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Prophylactic Multi-Subunit Vaccine against Chlamydia trachomatis: In Vivo Evaluation in Mice.

ABSTRACT: Chlamydia trachomatis is the most frequent sexually-transmitted disease-causing bacterium. Urogenital serovars of this intracellular pathogen lead to urethritis and cervicitis. Ascending infections result in pelvic inflammatory disease, salpingitis, and oophoritis. One of 200 urogenital infections leads to tubal infertility. Serovars A-C cause trachoma with visual impairment. There is an urgent need for a vaccine. We characterized a new five-component subunit vaccine in a mouse vaccination-lung challenge infection model. Four recombinant Pmp family-members and Ctad1 from C. trachomatis serovar E, all of which participate in adhesion and binding of chlamydial elementary bodies to host cells, were combined with the mucosal adjuvant cyclic-di-adenosine monophosphate. Intranasal application led to a high degree of cross-serovar protection against urogenital and ocular strains of C. trachomatis, which lasted at least five months. Critical evaluated parameters were body weight, clinical score, chlamydial load, a granulocyte marker and the cytokines IFN-γ/TNF-α in lung homogenate. Vaccine antigen-specific antibodies and a mixed Th1/Th2/Th17 T cell response with multi-functional CD4⁺ and CD8⁺ T cells correlate with protection. However, serum-transfer did not protect the recipients suggesting that circulating antibodies play only a minor role. In the long run, our new vaccine might help to prevent the feared consequences of human C. trachomatis infections.

SUBMITTER: Lanfermann C

PROVIDER: S-EPMC8226540 | biostudies-literature |

REPOSITORIES: biostudies-literature

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In silico vaccine design against <i>Chlamydia trachomatis</i> infection.

Project description:Chlamydia trachomatis, a gram-negative bacterium known to infect the genital sites mainly columnar epithelial cells of the cervix, urethra and rectum in women and causes acute epididymitis, urinary tract inflammation and DNA damage to the sperms in men, hence considered to be one of the major sexually transmitted infections. The infection is asymptomatic in many people and remains untreated leading to serious health complications, including pelvic inflammatory disease, ectopic pregnancy and infertility. The current treatment options include antibiotics, but the pathogen has gained resistance against many antibiotics. The present work involves an in silico reverse vaccinology approach for identifying the immunogens as vaccine candidates that can be effective against reinfections and should be capable of inducing long-term protective immunity against Chlamydial infections. This study identifies the putative vaccine candidates that are membrane bound with high antigenicity properties; antigenicity induces the immunogenicity which involves identification of T-cell and B-cell epitopes that induce both humoral and cell-mediated immunity. The epitopes 'LSWEMELAY', 'LSNTEGYRY', 'TSDLGQMEY', 'FIDLLQAIY' and 'FSNNFSDIY' were predicted as core sequences for class I MHC molecules. The identified epitopes showed promising ability to interact with the human leukocyte antigens (HLA). These epitopes showed maximum population coverage with epitope conservancy above 80%. Molecular docking was performed to test the binding affinities of the identified epitopes with the HLA molecule to study the binding cleft interactions. The vaccine candidate thus identified from this study showed to possess the potential to activate the B- and T-cell immune responses which are more specific and make the body stronger against infections and effective for reinfections.

| S-EPMC7283423 | biostudies-literature

A Recombinant Chlamydia trachomatis MOMP Vaccine Elicits Cross-serogroup Protection in Mice Against Vaginal Shedding and Infertility.

Project description:BackgroundChlamydia trachomatis is the most common sexually transmitted bacterial pathogen worldwide. Here, we determined the ability of a C. trachomatis recombinant major outer membrane protein (rMOMP) vaccine to elicit cross-serogroup protection.MethodsFemale C3H/HeN mice were vaccinated by mucosal and systemic routes with C. trachomatis serovar D (UW-3/Cx) rMOMP and challenged in the ovarian bursa with serovars D (UW-3/Cx), D (UCI-96/Cx), E (IOL-43), or F (N.I.1). CpG-1826 and Montanide ISA 720 were used as adjuvants.ResultsImmune responses following vaccination were more robust against the most closely related serovars. Following a genital challenge (as determined by number of mice with positive vaginal cultures, number of positive cultures, number of inclusion forming units recovered, and number of days with positive cultures) mice challenged with C. trachomatis serovars of the same complex were protected but not those challenged with serovar F (N.I.1) from a different subcomplex. Females were caged with male mice. Based on fertility rates, number of embryos, and hydrosalpinx formation, vaccinated mice were protected against challenges with serovars D (UW-3/Cx), D (UCI-96/Cx), and E (IOL-43) but not F (N.I.1).ConclusionsThis is the first subunit vaccine shown to protect mice against infection, pathology, and infertility caused by different C. trachomatis serovars.

| S-EPMC6935996 | biostudies-literature

Maternal immunity partially protects newborn mice against a Chlamydia trachomatis intranasal challenge.

