant New York vaccinia virus induces robust T-cell immunity in nonhuman primates
Immunization with HIV Gag targeted to dendritic cells followed by recombinant New York vaccinia virus induces robust T-cell immunity in nonhuman primates
复制标题
DOI：
10.1073/pnas.1103869108
复制
发表时间：
2011-04-26
影响因子：
11.1
通讯作者：
Seder, Robert
中科院分区：
文献类型：
--
作者：
Flynn, Barbara J.;Kastenmueller, Kathrin;Seder, Robert
蛋白质疫苗如果具有免疫原性，将有助于研制针对艾滋病毒和其他病原体的疫苗。我们比较了非人灵长类动物（NHPs）对树突状细胞上摄取受体DEC205（“DEC-HIV Gag p24”）的3G9抗体对HIV Gag p24的免疫反应，以及非靶向蛋白，有或没有poly ICLC（一种合成的双链RNA）作为佐剂。用60 μ g这两种HIV Gag p24疫苗启动sc，可诱导分泌IL-2、ifn - γ和tnf - α的强效CD4(+) T细胞，这些细胞也会增殖。应答随着三次免疫和识别多个Gag肽而增加。DEC-HIV Gag p24对CD8(+) T细胞表现出更好的交叉引物，而抗Gag抗体的亲和力与非靶向Gag 24蛋白相似，高出10倍。对于这两种蛋白疫苗，聚ICLC对t细胞和b细胞免疫至关重要。为了确定适应性反应是否可以进一步增强，动物接种了纽约牛痘病毒(NYVAC)-HIV Gag/Pol/Nef。抗原特异性CD4（+）和CD8(+) t细胞反应在蛋白疫苗和聚ICLC启动后显著增加。这些数据揭示了抗体和t细胞对DEC-HIV Gag p24和Gag p24蛋白反应的定性差异，并表明首先用蛋白和佐剂增强，然后再用NYVAC诱导有效的细胞免疫。
Protein vaccines, if rendered immunogenic, would facilitate vaccine development against HIV and other pathogens. We compared in nonhuman primates (NHPs) immune responses to HIV Gag p24 within 3G9 antibody to DEC205 ("DEC-HIV Gag p24"), an uptake receptor on dendritic cells, to nontargeted protein, with or without poly ICLC, a synthetic double stranded RNA, as adjuvant. Priming s.c. with 60 mu g of both HIV Gag p24 vaccines elicited potent CD4(+) T cells secreting IL-2, IFN-gamma, and TNF-alpha, which also proliferated. The responses increased with each of three immunizations and recognized multiple Gag peptides. DEC-HIV Gag p24 showed better cross-priming for CD8(+) T cells, whereas the avidity of anti-Gag antibodies was similar to 10-fold higher with nontargeted Gag 24 protein. For both protein vaccines, poly ICLC was essential for T-and B-cell immunity. To determine whether adaptive responses could be further enhanced, animals were boosted with New York vaccinia virus (NYVAC)-HIV Gag/Pol/Nef. Gag-specific CD4(+) and CD8(+) T-cell responses increased markedly after priming with both protein vaccines and poly ICLC. These data reveal qualitative differences in antibody and T-cell responses to DEC-HIV Gag p24 and Gag p24 protein and show that prime boost with protein and adjuvant followed by NYVAC elicits potent cellular immunity.