Novel Protein-Based Pneumococcal Vaccines: Assessing the Use of Distinct Protein Fragments Instead of Full-Length Proteins as Vaccine Antigens

Abstract

Non-serotype-specific protein-based pneumococcal vaccines have received extensive research focus due to the limitations of polysaccharide-based vaccines. Pneumococcal proteins (PnPs), universally expressed among serotypes, may induce broader immune responses, stimulating humoral and cellular immunity, while being easier to manufacture and less expensive. Such an approach has raised issues mainly associated with sequence/level of expression variability, chemical instability, as well as possible undesirable reactogenicity and autoimmune properties. A step forward employs the identification of highly-conserved antigenic regions within PnPs with the potential to retain the benefits of protein antigens. Besides, their low-cost and stable construction facilitates the combination of several antigenic regions or peptides that may impair different stages of pneumococcal disease offering even wider serotype coverage and more efficient protection. This review discusses the up-to-date progress on PnPs that are currently under clinical evaluation and the challenges for their licensure. Focus is given on the progress on the identification of antigenic regions/peptides within PnPs and their evaluation as vaccine candidates, accessing their potential to overcome the issues associated with full-length protein antigens. Particular mention is given of the use of newer delivery system technologies including conjugation to Toll-like receptors (TLRs) and reformulation into nanoparticles to enhance the poor immunogenicity of such antigens.

Next-Generation Whole-Cell Pneumococcal Vaccine

“…Nevertheless, there are several challenges before a protein or a whole-cell vaccines' licensure can be addressed [28]. Correlates of protection are needed to support the licensure of vaccines, for that, a network of investigators from different research centers around the world have to deliver high-quality standardized functional immune assays, studies protocols comparing the relationship between antibody concentrations and disease risk in a non-vaccinated, naturally exposed population [64,65].…”

“…Inhibits the activation of the complement, binds to lactoferrin, helping adherence and protecting bacteria from lactoferrin toxic effects. [24,25] PspC Surface Protein Adhesin, inhibits activation of complement binding factor H [24,25] PcpA Surface Protein Adhesin, Choline binding protein [26] PhtD Surface Lipoprotein Adhesin, Zn binding protein [27,28] Autolysin Cytoplasm/Cell Wall Autolytic response induced during the stationary growth phase [29] PiuA Surface Lipoprotein Iron uptake ABC transporter [25] PiaA Surface Lipoprotein Iron uptake ABC transporter [25] PsaA Surface Lipoprotein Mn + 2 uptake ABC transporter adhesin [30] Pilus Surface Protein Epithelial cell adhesion [23] Ply (pneumolysin); PspA (pneumococcal surface protein A); PspC (pneumococcal surface protein C); PcpA (pneumococcal choline-binding protein A); PhtD (polyhistidine triad protein D); PiuA (pneumococcal iron uptake A); PiaA (pneumococcal iron acquisition A); PsaA (Pneumococcal surface antigen A); Pilus (pilus proteins).…”

Development of Next Generation Streptococcus pneumoniae Vaccines Conferring Broad Protection

“…A pneumococcal vaccine that exhibits the potential to provide broad serotype coverage, induce mucosal and systemic immunity, and hinder primary intranasal colonization, as well as invasive disease, is much desired. Several pneumococcal proteins have been studied as vaccine candidates such as the pneumococcal surface protein A (PspA) pneumolysin (Ply), pneumococcal surface protein C (PspC), and pneumococcal surface adhesin A (PsaA), which have been comprehensively reviewed by many researchers [54][55][56][57]. Here, we focus on highlighting new approaches to developing the whole-cell vaccines, discovering new protein antigens or genetic manipulations of protein antigens to make more effective vaccines for the next generation S. pneumoniae vaccines.…”

Vaccines to Prevent Infectious Diseases in the Older Population: Immunological Challenges and Future Perspectives

“…Most of these candidate vaccines use pneumococcal histidine triad protein D (PhtD), detoxified pneumolysin derivative (PlyD) and pneumococcal surface protein (PspA) alone or in different combinations and are immunogenic in humans while showing acceptable safety profiles (177,178). As a next step highly conserved protein fragments or peptides were investigated as potential vaccine antigens and showed immunogenicity and protective effects in mouse models (179). Further clinical studies are needed to demonstrate immunogenicity and ultimately clinical efficacy in humans.…”

“…Other TLR agonists have also been shown to enhance immune responses and protection in mouse models (207,208). Several other adjuvants and advanced delivery systems with the potential to increase efficacy of pneumococcal protein and peptide vaccines are in pre-clinical development (179).…”