Epitope-Based Vaccines against the Chlamydia trachomatis Major Outer Membrane Protein Variable Domain 4 Elicit Protection in Mice

Abstract

Chlamydia trachomatis (Ct) is the most common bacterial sexual transmitted pathogen, yet a vaccine is not currently available. Here, we used the immunogenic bacteriophage MS2 virus-like particle (VLP) technology to engineer vaccines against the Ct major outer membrane protein variable domain 4 (MOMP-VD4), which contains a conserved neutralizing epitope (TTLNPTIAG). A previously described monoclonal antibody to the MOMP-VD4 (E4 mAb) is capable of neutralizing all urogenital Ct serovars and binds this core epitope, as well as several non-contiguous amino acids. This suggests that this core epitope may require conformational context in order to elicit neutralizing antibodies to Ct. In order to identify immunogens that could elicit neutralizing antibodies to the TTLNPTIAG epitope, we used two approaches. First, we used affinity selection with a bacteriophage MS2-VLP library displaying random peptides in a constrained, surface-exposed loop to identify potential E4 mAb mimotopes. After four rounds of affinity selection, we identified a VLP-displayed peptide (HMVGSTKWTN) that could bind to the E4 mAb and elicited serum IgG that bound weakly to Ct elementary bodies by ELISA. Second, two versions of the core conserved TTLNPTIAG epitope (TTLNPTIAG and TTLNPTIAGA) were recombinantly expressed on the coat protein of the MS2 VLP in a constrained, surface-exposed loop. Mouse immune sera IgG bound to Ct elementary bodies by ELISA. Immunization with these MS2 VLPs provided protection from vaginal Chlamydia infection in a murine challenge model. These data suggest that short peptide epitopes targeting the MOMP-VD4 could be appropriate for Ct vaccine design when displayed on an immunogenic bacteriophage VLP vaccine platform.

Aspects of Phage-Based Vaccines for Protein and Epitope Immunization

“…An alternative was to express the TTLNPTIAG epitope on the surface of the VLPs of bacteriophage MS2. In a mouse challenge model, mice immunized with MS2 VLPs generated IgG that identified C. trachomatis and gave protection against vaginal Chlamydia infection [ 49 ].…”

The impact of AlphaFold Protein Structure Database on the fields of life sciences

“…In addition to structure‐based drug discovery, AlphaFold models are helping in vaccine development, as demonstrated by Collar et al. [54]. They investigated the target epitopes of MOMP proteins from various Chlamydia species.…”

“…In addition to structure-based drug discovery, AlphaFold models are helping in vaccine development, as demonstrated by Collar et al [54].…”

PDBe and PDBe‐KB: Providing high‐quality, up‐to‐date and integrated resources of macromolecular structures to support basic and applied research and education

“…The advent of these advanced computationally predicted models disrupted several fields in the life sciences, from structure‐based drug discovery and bioinformatics analysis to software development and structure determination efforts. 41 , 42 , 43 , 44 , 45 , 46 , 47 , 48 Researchers regularly use AlphaFold models to solve protein structures using their (sometimes old) experimental data.…”