Challenges for the evaluation of<i>Staphylococcus aureus</i>protein based vaccines: Monitoring antigenic diversity

Murphy, Ellen; Lin, Shuo; Nuñez, Lorna; Andrew, Lubomira; Fink, Pamela S.; Dilts, Deborah A.; Hoiseth, Susan K.; Jansen, Kathrin U.; Anderson, Annaliesa S.

doi:10.4161/hv.7.0.14562

Cited by 43 publications

(45 citation statements)

References 44 publications

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“…1), with only L508 appearing to be internal. These results agree with those of Murphy et al, where structural mapping of 39 ClfA variants indicated that the majority of diverse sites were surface exposed (15). Because the crystal structure elaborates the N2 and N3 subdomains of the ClfA fibrinogen binding domain but lacks the N1 subdomain (amino acids 40 to 220), we could not examine the locations of amino acid variations in the N1 subdomain.…”

supporting

confidence: 76%

“…Up to 14% of the primary amino acid sequence of ClfA varies between sequenced isolates (15,16), which could alter epitope composition and change ClfA antigenicity and immunogenicity between S. aureus strains. The crystal structure of the N2 and N3 subdomains (amino acids 221 to 559) of the fibrinogen-binding domain of ClfA (17,18) was used by Murphy and colleagues (15) to map the sequence diversity in the N2 and N3 subdomains of 39 ClfA strain variants.…”

mentioning

confidence: 99%

“…The crystal structure of the N2 and N3 subdomains (amino acids 221 to 559) of the fibrinogen-binding domain of ClfA (17,18) was used by Murphy and colleagues (15) to map the sequence diversity in the N2 and N3 subdomains of 39 ClfA strain variants. They found that the large majority of the variant regions were surface exposed.…”

mentioning

confidence: 99%

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Immunogenicity Analysis of Staphylococcus aureus Clumping Factor A Genetic Variants

Brady

Mocca

Burns

2013

Clin Vaccine Immunol

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The staphylococcal adhesin clumping factor A (ClfA) has a variant amino acid sequence, generating the potential for alterations in epitope structure and immunogenicity of this vaccine candidate. We demonstrated for two recombinant ClfA 40 -531 (a slightly truncated version of the fibrinogen-binding domain of ClfA containing amino acids 40 to 531) genetic variants that strain-specific epitopes are immunodominant. This work indicates that immune responses elicited by ClfA may, at least in part, be dependent on the strain of origin of the ClfA.

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supporting

confidence: 76%

mentioning

confidence: 99%

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Immunogenicity Analysis of Staphylococcus aureus Clumping Factor A Genetic Variants

Brady

Mocca

Burns

2013

Clin Vaccine Immunol

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“…These results suggest that Fg or fibrin binding by these proteins facilitates early dissemination of the pathogen in the blood. Compared with ClfA, the relatively high frequency of ClfB-encoding pseudogenes identified among unrelated S. aureus lineages limits this protein's utility as a vaccine antigen (29).…”

Section: Discussionmentioning

confidence: 99%

“…Cells were pelleted at 3,700 ϫ g for 15 min, resuspended in 20% glycerol Dulbecco's phosphate-buffered saline (DPBS; Invitrogen), aliquoted into 2-ml cryotubes (Corning), and stored at Ϫ70°C. Invasive clinical strains from the previously described Diversity collection and the Centers for Disease Control and Prevention MRSA collection were used, which were selected to maximize the diversity of S. aureus sequence types and to represent MRSA disease isolates circulating in the United States during 2005 (29). A previously described clfA::Tn917 mutant of strain PFESA0237 (Newman) was used as a negative control in the Fg binding inhibition assay (26).…”

Section: Methodsmentioning

confidence: 99%

A Recombinant Clumping Factor A-Containing Vaccine Induces Functional Antibodies to Staphylococcus aureus That Are Not Observed after Natural Exposure

Hawkins

Kodali

Matsuka

et al. 2012

Clin Vaccine Immunol

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Staphylococcus aureus is a Gram-positive pathogen that causes devastating disease and whose pathogenesis is dependent on interactions with host cell factors. Staphylococcal clumping factor A (ClfA) is a highly conserved fibrinogen (Fg)-binding protein and virulence factor that contributes to host tissue adhesion and initiation of infection. ClfA is being investigated as a possible component of a staphylococcal vaccine. We report the development of an Fg-binding assay that is specific for ClfA-mediated binding. Using the assay, we show that despite the presence of anti-ClfA antibodies, human sera from unvaccinated subjects are unable to prevent the binding of S. aureus to an Fg-coated surface. In contrast, antibodies elicited by a recombinant ClfA-containing vaccine were capable of blocking the ClfA-dependent binding of a diverse and clinically relevant collection of staphylococcal strains to Fg. These functional antibodies were also able to displace S. aureus already bound to Fg, suggesting that the ligand-binding activity of ClfA can be effectively neutralized through vaccination.

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Cell Surface Antigen – Manganese‐Binding ProteinMntCfromStaphylococcus Aureus

Gribenko

Liberator

Anderson

et al. 2015

Encyclopedia of Inorganic and Bioinorganic Chemistry

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MntC is the metal‐binding protein component of the Mn 2+ ‐specific MntABC transporter from the human pathogen Staphylococcus aureus . MntC orthologs are found in all Gram positive bacteria, the protein is attached to the bacterial membrane through a lipid anchor and captures Mn 2+ ion from the environment with high affinity for subsequent transport across the transmembrane channel of the transporter. MntC consists of two homologous domains connected through a long ‘backbone’ α‐helix, with a metal‐binding site located at the interface of those domains. The long α‐helix restricts domain mobility, making it harder for the bound ligand (Mn 2+ ) to escape the binding site and, correspondingly, increasing the metal‐binding affinity of the protein. The physiological role of Mn 2+ binding by MntC in bacterial resistance to oxidative stress is well documented. MntC is also able to bind other divalent metals (Zn 2+ , Co 2+ , Ni 2+ , and Cd 2+ ), although it is not yet clear whether this has any biological relevance. Binding of divalent metals to the protein can be reversible and irreversible, depending on the nature of the metal. X‐ray data provide a plausible explanation for the two binding modes: the X‐ray structure contains two molecules in the asymmetric unit, with the metal‐binding site being solvent accessible in one molecule and inaccessible in the other. Serum antibodies to MntC (or orthologs of MntC) are detected following exposure to staphylococcal species in animal models as well as in human sera from patients with S. aureus infections. Immunization with a recombinant expressed MntC protein antigen induces protective immunity against S. aureus in preclinical models of infection. As such, MntC is a promising vaccine candidate and is currently being tested in human clinical trials as a component of a multiantigen vaccine for the prevention of staphylococcal infections.

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Challenges for the evaluation ofStaphylococcus aureusprotein based vaccines: Monitoring antigenic diversity

Cited by 43 publications

References 44 publications

Immunogenicity Analysis of Staphylococcus aureus Clumping Factor A Genetic Variants

Immunogenicity Analysis of Staphylococcus aureus Clumping Factor A Genetic Variants

A Recombinant Clumping Factor A-Containing Vaccine Induces Functional Antibodies to Staphylococcus aureus That Are Not Observed after Natural Exposure

Cell Surface Antigen – Manganese‐Binding ProteinMntCfromStaphylococcus Aureus

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