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表达猴免疫缺陷病毒抗原的新型复制缺陷型淋巴细胞性脉络丛脑膜炎病毒载体的研发。

Development of novel replication-defective lymphocytic choriomeningitis virus vectors expressing SIV antigens.

作者信息

Penaloza MacMaster Pablo, Shields Jennifer L, Alayo Quazim A, Cabral Crystal, Jimenez Jessica, Mondesir Jade, Chandrashekar Abishek, Cabral Joseph M, Lim Matthew, Iampietro M Justin, Provine Nicholas M, Bricault Christine A, Seaman Michael, Orlinger Klaus, Aspoeck Andreas, Fuhrmann Gerhard, Lilja Anders E, Monath Thomas, Mangeat Bastien, Pinschewer Daniel D, Barouch Dan H

机构信息

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Department of Microbiology-Immunology, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.

Center for Virology and Vaccine Research, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA.

出版信息

Vaccine. 2017 Jan 3;35(1):1-9. doi: 10.1016/j.vaccine.2016.11.063. Epub 2016 Nov 26.

Abstract

An important focus in vaccine research is the design of vaccine vectors with low seroprevalence and high immunogenicity. Replication-incompetent lymphocytic choriomeningitis virus (rLCMV) vectors do not elicit vector-neutralizing antibody responses, and homologous prime-boost regimens with rLCMV vectors induce boostable and protective T cell responses to model antigens in mice. However, cellular and humoral immune responses following homologous rLCMV vaccine regimens have not been rigorously evaluated in non-human primates (NHPs). To test whether rLCMV vectors constitute an effective vaccine platform in NHPs, we developed rLCMV vectors expressing SIVmac239 Env and Gag antigens and assessed their immunogenicity in mice and cynomolgus macaques. Immunization with rLCMV vaccine vectors expressing SIV Env and Gag was effective at generating SIV-specific T cell and antibody responses in both mice and NHPs. Epitope mapping using SIV Env in C57BL/6 mice demonstrated that rLCMV vectors induced sustained poly-functional responses to both dominant and subdominant epitopes. Our results suggest the potential of rLCMV vectors as vaccine candidates. Future SIV challenge experiments in rhesus macaques will be needed to assess immune protection by these vaccine vectors.

摘要

疫苗研究的一个重要重点是设计血清阳性率低且免疫原性高的疫苗载体。无复制能力的淋巴细胞性脉络丛脑膜炎病毒(rLCMV)载体不会引发载体中和抗体反应,并且用rLCMV载体进行的同源初免-加强免疫方案可诱导小鼠对模型抗原产生可增强的保护性T细胞反应。然而,在非人类灵长类动物(NHP)中,同源rLCMV疫苗方案后的细胞免疫和体液免疫反应尚未得到严格评估。为了测试rLCMV载体是否构成NHP中的有效疫苗平台,我们开发了表达SIVmac239 Env和Gag抗原的rLCMV载体,并评估了它们在小鼠和食蟹猕猴中的免疫原性。用表达SIV Env和Gag的rLCMV疫苗载体免疫在小鼠和NHP中均有效地产生了SIV特异性T细胞和抗体反应。在C57BL / 6小鼠中使用SIV Env进行表位作图表明,rLCMV载体诱导了对显性和隐性表位的持续多功能反应。我们的结果表明rLCMV载体作为候选疫苗的潜力。未来需要在恒河猴中进行SIV攻击实验,以评估这些疫苗载体的免疫保护作用。

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