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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.
Highlights
Effective vaccination against infections due to Staphylococcus aureus, one of the most common causes of both communityacquired and life-threatening nosocomial infections [1,2] has a clear and high priority
Despite promising preclinical data obtained from protection studies in animals, vaccines that targeted S. aureus capsular polysaccharides (CP) type 5 (CP5) and type 8 (CP8) antigens [3], the iron-surface determinant B (IsdB) protein [4,5], a monoclonal antibody to lipoteichoic acid, as well as an immune globulin selected from plasma donors with high titers of antibody to clumping factor A (ClfA) [6], all failed to protect patients against staphylococcal infections in phase III clinical trials [3,7,8]
We chose to incorporate into our candidate vaccine the three known major surface polysaccharides, poly-N-acetyl glucosamine (PNAG), CP5 and CP8, as representative of antigens that have been used successfully in other bacterial vaccines [53,54], and three proteins, non-toxic Hla, IsdB and clumping factor B (ClfB), due to support from other studies of protective efficacy in animal settings [5,16,21]
Summary
Effective vaccination against infections due to Staphylococcus aureus, one of the most common causes of both communityacquired and life-threatening nosocomial infections [1,2] has a clear and high priority. Using empiric approaches derived from protective efficacy observed in animal studies of S. aureus infection, candidates for inclusion in a multi-component staphylococcal vaccine encompass the polysaccharide antigens poly-N-acetyl glucosamine (PNAG), expressed by .95% of strains [9], and CP5 and CP8, produced by ,75% of strains. The validity of raising antibody to the deacetylated glycoform of PNAG to produce protective antibody was strongly validated in work that used a synthetic oligosaccharide composed of nine b-1-6-linked monomers of glucosamine (9GlcNH2) conjugated to tetanus toxoid (TT) as a vaccine. This glycoform engendered opsonic and protective antibody whereas the fully acetylated synthetic glycoform conjugated to TT, 9GlcNAc-TT, did not induce protective immunity. Whether the antibodies elicited to the synthetic oligosaccharide would interact in a negative manner with antibodies to CP5 or CP8 was not investigated
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