{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,5,1]],"date-time":"2026-05-01T16:20:10Z","timestamp":1777652410653,"version":"3.51.4"},"reference-count":68,"publisher":"MDPI AG","issue":"5","license":[{"start":{"date-parts":[[2025,4,27]],"date-time":"2025-04-27T00:00:00Z","timestamp":1745712000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"National Institute of Allergy and Infectious Diseases of the National Institutes of Health","award":["R01AI162709-03"],"award-info":[{"award-number":["R01AI162709-03"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Vaccines"],"abstract":"<jats:p>Background\/Objectives:\u00a0Chlamydia trachomatis (Ct) is the leading bacterial cause of sexually transmitted infection globally. If undiagnosed or left untreated, these infections can lead to serious complications such as infertility, ectopic pregnancies, and chronic pelvic pain. Despite the high prevalence and potential for serious health complications, no vaccine has been licensed. Pigs offer a valuable biomedical model for chlamydia research: they have an overall high degree of similarity to humans and serve as natural hosts for Chlamydia suis (Cs), a close relative of Ct. Thus, in this study, the pig model was used to evaluate a vaccine candidate against Ct. Methods: The vaccine candidate consists of chlamydial-protease-like activity factor (CPAF) protein adjuvanted with STING (Stimulator of Interferon Genes) pathway agonist cyclic-di-AMP (c-di-AMP). Pigs received two doses intramuscularly followed by two intranasal doses. Each week, the systemic T cell response was assessed via IFN-\u03b3 and IL-17 ELISpots, as well as multi-parameter flow cytometry on 0, 14, and 28 days post vaccination (dpv). The humoral immune response was analyzed by measuring CPAF-specific antibody levels and avidity via ELISAs. Results: Vaccination with c-di-AMP adjuvanted CPAF triggered low-level systemic IFN-\u03b3 and multifunctional IFN-\u03b3+TNF-\u03b1+ CD4 T cell responses. Despite the rather low systemic effector cytokine production, robust anti-CPAF IgG responses were detected in serum, vaginal swab eluates, and oviduct flushes. Genital Ct challenge 42 dpv resulted in only transient infection, precluding a confident assessment of vaccine efficacy of the tested CPAF\/c-di-AMP vaccine candidate. However, after challenge, vaccinated pigs exhibited boosted systemic anti-CPAF IFN-\u03b3 and mucosal IgG responses compared to unvaccinated pigs. Conclusions: Thus, while vaccine efficacy remains elusive, the CPAF\/c-di-AMP vaccine candidate was immunogenic: it elicited a low-level systemic cell-mediated response and robust humoral immune responses. Future studies will incorporate a STING agonist directly conjugated to CPAF as well as addition of other Th1-inducing adjuvants to enhance cellular immunity.<\/jats:p>","DOI":"10.3390\/vaccines13050468","type":"journal-article","created":{"date-parts":[[2025,4,29]],"date-time":"2025-04-29T09:00:39Z","timestamp":1745917239000},"page":"468","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":2,"title":["A Cyclic-di-AMP Adjuvanted CPAF Protein Vaccine Is Immunogenic in Swine, but It Fails to Reduce Genital Chlamydia trachomatis Burden"],"prefix":"10.3390","volume":"13","author":[{"given":"Leonie","family":"Bettin","sequence":"first","affiliation":[{"name":"Department of Biological Sciences and Pathobiology, Center of Pathobiology, Immunology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maria","family":"Stadler","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Pathobiology, Center of Pathobiology, Immunology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4965-2088","authenticated-orcid":false,"given":"Christine","family":"Unterweger","sequence":"additional","affiliation":[{"name":"Clinical Department for Farm Animals and Food System Science, Clinical Centre for Population Medicine in Fish, Pig and Poultry, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maximiliane","family":"Dippel","sequence":"additional","affiliation":[{"name":"Clinical