Antibody responses inKlebsiella pneumoniaebloodstream infection: a cohort study Article Swipe
Wontae Hwang
,
Paeton L. Wantuch
,
Biana Bernshtein
,
Julia A. Zhiteneva
,
Damien Slater
,
Kian Hutt Vater
,
Sushmita Sridhar
,
Elizabeth Oliver
,
David J. Roach
,
Sowmya R. Rao
,
Sarah E. Turbett
,
Cory J. Knoot
,
Christian M. Harding
,
Mohammed A. Amin
,
Alan S. Cross
,
Regina C. LaRocque
,
David A. Rosen
,
Jason B. Harris
·
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.05.01.591958
YOU?
·
· 2024
· Open Access
·
· DOI: https://doi.org/10.1101/2024.05.01.591958
Summary Background Klebsiella pneumonia (Kpn) is the fourth leading cause of infection-related deaths globally, yet little is known about human antibody responses to invasive Kpn. In this study, we sought to determine whether the O-specific polysaccharide (OPS) antigen, a vaccine candidate, is immunogenic in humans with Kpn bloodstream infection (BSI). We also sought to define the cross-reactivity of human antibody responses among structurally related Kpn OPS subtypes and to assess the impact of capsule production on OPS-targeted antibody binding and function. Methods We measured plasma antibody responses to OPS (and MrkA, a fimbrial protein) in a cohort of patients with Kpn BSI and compared these with controls, including a cohort of healthy individuals and a cohort of individuals with Enterococcus BSI. We performed flow cytometry to measure the impact of Kpn capsule production on whole cell antibody binding and complement deposition, utilizing patient isolates with variable levels of capsule production and isogenic capsule-deficient strains derived from these isolates. Findings We enrolled 69 patients with Kpn BSI. Common OPS serotypes accounted for 57/69 (83%) of infections. OPS was highly immunogenic in patients with Kpn BSI, and peak OPS-IgG antibody responses in patients were 10 to 30-fold higher than antibody levels detected in healthy controls, depending on the serotype. There was significant cross-reactivity among structurally similar OPS subtypes, including the O1v1/O1v2, O2v1/O2v2 and O3/O3b subtypes. Physiological amounts of capsule produced by both hyperencapsulated and non-hyperencapsulated Kpn significantly inhibited OPS-targeted antibody binding and function. Interpretation OPS was highly immunogenic in patients with Kpn BSI, supporting its potential as a candidate vaccine antigen. The strong cross-reactivity observed between similar OPS subtypes in humans with Kpn BSI suggests that it may not be necessary to include all subtypes in an OPS-based vaccine. However, these observations are tempered by the fact that capsule production, even in non-highly encapsulated strains, has the potential to interfere with OPS antibody binding. This may limit the effectiveness of vaccines that exclusively target OPS. Funding National Institute of Allergy and Infectious Diseases at the National Institutes of Health. Research in Context Evidence before this study Despite the potential of O-specific polysaccharide (OPS) as a vaccine antigen against Klebsiella pneumoniae (Kpn), the immunogenicity of OPS in humans remains largely unstudied, creating a significant knowledge gap with regard to vaccine development. A search of PubMed for publications up to March 18, 2024, using the terms “ Klebsiella pneumoniae ” and “O-specific polysaccharide” or “O-antigen” or “lipopolysaccharide” revealed no prior studies addressing OPS antibody responses in humans with Kpn bloodstream infections (BSI). One prior study 1 evaluated antibody response to a single lipopolysaccharide (which contains one subtype of OPS) in humans with invasive Kpn infection; however, in this study OPS typing of the infecting strains and target antigen were not described. Added value of this study Our investigation into OPS immunogenicity in a human cohort marks a significant advance. Analyzing plasma antibody responses in 69 patients with Kpn BSI, we found OPS to be broadly immunogenic across all the types and subtypes examined, and there was significant cross-reactivity among structurally related OPS antigens. We also demonstrated that Kpn capsule production inhibit OPS antibody binding and the activation of complement on the bacterial surface, even in classical Kpn strains expressing lower levels of capsule. Implications of all the available evidence While the immunogenicity and broad cross-reactivity of OPS in humans with Kpn BSI suggests it is a promising vaccine candidate, the obstruction of OPS antibody binding and engagement by physiologic levels of Kpn capsule underscores the potential limitations of an exclusively OPS-antigen based vaccine for Kpn. Our study provides insights for the strategic development of vaccines aimed at combating Kpn infections, an important antimicrobial resistant pathogen.
