Protective efficacy of a parenterally administered MOMP-derived synthetic oligopeptide vaccine in a murine model of Chlamydia trachomatis genital tract infection: serum neutralizing IgG antibodies do not protect against chlamydial genital tract infection

doi:10.1016/0264-410X(95)00017-U

Vaccine

Volume 13, Issue 11, 1995, Pages 1023-1032

https://doi.org/10.1016/0264-410X(95)00017-U Get rights and content

Abstract

The protective efficacy of an alum-adsorbed, parenterally administered synthetic oligopeptide immunogen corresponding to antigenically common T-helper and neutralizing B-cell epitopes of the Chlamydia trachomatis major outer membrane protein was studied in a murine model of chlamydial genital tract infection. Mice produced high levels of anti-chlamydial serum IgG neutralizing antibodies following subcutaneous immunization with the alum-adsorbed oligopeptide. Lower but detectable levels of chlamydial specific IgG antibodies were found in vaginal washes. IgG1 was the predominant isotype present in sera and vaginal washes. Chlamydial-specific IgA was not present in either the sera or vaginal washes of immunized mice. Vaccinated and control mice were challenged intravaginally or intrauterinally with low, medium, or high doses of C. trachomatis serovar D challenge inocula. Protection was assessed by performing quantitative chlamydial cervico-vaginal cultures over the course of the infection period. There were no statistically significant differences between groups of immunized and control mice in either colonization, shedding, or duration of infection. These findings demonstrate that parenteral immunization with the oligopeptide (serum-neutralizing antibodies) is ineffective in preventing chlamydial genital tract infection. It is possible, since chlamydial infection is restricted to the genital tract mucosae, that a more accurate evaluation of the oligopeptide vaccine potential will require local rather than systemic immunization.

