An Immunodominant Epitope-Specific Monoclonal Antibody Cocktail Improves Survival in a Mouse Model of Staphylococcus aureus Bacteremia

Abstract To date, no vaccine or monoclonal antibody (mAb) against Staphylococcus aureus has been approved for use in humans. Our laboratory has developed a 5-antigen S. aureus vaccine (rFSAV), which is now under efficacy evaluation in a phase 2 clinical trial. In the current study, using overlapping peptides and antiserum from rFSAV-immunized volunteers, we identified 7 B-cell immunodominant epitopes on 4 antigens in rFSAV, including 5 novel epitopes (Hla48-65, IsdB402-419, IsdB432-449, SEB78-95, and MntC7-24). Ten immunodominant epitope mAbs were generated against these epitopes, and all of them exhibited partial protection in a mouse sepsis model. Four robust mAbs were used together as an mAb cocktail to prevent methicillin-resistant S. aureus strain 252 infection. The results showed that the mAb cocktail was efficient in combating S. aureus infection and that its protective efficacy correlated with a reduced bacterial burden and decreased infection pathology, which demonstrates that the mAb cocktail is a promising S. aureus vaccine candidate.

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A human monoclonal antibody targeting the conserved staphylococcal antigen IsaA protects mice against Staphylococcus aureus bacteremia

International Journal of Medical Microbiology ◽

10.1016/j.ijmm.2014.11.002 ◽

2015 ◽

Vol 305 (1) ◽

pp. 55-64 ◽

Cited By ~ 29

Author(s):

Sanne van den Berg ◽

Hendrik P.J. Bonarius ◽

Kok P.M. van Kessel ◽

Goffe S. Elsinga ◽

Neeltje Kooi ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Monoclonal Antibody ◽

Human Monoclonal Antibody ◽

Staphylococcus Aureus Bacteremia ◽

Antibody Targeting

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Immunodominance of Epitopes and Protective Efficacy of HI Antigen Are Differentially Altered Using Different Adjuvants in a Mouse Model of Staphylococcus aureus Bacteremia

Frontiers in Immunology ◽

10.3389/fimmu.2021.684823 ◽

2021 ◽

Vol 12 ◽

Author(s):

Zhifu Chen ◽

Qiang Gou ◽

Qingshan Xiong ◽

Lianli Duan ◽

Yue Yuan ◽

...

Keyword(s):

B Cell ◽

Protective Immunity ◽

Vaccine Development ◽

Protective Efficacy ◽

Humoral Immune ◽

Staphylococcus Aureus Bacteremia ◽

Phase Ii Clinical Trials ◽

Ifn Γ ◽

The Difference ◽

Immunodominant Epitopes

HI, a fusion protein that consists of the alpha-toxin (Hla) and the N2 domain of iron surface determinant B (IsdB), is one of the antigens in the previously reported S. aureus vaccine rFSAV and has already entered phase II clinical trials. Previous studies revealed that HI is highly immunogenic in both mice and healthy volunteers, and the humoral immune response plays key roles in HI-mediated protection. In this study, we further investigated the protective efficacy of immunization with HI plus four different adjuvants in a mouse bacteremia model. Results showed that HI-mediated protection was altered in response to different adjuvants. Using antisera from immunized mice, we identified seven B-cell immunodominant epitopes on Hla and IsdB, including 6 novel epitopes (Hla1-18, Hla84-101, Hla186-203, IsdB342-359, IsdB366-383, and IsdB384-401). The immunodominance of B-cell epitopes, total IgG titers and the levels of IFN-γ and IL-17A from mice immunized with HI plus different adjuvants were different from each other, which may explain the difference in protective immunity observed in each immunized group. Thus, our results indicate that adjuvants largely affected the immunodominance of epitopes and the protective efficacy of HI, which may guide further adjuvant screening for vaccine development and optimization.

