Human Retrovirus Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, United States.
Human Retrovirus Pathogenesis Section, Vaccine Branch, Center for Cancer Research, National Cancer Institute at Frederick, Frederick, MD, United States.
Front Immunol. 2022 Jul 22;13:945706. doi: 10.3389/fimmu.2022.945706. eCollection 2022.
Immunogenicity of HIV-1 mRNA vaccine regimens was analyzed in a non-human primate animal model. Rhesus macaques immunized with mRNA in lipid nanoparticle (mRNA/LNP) formulation expressing HIV-1 Gag and Gag conserved regions (CE) as immunogens developed robust, durable antibody responses but low adaptive T-cell responses. Augmentation of the dose resulted in modest increases in vaccine-induced cellular immunity, with no difference in humoral responses. The mRNA/lipid nanoparticle (LNP) vaccine provided suboptimal priming of T cell responses for a heterologous DNA booster vaccination regimen. In contrast, a single immunization with mRNA/LNP efficiently boosted both humoral and cellular responses in macaques previously primed by a DNA-based vaccine. These anamnestic cellular responses were mediated by activated CD8 T cells with a phenotype of differentiated T-bet cytotoxic memory T lymphocytes. The heterologous prime/boost regimens combining DNA and mRNA/LNP vaccine modalities maximized vaccine-induced cellular and humoral immune responses. Analysis of cytokine responses revealed a transient systemic signature characterized by the release of type I interferon, IL-15 and IFN-related chemokines. The pro-inflammatory status induced by the mRNA/LNP vaccine was also characterized by IL-23 and IL-6, concomitant with the release of IL-17 family of cytokines. Overall, the strong boost of cellular and humoral immunity induced by the mRNA/LNP vaccine suggests that it could be useful as a prophylactic vaccine in heterologous prime/boost modality and in immune therapeutic interventions against HIV infection or other chronic human diseases.
在非人类灵长类动物模型中分析了 HIV-1 mRNA 疫苗方案的免疫原性。用脂质纳米颗粒（mRNA/LNP）制剂中的 mRNA 免疫的恒河猴表达 HIV-1 Gag 和 Gag 保守区（CE）作为免疫原，产生了强大、持久的抗体反应，但适应性 T 细胞反应较低。增加剂量导致疫苗诱导的细胞免疫适度增加，但体液反应无差异。mRNA/LNP 疫苗对异源 DNA 增强疫苗接种方案的 T 细胞反应提供了不理想的初始免疫。相比之下，先前用 DNA 疫苗进行基础免疫的恒河猴单次接种 mRNA/LNP 可有效增强体液和细胞反应。这些回忆性细胞反应是由激活的 CD8 T 细胞介导的，其表型为分化的 Tbet 细胞毒性记忆 T 淋巴细胞。结合 DNA 和 mRNA/LNP 疫苗方式的异源初免-增强方案最大限度地提高了疫苗诱导的细胞和体液免疫应答。细胞因子反应分析显示出短暂的全身特征，其特征是释放 I 型干扰素、IL-15 和 IFN 相关趋化因子。mRNA/LNP 疫苗诱导的促炎状态还表现为 IL-23 和 IL-6，同时释放细胞因子 IL-17 家族。总的来说，mRNA/LNP 疫苗诱导的强大细胞和体液免疫增强提示它可作为异源初免-增强模式的预防性疫苗，以及针对 HIV 感染或其他慢性人类疾病的免疫治疗干预措施。
