Alpha C Protein as a Carrier for Type III Capsular Polysaccharide and as a Protective Protein in Group B Streptococcal Vaccines

Abstract

The alpha C protein, a protective surface protein of group B streptococci (GBS), is present in most non-type III GBS strains. Conjugate vaccines composed of the alpha C protein and type III capsular polysaccharide (CPS) might be protective against most GBS infections. In this study, the type III CPS was covalently coupled to full-length, nine-repeat alpha C protein (resulting in III-α9r conjugate vaccine) or to two-repeat alpha C protein (resulting in III-α2r conjugate vaccine) by reductive amination. Initial experiments with the III-α9r vaccine showed that it was poorly immunogenic in mice with respect to both vaccine antigens and was suboptimally efficacious in providing protection in mice against challenge with GBS. Therefore, modified vaccination protocols were used with the III-α2r vaccine. Female mice were immunized three times with 0.5, 5, or 20 μg of the III-α2r vaccine with an aluminum hydroxide adjuvant and bred. Ninety-five percent of neonatal mice born to dams immunized with the III-α2r vaccine survived challenge with GBS expressing type III CPS, and 60% survived challenge with GBS expressing wild-type (nine-repeat) alpha C protein; 18 and 17%, respectively, of mice in the negative control groups survived (P, <0.0001). These protection levels did not differ significantly from those obtained with the type III CPS-tetanus toxoid conjugate vaccine and the unconjugated two-repeat alpha C protein, which protected 98 and 58% of neonates from infection with GBS expressing type III CPS or the alpha C protein, respectively. Thus, the two-repeat alpha C protein in the vaccine was immunogenic and simultaneously enhanced the immunogenicity of type III CPS. III-α vaccines may be alternatives to GBS polysaccharide-tetanus toxoid vaccines, eliciting additional antibodies protective against GBS infection.

Alpha C protein-specific immunity in humans with group B streptococcal colonization and invasive disease

“…Further investigations showed that gene recombination led to variation in the number of repeats and protein size; these cloned or purified α C proteins elicited protective antibody in mice challenged with α C-expressing GBS strains [18,24,25]. An α C protein conjugated to type III CPS used as a vaccine in mice demonstrated that α C protein functioned as a carrier for type III CPS and as an antigen that stimulated a brisk immune response protective against non-type III α C-expressing strains [11].…”

“…Animal studies have demonstrated that α C protein can function as an effective carrier and simultaneously induce protective immunity against strains of multiple CPS types expressing this surface protein [11]. Thus, α C protein is an attractive candidate GBS vaccine component.…”

Progress toward a group B streptococcal vaccine

“…Preclinical vaccine investigations of the AlphaC, Alp3, and Rib proteins have been conducted, but the use of Alp proteins as universal vaccines has been limited due to the heterogeneity of the Alp sequence.. 114,[120][121][122][123] Nevertheless, MinervaX Inc. recently reported that the fusion protein of the highly immunogenic N-terminal domains of AlphC and Rib (GBS-NN) led to over 30-fold increase of GBS-NN-specific antibody in their phase I clinical trial with 240 healthy adult women (NCT02459262). 124 Serine-rich repeat proteins Doro et al 125 performed surfome analysis to identify GBS proteins with domains protruding from the bacterial surface.…”

Association between antibodies against group B Streptococcus surface proteins and recto-vaginal colonisation during pregnancy

“…Several surface proteins such as the C proteins, BibA, Sip, and pilus island proteins have been reported to confer protection against GBS disease in murine models 21 – 24 . Furthermore, studies have demonstrated that conjugating CPS to GBS surface proteins results in serotype-independent protection 25 – 27 . Also, natural induced α-C protein antibodies from pregnant women were shown to be capable of inducing opsonophagocytic killing 28 .…”