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A natural human monoclonal antibody targeting Staphylococcus Protein A protects against Staphylococcus aureus bacteremia

PLoS ONE ◽

10.1371/journal.pone.0190537 ◽

2018 ◽

Vol 13 (1) ◽

pp. e0190537 ◽

Cited By ~ 18

Author(s):

Avanish K. Varshney ◽

Galina A. Kuzmicheva ◽

Jian Lin ◽

Kevin M. Sunley ◽

Rodney A. Bowling ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Monoclonal Antibody ◽

Human Monoclonal Antibody ◽

Protein A ◽

Staphylococcus Aureus Bacteremia ◽

Antibody Targeting

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Isotype Switching Increases Efficacy of Antibody Protection against Staphylococcal Enterotoxin B-Induced Lethal Shock and Staphylococcus aureus Sepsis in Mice

mBio ◽

10.1128/mbio.01007-14 ◽

2014 ◽

Vol 5 (3) ◽

Cited By ~ 27

Author(s):

Avanish K. Varshney ◽

Xiaobo Wang ◽

Jorge L. Aguilar ◽

Matthew D. Scharff ◽

Bettina C. Fries

Keyword(s):

Staphylococcus Aureus ◽

Monoclonal Antibody ◽

Protective Efficacy ◽

Staphylococcal Enterotoxin ◽

Staphylococcal Enterotoxin B ◽

Antigen Specificity ◽

Content Type ◽

Lethal Shock ◽

Enterotoxin B

ABSTRACTStaphylococcal enterotoxin B (SEB) is a potent toxin that is produced byStaphylococcus aureusstrains and is classified as a category B select agent. We have previously shown that monoclonal antibody (MAb) 20B1, a murine anti-SEB IgG1, successfully treats SEB-induced lethal shock (SEBILS) and bacteremia that is caused by SEB-producingS. aureus. In this study, we have generated two isotype switch variants of the original IgG1 MAb 20B1, an IgG2a and IgG2b, both bearing the same variable region sequence, and compared their neutralizing and protective activity inin vitroandin vivoassays, respectively. All 3 isotypes demonstrated comparable affinity to SEB and comparable 50% inhibitory concentrations (IC50s) in T cell proliferation assays.In vivo, however, the IgG2a isotype variant of 20B1 exhibited significantly greater protection than IgG1 or IgG2b in murine SEB intoxication andS. aureussepsis models. Protection was associated with downmodulation of inflammatory host response. Our data demonstrate that changing the isotype of already protective MAbs, without affecting their antigen specificity or sensitivity, can result in an enhancement of their protective ability. Isotype selection, therefore, should be carefully considered in the development of toxin-neutralizing MAbs and the design of antibody therapeutics.IMPORTANCEThe purpose of this study was to enhance the protective efficacy of an existing, protective monoclonal antibody against staphylococcal enterotoxin B. Using twoin vivomouse models, our study demonstrates that the protective efficacy of a monoclonal antibody may be improved by inducing an isotype switch at the Fc region of an antibody, without altering the antigen specificity or sensitivity of the antibody. The development of therapeutic MAbs with higher efficacy may allow for the achievement of equal therapeutic benefit with a lower dosage. In turn, the use of lower doses may reduce the cost of these therapies, while reducing the potential for adverse side effects.

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Protective Efficacy of Monoclonal Antibodies Neutralizing Alpha-Hemolysin and Bicomponent Leukocidins in a Rabbit Model of Staphylococcus aureus Necrotizing Pneumonia

Antimicrobial Agents and Chemotherapy ◽

10.1128/aac.02220-19 ◽

2019 ◽

Vol 64 (3) ◽

Cited By ~ 1

Author(s):

Trang T. T. Vu ◽

Nhu T. Q. Nguyen ◽

Vuvi G. Tran ◽

Emmanuelle Gras ◽

Yanjie Mao ◽

...

Keyword(s):

Staphylococcus Aureus ◽

Protective Efficacy ◽

Rabbit Model ◽

Passive Immunization ◽

Necrotizing Pneumonia ◽

Partial Protection ◽

Content Type ◽

Alpha Hemolysin ◽

Wide Range ◽

Panton Valentine Leukocidin

ABSTRACT Staphylococcus aureus is a major human pathogen that causes a wide range of infections by producing an arsenal of cytotoxins. We found that passive immunization with either a monoclonal antibody (MAb) neutralizing alpha-hemolysin or a broadly cross-reactive MAb neutralizing Panton-Valentine leukocidin, leukocidin ED, and gamma-hemolysins HlgAB and HlgCB conferred only partial protection, whereas the combination of those two MAbs conferred significant protection in a rabbit model of necrotizing pneumonia caused by the USA300 methicillin-resistant S. aureus epidemic clone.

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