Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot
Staphylococcus aureus osteomyelitis remains a very challenging condition; recent clinical studies have shown infection control rates following surgery/antibiotics to be ~60%. Additionally, prior efforts to produce an effective S. aureus vaccine have failed, in part due to lack of knowledge of protec...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2022-07-01
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| Series: | Frontiers in Cellular and Infection Microbiology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fcimb.2022.876898/full |
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| author | Shardulendra Prasad Sherchand Rajan P. Adhikari Gowrishankar Muthukrishnan Tulasikumari Kanipakala John R. Owen Chao Xie M. Javad Aman Richard A. Proctor Edward M. Schwarz Stephen L. Kates |
| author_facet | Shardulendra Prasad Sherchand Rajan P. Adhikari Gowrishankar Muthukrishnan Tulasikumari Kanipakala John R. Owen Chao Xie M. Javad Aman Richard A. Proctor Edward M. Schwarz Stephen L. Kates |
| author_sort | Shardulendra Prasad Sherchand |
| collection | DOAJ |
| description | Staphylococcus aureus osteomyelitis remains a very challenging condition; recent clinical studies have shown infection control rates following surgery/antibiotics to be ~60%. Additionally, prior efforts to produce an effective S. aureus vaccine have failed, in part due to lack of knowledge of protective immunity. Previously, we demonstrated that anti-glucosaminidase (Gmd) antibodies are protective in animal models but found that only 6.7% of culture-confirmed S. aureus osteomyelitis patients in the AO Clinical Priority Program (AO-CPP) Registry had basal serum levels (>10 ng/ml) of anti-Gmd at the time of surgery (baseline). We identified a small subset of patients with high levels of anti-Gmd antibodies and adverse outcomes following surgery, not explained by Ig class switching to non-functional isotypes. Here, we aimed to test the hypothesis that clinical cure following surgery is associated with anti-Gmd neutralizing antibodies in serum. Therefore, we first optimized an in vitro assay that quantifies recombinant Gmd lysis of the M. luteus cell wall and used it to demonstrate the 50% neutralizing concentration (NC50) of a humanized anti-Gmd mAb (TPH-101) to be ~15.6 μg/ml. We also demonstrated that human serum deficient in anti-Gmd antibodies can be complemented by TPH-101 to achieve the same dose-dependent Gmd neutralizing activity as purified TPH-101. Finally, we assessed the anti-Gmd physical titer and neutralizing activity in sera from 11 patients in the AO-CPP Registry, who were characterized into four groups post-hoc. Group 1 patients (n=3) had high anti-Gmd physical and neutralizing titers at baseline that decreased with clinical cure of the infection over time. Group 2 patients (n=3) had undetectable anti-Gmd antibodies throughout the study and adverse outcomes. Group 3 (n=3) had high titers +/− neutralizing anti-Gmd at baseline with adverse outcomes. Group 4 (n=2) had low titers of non-neutralizing anti-Gmd at baseline with delayed high titers and adverse outcomes. Collectively, these findings demonstrate that both neutralizing and non-neutralizing anti-Gmd antibodies exist in S. aureus osteomyelitis patients and that screening for these antibodies could have a value for identifying patients in need of passive immunization prior to surgery. Future prospective studies to test the prognostic value of anti-Gmd antibodies to assess the potential of passive immunization with TPH-101 are warranted. |
| first_indexed | 2024-12-12T01:42:17Z |
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| id | doaj.art-86befead12a24ee4bec39e7017d85dbf |
| institution | Directory Open Access Journal |
| issn | 2235-2988 |
| language | English |
| last_indexed | 2024-12-12T01:42:17Z |
| publishDate | 2022-07-01 |
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| series | Frontiers in Cellular and Infection Microbiology |
