McCurley Nathanael P, Domi Arban, Basu Rahul, Saunders Kevin O, LaBranche Celia C, Montefiori David C, Haynes Barton F, Robinson Harriet L
GeoVax Inc., Smyrna, GA, United States of America.
Duke Human Vaccine Institute, Durham, NC, United States of America.
PLoS One. 2017 Oct 11;12(10):e0177863. doi: 10.1371/journal.pone.0177863. eCollection 2017.
Here we report the construction, antigenicity and initial immunogenicity testing of DNA and modified vaccinia Ankara (MVA) vaccines expressing virus-like particles (VLPs) displaying sequential clade C Envelopes (Envs) that co-evolved with the elicitation of broadly neutralizing antibodies (bnAbs) to the CD4 binding site (CD4bs) in HIV-infected individual CH0505. The VLP-displayed Envs showed reactivity for conformational epitopes displayed on the receptor-binding form of Env. Two inoculations of the DNA-T/F vaccine, followed by 3 inoculations of the MVA-T/F vaccine and a final inoculation of the MVA-T/F plus a gp120-T/F protein vaccine elicited nAb to the T/F virus in 2 of 4 rhesus macaques (ID50 of ~175 and ~30). Neutralizing Ab plateaued at 100% neutralization and mapped to the CD4bs like the bnAbs elicited in CH0505. The nAb did not have breadth for other tier 2 viruses. Immunizations with T/F followed by directed-lineage vaccines, both with and without co-delivery of directed-lineage gp120 boosts, failed to elicit tier 2 neutralizing Ab for the CD4bs. Thus, pulsed exposures to DNA and MVA-expressed VLPs plus gp120 protein of a T/F Env can induce autologous tier 2 nAbs to the CD4bs.
在此，我们报告了表达病毒样颗粒（VLP）的DNA疫苗和改良痘苗病毒安卡拉（MVA）疫苗的构建、抗原性及初始免疫原性测试，这些VLP展示了与HIV感染个体CH0505中针对CD4结合位点（CD4bs）的广泛中和抗体（bnAb）诱导共同进化的连续C亚型包膜（Env）。VLP展示的Env对Env受体结合形式上展示的构象表位具有反应性。两次接种DNA-T/F疫苗，随后三次接种MVA-T/F疫苗，最后接种一次MVA-T/F加gp120-T/F蛋白疫苗，在4只恒河猴中的2只中诱导出针对T/F病毒的nAb（ID50约为175和30）。中和抗体在100%中和时达到平台期，且与CH0505中诱导出的bnAb一样定位到CD4bs。该nAb对其他2级病毒没有广度。用T/F疫苗免疫，随后接种定向谱系疫苗，无论是否共同递送定向谱系gp120加强剂，均未能诱导出针对CD4bs的2级中和抗体。因此，脉冲式暴露于DNA和MVA表达的VLP加T/F Env的gp120蛋白可诱导针对CD4bs的自体2级nAb。