Related Topics
Concepts
Klebsiella pneumoniae
Bloodstream infection
Microbiology
Cohort
Antibody
Klebsiella
Medicine
Virology
Biology
Immunology
Internal medicine
Escherichia coli
Gene
Genetics
Metadata
- Type
- preprint
- Language
- en
- Landing Page
- https://doi.org/10.1101/2024.05.01.591958
- https://www.biorxiv.org/content/biorxiv/early/2024/05/03/2024.05.01.591958.full.pdf
- OA Status
- green
- Cited By
- 2
- References
- 34
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W4396640502
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
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https://openalex.org/W4396640502Canonical identifier for this work in OpenAlex
- DOI
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https://doi.org/10.1101/2024.05.01.591958Digital Object Identifier
- Title
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Antibody responses inKlebsiella pneumoniaebloodstream infection: a cohort studyWork title
- Type
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preprintOpenAlex work type
- Language
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enPrimary language
- Publication year
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2024Year of publication
- Publication date
-
2024-05-03Full publication date if available
- Authors
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Wontae Hwang, Paeton L. Wantuch, Biana Bernshtein, Julia A. Zhiteneva, Damien Slater, Kian Hutt Vater, Sushmita Sridhar, Elizabeth Oliver, David J. Roach, Sowmya R. Rao, Sarah E. Turbett, Cory J. Knoot, Christian M. Harding, Mohammed A. Amin, Alan S. Cross, Regina C. LaRocque, David A. Rosen, Jason B. HarrisList of authors in order
- Landing page
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https://doi.org/10.1101/2024.05.01.591958Publisher landing page
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https://www.biorxiv.org/content/biorxiv/early/2024/05/03/2024.05.01.591958.full.pdfDirect link to full text PDF
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YesWhether a free full text is available
- OA status
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greenOpen access status per OpenAlex
- OA URL
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https://www.biorxiv.org/content/biorxiv/early/2024/05/03/2024.05.01.591958.full.pdfDirect OA link when available
- Concepts
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Klebsiella pneumoniae, Bloodstream infection, Microbiology, Cohort, Antibody, Klebsiella, Medicine, Virology, Biology, Immunology, Internal medicine, Escherichia coli, Gene, GeneticsTop concepts (fields/topics) attached by OpenAlex
- Cited by
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2Total citation count in OpenAlex
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2025: 2Per-year citation counts (last 5 years)
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34Number of works referenced by this work
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10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.OPS-IgG | 186 |
| abstract_inverted_index.Summary | 0 |
| abstract_inverted_index.against | 355 |
| abstract_inverted_index.amounts | 224 |
| abstract_inverted_index.antigen | 354, 453 |
| abstract_inverted_index.between | 263 |
| abstract_inverted_index.binding | 78, 137, 238, 519, 570 |
| abstract_inverted_index.broadly | 490 |
| abstract_inverted_index.capsule | 73, 131, 148, 226, 296, 514, 578 |
| abstract_inverted_index.derived | 154 |
| abstract_inverted_index.healthy | 111, 201 |
| abstract_inverted_index.include | 280 |
| abstract_inverted_index.inhibit | 516 |
| abstract_inverted_index.largely | 366 |
| abstract_inverted_index.leading | 8 |
| abstract_inverted_index.measure | 126 |
| abstract_inverted_index.patient | 142 |
