Retention of Anti-pertussis Toxin Antibodies after Whooping Cough-containing Vaccination in Healthcare Workers and the Appropriate Timing for Booster Inoculation

AbstractWhooping cough is caused by Bordetella pertussis that releases pertussis toxin (PT) which comprises enzyme A-subunit PTS1 and binding/transport B-subunit. After receptor-mediated endocytosis, PT reaches the endoplasmic reticulum from where unfolded PTS1 is transported to the cytosol. PTS1 ADP-ribosylates G-protein α-subunits resulting in increased cAMP signaling. Here, a role of target cell chaperones Hsp90, Hsp70, cyclophilins and FK506-binding proteins for cytosolic PTS1-uptake is demonstrated. PTS1 specifically and directly interacts with chaperones in vitro and in cells. Specific pharmacological chaperone inhibition protects CHO-K1, human primary airway basal cells and a fully differentiated airway epithelium from PT-intoxication by reducing intracellular PTS1-amounts without affecting cell binding or enzyme activity. PT is internalized by human airway epithelium secretory but not ciliated cells and leads to increase of apical surface liquid. Cyclophilin-inhibitors reduced leukocytosis in infant mouse model of pertussis, indicating their promising potential for developing novel therapeutic strategies against whooping cough.

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Pertussis Toxin composite nanofibers as a non-invasive whooping cough vaccine

2007 IEEE 33rd Annual Northeast Bioengineering Conference ◽

10.1109/nebc.2007.4413371 ◽

2007 ◽

Author(s):

T.A. Gawade ◽

K.M. Sawicka ◽

E.J. Roemer ◽

S.R. Simon

Keyword(s):

Pertussis Toxin ◽

Composite Nanofibers ◽

Whooping Cough ◽

Non Invasive

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Purification and immunological characterization of HPLC-purified pertussis toxin subunits

Biochemistry and Cell Biology ◽

10.1139/o91-052 ◽

1991 ◽

Vol 69 (5-6) ◽

pp. 336-340

Author(s):

Pele Chong ◽

Stephen Cockle ◽

Heather Boux ◽

Michel Klein

Keyword(s):

High Performance Liquid Chromatography ◽

Liquid Chromatography ◽

Pertussis Toxin ◽

High Performance ◽

Whooping Cough ◽

Chinese Hamster Ovary Cells ◽

Chinese Hamster ◽

Active Immunization ◽

Single Step ◽

Nad Glycohydrolase

Pertussis toxin (PT), an oligomeric exotoxin of Bordetella pertussis containing five dissimilar subunits, is considered to be an essential immunogen in acellular and component pertussis vaccines against whooping cough. A rapid single-step procedure for isolating PT subunits was developed using reverse-phase high-performance liquid chromatography. Recoveries of individual subunits were 75% (S1), 70% (S2), > 90% (S3), > 90% (S4), and 50% (S5), as judged by SDS-PAGE and amino acid analysis. Lyophilized subunits were solubilized in urea followed by step-wise dialysis to remove the urea. All subunits were inactive in histamine sensitization, lymphocytosis, and hemagglutination assays. However, purified S1 retained residual NAD-glycohydrolase and ADP-ribosyltransferase activity. A partially active holotoxin could be generated by mixing the five individual subunits. All subunits were immunogenic in rabbits and mice. Monospecific antisera raised in both animal species were able to neutralize the PT-mediated clustering of Chinese hamster ovary cells, but active immunization of mice with single subunits failed to protect them in the intracerebral challenge assay. These subunit preparations therefore retained neutralizing determinants, but did not contain protective epitopes.Key words: pertussis toxin, high-performance liquid chromatography, purification, pertussis vaccine.

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A cocktail of humanized anti–pertussis toxin antibodies limits disease in murine and baboon models of whooping cough

Science Translational Medicine ◽

10.1126/scitranslmed.aad0966 ◽

2015 ◽

Vol 7 (316) ◽

pp. 316ra195-316ra195 ◽

Cited By ~ 30

Author(s):

Annalee W. Nguyen ◽

Ellen K. Wagner ◽

Joshua R. Laber ◽

Laura L. Goodfield ◽

William E. Smallridge ◽

...

Keyword(s):

Pertussis Toxin ◽

Whooping Cough

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Pertussis Toxin: A Key Component in Pertussis Vaccines?

Toxins ◽

10.3390/toxins11100557 ◽

2019 ◽

Vol 11 (10) ◽

pp. 557

Author(s):

Kelsey A. Gregg ◽

Tod J. Merkel

Keyword(s):

Immune Responses ◽

Pertussis Toxin ◽

Whooping Cough ◽

Protective Role ◽

Clear Understanding ◽

Correlates Of Protection ◽

Vaccine Antigens ◽

Specific Pathogen ◽

Human Specific

B. pertussis is a human-specific pathogen and the causative agent of whooping cough. The ongoing resurgence in pertussis incidence in high income countries is likely due to faster waning of immunity and increased asymptomatic colonization in individuals vaccinated with acellular pertussis (aP) vaccine relative whole-cell pertussis (wP)-vaccinated individuals. This has renewed interest in developing more effective vaccines and treatments and, in support of these efforts, defining pertussis vaccine correlates of protection and the role of vaccine antigens and toxins in disease. Pertussis and its toxins have been investigated by scientists for over a century, yet we still do not have a clear understanding of how pertussis toxin (PT) contributes to disease symptomology or how anti-PT immune responses confer protection. This review covers PT’s role in disease and evidence for its protective role in vaccines. Clinical data suggest that PT is a defining and essential toxin for B. pertussis pathogenesis and, when formulated into a vaccine, can prevent disease. Additional studies are required to further elucidate the role of PT in disease and vaccine-mediated protection, to inform the development of more effective treatments and vaccines.