Project description:To determine the role of maternal immunity in protecting newborn mice against a Chlamydia trachomatis infection, female BALB/c mice were immunized intranasally (i.n.) with 10? inclusion forming units (IFU) of the C. trachomatis mouse pneumonitis biovar (MoPn). As a control, another group of female mice was sham-immunized i.n. with HeLa cell extracts. Immunized animals mounted strong immune responses as evidenced by high Chlamydia-specific antibody titers in serum and milk. Newborn mice born from immunized and sham-immunized dams were challenged i.n. with 10³IFU of MoPn at two post-natal days (PND). Following inoculation, newborn mice were euthanized at 7- and 18-PND and the lungs, spleen and intestine were cultured for Chlamydia. Overall, no significant differences were observed between the mice born from and fed by immunized dams and mice born from and fed by sham-immunized dams. Of the mice born from immunized dams, 75 and 25% had positive lung cultures at 7- and 18-PND, respectively. Of the mice born from sham-immunized dams, 82 and 50% had positive lung cultures for those same days. When the number of IFU recovered from the lungs and spleens was compared between the two groups no significant differences were observed. However, when the number of IFU recovered from the small intestine was compared, significant differences were observed between the two groups of newborn mice (2×10? versus 32×10? at 7-PND and 9.2×10? versus 85×10? at 18-PND). In conclusion, maternal immunity plays a limited role in protecting newborn mice against a Chlamydia infection.

| S-EPMC2949516 | biostudies-literature

VACCINES. A mucosal vaccine against Chlamydia trachomatis generates two waves of protective memory T cells.

Project description:Genital Chlamydia trachomatis (Ct) infection induces protective immunity that depends on interferon-?-producing CD4 T cells. By contrast, we report that mucosal exposure to ultraviolet light (UV)-inactivated Ct (UV-Ct) generated regulatory T cells that exacerbated subsequent Ct infection. We show that mucosal immunization with UV-Ct complexed with charge-switching synthetic adjuvant particles (cSAPs) elicited long-lived protection in conventional and humanized mice. UV-Ct-cSAP targeted immunogenic uterine CD11b(+)CD103(-) dendritic cells (DCs), whereas UV-Ct accumulated in tolerogenic CD11b(-)CD103(+) DCs. Regardless of vaccination route, UV-Ct-cSAP induced systemic memory T cells, but only mucosal vaccination induced effector T cells that rapidly seeded uterine mucosa with resident memory T cells (T(RM) cells). Optimal Ct clearance required both T(RM) seeding and subsequent infection-induced recruitment of circulating memory T cells. Thus, UV-Ct-cSAP vaccination generated two synergistic memory T cell subsets with distinct migratory properties.

| S-EPMC4605428 | biostudies-literature

Protective Effect of Vaccine Promoted Neutralizing Antibodies against the Intracellular Pathogen <i>Chlamydia trachomatis</i>.

Project description:There is an unmet need for a vaccine to control Chlamydia trachomatis (C.t.) infections. We have recently designed a multivalent heterologous immuno-repeat 1 (Hirep1) vaccine construct based on major outer membrane protein variable domain (VD) 4 regions from C.t. serovars (Svs) D-F. Hirep1 administered in the Cationic Adjuvant Formulation no. 1 (CAF01) promoted neutralizing antibodies in concert with CD4+ T cells and protected against genital infection. In the current study, we examined the protective role of the antibody (Ab) response in detail. Mice were vaccinated with either Hirep1 or a vaccine construct based on a homologous multivalent construct of extended VD4's from SvF (extVD4F*4), adjuvanted in CAF01. Hirep1 and extVD4F*4 induced similar levels of Ab and cell-mediated immune responses but differed in the fine specificity of the B cell epitopes targeted in the VD4 region. Hirep1 induced a strong response toward a neutralizing epitope (LNPTIAG) and the importance of this epitope for neutralization was demonstrated by competitive inhibition with the corresponding peptide. Immunization with extVD4F*4 skewed the response to a non-neutralizing epitope slightly upstream in the sequence. Vaccination with Hirep1 as opposed to extVD4F*4 induced significant protection against infection in mice both in short- and long-term vaccination experiments, signifying a key role for Hirep1 neutralizing antibodies during protection against C.t. Finally, we show that passive immunization of Rag1 knockout mice with Hirep1 antibodies completely prevented the establishment of infection in 48% of the mice, demonstrating an isolated role for neutralizing antibodies in controlling infection. Our data emphasize the role of antibodies in early protection against C.t. and support the inclusion of neutralizing targets in chlamydia vaccines.

| S-EPMC5732375 | biostudies-literature

A multi-subunit Chlamydia vaccine inducing neutralizing antibodies and strong IFN-?? CMI responses protects against a genital infection in minipigs.

