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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

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 ge...

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Autores principales: Liu, Yingru, Hammer, Laura A., Daamen, Jikke, Stork, Michiel, Egilmez, Nejat K., Russell, Michael W.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Society for Microbiology 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942569/
https://www.ncbi.nlm.nih.gov/pubmed/36537786
http://dx.doi.org/10.1128/msphere.00388-22
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author Liu, Yingru
Hammer, Laura A.
Daamen, Jikke
Stork, Michiel
Egilmez, Nejat K.
Russell, Michael W.
author_facet Liu, Yingru
Hammer, Laura A.
Daamen, Jikke
Stork, Michiel
Egilmez, Nejat K.
Russell, Michael W.
author_sort Liu, Yingru
collection PubMed
description 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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spelling pubmed-99425692023-02-22 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 Liu, Yingru Hammer, Laura A. Daamen, Jikke Stork, Michiel Egilmez, Nejat K. Russell, Michael W. mSphere Research Article 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. American Society for Microbiology 2022-12-20 /pmc/articles/PMC9942569/ /pubmed/36537786 http://dx.doi.org/10.1128/msphere.00388-22 Text en Copyright © 2022 Liu et al. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution 4.0 International license (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Research Article
Liu, Yingru
Hammer, Laura A.
Daamen, Jikke
Stork, Michiel
Egilmez, Nejat K.
Russell, Michael W.
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
title 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
title_full 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
title_fullStr 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
title_full_unstemmed 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
title_short 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
title_sort 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
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9942569/
https://www.ncbi.nlm.nih.gov/pubmed/36537786
http://dx.doi.org/10.1128/msphere.00388-22
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