Department for Farm Animals and Food System Science, Clinical Centre for Population Medicine in Fish, Pig and Poultry, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4209-2380","authenticated-orcid":false,"given":"Jonathan M.","family":"Harris","sequence":"additional","affiliation":[{"name":"Centre for Immunology and Infection Control, Queensland University of Technology, Brisbane, QLD 4000, Australia"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5037-7269","authenticated-orcid":false,"given":"Andrea","family":"Buzanich-Ladinig","sequence":"additional","affiliation":[{"name":"Clinical Department for Farm Animals and Food System Science, Clinical Centre for Population Medicine in Fish, Pig and Poultry, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5985-4153","authenticated-orcid":false,"given":"Taylor B.","family":"Poston","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Toni","family":"Darville","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8764-7971","authenticated-orcid":false,"given":"Tobias","family":"K\u00e4ser","sequence":"additional","affiliation":[{"name":"Department of Biological Sciences and Pathobiology, Center of Pathobiology, Immunology, University of Veterinary Medicine Vienna, 1210 Vienna, Austria"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2025,4,27]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"448","DOI":"10.1038\/s41579-023-00860-y","article-title":"Intracellular Lifestyle of Chlamydia Trachomatis and Host\u2013Pathogen Interactions","volume":"21","author":"Stelzner","year":"2023","journal-title":"Nat. Rev. Microbiol."},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"1517","DOI":"10.1093\/cid\/ciz429","article-title":"Chlamydia Trachomatis and the Risk of Pelvic Inflammatory Disease, Ectopic Pregnancy, and Female Infertility: A Retrospective Cohort Study Among Primary Care Patients","volume":"69","author":"Hoebe","year":"2019","journal-title":"Clin. Infect. Dis."},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"S23","DOI":"10.1093\/infdis\/jiab116","article-title":"A Review of the Challenges and Complexities in the Diagnosis, Etiology, Epidemiology, and Pathogenesis of Pelvic Inflammatory Disease","volume":"224","author":"Hillier","year":"2021","journal-title":"J. Infect. Dis."},{"key":"ref_4","doi-asserted-by":"crossref","unstructured":"Kiekens, C., Morr\u00e9, S.A., and Vanrompay, D. (2024). Advances in Chlamydia Trachomatis Vaccination: Unveiling the Potential of Major Outer Membrane Protein Derivative Constructs. Microorganisms, 12.","DOI":"10.3390\/microorganisms12061196"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1091","DOI":"10.1016\/S1473-3099(19)30279-8","article-title":"Safety and Immunogenicity of the Chlamydia Vaccine Candidate CTH522 Adjuvanted with CAF01 Liposomes or Aluminium Hydroxide: A First-in-Human, Randomised, Double-Blind, Placebo-Controlled, Phase 1 Trial","volume":"19","author":"Abraham","year":"2019","journal-title":"Lancet Infect. Dis."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"829","DOI":"10.1016\/S1473-3099(24)00147-6","article-title":"An Investigation of Trachoma Vaccine Regimens by the Chlamydia Vaccine CTH522 Administered with Cationic Liposomes in Healthy Adults (CHLM-02): A Phase 1, Double-Blind Trial","volume":"24","author":"Pollock","year":"2024","journal-title":"Lancet Infect. Dis."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"95","DOI":"10.1016\/j.molimm.2021.04.004","article-title":"Swine as Biomedical Animal Model for T-Cell Research\u2014Success and Potential for Transmittable and Non-Transmittable Human Diseases","volume":"135","year":"2021","journal-title":"Mol. Immunol."},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"287","DOI":"10.1007\/s00441-020-03206-9","article-title":"The Pig as a Model for Immunology Research","volume":"380","author":"Pabst","year":"2020","journal-title":"Cell Tissue Res."