Naval Medical Research Center, Silver Spring, MD, United States.
Henry Jackson Foundation for the Advancement of Military Medicine, Bethesda, MD, United States.
Vaccine. 2021 Dec 17;39(51):7510-7520. doi: 10.1016/j.vaccine.2021.10.017. Epub 2021 Nov 22.
We previously reported the efficacy of prime-boost vaccination using three tetravalent (T) dengue vaccines, DNA (TDNA), purified inactivated vaccine (TPIV), and live attenuated vaccine (TLAV). We demonstrated that the TPIV/TLAV prime-boost vaccination yielded the highest and most durable neutralizing antibodies and 100% protection to all 4 serotypes of dengue virus in rhesus macaques. This study compares gene transcription, T and B cell responses elicited by these prime-boost combinations in rhesus macaques. This study shows that the TLAV vaccine increased the expression of the innate immune genes, DDX58 and TLR7, IL1A, IL1B, TNF, CXCL8, CXCL10, IRF1, IRF7, and IFNB, more robustly as compared to TDNA and TPIV vaccines. Overall, two doses of TDNA and one dose of TLAV efficiently elicited a T cell IFNγ response to PrM/E with a comparable magnitude. Compared to TDNA vaccine, the TLAV vaccine elicited additional IFNγ response to C, NS1, NS3, and NS5. The TPIV vaccine alone produced poor IFNγ response; however, the TLAV significantly boosted its IFNγ response. The T cell response repertoire associated with TPIV/TLAV prime-boost was to both the structural C/PrM/E and NS proteins, and the T cells were multifunctional as the CD4 T cells produced IFNγ, TNF α, and IL2 and the CD8 cells produced TNF α and IFNγ. Opposite to the pattern of CMI, the TPIV vaccine alone elicited the highest B compared to the other two vaccines, which continuously remained as the highest after boosting. In summary, the TDNA and TLAV vaccines elicited a strong T cell response whereas the TPIV vaccine elicited a superior B. The T cell response of the TPIV vaccine was significantly boosted by the TLAV vaccine. The elevated T cell response may have provided T cell help for a sustained antibody response for TPIV/TLAV vaccines, which is required for a protective immunity against a live virus challenge.
我们之前报道了使用三种四价（T）登革热疫苗，即 DNA（TDNA）、纯化的灭活疫苗（TPIV）和减毒活疫苗（TLAV）进行的初免-加强免疫接种的疗效。我们证明，TPIV/TLAV 初免-加强免疫接种可在恒河猴中产生最高和最持久的中和抗体，并对所有 4 种血清型登革热病毒提供 100%的保护。本研究比较了这些初免-加强组合在恒河猴中引起的基因转录、T 细胞和 B 细胞反应。本研究表明，与 TDNA 和 TPIV 疫苗相比，TLAV 疫苗更能增强先天免疫基因 DDX58 和 TLR7、IL1A、IL1B、TNF、CXCL8、CXCL10、IRF1、IRF7 和 IFNB 的表达。总的来说，两剂 TDNA 和一剂 TLAV 能有效地诱导 PrM/E 产生 T 细胞 IFNγ 反应，其幅度相当。与 TDNA 疫苗相比，TLAV 疫苗还能诱导对 C、NS1、NS3 和 NS5 的 IFNγ 反应。单独使用 TPIV 疫苗产生的 IFNγ 反应较差，但 TLAV 能显著增强其 IFNγ 反应。TPIV/TLAV 初免-加强产生的 T 细胞反应谱与结构蛋白 C/PrM/E 和 NS 蛋白有关，T 细胞具有多功能性，因为 CD4 T 细胞产生 IFNγ、TNFα 和 IL2，而 CD8 细胞产生 TNFα 和 IFNγ。与细胞免疫反应模式相反，单独使用 TPIV 疫苗比其他两种疫苗产生的 B 细胞最多，而在加强免疫后，其 B 细胞仍保持最高水平。综上所述，TDNA 和 TLAV 疫苗能诱导强烈的 T 细胞反应，而 TPIV 疫苗能诱导强烈的 B 细胞反应。TLAV 疫苗显著增强了 TPIV 疫苗的 T 细胞反应。升高的 T 细胞反应可能为 TPIV/TLAV 疫苗提供了针对活病毒挑战的保护性免疫所需的持续抗体反应的 T 细胞帮助。
