PMID- 31207937
OWN - NLM
STAT- MEDLINE
DCOM- 20200316
LR  - 20210502
IS  - 2072-6651 (Electronic)
IS  - 2072-6651 (Linking)
VI  - 11
IP  - 6
DP  - 2019 Jun 14
TI  - Rational Design of Toxoid Vaccine Candidates for Staphylococcus aureus Leukocidin 
      AB (LukAB).
LID - 10.3390/toxins11060339 [doi]
LID - 339
AB  - Staphylococcus aureus (SA) infections cause high mortality and morbidity in 
      humans. Being central to its pathogenesis, S. aureus thwarts the host defense by 
      secreting a myriad of virulence factors, including bicomponent, pore-forming 
      leukotoxins. While all vaccine development efforts that aimed at achieving 
      opsonophagocytic killing have failed, targeting virulence by toxoid vaccines 
      represents a novel approach to preventing mortality and morbidity that are caused 
      by SA. The recently discovered leukotoxin LukAB kills human phagocytes and 
      monocytes and it is present in all known S. aureus clinical isolates. While using 
      a structure-guided approach, we generated a library of mutations that targeted 
      functional domains within the LukAB heterodimer to identify attenuated toxoids as 
      potential vaccine candidates. The mutants were evaluated based on expression, 
      solubility, yield, biophysical properties, cytotoxicity, and immunogenicity, and 
      several fully attenuated LukAB toxoids that were capable of eliciting high 
      neutralizing antibody titers were identified. Rabbit polyclonal antibodies 
      against the lead toxoid candidate provided potent neutralization of LukAB. While 
      the neutralization of LukAB alone was not sufficient to fully suppress 
      leukotoxicity in supernatants of S. aureus USA300 isolates, a combination of 
      antibodies against LukAB, alpha-toxin, and Panton-Valentine leukocidin completely 
      neutralized the cytotoxicity of these strains. These data strongly support the 
      inclusion of LukAB toxoids in a multivalent toxoid vaccine for the prevention of 
      S. aureus disease.
FAU - Kailasan, Shweta
AU  - Kailasan S
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      skailasan@IntegratedBiotherapeutics.com.
FAU - Kort, Thomas
AU  - Kort T
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      Tom@IntegratedBiotherapeutics.com.
FAU - Mukherjee, Ipsita
AU  - Mukherjee I
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      imukher@integratedbio.onmicrosoft.com.
FAU - Liao, Grant C
AU  - Liao GC
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      gliao@IntegratedBiotherapeutics.com.
FAU - Kanipakala, Tulasikumari
AU  - Kanipakala T
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      Tula@IntegratedBiotherapeutics.com.
FAU - Williston, Nils
AU  - Williston N
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      nils.williston@gmail.com.
FAU - Ganjbaksh, Nader
AU  - Ganjbaksh N
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      nader@IntegratedBiotherapeutics.com.
FAU - Venkatasubramaniam, Arundhathi
AU  - Venkatasubramaniam A
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      arundathi@IntegratedBiotherapeutics.com.
FAU - Holtsberg, Frederick W
AU  - Holtsberg FW
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      rick@IntegratedBiotherapeutics.com.
FAU - Karauzum, Hatice
AU  - Karauzum H
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      hkarauzum@IntegratedBiotherapeutics.com.
FAU - Adhikari, Rajan P
AU  - Adhikari RP
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      rajan@integratedbiotherapeutics.com.
FAU - Aman, M Javad
AU  - Aman MJ
AD  - Integrated Biotherapeutics Inc., Rockville, MD 20850, USA. 
      javad@integratedbiotherapeutics.com.
LA  - eng
GR  - R01 AI111205/AI/NIAID NIH HHS/United States
GR  - R01-AI111205/National Institute of Allergy and Infectious Diseases/International
PT  - Journal Article
PT  - Research Support, N.I.H., Extramural
PT  - Research Support, Non-U.S. Gov't
DEP - 20190614
PL  - Switzerland
TA  - Toxins (Basel)
JT  - Toxins
JID - 101530765
RN  - 0 (Bacterial Proteins)
RN  - 0 (Bacterial Vaccines)
RN  - 0 (Leukocidins)
RN  - 0 (Toxoids)
RN  - 0 (leukocidin AB, Staphylococcus aureus)
SB  - IM
MH  - Animals
MH  - Bacterial Proteins/genetics/*immunology
MH  - *Bacterial Vaccines
MH  - Cell Survival
MH  - Escherichia coli/genetics
MH  - Female
MH  - HL-60 Cells
MH  - Humans
MH  - Leukocidins/genetics/*immunology
MH  - Mice, Inbred ICR
MH  - Monocytes
MH  - Staphylococcal Infections/*prevention & control
MH  - THP-1 Cells
MH  - Toxoids/genetics/*immunology
PMC - PMC6628420
OTO - NOTNLM
OT  - Leukocidin
OT  - LukAB
OT  - LukGH
OT  - Staphylococcus aureus
OT  - polyclonal antibody
OT  - toxin neutralization
OT  - toxoid vaccine
COIS- MJA has stocks and RPA, FWH, and HK have stock options in Integrated 
      Biotherapeutics Inc. The funders had no role in the design of the study; in the 
      collection, analyses, or interpretation of data; in the writing of the 
      manuscript, or in the decision to publish the results.
EDAT- 2019/06/19 06:00
MHDA- 2020/03/17 06:00
PMCR- 2019/06/01
CRDT- 2019/06/19 06:00
PHST- 2019/05/01 00:00 [received]
PHST- 2019/06/10 00:00 [revised]
PHST- 2019/06/12 00:00 [accepted]
PHST- 2019/06/19 06:00 [entrez]
PHST- 2019/06/19 06:00 [pubmed]
PHST- 2020/03/17 06:00 [medline]
PHST- 2019/06/01 00:00 [pmc-release]
AID - toxins11060339 [pii]
AID - toxins-11-00339 [pii]
AID - 10.3390/toxins11060339 [doi]
PST - epublish
SO  - Toxins (Basel). 2019 Jun 14;11(6):339. doi: 10.3390/toxins11060339.