Chlamydia trachomatis, an obligate intracellular gram-negative organism, is the most common cause of bacterial sexually transmitted infections worldwide. Chlamydia infections cause cervicitis and pelvic inflammatory disease (PID) in women, resulting in chronic long-term sequelae such as ectopic pregnancy and infertility, and can also facilitate HIV transmission and human papilloma virus-induced neoplasia. Existing antibiotic treatments are not sufficient to prevent recurring infections. Development of a vaccine against Chlamydia is a largely unmet need for prevention of this disease. Live and inactivated whole organisms-based vaccines only confer limited protection from Chlamydia infections, with a short-lived, serovar/subgroup-specific protective immunity, and there is concern for hypersensitivity reactions. The Chlamydia major outer membrane protein, MOMP, is a prime antigen candidate for a subunit vaccine. MOMP contains 4 regions of sequence variability (variable domains, VDs) that elicit neutralizing antibodies when this protein is used in experimental immunization models. The VDs also contain epitopes that are recognized by T cells, favoring establishment of a desired Th1-cell mediated immunity against this intracellular pathogen. MOMP VDs are unique for each serovar and can therefore ensure broad coverage against all infecting strains, if combined in a single vaccine. However, development of a MOMP-based vaccine has encountered barriers for scaling-up manufacture of a highly antigenic product for use in humans. To fill the current gaps for the use of MOMP in a Chlamydia vaccine, we propose to engineer novel recombinant antigens in which the VDs are expressed into a carrier protein structurally similar to MOMP, specifically the PorB porin from the human commensal organism N. lactamica. This recombinant antigen will be suitable for purification in high amounts, in the correctly folded form and in the absence of detergents, thus fulfilling the unmet requirements for the successful use of MOMP in a vaccine against Chlamydia. Our approach will permit presentation of the VDs for immune recognition in a vaccine formulated with Th1-skewing immune adjuvants, to ensure that both humoral and T-cell mediated immunity are elicited in vivo. The proposed strategy will also permit insertion of VDs from different strain into the carrier protein, thus creating recombinant antigens for broad protection against the major Chlamydia serovars. Our work will lay the basis for a novel translational approach to prevent C. trachomatis infections in humans.
There is no vaccine against Chlamydia trachomatis infection in humans and existing antibiotic treatments are not sufficient to prevent recurring infections. The major Chlamydia outer membrane protein MOMP is the most promising antigen candidate, but significant challenges in production and scale-up hinder its use as a vaccine component. Our proposal will address these shortcomings by expressing novel recombinant MOMP-based antigens for induction of protective immunity, providing a novel tool with broad impact in the Chlamydia field including against human C. trachomatis serovars.
|Madico, Guillermo; Gursky, Olga; Fairman, Jeff et al. (2017) Structural and Immunological Characterization of Novel Recombinant MOMP-Based Chlamydial Antigens. Vaccines (Basel) 6:|