Antibodies to Variable Domain 4 Linear Epitopes of theChlamydia trachomatisMajor Outer Membrane Protein Are Not Associated with Chlamydia Resolution or Reinfection in Women

Abstract

Chlamydia trachomatis is an obligate intracellular bacterium. C. trachomatis infection is the most prevalent bacterial sexually transmitted infection and can lead to pelvic inflammatory disease and infertility in women. There is no licensed vaccine for C. trachomatis prevention, in part due to gaps in our knowledge of C. trachomatis-specific immune responses elicited during human infections. Previous investigations of the antibody response to C. trachomatis have identified immunodominant antigens and antibodies that can neutralize infection in cell culture. However, epitope-specific responses to C. trachomatis are not well characterized, and the impact of these antibodies on infection outcome is unknown. We recently developed a technology called deep sequence-coupled biopanning that uses bacteriophage virus-like particles to display peptides from antigens and affinity select against human serum IgG. Here, we used this technology to map C. trachomatis-specific antibodies in groups of women with defined outcomes following C. trachomatis infection: (i) C. trachomatis negative upon presentation for treatment (“spontaneous resolvers”), (ii) C. trachomatis negative at a 3-month follow-up visit after treatment (“nonreinfected”), and (iii) C. trachomatis positive at a 3-month follow-up after treatment (“reinfected”). This analysis yielded immunodominant epitopes that had been previously described but also identified new epitopes targeted by human antibody responses to C. trachomatis. We focused on human antibody responses to the C. trachomatis variable domain 4 serovar-conserved region of the major outer membrane protein (VD4-MOMP), a previously described immunodominant epitope. All three groups of women produced IgG to the VD4-MOMP, suggesting that detection of serum antibodies to VD4-MOMP in women with urogenital C. trachomatis infection is not associated with protection against reinfection. IMPORTANCE C. trachomatis infection is the most common bacterial sexually transmitted infection, and infection in women can lead to pelvic inflammatory disease and infertility. No licensed vaccine exists to prevent C. trachomatis infection, and investigations of the natural immune response may inform the design of targeted vaccines for C. trachomatis. Our study fills a gap in knowledge regarding the epitope specificity of antibody responses that are elicited in response to C. trachomatis infection in women. We identified several new B cell epitopes for C. trachomatis antigens and confirmed B cell epitopes that have been identified by other methods. Our finding that women produce antibodies to the VD4-MOMP regardless of infection outcome provides insight into vaccine development, suggesting that vaccines targeting VD4-MOMP may need to elicit higher-titer antibody responses than natural infection imparts or that additional vaccine targets should be pursued in the future.

Engineering an Antibody V Gene-Selective Vaccine

“…Short (6-15 amino acid) random peptide insertions at this site are highly compatible with VLP assembly and are displayed multivalently on the VLP surface ( 54 , 55 , 69 ). VLPs with specific binding characteristics can be affinity selected from large libraries of VLPs displaying random peptides using, for example, mAbs ( 71 , 72 ) or polyclonal IgG ( 73 , 74 ). We generated nine independent VLP libraries (displaying random 6-, 7-, 8-, 9-, 10-, 11-, 12-, 13-, & 15-amino acid inserts, respectively) using methods established previously ( 54 , 55 ).…”

Immunogenicity and Protective Capacity of a Virus-like Particle Vaccine against Chlamydia trachomatis Type 3 Secretion System Tip Protein, CT584

“…Human serum samples. Collection and use of human serum samples was approved as previously described [12] by the University of Alabama at Birmingham Institutional Review Board, the Jefferson County Department of Health (JCDH) in Birmingham, AL, USA, and the University of New Mexico Health Sciences Center Human Research Review Committee. Participants were enrolled from two populations: (1) predominantly African-American C. trachomatis-infected women aged >16 years presenting to the JCDH STD Clinic in Birmingham, AL, USA, and (2) Hispanic and non-Hispanic white virgin women aged 18-40 years presenting for routine gynecologic examinations in Albuquerque, NM, USA.…”

“…In a clinical trial, the MOMP-VD4 CTH522 vaccine was shown to be safe and immunogenic in 15 women, inducing neutralizing antibody in serum after three intramuscular injections, though MOMP-specific IgG and IgA were less prevalent in mucosal secretions and not shown to be neutralizing [8]. As with vaccination with CTH522, genital infection with C. trachomatis induces a robust antibody response against MOMP-VD4 [11,12]. However, this response is not protective: re-infection with the same C. trachomatis serovar is common [13] and not associated with the quantity or quality of the MOMP-VD4 antibody response [12].…”

“…As with vaccination with CTH522, genital infection with C. trachomatis induces a robust antibody response against MOMP-VD4 [11,12]. However, this response is not protective: re-infection with the same C. trachomatis serovar is common [13] and not associated with the quantity or quality of the MOMP-VD4 antibody response [12]. Whether vaccination with CTH522 protects against infection with C. trachomatis will need to be determined by further clinical trials.…”

RNA Phage VLP-Based Vaccine Platforms

“…The selected population was analyzed by Ion Torrent sequence analysis, allowing creation of a profile representing the various linear epitopes recognized by antibodies in infected individuals. We have extended the method to other viral and bacterial pathogens, including Zika virus (unpublished) and Chlamydia trachomatis [ 24 ].…”