Conjugation of PspA4Pro with Capsular Streptococcus pneumoniae Polysaccharide Serotype 14 Does Not Reduce the Induction of Cross-Reactive Antibodies

Abstract

Current pneumococcal vaccines are composed of bacterial polysaccharides as antigens, plain or conjugated to carrier proteins. While efficacious against vaccine serotypes, epidemiologic data show an increasing incidence of infections caused by nonvaccine serotypes of The use of pneumococcal surface protein A (PspA) as a carrier protein in a conjugate vaccine could help prevent serotype replacement by increasing vaccine coverage and reducing selective pressure of serotypes. PspA is present in all pneumococcal strains, is highly immunogenic, and is known to induce protective antibodies. Based on its sequence, PspA has been classified into three families and six clades. A PspA fragment derived from family 2, clade 4 (PspA4Pro), was shown to generate antibodies with a broad range of cross-reactivity, across clades and families. Here, PspA4Pro was modified and conjugated to capsular polysaccharide serotype 14 (PS14). We investigated the impact of conjugation on the immune response induced to PspA4Pro and PS14. Mice immunized with the PS14-mPspA4Pro conjugate produced higher titers of anti-PS14 antibodies than the animals that received coadministered antigens. The conjugate induced antibodies with opsonophagocytic activity against PS14-carrying strains, as well as against a panel of strains bearing PspAs from five clades (encompassing families 1 and 2) bearing a non-PS14 serotype. Furthermore, mice immunized with PS14-mPspA4Pro were protected against nasal colonization with a nonrelated strain bearing PspA from clade 1, serotype 6B. These results demonstrate that the cross-reactivity mediated by PspA4Pro is retained following conjugation, supporting the use of PspA4 as a carrier protein in order to enhance pneumococcal vaccine coverage and encourage its further investigation as a candidate in future vaccine designs.

Exploration of Recombinant Fusion Proteins YAPO and YAPL as Carrier Proteins for Glycoconjugate Vaccine Design against Streptococcus pneumoniae Infection

“…Pneumococcal surface protein A (PspA) is a highly immunogenic surface protein that can block complement binding to Spn cells and suppress the functions of host lactoferrin. , Pneumococcal surface adhesin A (PsaA) is involved in Spn adhesion and invasion and participates in transporting magnesium and zinc ions into Spn cells . It has been disclosed that PlyD1 (a detoxified mutant of Ply), PspA, and PsaA could elicit robust antibodies and afford effective protection against Spn infection in animal models. , Furthermore, all these surface proteins have also been employed solely as carrier proteins for conjugation of Spn polysaccharide, and their resultant glycoconjugates could also provide broad protection against those uncovered Spn serotypes. − In addition, several studies have revealed that the fusion of pneumococcal proteins could improve the immune response and increase protection against fatal pneumococcal challenge compared with the proteins alone. − The main advantages of this pattern are possibly featured with the enhancement in immunogenicity, exposure of hidden antigenic epitopes, and reduction in production costs . Thus, the utilization of fusion proteins as antigen or carrier for carbohydrate antigen has been an attractive strategy for pneumococcal vaccine development.…”

Evaluation of polymer choice on immunogenicity of chitosan coated PLGA NPs with surface-adsorbed pneumococcal protein antigen PspA4Pro

“…In this experiment, PspA4Pro, which is a recombinant protein found on the surface of S. pneumoniae, was incorporated on the surface of the NPs. The protein offers potentially greater protective coverage between different S. pneumoniae serotypes, compared to commercially available conjugate pneumococcal vaccines ( da Silva et al, 2017 ). The immunogenic properties of PspA4Pro are also advantageous compared to polysaccharide antigen that are T cell independent and induce poor memory responses ( da Silva et al, 2017 ).…”

“…The protein offers potentially greater protective coverage between different S. pneumoniae serotypes, compared to commercially available conjugate pneumococcal vaccines ( da Silva et al, 2017 ). The immunogenic properties of PspA4Pro are also advantageous compared to polysaccharide antigen that are T cell independent and induce poor memory responses ( da Silva et al, 2017 ). In the current study, the incorporation of the PspA4Pro to the surface of the particles could be formed through the formation of electrostatic and hydrophobic interaction with the surface of the PLGA NP.…”

Progress in mucosal immunization for protection against pneumococcal pneumonia

“…The serotype replacement mitigates the benefits of vaccination and has compelled pharmaceutical companies to develop higher-valency PCVs [33][34][35][36]. In addition, several initiatives are being directed to the development serotype-independent vaccines [37][38][39][40][41], including the addition of pneumococcal proteins to PCV formulations [42][43][44].…”