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Citation Excerpt :
While B cells and antibody clearly have a positive role in immunity based on the C. muridarum mouse model [48], the understanding of humoral immunity in human C. trachomatis infection is incomplete. Previous investigations in the C. caviae and C. muridarum rodent models using passive transfer of antibody, immunization with a neutralizing peptide epitope, and adoptive transfer of B cell hybridomas secreting neutralizing antibodies, showed that neutralizing antibody alone prevented infection only with low IFU inocula [51–53]. Human investigation has shown that high titers of anti-EB antibody are associated with poor infertility outcomes [54], and a greater risk of incident infection and do not prevent ascending infection [55].
The Chlamydial outer membrane complex (COMC) from the elementary body (EB) is a protein rich insoluble outer membrane shell from which cytosolic proteins have been extracted with detergent. In this study we conducted mass spectrometry experiments to detect proteins in the COMC prepared from C. muridarum EB. Proteomic analysis showed that the COMC contained 75 proteins that included 10 outer membrane proteins (OMPs) such as the major outer membrane protein (MOMP) and polymorphic membrane proteins (Pmps) that were previously identified as CD4 T cell vaccine candidates. We tested the vaccine efficacy of COMC in comparison to individual or combination of recombinant OMPs formulated with Th1 polarizing adjuvant DDA/MPL in two murine genital tract models (C. muridarum and C. trachomatis) by measuring organismal shedding, tubal pathology and immune responses including neutralizing antibodies. In the C. muridarum model, the COMC vaccine generated broadly reactive immune responses against multiple outer membrane proteins, high levels of EB binding and neutralizing antibody and exhibited superior protection against genital infection and pathology when compared to the recombinant PmpG vaccine. Denaturing the COMC by boiling significantly reduced protection. In the C. trachomatis model, the COMC vaccine also conferred greater protection compared to individual or multiple recombinant outer membrane proteins. Immunization with multiple COMCs from C. trachomatis serovars D, F and J generated neutralizing antibodies against multiple C. trachomatis serovars. We conclude that broader immunogenicity and generation of neutralizing antibody may explain the superior efficacy of COMC vaccine. The study suggests that conformationally intact proteins will be necessary for a successful recombinant OMP vaccine.
The cationic liposomal adjuvants CAF01 and CAF09 formulated with the major outer membrane protein elicit robust protection in mice against a Chlamydia muridarum respiratory challenge
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Citation Excerpt :
CAF09 induces strong Th1 responses with high antibody levels and has also been demonstrated to cross prime CD8 T-cell responses [22]. Several investigators have evaluated the efficacy of MOMP as a vaccine antigen, using various adjuvants, and observed different levels of protection against respiratory and genital challenges [13,14,18,27–31]. We formulated CAF01 and CAF09 with the native, or the recombinant, MOMP (nMOMP or rMOMP) with the goal of determining which of these adjuvant/antigen combinations is the most effective at protecting mice against an intranasal (i.n.) challenge with C. muridarum.
Two cationic liposomal adjuvants CAF01 and CAF09 were formulated with the native or the recombinant Chlamydia muridarum major outer membrane protein (nMOMP and rMOMP). BALB/c mice were immunized with the four vaccine formulations using the subcutaneous followed by the intranasal (i.n.) routes. As positive controls mice were inoculated i.n. with live C. muridarum and negative controls received i.n. minimal essential medium (MEM). Four weeks after the last immunization mice were challenged i.n. with 10⁴ inclusion forming units (IFU) of C. muridarum. Following the challenge the mice were weighed daily. At 10 days post-challenge the mice were euthanized, their lungs weighed and the number of C. muridarum IFU determined. Serum collected the day before the challenge showed that all four groups of mice immunized with CAF01, or CAF09 and MOMP had significant C. muridarum-specific antibody titers. As determined by a T-cell lymphoproliferative assay, these four groups of mice also mounted robust cell mediated immune responses with high production of IFN-γ and IL17 and low levels of IL-4. Following the challenge the four groups of mice lost significantly less body weight than the MEM-immunized group. Lungs of mice vaccinated with CAF01, or CAF09, and nMOMP were significantly lighter than those from mice immunized using rMOMP. The number of IFU recovered from the lungs of mice vaccinated with CAF01, or CAF09, and nMOMP was similar to the number of IFU recovered from mice immunized with live EB. Mice that received rMOMP had significantly higher numbers of IFU than other groups. In conclusion, CAF01 and CAF09 elicited very robust protective humoral and cellular immune responses and were equally effective at adjuntavizing the C. muridarum MOMP. Mice vaccinated with nMOMP were significantly better protected than those immunized with rMOMP, indicative of the importance of the structural conformation of this antigen in protection.
Induction of protective immunity against Chlamydia muridarum intravaginal infection with the chlamydial immunodominant antigen macrophage infectivity potentiator
2013, Microbes and Infection
We previously reported that 5 Chlamydia muridarum antigens reacted with antisera from >90% mice urogenitally infected with C. muridarum and they are TC0660 (ABC transporter or ArtJ), TC0727 (outer membrane complex protein B or OmcB), TC0828 (macrophage infectivity potentiator or MIP), TC0726 (inclusion membrane protein or Inc) & TC0268 (hypothetical protein or HP). The orthologs of these antigens in Chlamydia trachomatis were also highly reactive with antisera from women urogenitally infected with C. trachomatis. In the current study, we evaluated these C. muridarum antigens for their ability to induce protection against a C. muridarum intravaginal challenge infection in mice. We found that only MIP induced the most pronounced protection against C. muridarum infection. The protection correlated well with robust C. muridarum MIP-specific antibody and Th1-dominant T cell responses. The MIP-immunized mice displayed significantly reduced live organism shedding from the lower genital tract and highly attenuated inflammatory pathologies in the upper genital tissues. These results demonstrate that MIP, an immunodominant antigen identified by both human and mouse antisera, may be considered a component of a multi-subunit chlamydial vaccine for inducing protective immunity.
Immune markers and correlates of protection for vaccine induced immune responses
2012, Vaccine
Vaccines have been a major innovation in the history of mankind and still have the potential to address the challenges posed by chronic intracellular infections including tuberculosis, HIV and malaria which are leading causes of high morbidity and mortality across the world. Markers of an appropriate humoral response currently remain the best validated correlates of protective immunity after vaccination. Despite advancements in the field of immunology over the past few decades currently there are, however, no sufficiently validated immune correlates of vaccine induced protection against chronic infections in neither human nor veterinary medicine. Technological and conceptual advancements within cell-mediated immunology have led to a number of new immunological read-outs with the potential to emerge as correlates of vaccine induced protection. For T_H1 type responses, antigen-specific production of interferon-gamma (IFN-γ) has been promoted as a quantitative marker of protective cell-mediated immune responses over the past couple of decades. More recently, however, evidence from several infections has pointed towards the quality of the immune response, measured through increased levels of antigen-specific polyfunctional T cells capable of producing a triad of relevant cytokines, as a better correlate of sustained protective immunity against this type of infections. Also the possibilities to measure antigen-specific cytotoxic T cells (CTL) during infection or in response to vaccination, through recombinant major histocompatibility complex (MHC) class I tetramers loaded with relevant peptides, has opened a new vista to include CTL responses in the evaluation of protective immune responses. Here, we review different immune markers and new candidates for correlates of a protective vaccine induced immune response against chronic infections and how successful they have been in defining the protective immunity in human and veterinary medicine.
Protection of mice against Chlamydophila abortus infection with a bacteriophage-mediated DNA vaccine expressing the major outer membrane protein
2011, Veterinary Immunology and Immunopathology
Citation Excerpt :
The immunodominant protein of C. abortus, termed the major outer membrane protein (MOMP) and sometimes referred to as the OMPA protein, is regarded as the most promising candidate antigen for both recombinant protein and DNA vaccines. Native MOMP (Tan et al., 1990; Zhang et al., 1997), recombinant MOMP (Verminnen et al., 2005; Zhang et al., 2009) synthetic MOMP peptides (Su et al., 1995) and various DNA vaccines (Zhang et al., 1997, 2000; Vanrompay et al., 1999; Héchard et al., 2003; Longbottom and Coulter, 2003) have been evaluated in a variety of animal model systems. It has been suggested that a combination of DNA and protein-based vaccines may be the most effective approach (Verminnen et al., 2005).
A bacteriophage-delivered DNA vaccine against Chlamydophila abortus was constructed by cloning a eukaryotic cassette containing the ompA gene (which expresses the Major Outer Membrane Protein) into a bacteriophage lambda vector. Four groups, each of 20 BALB/c mice were inoculated separately with the phage vaccine, a conventional DNA vaccine based on the same ompA expression cassette, a live attenuated vaccine (strain 1B) or the empty phage vector. The phage and DNA vaccines and empty phage vector were administered intramuscularly on days 0, 14 and 28; the attenuated vaccine was given once on day 0. Half the animals in each group were challenged on day 42 by intraperitoneal injection of live C. abortus and sacrificed on day 49. Phage-vaccinated mice developed moderate antibody levels against C. abortus and yielded higher levels of IFN-γ and IL-2 compared with the attenuated live vaccine group. Clearance of chlamydiae from spleens was significantly better in the attenuated vaccine group compared with the phage vaccine group, while both groups were significantly superior to the DNA vaccine and control groups (p < 0.01). Although levels of protection in the mouse model were lower in phage-vaccinated animals, than in 1B vaccinated animals, phage vaccines offer several other advantages, such as easier handling and safety, potentially cheaper production and no chance of reversion to virulence. Although these are preliminary results in a model system, it is possible that with further optimisation immunization with phage vaccines may provide a novel way to improve protection against C. abortus infection and trials in large animals are currently being initiated.
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The need to simultaneously target infections with epidemiological overlap in the population with a single vaccine provides the basis for developing combination vaccines. Vibrio cholerae ghosts (rVCG) offer an attractive approach for developing vaccines against a number of human and animal pathogens. In this study, we constructed a multisubunit vaccine candidate co-expressing the serovar D-derived Porin B and polymorphic membrane protein-D proteins of Chlamydia trachomatis and evaluated its ability to simultaneously induce broad-based chlamydial immunity and elicit a vibriocidal antibody response to the Vibrio carrier envelope. Intramuscular (IM) immunization with the vaccine candidate elicited high levels of antigen-specific genital mucosal and systemic Th1 cell-mediated and humoral immune responses against heterologous serovars and strains, including serovars E–H and L. Also, in addition to the multisubunit vaccine, the single subunit constructs conferred significant cross protection against the heterologous mouse strain, Chlamydia muridarum. Furthermore, all mice immunized with rVCG vaccine constructs responded with a significant rise in vibriocidal antibody titer, the surrogate marker for protection in cholera. These findings demonstrate the ability of the multisubunit vaccine to induce cross protective chlamydial as well as vibriocidal immunity and establish the possibility of developing a broadly efficacious Chlamydia–cholera combination vaccine.