},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"eabd5758","DOI":"10.1126\/scitranslmed.abd5758","article-title":"Importance of the Pig as a Human Biomedical Model","volume":"13","author":"Lunney","year":"2021","journal-title":"Sci. Transl. Med."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/j.vaccine.2010.12.042","article-title":"Protection of Pigs against Chlamydia Trachomatis Challenge by Administration of a MOMP-Based DNA Vaccine in the Vaginal Mucosa","volume":"29","author":"Schautteet","year":"2011","journal-title":"Vaccine"},{"key":"ref_11","doi-asserted-by":"crossref","unstructured":"Erneholm, K., Lorenzen, E., B\u00f8je, S., Olsen, A.W., Jungersen, G., Jensen, H.E., Cassidy, J.P., Andersen, P., Agerholm, J.S., and Follmann, F. (2019). Genital Infiltrations of CD4+ and CD8+ T Lymphocytes, IgA+ and IgG+ Plasma Cells and Intra-Mucosal Lymphoid Follicles Associate With Protection Against Genital Chlamydiatrachomatis Infection in Minipigs Intramuscularly Immunized With UV-Inactivated Bacteria Adjuvanted With CAF01. Front. Microbiol., 10.","DOI":"10.3389\/fmicb.2019.00197"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"185","DOI":"10.1038\/icb.2015.79","article-title":"A Multi-Subunit Chlamydia Vaccine Inducing Neutralizing Antibodies and Strong IFN-\u0393+ CMI Responses Protects against a Genital Infection in Minipigs","volume":"94","author":"Olsen","year":"2016","journal-title":"Immunol. Cell Biol."},{"key":"ref_13","doi-asserted-by":"crossref","unstructured":"Proctor, J., Stadler, M., Cortes, L.M., Brodsky, D., Poisson, L., Gerdts, V., Smirnov, A.I., Smirnova, T.I., Barua, S., and Leahy, D. (2024). A TriAdj-Adjuvanted Chlamydia Trachomatis CPAF Protein Vaccine Is Highly Immunogenic in Pigs. Vaccines, 12.","DOI":"10.20944\/preprints202403.0298.v1"},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"ftaa035","DOI":"10.1093\/femspd\/ftaa035","article-title":"Comprehensive Genome Analysis and Comparisons of the Swine Pathogen, Chlamydia Suis Reveals Unique ORFs and Candidate Host-Specificity Factors","volume":"79","author":"Dimond","year":"2020","journal-title":"Pathog. Dis."},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"H\u00e4cker, G. (2024). Chlamydia in Pigs: Intriguing Bacteria Associated with Sub-Clinical Carriage and Clinical Disease, and with Zoonotic Potential. Front. Cell Dev. Biol., 12.","DOI":"10.3389\/fcell.2024.1301892"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"29","DOI":"10.1186\/1297-9716-42-29","article-title":"Chlamydiaceae Infections in Pig","volume":"42","author":"Schautteet","year":"2011","journal-title":"Vet. Res."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"91","DOI":"10.1016\/j.vaccine.2016.11.050","article-title":"Chlamydia Suis and Chlamydia Trachomatis Induce Multifunctional CD4 T Cells in Pigs","volume":"35","author":"Pasternak","year":"2017","journal-title":"Vaccine"},{"key":"ref_18","doi-asserted-by":"crossref","unstructured":"Amaral, A.F., Rahman, K.S., Kick, A.R., Cortes, L.M., Robertson, J., Kaltenboeck, B., Gerdts, V., O\u2019Connell, C.M., Poston, T.B., and Zheng, X. (2020). Mucosal Vaccination with UV-Inactivated Chlamydia Suis in Pre-Exposed Outbred Pigs Decreases Pathogen Load and Induces CD4 T-Cell Maturation into IFN-\u0393+ Effector Memory Cells. Vaccines, 8.","DOI":"10.3390\/vaccines8030353"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1032","DOI":"10.1128\/iai.65.3.1032-1044.1997","article-title":"Genital Tract Infection with Chlamydia Trachomatis Fails to Induce Protective Immunity in Gamma Interferon Receptor-Deficient Mice despite a Strong Local Immunoglobulin A Response","volume":"65","author":"Johansson","year":"1997","journal-title":"Infect. Immun."