Protein Antigens Increase the Protective Efficacy of a Capsule-Based Vaccine against Staphylococcus aureus in a Rat Model of Osteomyelitis

Abstract

cStaphylococcus aureus is an invasive bacterial pathogen, and antibiotic resistance has impeded adequate control of infections caused by this microbe. Moreover, efforts to prevent human infections with single-component S. aureus vaccines have failed. In this study, we evaluated the protective efficacy in rats of vaccines containing both S. aureus capsular polysaccharides (CPs) and proteins. The serotypes 5 CP (CP5) and 8 CP (CP8) were conjugated to tetanus toxoid and administered to rats alone or together with domain A of clumping factor A (ClfA) or genetically detoxified alpha-toxin (dHla). The vaccines were delivered according to a preventive or a therapeutic regimen, and their protective efficacy was evaluated in a rat model of osteomyelitis. Addition of dHla (but not ClfA) to the CP5 or CP8 vaccine induced reductions in bacterial load and bone morphological changes compared with immunization with either conjugate vaccine alone. Both the prophylactic and therapeutic regimens were protective. Immunization with dHla together with a pneumococcal conjugate vaccine used as a control did not reduce staphylococcal osteomyelitis. The emergence of unencapsulated or small-colony variants during infection was negligible and similar for all of the vaccine groups. In conclusion, addition of dHla to a CP5 or CP8 conjugate vaccine enhanced its efficacy against S. aureus osteomyelitis, indicating that the inclusion of multiple antigens will likely enhance the efficacy of vaccines against both chronic and acute forms of staphylococcal disease.

MsaB activates capsule production at the transcription level in Staphylococcus aureus

“…Importantly, we have shown that the regulation of the cap operon by the msaABCR operon is similar in both serotypes. This is an important consideration because future therapeutic agents are being developed against the capsule and it is therefore important to understand whether strain differences are an important factor that must be taken into account (Fattom et al, 1993;Lattar et al, 2014;Bagnoli et al, 2012). However, we cannot rule out possible differences in the regulation of capsule production in other strains because we have only tested two representative strains.…”

Safety and immunogenicity of an investigational 4-componentStaphylococcus aureusvaccine with or without AS03Badjuvant: Results of a randomized phase I trial

“…39 The protective effect of AT and ClfA was demonstrated in different animal models of S. aureus pneumonia, bacteremia and skin infection. 33,[40][41][42] The combination of AT and CPS conjugates enhanced protection in a rat model of osteomyelitis, 43 while passive immunization with both CPS5 and ClfA antibodies inhibited the emergence of unencapsulated strains and significantly reduced the appearance of small colony variants. [44][45][46] Of note, IL-17-mediated cellular immunity has been found to play a key role in the protective effect induced by immunization with ClfA against S. aureus infection.…”

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

“…CP5 and CP8 are reportedly serologically distinct (12,13), and this has been attributed to differences in the linkages between the sugars and in the sites of O-acetylation. Staphylococcal CP conjugate vaccines elicit antibodies that promote opsonophagocytic killing (OPK) of S. aureus (6), and immunization has been shown to protect experimental animals against staphylococcal bacteremia, lethality, mastitis, osteomyelitis, and endocarditis (3,(14)(15)(16)(17)(18).…”