Project description:Chlamydia is the most widespread sexually transmitted bacterial disease and a prophylactic vaccine is highly needed. Ideally, this vaccine is required to induce a combined response of Th1 cell-mediated immune (CMI) response in concert with neutralizing antibodies. Using a novel Göttingen minipig animal model, we evaluated the immunogenicity and efficacy of a multi-subunit vaccine formulated in the strong Th1-inducing adjuvant CAF01. We evaluated a mixture of two fusion proteins (Hirep1 and CTH93) designed to promote either neutralizing antibodies or cell-mediated immunity, respectively. Hirep1 is a novel immunogen based on the variant domain (VD) 4 region from major outer membrane protein (MOMP) serovar (Sv) D, SvE and SvF, and CTH93 is a fusion molecule of three antigens (CT043, CT414 and MOMP). Pigs were immunized twice intramuscularly with either Hirep1+CTH93/CAF01, UV-inactivated Chlamydia trachomatis SvD bacteria (UV-SvD/CAF01) or CAF01. The Hirep1+CTH93/CAF01 vaccine induced a strong CMI response against the vaccine antigens and high titers of antibodies, particularly against the VD4 region of MOMP. Sera from Hirep1+CTH93/CAF01 immunized pigs neutralized C. trachomatis SvD and SvF infectivity in vitro. Both Hirep1+CTH93/CAF01 and UV-SvD/CAF01 vaccination protected pigs against a vaginal C. trachomatis SvD infection. In conclusion, the Hirep1+CTH93/CAF01 vaccine proved highly immunogenic and equally protective as UV-SvD/CAF01 showing promise for the development of a subunit vaccine against Chlamydia.

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Multi-Stage Tuberculosis Subunit Vaccine Candidate LT69 Provides High Protection against Mycobacterium tuberculosis Infection in Mice.

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Formulation of the microbicide INP0341 for in vivo protection against a vaginal challenge by Chlamydia trachomatis.

Project description:The salicylidene acylhydrazide (SA) compounds have exhibited promising microbicidal properties. Previous reports have shown the SA compounds, using cell cultures, to exhibit activity against Chlamydia trachomatis, herpes simplex virus and HIV-1. In addition, using an animal model of a vaginal infection the SA compound INP0341, when dissolved in a liquid, was able to significantly protect mice from a vaginal infection with C. trachomatis. To expand upon this finding, in this report INP0341 was formulated as a vaginal gel, suitable for use in humans. Gelling agents (polymers) with inherent antimicrobial properties were chosen to maximize the total antimicrobial effect of the gel. In vitro formulation work generated a gel with suitable rheology and sustained drug release. A formulation containing 1 mM INP0341, 1.6 wt% Cremophor ELP (solubility enhancer) and 1.5 wt% poly(acrylic acid) (gelling and antimicrobial agent), was chosen for studies of efficacy and toxicity using a mouse model of a vaginal infection. The gel formulation was able to attenuate a vaginal challenge with C. trachomatis, serovar D. Formulations with and without INP0341 afforded protection, but the inclusion of INP0341 increased the protection. Mouse vaginal tissue treated with the formulation showed no indication of gel toxicity. The lack of toxicity was confirmed by in vitro assays using EpiVaginal tissues, which showed that a 24 h exposure to the gel formulation did not decrease the cell viability or the barrier function of the tissue. Therefore, the gel formulation described here appears to be a promising vaginal microbicide to prevent a C. trachomatis infection with the potential to be expanded to other sexually transmitted diseases.

| S-EPMC4214720 | biostudies-literature

Chlamydia trachomatis RNA polymerase alpha subunit: sequence and structural analysis.

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| S-EPMC176926 | biostudies-other

CD8+ T cells define an unexpected role in live-attenuated vaccine protective immunity against Chlamydia trachomatis infection in macaques.

Project description:Trachoma, caused by the obligate intracellular organism Chlamydia trachomatis, is the world's leading cause of preventable blindness for which a vaccine is needed. We have previously shown that a plasmid-deficient live-attenuated trachoma vaccine delivered ocularly to macaques elicited either solid or partial protective immunity against a virulent ocular challenge. Solidly protected macaques shared the same MHC class II alleles implicating CD4(+) T cells in superior protective immunity. Understandably, we sought to define T cell immune correlates in these animals to potentially improve vaccine efficacy. In this study, following a 2-y resting period, these macaques were boosted i.m. with the live-attenuated trachoma vaccine and their peripheral T cell anamnestic responses studied. Both solidly and partially protected macaques exhibited a CD4(+) and CD8(+) T cell anamnestic response following booster immunization. CD8(+) but not CD4(+) T cells from solidly protected macaques proliferated against soluble chlamydial Ag. We observed a more rapid T cell inflammatory cytokine response in tears of solidly protected animals following ocular rechallenge. Most notably, depletion of CD8(+) T cells in solidly protected macaques completely abrogated protective immunity. Collectively, our findings support the conclusion that CD8(+) T cells play an important but unexpected role in live-attenuated trachoma vaccine-mediated protective immunity.

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