Opsonic and Protective Properties of Antibodies Raised to Conjugate Vaccines Targeting Six Staphylococcus aureus Antigens

Abstract

Staphylococcus aureus is a major cause of nosocomial and community-acquired infections for which a vaccine is greatly desired. Antigens found on the S. aureus outer surface include the capsular polysaccharides (CP) of serotype 5 (CP5) or 8 (CP8) and/or a second antigen, a β-(1→6)-polymer of N-acetyl-D-glucosamine (PNAG). Antibodies specific for either CP or PNAG antigens have excellent in vitro opsonic killing activity (OPKA), but when mixed together have potent interference in OPKA and murine protection. To ascertain if this interference could be abrogated by using a synthetic non-acetylated oligosaccharide fragment of PNAG, 9GlcNH2, in place of chemically partially deacetylated PNAG, three conjugate vaccines consisting of 9GlcNH2 conjugated to a non-toxic mutant of alpha-hemolysin (Hla H35L), CP5 conjugated to clumping factor B (ClfB), or CP8 conjugated to iron-surface determinant B (IsdB) were used separately to immunize rabbits. Opsonic antibodies mediating killing of multiple S. aureus strains were elicited for all three vaccines and showed carbohydrate antigen-specific reductions in the tissue bacterial burdens in animal models of S. aureus skin abscesses, pneumonia, and nasal colonization. Carrier-protein specific immunity was also shown to be effective in reducing bacterial levels in infected lungs and in nasal colonization. However, use of synthetic 9GlcNH2 to induce antibody to PNAG did not overcome the interference in OPKA engendered when these were combined with antibody to either CP5 or CP8. Whereas each individual vaccine showed efficacy, combining antisera to CP antigens and PNAG still abrogated individual OPKA activities, indicating difficulty in achieving a multi-valent vaccine targeting both the CP and PNAG antigens.

Antibodies to Staphylococcus aureus Serotype 8 Capsular Polysaccharide React with and Protect against Serotype 5 and 8 Isolates

“…S. aureus also has a wide spectrum of virulence factors and disease types, and as such, a single vaccine may not protect against the broad range of staphylococcal infections. Efforts to create multicomponent vaccines and to induce both cellular and humoral immune responses are under way by several groups (40)(41)(42), and these multivalent vaccines often include CP antigens. Despite the failure in clinical trials of CP5 and CP8 conjugate vaccines, staphylococcal CPs are still important vaccine targets, since they are expressed in 70 to 80% of S. aureus clinical isolates and are essential for bacterial survival in blood (6).…”

Targeting Surface Protein SasX by Active and Passive Vaccination To Reduce Staphylococcus aureus Colonization and Infection

“…In addition, we believe that virulence determinants that are found to strongly impact colonization and virulence phenotypes in MRSA strains with considerable epidemiological importance, wide geographical distribution, and likely further spread, such as SasX, should also be analyzed as potential vaccine targets. Other surface proteins, such as ClfA or IsdA, which impact nasal colonization in animal models, have previously shown success as immunogens in experimental animal colonization studies (22)(23)(24). For these reasons, we here analyzed whether active and passive immunization with SasX as the target reduces S. aureus skin and lung infection and has the potential to reduce S. aureus nasal colonization.…”

Comparative Exoproteomics and Host Inflammatory Response in Staphylococcus aureus Skin and Soft Tissue Infections, Bacteremia, and Subclinical Colonization

“…To date, several proteomic studies have been reported and this improved our understanding of staphylococcal cell physiology, virulence, and associated host responses (9,13,29,30). However, most of these studies were carried out with a single strain or infection type with limited follow-up using data on patient serum antibodies.…”

“…The exoproteins Hla, IsdB, IsaA, and ClfA elicit significantly higher levels of antibodies in patients than in healthy carriers. Such immunogens play key roles in host protection by enhancing opsonic activity and inducing cytokine and chemokine production to promote immune cell recruitment (12,13). Unfortunately, the efficacy of these protective actions has not been transformed into a licensed vaccine, underscoring the need for a better understanding of host responses to the different types of infection caused by S. aureus.…”