| abstract_inverted_index.related | 63, 506 |
| abstract_inverted_index.remains | 365 |
| abstract_inverted_index.similar | 213, 264 |
| abstract_inverted_index.strains | 153, 450, 533 |
| abstract_inverted_index.studies | 406 |
| abstract_inverted_index.subtype | 432 |
| abstract_inverted_index.vaccine | 39, 257, 353, 376, 563, 588 |
| abstract_inverted_index.whether | 32 |
| abstract_inverted_index.Diseases | 330 |
| abstract_inverted_index.Evidence | 340 |
| abstract_inverted_index.Findings | 158 |
| abstract_inverted_index.However, | 287 |
| abstract_inverted_index.National | 324, 333 |
| abstract_inverted_index.Research | 337 |
| abstract_inverted_index.advance. | 474 |
| abstract_inverted_index.antibody | 20, 59, 77, 85, 136, 187, 197, 237, 310, 409, 423, 477, 518, 569 |
| abstract_inverted_index.antigen, | 37 |
| abstract_inverted_index.antigen. | 258 |
| abstract_inverted_index.binding. | 311 |
| abstract_inverted_index.capsule. | 538 |
| abstract_inverted_index.compared | 103 |
| abstract_inverted_index.contains | 430 |
| abstract_inverted_index.creating | 368 |
| abstract_inverted_index.detected | 199 |
| abstract_inverted_index.enrolled | 160 |
| abstract_inverted_index.evidence | 544 |
| abstract_inverted_index.fimbrial | 92 |
| abstract_inverted_index.however, | 441 |
| abstract_inverted_index.insights | 594 |
| abstract_inverted_index.invasive | 23, 438 |
| abstract_inverted_index.isogenic | 151 |
| abstract_inverted_index.isolates | 143 |
| abstract_inverted_index.measured | 83 |
| abstract_inverted_index.observed | 262 |
| abstract_inverted_index.patients | 98, 162, 180, 190, 247, 481 |
| abstract_inverted_index.produced | 227 |
| abstract_inverted_index.protein) | 93 |
| abstract_inverted_index.provides | 593 |
| abstract_inverted_index.response | 424 |
| abstract_inverted_index.revealed | 403 |
| abstract_inverted_index.strains, | 302 |
| abstract_inverted_index.subtypes | 66, 266, 282, 497 |
| abstract_inverted_index.suggests | 272, 558 |
| abstract_inverted_index.surface, | 528 |
| abstract_inverted_index.tempered | 291 |
| abstract_inverted_index.vaccine. | 286 |
| abstract_inverted_index.vaccines | 318, 600 |
| abstract_inverted_index.variable | 145 |
| abstract_inverted_index.Analyzing | 475 |
| abstract_inverted_index.Institute | 325 |
| abstract_inverted_index.O2v1/O2v2 | 219 |
| abstract_inverted_index.OPS-based | 285 |
| abstract_inverted_index.accounted | 169 |
| abstract_inverted_index.antigens. | 508 |
| abstract_inverted_index.available | 543 |
| abstract_inverted_index.bacterial | 527 |
| abstract_inverted_index.candidate | 256 |
| abstract_inverted_index.classical | 531 |
| abstract_inverted_index.combating | 603 |
| abstract_inverted_index.controls, | 106, 202 |
| abstract_inverted_index.cytometry | 124 |
| abstract_inverted_index.depending | 203 |
| abstract_inverted_index.determine | 31 |
| abstract_inverted_index.evaluated | 422 |
| abstract_inverted_index.examined, | 498 |
| abstract_inverted_index.function. | 80, 240 |
| abstract_inverted_index.globally, | 13 |
| abstract_inverted_index.important | 607 |
| abstract_inverted_index.including | 107, 216 |
| abstract_inverted_index.infecting | 449 |
| abstract_inverted_index.infection | 48 |
| abstract_inverted_index.inhibited | 235 |
| abstract_inverted_index.interfere | 307 |
| abstract_inverted_index.isolates. | 157 |
| abstract_inverted_index.knowledge | 371 |
| abstract_inverted_index.necessary | 278 |
| abstract_inverted_index.pathogen. | 610 |
| abstract_inverted_index.performed | 122 |
| abstract_inverted_index.pneumonia | 3 |
| abstract_inverted_index.potential | 253, 305, 346, 581 |
| abstract_inverted_index.promising | 562 |
| abstract_inverted_index.resistant | 609 |
| abstract_inverted_index.responses | 21, 60, 86, 188, 410, 478 |
