Microencapsulated IL-12 Drives Genital Tract Immune Responses to Intranasal Gonococcal Outer Membrane Vesicle Vaccine and Induces Resistance to Vaginal Infection with Diverse Strains of Neisseria gonorrhoeae.
Microencapsulated IL-12 Drives Genital Tract Immune Responses to Intranasal Gonococcal Outer Membrane Vesicle Vaccine and Induces Resistance to Vaginal Infection with Diverse Strains of Neisseria gonorrhoeae.
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由外膜囊泡（OMV）和微球（ms）封装的白细胞介素-12（IL-12 ms）组成的实验性淋球菌疫苗在阴道内（i.vag.）在雌性小鼠中施用，并产生对阴道攻击感染的抗性。因为i.vag.给药不适用于男性并且可能不被女性接受，我们确定鼻内（i.n.）给药将产生针对N.淋病将雌性和雄性小鼠i.n.淋球菌OMV加IL-12 ms或空白微球（空白ms）。对I. N的回应免疫与i.vag.免疫接种，用血清IgG、唾液伊加和阴道IgG和伊加抗淋球菌抗体诱导，当OMV与IL-12 ms一起施用时。雄性小鼠血清IgG和唾液伊加抗体的反应与雌性小鼠相似。髂淋巴结CD 4 + T细胞产生的γ-干扰素（IFN-γ）在i.n.或I.vag.用OMV加IL-12 ms免疫。用OMV加IL-12 ms通过任一途径免疫的雌性小鼠抵抗N.淋病在同等程度上，和由i.n.免疫扩展到N.淋病去污剂提取的OMV，其具有减少的脂寡糖，产生保护性免疫力的挑战类似于天然OMV。突变体N.淋病，其中Rmp和LpxL 1的基因被删除以消除针对Rmp的阻断抗体的诱导并减少脂寡糖内毒性，当i.n. IL-12 ms重要性我们以前证明，雌性小鼠可以阴道内接种淋球菌外膜囊泡（OMV）加微球（ms）封装的白细胞介素-12（IL-12 ms），以诱导抗淋球菌抗体和对活淋病奈瑟菌生殖道攻击的抵抗。然而，这种疫苗接种途径对于人类疫苗开发可能是不切实际的，并且不适用于男性。因为鼻内免疫先前已显示在男性和女性生殖道中诱导抗体应答，所以我们已经用淋球菌OMV加IL-12 ms评估了这种免疫途径。此外，我们已经改进了淋球菌OMV的组成，以减少脂寡糖的内毒性，并消除膜蛋白Rmp，其诱导反作用的封闭抗体。由此产生的疫苗可能更适合于最终转化为人类应用，以对抗性传播感染淋病，这种淋病对抗生素治疗的耐药性越来越强。
An experimental gonococcal vaccine consisting of outer membrane vesicles (OMVs) and microsphere (ms)-encapsulated interleukin-12 (IL-12 ms) induces Th1-driven immunity, with circulating and genital antibodies to Neisseria gonorrhoeae, after intravaginal (i.vag.) administration in female mice, and generates resistance to vaginal challenge infection. Because i.vag. administration is inapplicable to males and may not be acceptable to women, we determined whether intranasal (i.n.) administration would generate protective immunity against N. gonorrhoeae. Female and male mice were immunized i.n. with gonococcal OMVs plus IL-12 ms or blank microspheres (blank ms). Responses to i.n. immunization were similar to those with i.vag. immunization, with serum IgG, salivary IgA, and vaginal IgG and IgA antigonococcal antibodies induced when OMVs were administered with IL-12 ms. Male mice responded with serum IgG and salivary IgA antibodies similarly to female mice. Gamma interferon (IFN-γ) production by CD4+ T cells from iliac lymph nodes was elevated after i.n. or i.vag. immunization with OMVs plus IL-12 ms. Female mice immunized with OMVs plus IL-12 ms by either route resisted challenge with N. gonorrhoeae to an equal extent, and resistance generated by i.n. immunization extended to heterologous strains of N. gonorrhoeae. Detergent-extracted OMVs, which have diminished lipooligosaccharide, generated protective immunity to challenge similar to native OMVs. OMVs from mutant N. gonorrhoeae, in which genes for Rmp and LpxL1 were deleted to eliminate the induction of blocking antibodies against Rmp and diminish lipooligosaccharide endotoxicity, also generated resistance to challenge infection similar to wild-type OMVs when administered i.n. with IL-12 ms. IMPORTANCE We previously demonstrated that female mice can be immunized intravaginally with gonococcal outer membrane vesicles (OMVs) plus microsphere (ms)-encapsulated interleukin-12 (IL-12 ms) to induce antigonococcal antibodies and resistance to genital tract challenge with live Neisseria gonorrhoeae. However, this route of vaccination may be impractical for human vaccine development and is inapplicable to males. Because intranasal immunization has previously been shown to induce antibody responses in both male and female genital tracts, we have evaluated this route of immunization with gonococcal OMVs plus IL-12 ms. In addition, we have refined the composition of gonococcal OMVs to reduce the endotoxicity of lipooligosaccharide and to eliminate the membrane protein Rmp, which induces countereffective blocking antibodies. The resulting vaccine may be more suitable for ultimate translation to human application against the sexually transmitted infection gonorrhea, which is becoming increasingly resistant to treatment with antibiotics.
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