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"e00191-20","DOI":"10.1128\/mBio.00191-20","article-title":"Gamma Interferon Is Required for Chlamydia Clearance but Is Dispensable for T Cell Homing to the Genital Tract","volume":"11","author":"Helble","year":"2020","journal-title":"mBio"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Bakshi, R.K., Gupta, K., Jordan, S.J., Chi, X., Lensing, S.Y., Press, C.G., and Geisler, W.M. (2018). An Adaptive Chlamydia Trachomatis-Specific IFN-\u03b3-Producing CD4+ T Cell Response Is Associated With Protection Against Chlamydia Reinfection in Women. Front. Immunol., 9.","DOI":"10.3389\/fimmu.2018.01981"},{"key":"ref_22","doi-asserted-by":"crossref","unstructured":"Yu, H., Geisler, W.M., Dai, C., Gupta, K., Cutter, G., and Brunham, R.C. (2024). Antibody Responses to Chlamydia Trachomatis Vaccine Candidate Antigens in Chlamydia-Infected Women and Correlation with Antibody-Mediated Phagocytosis of Elementary Bodies. Front. Cell. Infect. Microbiol., 14.","DOI":"10.3389\/fcimb.2024.1342621"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"e13103","DOI":"10.1111\/aji.13103","article-title":"Anti-Chlamydia IgG and IgA Are Insufficient to Prevent Endometrial Chlamydia Infection in Women, and Increased Anti-Chlamydia IgG Is Associated with Enhanced Risk for Incident Infection","volume":"81","author":"Darville","year":"2019","journal-title":"Am. J. Reprod. Immunol."},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"727","DOI":"10.1007\/s00404-009-1225-7","article-title":"The Relationship between Serum Chlamydia Antibody Levels and Severity of Disease in Infertile Women with Tubal Damage","volume":"281","author":"Gordon","year":"2010","journal-title":"Arch. Gynecol. Obstet."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"2643","DOI":"10.1128\/IAI.69.4.2643-2649.2001","article-title":"Resolution of Secondary Chlamydia Trachomatis Genital Tract Infection in Immune Mice with Depletion of Both CD4+ and CD8+ T Cells","volume":"69","author":"Morrison","year":"2001","journal-title":"Infect. Immun."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"7536","DOI":"10.4049\/jimmunol.175.11.7536","article-title":"A Predominant Role for Antibody in Acquired Immunity to Chlamydial Genital Tract Reinfection1","volume":"175","author":"Morrison","year":"2005","journal-title":"J. Immunol."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"e385","DOI":"10.1093\/infdis\/jiae443","article-title":"Low-Frequency, Sustained CD4 T-Cell Responses Chlamydia Trachomatis in Women: Predominant Targeting of Chlamydial Proteaselike Activity Factor (CPAF)","volume":"231","author":"Li","year":"2024","journal-title":"J. Infect. Dis."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"a010256","DOI":"10.1101\/cshperspect.a010256","article-title":"Chlamydial Intracellular Survival Strategies","volume":"3","author":"Bastidas","year":"2013","journal-title":"Cold Spring Harb. Perspect. Med."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"824","DOI":"10.1038\/s41564-018-0182-y","article-title":"Chlamydia Trachomatis Paralyses Neutrophils to Evade the Host Innate Immune Response","volume":"3","author":"Rajeeve","year":"2018","journal-title":"Nat. Microbiol."},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e01427-16","DOI":"10.1128\/mBio.01427-16","article-title":"Chlamydial Protease-Like Activity Factor and Type III Secreted Effectors Cooperate in Inhibition of P65 Nuclear Translocation","volume":"7","author":"Patton","year":"2016","journal-title":"mBio"},{"key":"ref_31","doi-asserted-by":"crossref","unstructured":"Schott, B.H., Antonia, A.L., Wang, L., Pittman, K.J., Sixt, B.S., Barnes, A.B., Valdivia, R.H., and Ko, D.C. (2020). Modeling of Variables in Cellular Infection Reveals CXCL10 Levels Are Regulated by Human Genetic Variation and the Chlamydia-Encoded CPAF Protease. Sci. Rep., 10.","DOI":"10.1038\/s41598-020-75129-y"},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"114020","DOI":"10.1016\/j.addr.2021.114020","article-title":"Delivery of STING Agonists for Adjuvanting Subunit Vaccines","volume":"179","author":"Feng","year":"2021","journal-title":"Adv. Drug Deliv. Rev."