| abstract_inverted_index.serotype. | 206 |
| abstract_inverted_index.serotypes | 168 |
| abstract_inverted_index.strategic | 597 |
| abstract_inverted_index.subtypes, | 215 |
| abstract_inverted_index.subtypes. | 222 |
| abstract_inverted_index.utilizing | 141 |
| abstract_inverted_index.Background | 1 |
| abstract_inverted_index.Infectious | 329 |
| abstract_inverted_index.Institutes | 334 |
| abstract_inverted_index.Klebsiella | 2, 356, 393 |
| abstract_inverted_index.O-specific | 34, 348 |
| abstract_inverted_index.O1v1/O1v2, | 218 |
| abstract_inverted_index.activation | 522 |
| abstract_inverted_index.addressing | 407 |
| abstract_inverted_index.candidate, | 40, 564 |
| abstract_inverted_index.complement | 139, 524 |
| abstract_inverted_index.described. | 456 |
| abstract_inverted_index.engagement | 572 |
| abstract_inverted_index.expressing | 534 |
| abstract_inverted_index.infection; | 440 |
| abstract_inverted_index.infections | 416 |
| abstract_inverted_index.non-highly | 300 |
| abstract_inverted_index.pneumoniae | 357, 394 |
| abstract_inverted_index.production | 74, 132, 149, 515 |
| abstract_inverted_index.supporting | 251 |
| abstract_inverted_index.unstudied, | 367 |
| abstract_inverted_index.OPS-antigen | 586 |
| abstract_inverted_index.bloodstream | 47, 415 |
| abstract_inverted_index.deposition, | 140 |
| abstract_inverted_index.development | 598 |
| abstract_inverted_index.exclusively | 320, 585 |
| abstract_inverted_index.immunogenic | 42, 178, 245, 491 |
| abstract_inverted_index.individuals | 112, 117 |
| abstract_inverted_index.infections, | 605 |
| abstract_inverted_index.infections. | 174 |
| abstract_inverted_index.limitations | 582 |
| abstract_inverted_index.obstruction | 566 |
| abstract_inverted_index.physiologic | 574 |
| abstract_inverted_index.production, | 297 |
| abstract_inverted_index.significant | 209, 370, 473, 502 |
| abstract_inverted_index.underscores | 579 |
| abstract_inverted_index.Enterococcus | 119 |
| abstract_inverted_index.Implications | 539 |
| abstract_inverted_index.OPS-targeted | 76, 236 |
| abstract_inverted_index.demonstrated | 511 |
| abstract_inverted_index.development. | 377 |
| abstract_inverted_index.encapsulated | 301 |
| abstract_inverted_index.observations | 289 |
| abstract_inverted_index.publications | 383 |
| abstract_inverted_index.structurally | 62, 212, 505 |
| abstract_inverted_index.Physiological | 223 |
| abstract_inverted_index.antimicrobial | 608 |
| abstract_inverted_index.effectiveness | 316 |
| abstract_inverted_index.investigation | 463 |
| abstract_inverted_index.significantly | 234 |
| abstract_inverted_index.“O-specific | 397 |
| abstract_inverted_index.Interpretation | 241 |
| abstract_inverted_index.immunogenicity | 360, 466, 547 |
| abstract_inverted_index.polysaccharide | 35, 349 |
| abstract_inverted_index.“O-antigen” | 400 |
| abstract_inverted_index.cross-reactivity | 56, 210, 261, 503, 550 |
| abstract_inverted_index.capsule-deficient | 152 |
| abstract_inverted_index.hyperencapsulated | 230 |
| abstract_inverted_index.infection-related | 11 |
| abstract_inverted_index.polysaccharide” | 398 |
| abstract_inverted_index.lipopolysaccharide | 428 |
| abstract_inverted_index.non-hyperencapsulated | 232 |
| abstract_inverted_index.“lipopolysaccharide” | 402 |
| cited_by_percentile_year.max | 97 |
| cited_by_percentile_year.min | 95 |
| corresponding_author_ids | https://openalex.org/A5084859141 |
| countries_distinct_count | 1 |
| institutions_distinct_count | 18 |
| corresponding_institution_ids | https://openalex.org/I4210087915 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.8399999737739563 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.56607191 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | False |