Development of a multicomponent<i>Staphylococcus aureus</i>vaccine designed to counter multiple bacterial virulence factors

Anderson, Annaliesa S.; Miller, Alita A.; Donald, Robert G. K.; Scully, Ingrid L.; Nanra, Jasdeep S.; Cooper, David A.; Jansen, Kathrin U.

doi:10.4161/hv.21872

Cited by 93 publications

(87 citation statements)

References 112 publications

(125 reference statements)

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“…CP5/CP8-based conjugate vaccines alone failed in clinical trials aimed at reducing bacteremia in hemodialysis patients (34,35). Similarly, a vaccine targeting a single protein (IsdB) failed to reduce surgical wound infections in patients undergoing a median sternotomy (26,28,36). Because the nature of S. aureus pathogenicity is multifactorial, it is likely that the protective responses required to prevent infection should necessarily target a number of virulence factors (37,38).…”

Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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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.

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Section: Discussionmentioning

confidence: 99%

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

et al. 2014

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“…Furthermore, the antibody responses elicited are functional and either kill the bacteria or neutralize the virulence factors. 51 …”

Section: Vaccines In Late Stage Development With Potential To Reduce Amrmentioning

confidence: 99%

The role of vaccines in fighting antimicrobial resistance (AMR)

Jansen

Anderson

2018

Human Vaccines & Immunotherapeutics

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107

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The problem of antimicrobial resistance (AMR) and the associated morbidity and mortality due to antibiotic resistant bacterial pathogens is not new. However, AMR has been increasing at an alarming rate with appearances of diseases caused by bacteria exhibiting resistance to not just one but multiple classes of antibiotics. The World Health Organization (WHO) supported by governments, health ministries and health agencies has formulated global action plans to combat the rise in AMR, supporting a number of proven initiatives such as antimicrobial stewardship, investments in development of new classes of antibiotics, and educational programs designed to eliminate inappropriate antibiotic use. Vaccines as tools to reduce AMR have historically been under-recognized, yet the positive effect in reducing AMR has been well established. For example Haemophilus influenzae type B (Hib) as well as Streptococcus pneumoniae (pneumococcal) conjugate vaccines have impressive track records in not only preventing life threatening diseases caused by these bacteria, but also reducing antibiotic use and AMR. This paper will describe the drivers of antibiotic use and subsequent development of AMR; it will make the case how existing vaccines are already participating in combatting AMR, describe future prospects for the role of new vaccines in development to reduce AMR, and highlight challenges associated with future vaccine development to combat AMR.

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“…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).…”

Section: Figmentioning

confidence: 99%

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

Park

Gerber²,

Lee

2014

Infect Immun

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bMost Staphylococcus aureus isolates produce either a serotype 5 (CP5) or 8 (CP8) capsular polysaccharide, and the CP antigens are targets for vaccine development. Since CP5 and CP8 have similar trisaccharide repeating units, it is important to identify an epitope shared by both CP5 and CP8. To characterize cross-reactivity between CP5 and CP8, the immunogenicity of CP5 and CP8 conjugate vaccines in mice and rabbits was evaluated by serological assays. Immune sera were also tested for functional activity by in vitro opsonophagocytic-killing assays and a murine bacteremia model. Antibodies to the CP5-cross-reactive material 197 (CRM197) conjugate vaccine bound only to purified CP5. In contrast, antibodies to the CP8-CRM conjugate vaccine reacted with CP8 and (to a lesser extent) CP5. De-O-acetylation of CP5 increased its reactivity with CP8 antibodies. Moreover, CP8 antibodies bound to Pseudomonas aeruginosa O11 lipopolysaccharide, which has a trisaccharide repeating unit similar to that of the S. aureus CPs. CP8-CRM antibodies mediated in vitro opsonophagocytic killing of S. aureus expressing CP5 or CP8, whereas CP5-CRM antibodies were serotype specific. Passive immunization with antiserum to CP5-CRM or CP8-CRM protected mice against bacteremia induced by a serotype 5 S. aureus isolate, suggesting that CP8-CRM elicits antibodies cross-reactive to CP5. The identification of epitopes shared by CP5 and CP8 may inform the rational design of a vaccine to protect against infections caused by CP5-or CP8-producing strains of S. aureus.

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Development of a multicomponentStaphylococcus aureusvaccine designed to counter multiple bacterial virulence factors

Cited by 93 publications

References 112 publications

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

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

The role of vaccines in fighting antimicrobial resistance (AMR)

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

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