The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae.
The serogroup B meningococcal outer membrane vesicle-based vaccine 4CMenB induces cross-species protection against Neisseria gonorrhoeae.
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血清群B脑膜炎球菌外膜囊泡基疫苗4CMENB可诱导针对淋病奈瑟氏菌的跨物种保护。
DOI：
10.1371/journal.ppat.1008602
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发表时间：
2020-12
期刊：
影响因子：
6.7
通讯作者：
Jerse AE
中科院分区：
文献类型：
--
作者：
Leduc I;Connolly KL;Begum A;Underwood K;Darnell S;Shafer WM;Balthazar JT;Macintyre AN;Sempowski GD;Duncan JA;Little MB;Rahman N;Garges EC;Jerse AE
由于全球范围内与淋球菌感染相关的高疾病负担以及淋病奈瑟菌 (Ng) 抗生素耐药性的快速演变，迫切需要淋病疫苗。目前的淋病疫苗研究正处于抗原发现和保护性免疫反应识别阶段，30多年来没有任何疫苗经过临床试验。然而，最近一项回顾性病例对照研究报告称，人类接种 B 群脑膜炎奈瑟菌 (Nm) 外膜囊泡 (OMV) 疫苗 (MeNZB) 与淋病发病率降低相关。在这里，我们直接测试了这样的假设：Nm OMV 在一个明确的 Ng 生殖道感染雌性小鼠模型中诱导针对淋病的交叉保护。我们发现，与施用明矾或 PBS 相比，使用获得许可的基于 Nm OMV 的疫苗 4CMenB (Bexsero) 进行免疫可显着加速清除速度并减少 Ng 细菌负荷。通过皮下或腹膜内途径接种 4CMenB 疫苗可诱导血清 IgG 以及与 Ng OMV 发生交叉反应的阴道 IgA 和 IgG。来自接种疫苗的小鼠的抗体可识别多种 Ng 表面蛋白，包括 PilQ、BamA、MtrE、NHBA（已知可被人类识别）、PorB 和 Opa。来自小鼠和人类的免疫血清均识别 Ng PilQ 和几种表观分子量相似的蛋白质，但 MtrE 仅被小鼠血清识别。来自 4CMenB 免疫小鼠的混合血清显示，针对攻击菌株的血清杀菌滴度增加了 4 倍；相反，当比较 4CMenB 免疫和未免疫受试者的血清时，未检测到杀菌活性的显着差异。我们的研究结果直接支持了流行病学证据，即 Nm OMV 具有针对淋病的跨物种保护作用，并表明几种 Ng 表面抗原是潜在的保护目标。此外，本研究进一步明确了小鼠感染模型作为淋病疫苗开发的相关实验系统的有用性。全球每年发生 8700 万例淋病奈瑟菌 (Ng) 感染，由于缺乏强有力的证据表明可以对淋病产生免疫力，因此通过疫苗接种来控制淋病面临着挑战。这一论点最近受到流行病学证据的挑战，流行病学证据表明，来自相关物种脑膜炎奈瑟菌 (Nm) 的外膜囊泡 (OMV) 疫苗可以保护人类免受淋病的侵害。在这里，我们通过证明这种基于 Nm OMV 的疫苗的许可改良版本可加速小鼠感染模型中 Ng 的清除，提供支持这一假设的实验证据。这些结果证实了跨物种保护的可能性，并且很重要，因为它们支持了疫苗诱导的淋病免疫的生物学可行性。我们还表明，来自接种疫苗的小鼠的抗血清可以识别几种可能作为疫苗保护靶标的 Ng 外膜蛋白，其中至少两种（PilQ 和 NHBA）也在来自 4CMenB 免疫人类受试者的血清中检测到。我们证明，一种可以降低人类患淋病风险的疫苗可以保护小鼠免受 Ng（一种高度宿主限制性病原体）的侵害，这也验证了小鼠模型作为指导其他候选淋病疫苗开发的有用工具。
There is a pressing need for a gonorrhea vaccine due to the high disease burden associated with gonococcal infections globally and the rapid evolution of antibiotic resistance in Neisseria gonorrhoeae (Ng). Current gonorrhea vaccine research is in the stages of antigen discovery and the identification of protective immune responses, and no vaccine has been tested in clinical trials in over 30 years. Recently, however, it was reported in a retrospective case-control study that vaccination of humans with a serogroup B Neisseria meningitidis (Nm) outer membrane vesicle (OMV) vaccine (MeNZB) was associated with reduced rates of gonorrhea. Here we directly tested the hypothesis that Nm OMVs induce cross-protection against gonorrhea in a well-characterized female mouse model of Ng genital tract infection. We found that immunization with the licensed Nm OMV-based vaccine 4CMenB (Bexsero) significantly accelerated clearance and reduced the Ng bacterial burden compared to administration of alum or PBS. Serum IgG and vaginal IgA and IgG that cross-reacted with Ng OMVs were induced by 4CMenB vaccination by either the subcutaneous or intraperitoneal routes. Antibodies from vaccinated mice recognized several Ng surface proteins, including PilQ, BamA, MtrE, NHBA (known to be recognized by humans), PorB, and Opa. Immune sera from both mice and humans recognized Ng PilQ and several proteins of similar apparent molecular weight, but MtrE was only recognized by mouse serum. Pooled sera from 4CMenB-immunized mice showed a 4-fold increase in serum bactericidal50 titers against the challenge strain; in contrast, no significant difference in bactericidal activity was detected when sera from 4CMenB-immunized and unimmunized subjects were compared. Our findings directly support epidemiological evidence that Nm OMVs confer cross-species protection against gonorrhea, and implicate several Ng surface antigens as potentially protective targets. Additionally, this study further defines the usefulness of murine infection model as a relevant experimental system for gonorrhea vaccine development. Eighty-seven million Neisseria gonorrhoeae (Ng) infections occur globally each year and control of gonorrhea through vaccination is challenged by a lack of strong evidence that immunity to gonorrhea is possible. This contention was recently challenged by epidemiological evidence suggesting that an outer membrane vesicle (OMV) vaccine from the related species Neisseria meningitidis (Nm) protected humans against gonorrhea. Here we provide experimental evidence in support of this hypothesis by demonstrating that a licensed, modified version of this Nm OMV-based vaccine accelerates clearance of Ng in a mouse infection model. These results confirm the possibility cross-species protection and are important in that they support the biological feasibility of vaccine-induced immunity against gonorrhea. We also showed that several Ng outer membrane proteins that may be protective targets of the vaccine are recognized by antiserum from vaccinated mice, at least two of which (PilQ and NHBA) are also detected with sera from 4CMenB-immunized human subjects. Our demonstration that a vaccine that may reduce the risk of gonorrhea in humans protects mice against Ng, a highly host-restricted pathogen, also validates the mouse model as a useful tool for guiding the development of other candidate gonorrhea vaccines.
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影响因子：
--
作者：
Dillard JP
通讯作者：
Dillard JP
DOI：
10.1073/pnas.95.18.10872
发表时间：
1998-09-01
影响因子：
11.1
作者：
Banerjee, A;Wang, R;Stein, DC
通讯作者：
Stein, DC
影响因子：
6.4
作者：
Cohen, MS;Cannon, JG
通讯作者：
Cannon, JG
影响因子：
4.9
作者：
Golparian, Daniel;Shafer, William M.;Unemo, Magnus
通讯作者：
Unemo, Magnus
DOI：
10.1111/j.1468-3083.2011.04194.x
发表时间：
2012-08-01
影响因子：
9.2
作者：
Borges-Costa, J.;Matos, C.;Pereira, F.
通讯作者：
Pereira, F.