Zhu Weiyan, Waltmann Andreea, Little Marguerite B, Connolly Kristie L, Matthias Kathryn A, Thomas Keena S, Gray Mary C, Sikora Aleksandra E, Criss Alison K, Bash Margaret C, Macintyre Andrew N, Jerse Ann E, Duncan Joseph A
Division of Infectious Diseases, University of North Carolina School of Medicine, Chapel Hill, NC, United States.
Department of Pharmacology, University of North Carolina School of Medicine, Chapel Hill, NC, United States.
Front Immunol. 2025 Apr 11;16:1539795. doi: 10.3389/fimmu.2025.1539795. eCollection 2025.
Limited protective immunologic responses to natural infection and a lack of knowledge about mechanisms of protection have hampered development of an effective vaccine. Recent studies in humans and mice have found meningococcal outer membrane vesicle-containing vaccines (OMV) induce cross species immune responses against gonococci and are associated with protection. The exact mechanisms or how humoral and cellular immunity are related to protection, remain unclear.
To study this, we immunized mice with two meningococcal OMV-containing vaccines known to accelerate clearance of , 4CMenB and OMV from an engineered strain lacking major surface antigens PorA, PorB, and Rmp (MC58 ΔABR). We assessed serologic and cellular immune signatures associated with these immunizations and assessed bacterial clearance in the mice using a vaginal/cervical gonococcal infection model.
Mice immunized with 4CMenB or MC58 ΔABR demonstrated shortened courses of recovery of vaginal compared to control mice immunized with alum alone. Vaccination with 4CMenB or MC58ΔABR OMV elicited serum and vaginal cross-reactive anti-Ng-OMV antibody responses that were augmented after vaginal challenge with . Further, splenocytes in 4CMenB and MC58 ΔABR immunized mice exhibited elevated cytokine production after restimulation with heterologous OMV when compared to splenocytes from Alum immunized mice. We further tested for correlations between bacterial burden and the measured anti-gonococcal immune responses within each vaccination group and found different immunologic parameters associated with reduced bacterial burden for each vaccine.
Our findings suggest the cross-protection against gonococcal infection induced by different meningococcal OMV vaccines is likely multifactorial and mediated by different humoral and cellular immune responses induced by these two vaccines.
对自然感染的保护性免疫反应有限，且对保护机制缺乏了解，这阻碍了有效疫苗的研发。最近在人类和小鼠身上的研究发现，含脑膜炎球菌外膜囊泡的疫苗（OMV）可诱导针对淋球菌的跨物种免疫反应，并与保护作用相关。然而，确切的机制以及体液免疫和细胞免疫如何与保护作用相关，仍不清楚。
为了研究这一问题，我们用两种已知能加速清除特定菌株中病原体的含脑膜炎球菌OMV疫苗免疫小鼠，这两种疫苗分别是4CMenB和来自缺乏主要表面抗原PorA、PorB和Rmp的工程菌株（MC58 ΔABR）的OMV。我们评估了与这些免疫接种相关的血清学和细胞免疫特征，并使用阴道/宫颈淋球菌感染模型评估了小鼠体内的细菌清除情况。
与仅用明矾免疫的对照小鼠相比，用4CMenB或MC58 ΔABR免疫的小鼠阴道病原体恢复过程缩短。用4CMenB或MC58ΔABR OMV进行疫苗接种可引发血清和阴道交叉反应性抗淋球菌OMV抗体反应，在用特定病原体进行阴道攻击后这种反应增强。此外，与明矾免疫小鼠的脾细胞相比，用4CMenB和MC58 ΔABR免疫的小鼠脾细胞在用异源特定病原体OMV再次刺激后细胞因子产生增加。我们进一步测试了每个疫苗接种组内细菌载量与所测抗淋球菌免疫反应之间的相关性，发现每种疫苗与降低细菌载量相关的免疫参数不同。
我们的研究结果表明，不同的脑膜炎球菌OMV疫苗诱导的针对淋球菌感染的交叉保护作用可能是多因素的，并由这两种疫苗诱导的不同体液免疫和细胞免疫反应介导。
