MRC Human Immunology Unit, Weatherall Institute of Molecular Medicine, University of Oxford, Oxford, United Kingdom.
PLoS One. 2011;6(5):e20067. doi: 10.1371/journal.pone.0020067. Epub 2011 May 13.
Acquired immunodeficiency syndrome and tuberculosis (TB) are two of the world's most devastating diseases. The first vaccine the majority of infants born in Africa receive is Mycobacterium bovis bacillus Calmette-Guérin (BCG) as a prevention against TB. BCG protects against disseminated disease in the first 10 years of life, but provides a variable protection against pulmonary TB and enhancing boost delivered by recombinant modified vaccinia virus Ankara (rMVA) expressing antigen 85A (Ag85A) of M. tuberculosis is currently in phase IIb evaluation in African neonates. If the newborn's mother is positive for human immunodeficiency virus type 1 (HIV-1), the baby is at high risk of acquiring HIV-1 through breastfeeding. We suggested that a vaccination consisting of recombinant BCG expressing HIV-1 immunogen administered at birth followed by a boost with rMVA sharing the same immunogen could serve as a strategy for prevention of mother-to-child transmission of HIV-1 and rMVA expressing an African HIV-1-derived immunogen HIVA is currently in phase I trials in African neonates. Here, we aim to develop a dual neonate vaccine platform against HIV-1 and TB consisting of BCG.HIVA administered at birth followed by a boost with MVA.HIVA.85A. Thus, mMVA.HIVA.85A and sMVA.HIVA.85A vaccines were constructed, in which the transgene transcription is driven by either modified H5 or short synthetic promoters, respectively, and tested for immunogenicity alone and in combination with BCG.HIVA(222). mMVA.HIVA.85A was produced markerless and thus suitable for clinical manufacture. While sMVA.HIVA.85A expressed higher levels of the immunogens, it was less immunogenic than mMVA.HIVA.85A in BALB/c mice. A BCG.HIVA(222)-mMVA.HIVA.85A prime-boost regimen induced robust T cell responses to both HIV-1 and M. tuberculosis. Therefore, proof-of-principle for a dual anti-HIV-1/M. tuberculosis infant vaccine platform is established. Induction of immune responses against these pathogens soon after birth is highly desirable and may provide a basis for lifetime protection maintained by boosts later in life.
获得性免疫缺陷综合征和结核病（TB）是世界上最具破坏性的两种疾病。在非洲，大多数出生的婴儿接种的第一种疫苗是牛分枝杆菌卡介苗（BCG），以预防结核病。BCG 可预防 10 年内的播散性疾病，但对肺结核的保护作用各不相同，而用表达结核分枝杆菌抗原 85A（Ag85A）的重组改良痘苗病毒安卡拉（rMVA）进行增强免疫接种，目前正在非洲新生儿中进行 IIb 期评估。如果新生儿的母亲 HIV-1 阳性，婴儿通过母乳喂养感染 HIV-1 的风险很高。我们建议，在出生时接种表达 HIV-1 免疫原的重组 BCG，然后用具有相同免疫原的 rMVA 进行增强免疫，作为预防母婴传播 HIV-1 和 rMVA 的策略，rMVA 表达非洲 HIV-1 衍生的免疫原 HIVA 目前正在非洲新生儿中进行 I 期试验。在这里，我们旨在开发一种针对 HIV-1 和 TB 的双重新生儿疫苗平台，该平台由出生时接种的 BCG.HIVA 组成，然后用 MVA.HIVA.85A 进行增强免疫。因此，构建了 mMVA.HIVA.85A 和 sMVA.HIVA.85A 疫苗，其中转基因转录分别由改良的 H5 或短合成启动子驱动，并单独测试了它们的免疫原性以及与 BCG.HIVA(222)的组合。mMVA.HIVA.85A 无标记生产，因此适合临床生产。虽然 sMVA.HIVA.85A 表达更高水平的免疫原，但它在 BALB/c 小鼠中的免疫原性低于 mMVA.HIVA.85A。BCG.HIVA(222)-mMVA.HIVA.85A 初免-加强方案诱导了对 HIV-1 和结核分枝杆菌的强烈 T 细胞反应。因此，建立了针对抗 HIV-1/M. tuberculosis 婴儿疫苗平台的双重原理验证。出生后不久诱导针对这些病原体的免疫反应是非常理想的，这可能为以后生活中的增强免疫接种提供终生保护的基础。
