Heterologous prime-boost vaccination with DNA and MVA vaccines, expressing HIV-1 subtype C mosaic Gag virus-like particles, is highly immunogenic in mice.
Heterologous prime-boost vaccination with DNA and MVA vaccines, expressing HIV-1 subtype C mosaic Gag virus-like particles, is highly immunogenic in mice.
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DOI：
10.1371/journal.pone.0173352
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发表时间：
2017
期刊：
影响因子：
3.7
通讯作者：
Williamson AL
中科院分区：
文献类型：
--
作者：
Chapman R;Jongwe TI;Douglass N;Chege G;Williamson AL
为了使负担得起的疫苗适用于受HIV-1影响最严重的地区，我们构建了表达HIV-1亚型C嵌合Gag免疫原（BCG-GagM，MVA-GagM和DNA-GagM）的稳定疫苗。镶嵌免疫原的设计是为了解决这种病毒的巨大多样性。在这里，我们已经表明，GagM芽从细胞感染和转染MVA-GagM和DNA-GagM分别形成病毒样颗粒。先前我们表明，BCG-GagM初免MVA-GagM加强在小鼠中产生强烈的细胞免疫应答。在本研究中，在同源和异源初免-加强疫苗接种中评价了对DNA-GagM和MVA-GagM疫苗的免疫应答。DNA同源初免加强疫苗接种主要诱导CD 8 + T细胞，而同源MVA疫苗接种主要诱导CD 4 + T细胞。异源DNA-GagM初免MVA-GagM加强诱导强的、更平衡的Gag CD 8+和CD 4 + T细胞应答，并且主要是效应记忆表型。使用DNA同源疫苗接种方案将嵌合Gag（GagM）的免疫原性与天然存在的亚型C Gag（GagN）进行比较。DNA-GagN表达天然Gag，其序列与在南非采样的C亚型病毒的共有序列最接近。DNA-GagM同源疫苗接种诱导的累积HIV-1 Gag特异性IFN-γ ELISPOT应答比DNA-GagN疫苗接种诱导的应答高6.5倍。类似地，DNA-GagM疫苗接种产生比DNA-GagN高7倍水平的精氨酸阳性CD 8 + T细胞，表明这种亚型C嵌合型Gag产生比共有型Gag强得多的免疫应答。用DNA-GagM和MVA-GagM分别转染和感染细胞，表达高水平的GagM，并产生出芽的病毒样颗粒。我们的数据表明，使用表达HIV-1亚型C嵌合Gag的DNA和MVA疫苗的异源初免加强方案在小鼠中具有高度免疫原性，并需要在非人灵长类动物中进行进一步研究。
In an effort to make affordable vaccines suitable for the regions most affected by HIV-1, we have constructed stable vaccines that express an HIV-1 subtype C mosaic Gag immunogen (BCG-GagM, MVA-GagM and DNA-GagM). Mosaic immunogens have been designed to address the tremendous diversity of this virus. Here we have shown that GagM buds from cells infected and transfected with MVA-GagM and DNA-GagM respectively and forms virus-like particles. Previously we showed that a BCG-GagM prime MVA-GagM boost generated strong cellular immune responses in mice. In this study immune responses to the DNA-GagM and MVA-GagM vaccines were evaluated in homologous and heterologous prime-boost vaccinations. The DNA homologous prime boost vaccination elicited predominantly CD8+ T cells while the homologous MVA vaccination induced predominantly CD4+ T cells. A heterologous DNA-GagM prime MVA-GagM boost induced strong, more balanced Gag CD8+ and CD4+ T cell responses and that were predominantly of an effector memory phenotype. The immunogenicity of the mosaic Gag (GagM) was compared to a naturally occurring subtype C Gag (GagN) using a DNA homologous vaccination regimen. DNA-GagN expresses a natural Gag with a sequence that was closest to the consensus sequence of subtype C viruses sampled in South Africa. DNA-GagM homologous vaccination induced cumulative HIV-1 Gag-specific IFN-γ ELISPOT responses that were 6.5-fold higher than those induced by the DNA-GagN vaccination. Similarly, DNA-GagM vaccination generated 7-fold higher levels of cytokine-positive CD8+ T cells than DNA-GagN, indicating that this subtype C mosaic Gag elicits far more potent immune responses than a consensus-type Gag. Cells transfected and infected with DNA-GagM and MVA-GagM respectively, expressed high levels of GagM and produced budding virus-like particles. Our data indicates that a heterologous prime boost regimen using DNA and MVA vaccines expressing HIV-1 subtype C mosaic Gag is highly immunogenic in mice and warrants further investigation in non-human primates.