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"4963","DOI":"10.1016\/j.vaccine.2019.07.019","article-title":"The STING Activator C-Di-AMP Exerts Superior Adjuvant Properties than the Formulation Poly(I:C)\/CpG after Subcutaneous Vaccination with Soluble Protein Antigen or DEC-205-Mediated Antigen Targeting to Dendritic Cells","volume":"37","author":"Volckmar","year":"2019","journal-title":"Vaccine"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1435","DOI":"10.1016\/j.celrep.2018.04.003","article-title":"STING-Activating Adjuvants Elicit a Th17 Immune Response and Protect against Mycobacterium Tuberculosis Infection","volume":"23","author":"Sogi","year":"2018","journal-title":"Cell Rep."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"126526","DOI":"10.1016\/j.vaccine.2024.126526","article-title":"Intranasal Immunization with CPAF Combined with ADU-S100 Induces an Effector CD4 T Cell Response and Reduces Bacterial Burden Following Intravaginal Infection with Chlamydia Muridarum","volume":"43","author":"Poston","year":"2025","journal-title":"Vaccine"},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"473","DOI":"10.1016\/j.cimid.2009.08.002","article-title":"Detection of All Chlamydophila and Chlamydia Spp. of Veterinary Interest Using Species-Specific Real-Time PCR Assays","volume":"33","author":"Pantchev","year":"2010","journal-title":"Comp. Immunol. Microbiol. Infect. Dis."},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"385","DOI":"10.1016\/j.vetmic.2011.05.024","article-title":"Waddlia, Parachlamydia and Chlamydiaceae in Bovine Abortion","volume":"152","author":"Blumer","year":"2011","journal-title":"Vet. Microbiol."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"1768","DOI":"10.1002\/med.22016","article-title":"cGAS-STING Pathway Agonists Are Promising Vaccine Adjuvants","volume":"44","author":"Tian","year":"2024","journal-title":"Med. Res. Rev."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"4486","DOI":"10.1016\/j.vaccine.2017.05.067","article-title":"A Novel Combination Adjuvant Platform for Human and Animal Vaccines","volume":"35","author":"Garg","year":"2017","journal-title":"Vaccine"},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"78","DOI":"10.1016\/j.antiviral.2018.07.021","article-title":"A Chimeric Glycoprotein Formulated with a Combination Adjuvant Induces Protective Immunity against Both Human Respiratory Syncytial Virus and Parainfluenza Virus Type 3","volume":"158","author":"Garg","year":"2018","journal-title":"Antivir. Res."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"2387","DOI":"10.1016\/j.vaccine.2020.01.051","article-title":"Innate Immunemodulator Containing Adjuvant Formulated HA Based Vaccine Protects Mice from Lethal Infection of Highly Pathogenic Avian Influenza H5N1 Virus","volume":"38","author":"Lu","year":"2020","journal-title":"Vaccine"},{"key":"ref_42","doi-asserted-by":"crossref","unstructured":"Cheng, X., Ning, J., Xu, X., and Zhou, X. (2022). The Role of Bacterial Cyclic Di-Adenosine Monophosphate in the Host Immune Response. Front. Microbiol., 13.","DOI":"10.3389\/fmicb.2022.958133"},{"key":"ref_43","doi-asserted-by":"crossref","first-page":"6758","DOI":"10.1016\/j.vaccine.2014.10.010","article-title":"The Bovine Viral Diarrhea Virus E2 Protein Formulated with a Novel Adjuvant Induces Strong, Balanced Immune Responses and Provides Protection from Viral Challenge in Cattle","volume":"32","author":"Snider","year":"2014","journal-title":"Vaccine"},{"key":"ref_44","doi-asserted-by":"crossref","unstructured":"Ebensen, T., Delandre, S., Prochnow, B., Guzm\u00e1n, C.A., and Schulze, K. (2019). The Combination Vaccine Adjuvant System Alum\/c-Di-AMP Results in Quantitative and Qualitative Enhanced Immune Responses Post Immunization. Front. Cell. Infect. Microbiol., 9.","DOI":"10.3389\/fcimb.2019.00031"},{"key":"ref_45","doi-asserted-by":"crossref","first-page":"4973","DOI":"10.1016\/j.vaccine.2011.04.094","article-title":"Intranasal C-Di-GMP-Adjuvanted Plant-Derived H5 Influenza Vaccine Induces Multifunctional Th1 CD4+ Cells and Strong Mucosal and Systemic Antibody Responses in Mice","volume":"29","author":"Madhun","year":"2011","journal-title":"Vaccine"},{"key":"ref_46","doi-asserted-by":"crossref","first-page":"2183","DOI":"10.1016\/j.jid.2016.05.105","article-title":"Natural STING Agonist as an \u201cIdeal\u201d Adjuvant for Cutaneous Vaccination","volume":"136","author":"Wang","year":"2016","journal-title":"J. Investig. Dermatol."