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PaperProtective efficacy of a parenterally administered MOMP-derived synthetic oligopeptide vaccine in a murine model of Chlamydia trachomatis genital tract infection: serum neutralizing IgG antibodies do not protect against chlamydial genital tract infection

Abstract

Vaccine

Adv. Immun.

Adv. Immun.

Gene

New knowledge of chlamydiae and the diseases they cause

J. Infect. Dis.

Chlamydial infections (third of three parts)

N. Engl. J. Med.

The intracellular life of Chlamydia

Curr. Top. Microbiol. Immun.

Chlamydial infections

Annu. Rev. Med.

Immunotypes of Chlamydia trachomatis isolates in Seattle, Washington

Infect. Immun.

Immunology of Chlamydia trachomatis infections: immunoprotective and immunopathogenetic responses

Purification and partial characterization of the major outer membrane protein of Chlamydia trachomatis

Infect. Immun.

A simple method of estimating fifty per cent endpoints

Am. J. Hyg.

Identification and characterization of T helper cell epitopes of the major outer membrane protein of Chlamydia trachomatis

J. Exp. Med.

In vitro neutralization of Chlamydia trachomatis by monovalent Fab antibody specific to the major outer membrane protein

Infect. Immun.

Cholera toxin discriminates between T helper 1 and 2 cells in T cell receptor-mediated activation: role of cAMP in T cell proliferation

J. Exp. Med.

Interferon-gamma and B cell stimulatory factor-1 reciprocally regulate Ig isotype production

Science

Lymphokine control of in vivo immunoglobulin isotype selection

Annu. Rev. Immun.

Neutralization of Chlamydia trachomatis cell culture infection by serovar-specific monoclonal antibodies

Infect. Immun.

Paper
Protective efficacy of a parenterally administered MOMP-derived synthetic oligopeptide vaccine in a murine model of Chlamydia trachomatis genital tract infection: serum neutralizing IgG antibodies do not protect against chlamydial genital tract infection