Department of Entomology, Virginia Tech, Blacksburg, Virginia, United States of America.
Department of Microbiology & Immunology, University of Texas Medical Branch, Galveston, Texas, United States of America.
PLoS Pathog. 2024 Oct 10;20(10):e1012566. doi: 10.1371/journal.ppat.1012566. eCollection 2024 Oct.
Flaviviruses represent a significant global health threat and relatively few licensed vaccines exist to protect against them. Insect-specific flaviviruses (ISFVs) are incapable of replication in humans and have emerged as a novel and promising tool for flavivirus vaccine development. ISFV-based flavivirus vaccines have shown exceptional safety, immunogenicity, and efficacy, however, a detailed assessment of the correlates of protection and immune responses induced by these vaccines are still needed for vaccine optimization. Here, we explore the mechanisms of protective immunity induced by a previously created pre-clinical Zika virus (ZIKV) vaccine candidate, called Aripo/Zika (ARPV/ZIKV). In brief, immunocompromised IFN-αβR-/- mice passively immunized with ARPV/ZIKV immune sera experienced protection after lethal ZIKV challenge, although this protection was incomplete. ARPV/ZIKV-vaccinated IFN-αβR-/- mice depleted of CD4+ or CD8+ T-cells at the time of ZIKV challenge showed no morbidity or mortality. However, the adoptive transfer of ARPV/ZIKV-primed T-cells into recipient IFN-αβR-/- mice resulted in a two-day median increase in survival time compared to controls. Altogether, these results suggest that ARPV/ZIKV-induced protection is primarily mediated by neutralizing antibodies at the time of challenge and that T-cells may play a comparatively minor but cumulative role in the protection observed. Lastly, ARPV/ZIKV-vaccinated Tcra KO mice, which are deficient in T-cell responses, experienced significant mortality post-challenge. These results suggest that ARPV/ZIKV-induced cell-mediated responses are critical for development of protective immune responses at vaccination. Despite the strong focus on neutralizing antibody responses to novel flavivirus vaccine candidates, these results suggest that cell-mediated responses induced by ISFV-based vaccines remain important to overall protective responses.
黄病毒属是对全球健康的重大威胁，而用于预防它们的许可疫苗相对较少。昆虫特异性黄病毒（ISFV）在人类中无法复制，已成为开发黄病毒疫苗的一种新颖而有前途的工具。基于 ISFV 的黄病毒疫苗具有出色的安全性、免疫原性和功效，然而，仍需要对这些疫苗诱导的保护相关因素和免疫反应进行详细评估，以实现疫苗优化。在这里，我们探讨了先前开发的寨卡病毒（ZIKV）疫苗候选物 Aripo/Zika（ARPV/ZIKV）诱导的保护性免疫的机制。简而言之，用 ARPV/ZIKV 免疫血清被动免疫的免疫缺陷 IFN-αβR-/- 小鼠在致命 ZIKV 挑战后经历了保护，尽管这种保护并不完全。在 ZIKV 挑战时耗尽 ARPV/ZIKV 疫苗接种的 IFN-αβR-/- 小鼠的 CD4+或 CD8+T 细胞，没有出现发病或死亡。然而，将 ARPV/ZIKV 激发的 T 细胞过继转移到接受 IFN-αβR-/- 小鼠的受体中，与对照组相比，导致存活时间中位数增加了两天。总而言之，这些结果表明，ARPV/ZIKV 诱导的保护主要是在挑战时通过中和抗体介导的，而 T 细胞可能在观察到的保护中发挥相对较小但累积的作用。最后，在接种 ARPV/ZIKV 后，缺乏 T 细胞反应的 Tcra KO 小鼠在受到挑战后死亡率显著增加。这些结果表明，ARPV/ZIKV 诱导的细胞介导反应对于疫苗接种时保护性免疫反应的发展至关重要。尽管人们强烈关注针对新型黄病毒疫苗候选物的中和抗体反应，但这些结果表明，基于 ISFV 的疫苗诱导的细胞介导反应对于整体保护反应仍然很重要。