},{"key":"ref_47","doi-asserted-by":"crossref","first-page":"677","DOI":"10.1002\/bit.28027","article-title":"Biotechnological Production of Cyclic Dinucleotides\u2014Challenges and Opportunities","volume":"119","author":"Bartsch","year":"2022","journal-title":"Biotechnol. Bioeng."},{"key":"ref_48","doi-asserted-by":"crossref","first-page":"e202416353","DOI":"10.1002\/anie.202416353","article-title":"A Phosphotriester-Masked Dideoxy-cGAMP Derivative as a Cell-Permeable STING Agonist","volume":"63","author":"Halbritter","year":"2024","journal-title":"Angew. Chem. Int. Ed."},{"key":"ref_49","doi-asserted-by":"crossref","unstructured":"Yan, H., and Chen, W. (2021). The Promise and Challenges of Cyclic Dinucleotides as Molecular Adjuvants for Vaccine Development. Vaccines, 9.","DOI":"10.3390\/vaccines9080917"},{"key":"ref_50","doi-asserted-by":"crossref","unstructured":"Ning, H., Zhang, W., Kang, J., Ding, T., Liang, X., Lu, Y., Guo, C., Sun, W., Wang, H., and Bai, Y. (2021). Subunit Vaccine ESAT-6:C-Di-AMP Delivered by Intranasal Route Elicits Immune Responses and Protects Against Mycobacterium Tuberculosis Infection. Front. Cell. Infect. Microbiol., 11.","DOI":"10.3389\/fcimb.2021.647220"},{"key":"ref_51","doi-asserted-by":"crossref","first-page":"5210","DOI":"10.1016\/j.vaccine.2011.05.026","article-title":"Bis-(3\u2032,5\u2032)-Cyclic Dimeric Adenosine Monophosphate: Strong Th1\/Th2\/Th17 Promoting Mucosal Adjuvant","volume":"29","author":"Ebensen","year":"2011","journal-title":"Vaccine"},{"key":"ref_52","doi-asserted-by":"crossref","unstructured":"Sanchez, M.V., Ebensen, T., Schulze, K., Cargnelutti, D., Blazejewska, P., Scodeller, E.A., and Guzm\u00e1n, C.A. (2014). Intranasal Delivery of Influenza rNP Adjuvanted with C-Di-AMP Induces Strong Humoral and Cellular Immune Responses and Provides Protection against Virus Challenge. PLoS ONE, 9.","DOI":"10.1371\/journal.pone.0104824"},{"key":"ref_53","doi-asserted-by":"crossref","unstructured":"Longet, S., and Paul, S. (2023). Pivotal Role of Tissue-Resident Memory Lymphocytes in the Control of Mucosal Infections: Can Mucosal Vaccination Induce Protective Tissue-Resident Memory T and B Cells?. Front. Immunol., 14.","DOI":"10.3389\/fimmu.2023.1216402"},{"key":"ref_54","doi-asserted-by":"crossref","first-page":"aaa8205","DOI":"10.1126\/science.aaa8205","article-title":"A Mucosal Vaccine against Chlamydia Trachomatis Generates Two Waves of Protective Memory T Cells","volume":"348","author":"Stary","year":"2015","journal-title":"Science"},{"key":"ref_55","doi-asserted-by":"crossref","first-page":"467","DOI":"10.1038\/ni.2038","article-title":"Origins of CD4+ Effector and Central Memory T Cells","volume":"12","author":"Pepper","year":"2011","journal-title":"Nat. Immunol."},{"key":"ref_56","doi-asserted-by":"crossref","first-page":"6979","DOI":"10.1128\/IAI.68.12.6979-6987.2000","article-title":"Immunity to Murine Chlamydia Trachomatis Genital Tract Reinfection Involves B Cells and CD4+ T Cells but Not CD8+ T Cells","volume":"68","author":"Morrison","year":"2000","journal-title":"Infect. Immun."},{"key":"ref_57","doi-asserted-by":"crossref","first-page":"978","DOI":"10.1093\/infdis\/jiv137","article-title":"Protection Against Chlamydia Trachomatis Infection and Upper Genital Tract Pathological Changes by Vaccine-Promoted Neutralizing Antibodies Directed to the VD4 of the Major Outer Membrane Protein","volume":"212","author":"Olsen","year":"2015","journal-title":"J. Infect. Dis."