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

Everett Webster,Sarah Afzaal,Cosette M Wheeler,William M Geisler,Hannah Knapp-Broas,Muskan Shrestha,Amanda L Collar,Bryce Chackerian,Kathryn M Frietze,Rebeccah S Lijek,Susan B Core,June Graham,Kyra W Seiger

doi:10.3390/vaccines10010111

Abstract

An effective vaccine against Chlamydia trachomatis is urgently needed as infection rates continue to rise and C. trachomatis causes reproductive morbidity. An obligate intracellular pathogen, C. trachomatis employs a type 3 secretion system (T3SS) for host cell entry. The tip of the injectosome is composed of the protein CT584, which represents a potential target for neutralization with vaccine-induced antibody. Here, we investigate the immunogenicity and efficacy of a vaccine made of CT584 epitopes coupled to a bacteriophage virus-like particle (VLP), a novel platform for Chlamydia vaccines modeled on the success of HPV vaccines. Female mice were immunized intramuscularly, challenged transcervically with C. trachomatis, and assessed for systemic and local antibody responses and bacterial burden in the upper genital tract. Immunization resulted in a 3-log increase in epitope-specific IgG in serum and uterine homogenates and in the detection of epitope-specific IgG in uterine lavage at low levels. By contrast, sera from women infected with C. trachomatis and virgin controls had similarly low titers to CT584 epitopes, suggesting these epitopes are not systemically immunogenic during natural infection but can be rendered immunogenic by the VLP platform. C. trachomatis burden in the upper genital tract of mice varied after active immunization, yet passive protection was achieved when immune sera were pre-incubated with C. trachomatis prior to inoculation into the genital tract. These data demonstrate the potential for antibody against the T3SS to contribute to protection against C. trachomatis and the value of VLPs as a novel platform for C. trachomatis vaccines.

Highlights

Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen with an annual global incidence rate estimated at 127 million cases in 2016 [1]
For the virus-like particle (VLP), we selected the capsid from the bacteriophage Qβ, which was shown in clinical trials to be well-tolerated and to elicit robust antibody responses to the peptide conjugated to its surface without the need for adjuvant [37,38]
The two most optimal B-cell epitopes of CT584 identified by Immune Epitope Database (IEDB) were residues 70–77 and 154–164, both of which are surface-exposed on the outward face of the CT584 hexamer that assembles at the tip of the type 3 secretion system (T3SS) (Figure 1)

Summary

Introduction

Chlamydia trachomatis is the most common sexually transmitted bacterial pathogen with an annual global incidence rate estimated at 127 million cases in 2016 [1]. Despite aggressive treatment and control efforts, C. trachomatis infection rates are increasing, which underscores the need to develop a C. trachomatis vaccine as described recently by the World Health Organization (WHO) and the US National Institute of Allergy and Infectious Diseases (NIAID) [5,6]. 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]. 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

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