Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, United States; Division of Infectious Diseases, Department of Medicine, Emory University School of Medicine, Atlanta, GA 30307, United States.
Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, 954 Gatewood Road, Atlanta, GA 30329, United States.
Vaccine. 2018 May 11;36(20):2799-2808. doi: 10.1016/j.vaccine.2018.03.091. Epub 2018 Apr 12.
Cellular and humoral immune responses are both involved in protection against Plasmodium infections. The only malaria vaccine available, RTS,S, primarily induces short-lived antibodies and targets only a pre-erythrocytic stage antigen. Inclusion of erythrocytic stage targets and enhancing cellular immunogenicity are likely necessary for developing an effective second-generation malaria vaccine. Adenovirus vectors have been used to improve the immunogenicity of protein-based vaccines. However, the clinical assessment of adenoviral-vectored malaria vaccines candidates has shown the induction of robust Plasmodium-specific CD8+ but not CD4+ T cells. Signal peptides (SP) have been used to enhance the immunogenicity of DNA vaccines, but have not been tested in viral vector vaccine platforms.
The objective of this study was to determine if the addition of the SP derived from the murine IgGκ light chain within a recombinant adenovirus vector encoding a multistage P. vivax vaccine candidate could improve the CD4+ T cell response.
In this proof-of-concept study, we immunized CB6F1/J mice with either the recombinant simian adenovirus 36 vector containing the SP (SP-SAd36) upstream from a transgene encoding a chimeric P. vivax multistage protein or the same SAd36 vector without the SP. Mice were subsequently boosted twice with the corresponding recombinant proteins emulsified in Montanide ISA 51 VG. Immunogenicity was assessed by measurement of antibody quantity and quality, and cytokine production by T cells after the final immunization.
The SP-SAd36 immunization regimen induced significantly higher antibody avidity against the chimeric P. vivax proteins tested and higher frequencies of IFN-γ and IL-2 CD4+ and CD8+ secreting T cells, when compared to the unmodified SAd36 vector.
The addition of the murine IgGκ signal peptide significantly enhances the immunogenicity of a SAd36 vectored P. vivax multi-stage vaccine candidate in mice. The potential of this approach to improve upon existing viral vector vaccine platforms warrants further investigation.
细胞和体液免疫反应都参与了对疟原虫感染的保护。目前唯一可用的疟疾疫苗 RTS,S 主要诱导短暂的抗体，并且仅针对红细胞前期抗原。为了开发有效的第二代疟疾疫苗，可能需要包含红细胞期靶标并增强细胞免疫原性。腺病毒载体已被用于提高基于蛋白质的疫苗的免疫原性。然而，对腺病毒载体疟疾疫苗候选物的临床评估表明，诱导了强烈的疟原虫特异性 CD8+，但不是 CD4+ T 细胞。信号肽 (SP) 已被用于提高 DNA 疫苗的免疫原性，但尚未在病毒载体疫苗平台中进行测试。
本研究的目的是确定在编码间日疟原虫多阶段候选疫苗的重组腺病毒载体中添加来自小鼠 IgGκ 轻链的 SP 是否可以改善 CD4+ T 细胞反应。
在这项概念验证研究中，我们用含有 SP 的重组猿猴腺病毒 36 载体（SP-SAd36）或不含 SP 的相同 SAd36 载体免疫 CB6F1/J 小鼠。随后，用相应的重组蛋白在 Montanide ISA 51 VG 中乳化进行两次加强免疫。在最后一次免疫后，通过测量抗体数量和质量以及 T 细胞产生细胞因子来评估免疫原性。
与未修饰的 SAd36 载体相比，SP-SAd36 免疫方案诱导针对所测试的嵌合间日疟原虫蛋白的抗体亲和力显著提高，并且 IFN-γ 和 IL-2 的 CD4+和 CD8+分泌 T 细胞的频率更高。
添加小鼠 IgGκ 信号肽可显著提高 SAd36 载体间日疟原虫多阶段疫苗候选物在小鼠中的免疫原性。这种方法提高现有病毒载体疫苗平台的潜力值得进一步研究。