| spelling | doaj.art-86befead12a24ee4bec39e7017d85dbf2022-12-22T00:42:41ZengFrontiers Media S.A.Frontiers in Cellular and Infection Microbiology2235-29882022-07-011210.3389/fcimb.2022.876898876898Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical PilotShardulendra Prasad Sherchand0Rajan P. Adhikari1Gowrishankar Muthukrishnan2Tulasikumari Kanipakala3John R. Owen4Chao Xie5M. Javad Aman6Richard A. Proctor7Edward M. Schwarz8Stephen L. Kates9Integrated BioTherapeutics, Inc., Rockville, MD, United StatesIntegrated BioTherapeutics, Inc., Rockville, MD, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesIntegrated BioTherapeutics, Inc., Rockville, MD, United StatesDepartment of Orthopaedic Surgery, Virginia Commonwealth University, Richmond, VA, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesIntegrated BioTherapeutics, Inc., Rockville, MD, United StatesDepartments of Medical Microbiology/Immunology and Medicine, University of Wisconsin School of Medicine and Public Health, Madison, WI, United StatesCenter for Musculoskeletal Research, University of Rochester Medical Center, Rochester, NY, United StatesDepartment of Orthopaedic Surgery, Virginia Commonwealth University, Richmond, VA, United StatesStaphylococcus aureus osteomyelitis remains a very challenging condition; recent clinical studies have shown infection control rates following surgery/antibiotics to be ~60%. Additionally, prior efforts to produce an effective S. aureus vaccine have failed, in part due to lack of knowledge of protective immunity. Previously, we demonstrated that anti-glucosaminidase (Gmd) antibodies are protective in animal models but found that only 6.7% of culture-confirmed S. aureus osteomyelitis patients in the AO Clinical Priority Program (AO-CPP) Registry had basal serum levels (>10 ng/ml) of anti-Gmd at the time of surgery (baseline). We identified a small subset of patients with high levels of anti-Gmd antibodies and adverse outcomes following surgery, not explained by Ig class switching to non-functional isotypes. Here, we aimed to test the hypothesis that clinical cure following surgery is associated with anti-Gmd neutralizing antibodies in serum. Therefore, we first optimized an in vitro assay that quantifies recombinant Gmd lysis of the M. luteus cell wall and used it to demonstrate the 50% neutralizing concentration (NC50) of a humanized anti-Gmd mAb (TPH-101) to be ~15.6 μg/ml. We also demonstrated that human serum deficient in anti-Gmd antibodies can be complemented by TPH-101 to achieve the same dose-dependent Gmd neutralizing activity as purified TPH-101. Finally, we assessed the anti-Gmd physical titer and neutralizing activity in sera from 11 patients in the AO-CPP Registry, who were characterized into four groups post-hoc. Group 1 patients (n=3) had high anti-Gmd physical and neutralizing titers at baseline that decreased with clinical cure of the infection over time. Group 2 patients (n=3) had undetectable anti-Gmd antibodies throughout the study and adverse outcomes. Group 3 (n=3) had high titers +/− neutralizing anti-Gmd at baseline with adverse outcomes. Group 4 (n=2) had low titers of non-neutralizing anti-Gmd at baseline with delayed high titers and adverse outcomes. Collectively, these findings demonstrate that both neutralizing and non-neutralizing anti-Gmd antibodies exist in S. aureus osteomyelitis patients and that screening for these antibodies could have a value for identifying patients in need of passive immunization prior to surgery. Future prospective studies to test the prognostic value of anti-Gmd antibodies to assess the potential of passive immunization with TPH-101 are warranted.https://www.frontiersin.org/articles/10.3389/fcimb.2022.876898/fullStaphylococcus aureusosteomyelitisglucosaminidaseantibodiesimmunoassay |
| spellingShingle | Shardulendra Prasad Sherchand Rajan P. Adhikari Gowrishankar Muthukrishnan Tulasikumari Kanipakala John R. Owen Chao Xie M. Javad Aman Richard A. Proctor Edward M. Schwarz Stephen L. Kates Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot Frontiers in Cellular and Infection Microbiology Staphylococcus aureus osteomyelitis glucosaminidase antibodies immunoassay |
| title | Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot |
| title_full | Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot |
| title_fullStr | Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot |
| title_full_unstemmed | Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot |
| title_short | Evidence of Neutralizing and Non-Neutralizing Anti-Glucosaminidase Antibodies in Patients With S. Aureus Osteomyelitis and Their Association With Clinical Outcome Following Surgery in a Clinical Pilot |
| title_sort | evidence of neutralizing and non neutralizing anti glucosaminidase antibodies in patients with s aureus osteomyelitis and their association with clinical outcome following surgery in a clinical pilot |
| topic | Staphylococcus aureus osteomyelitis glucosaminidase antibodies immunoassay |
| url | https://www.frontiersin.org/articles/10.3389/fcimb.2022.876898/full |
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