},{"key":"ref_58","doi-asserted-by":"crossref","first-page":"213","DOI":"10.1046\/j.0019-2805.2001.01354.x","article-title":"Fc Receptor Regulation of Protective Immunity against Chlamydia Trachomatis","volume":"105","author":"Moore","year":"2002","journal-title":"Immunology"},{"key":"ref_59","doi-asserted-by":"crossref","first-page":"1005","DOI":"10.1016\/j.mucimm.2024.06.012","article-title":"Viral-Vectored Boosting of OmcB- or CPAF-Specific T-Cell Responses Fail to Enhance Protection from Chlamydia Muridarum in Infection-Immune Mice and Elicits a Non-Protective CD8-Dominant Response in Na\u00efve Mice","volume":"17","author":"Poston","year":"2024","journal-title":"Mucosal Immunol."},{"key":"ref_60","doi-asserted-by":"crossref","first-page":"271","DOI":"10.1111\/j.1574-695X.2008.00517.x","article-title":"A Limited Role for Antibody in Protective Immunity Induced by rCPAF and CpG Vaccination Against Primary Genital Chlamydia Muridarum Challenge","volume":"55","author":"Murthy","year":"2009","journal-title":"FEMS Immunol. Med. Microbiol."},{"key":"ref_61","doi-asserted-by":"crossref","first-page":"4414","DOI":"10.1128\/IAI.73.7.4414-4419.2005","article-title":"Inhibition of Proteolytic Activity of a Chlamydial Proteasome\/Protease-Like Activity Factor by Antibodies from Humans Infected with Chlamydia Trachomatis","volume":"73","author":"Sharma","year":"2005","journal-title":"Infect. Immun."},{"key":"ref_62","doi-asserted-by":"crossref","first-page":"846","DOI":"10.1093\/infdis\/jiab496","article-title":"Reduced Endometrial Ascension and Enhanced Reinfection Associated With Immunoglobulin G Antibodies to Specific Chlamydia Trachomatis Proteins in Women at Risk for Chlamydia","volume":"225","author":"Liu","year":"2022","journal-title":"J. Infect. Dis."},{"key":"ref_63","doi-asserted-by":"crossref","first-page":"669","DOI":"10.1016\/j.micinf.2016.07.002","article-title":"Neutralizing Antichlamydial Activity of Complement by Chlamydia-Secreted Protease CPAF","volume":"18","author":"Yang","year":"2016","journal-title":"Microbes Infect."},{"key":"ref_64","doi-asserted-by":"crossref","first-page":"402","DOI":"10.1016\/j.micinf.2015.02.005","article-title":"Chlamydia-Secreted Protease CPAF Degrades Host Antimicrobial Peptides","volume":"17","author":"Tang","year":"2015","journal-title":"Microbes Infect."},{"key":"ref_65","doi-asserted-by":"crossref","unstructured":"Pedersen, G.K., W\u00f8rzner, K., Andersen, P., and Christensen, D. (2020). Vaccine Adjuvants Differentially Affect Kinetics of Antibody and Germinal Center Responses. Front. Immunol., 11.","DOI":"10.3389\/fimmu.2020.579761"},{"key":"ref_66","doi-asserted-by":"crossref","first-page":"334","DOI":"10.1016\/j.micinf.2017.01.008","article-title":"Intrauterine Inoculation of Minipigs with Chlamydia Trachomatis during Diestrus Establishes a Longer Lasting Infection Compared to Vaginal Inoculation during Estrus","volume":"19","author":"Lorenzen","year":"2017","journal-title":"Microbes Infect."},{"key":"ref_67","doi-asserted-by":"crossref","unstructured":"Dirks, J.A.M.C., van Liere, G.A.F.S., Bogers, S., Dukers-Muijrers, N.H.T.M., Wolffs, P.F.G., and Hoebe, C.J.P.A. (2015). Natural Course of Chlamydia trachomatis Bacterial Load in the Time Interval between Screening and Treatment in Anogenital Samples. PLoS ONE, 10.","DOI":"10.1371\/journal.pone.0145693"},{"key":"ref_68","doi-asserted-by":"crossref","first-page":"1606","DOI":"10.1016\/j.fertnstert.2008.08.128","article-title":"Real-Time Polymerase Chain Reaction Shows That Density Centrifugation Does Not Always Remove Chlamydia Trachomatis from Human Semen","volume":"92","author":"Cross","year":"2009","journal-title":"Fertil. Steril."}],"container-title":["Vaccines"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/5\/468\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,9]],"date-time":"2025-10-09T17:22:31Z","timestamp":1760030551000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2076-393X\/13\/5\/468"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,4,27]]},"references-count":68,"journal-issue":{"issue":"5","published-online":{"date-parts":[[2025,5]]}},"alternative-id":["vaccines13050468"],"URL":"https:\/\/doi.org\/10.3390\/vaccines13050468","relation":{},"ISSN":["2076-393X"],"issn-type":[{"value":"2076-393X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,4,27]]}}}