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Incidence of Pertussis Infection in Healthcare Workers

Infection Control and Hospital Epidemiology ◽

10.1086/501593 ◽

1999 ◽

Vol 20 (02) ◽

pp. 120-123 ◽

Cited By ~ 57

Author(s):

Seth W. Wright ◽

Michael D. Decker ◽

Kathryn M. Edwards

Keyword(s):

Emergency Department ◽

Pertussis Toxin ◽

Healthcare Workers ◽

Tertiary Care ◽

Annual Incidence ◽

University Hospital ◽

Serological Evidence ◽

Pertussis Infection ◽

Symptomatic Disease ◽

Filamentous Hemagglutinin

AbstractObjective:To determine the incidence of pertussis infection in two groups of healthcare workers.Design:Retrospective cohort study.Setting:660-bed, urban, tertiary-care university hospital.Participants:106 resident physicians and 39 emergency department employees.Interventions:Antibodies to pertussis toxin and filamentous hemagglutinin were determined in fresh serum specimens and in stored sera collected 1 to 3 years previously. A 50% rise in both the pertussis toxin and filamentous hemagglutinin from the initial to the follow-up specimen was considered diagnostic of a pertussis infection.Results:Two of 106 residents had serological evidence of a pertussis infection during 151.3 subject-observation years, for an annual incidence rate of 1.3% (95% confidence interval [CI95], 0%-3.5%). Three of 39 emergency department employees had serological evidence of a pertussis infection during 81.2 subject-observation years, for an annual incidence of 3.6% (CI95,, 0%-9.6%). Of these 5 subjects, 2 had symptomatic disease.Conclusion:We found both symptomatic and asymptomatic pertussis infections in two cohorts of healthcare workers. Although the incidence rates were somewhat lower than found in other studies, they nonetheless were higher than for almost all other diseases for which we vaccinate healthcare workers. Our results would support the use of acellular pertussis vaccine in healthcare workers.

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Usefulness of Pulsed-Field Gel Electrophoresis in Assessing Nosocomial Transmission of Pertussis

Infection Control and Hospital Epidemiology ◽

10.1086/501579 ◽

1999 ◽

Vol 20 (11) ◽

pp. 758-760 ◽

Cited By ~ 13

Author(s):

Michèle Nouvellon ◽

Jean-François Gehanno ◽

Martine Pestel-Caron ◽

Christian Weber ◽

Jean-François Lemeland ◽

...

Keyword(s):

Bordetella Pertussis ◽

Gel Electrophoresis ◽

Healthcare Workers ◽

Whooping Cough ◽

Close Contact ◽

Pulsed Field Gel Electrophoresis ◽

Nosocomial Transmission ◽

Respiratory Protection ◽

Pulsed Field ◽

Protection Devices

AbstractDuring a 2-week period, three infants with a cough lasting at least 8 days with whoops, were admitted to the pediatric unit; Bordetella pertussis was isolated from nasopharyngeal aspirates collected from the three infants. Approximately 1 week later, a nurse working on the same unit developed influenza-like symptoms followed by whooping cough; B pertussis was isolated. Isolates from the nurse and from one of the infants were shown to be indistinguishable by pulsed-field gel electrophoresis. These data demonstrate that B pertussis transmission to healthcare workers is possible and emphasize the need to use respiratory protection devices (Droplet Precautions) for healthcare workers having close contact with infected children.

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Neutralizing Antibodies to Pertussis Toxin in Whooping Cough

The Journal of Infectious Diseases ◽

10.1093/infdis/151.4.646 ◽

1985 ◽

Vol 151 (4) ◽

pp. 646-649 ◽

Cited By ~ 30

Author(s):

M. Granstrom ◽

G. Granstrom ◽

P. Gillenius ◽

P. Askelof

Keyword(s):

Pertussis Toxin ◽

Neutralizing Antibodies ◽

Whooping Cough

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G Proteins Gαi1/3Are Critical Targets for Bordetella pertussis Toxin-Induced Vasoactive Amine Sensitization

Infection and Immunity ◽

10.1128/iai.00971-13 ◽

2013 ◽

Vol 82 (2) ◽

pp. 773-782 ◽

Cited By ~ 7

Author(s):

Sean A. Diehl ◽

Benjamin McElvany ◽

Rajkumar Noubade ◽

Nathan Seeberger ◽

Brock Harding ◽

...

Keyword(s):

Pertussis Toxin ◽

Bordetella Pertussis ◽

Inflammatory Responses ◽

Whooping Cough ◽

Differential Susceptibility ◽

Inbred Strains ◽

Content Type ◽

Multiple Loci ◽

Inbred Strains Of Mice

ABSTRACTPertussis toxin (PTX) is an AB5-type exotoxin produced by the bacteriumBordetella pertussis, the causative agent of whooping cough.In vivointoxication with PTX elicits a variety of immunologic and inflammatory responses, including vasoactive amine sensitization (VAAS) to histamine (HA), serotonin (5-HT), and bradykinin (BDK). Previously, by using a forward genetic approach, we identified the HA H1receptor (Hrh1/H1R) as the gene in mice that controls differential susceptibility toB. pertussisPTX-induced HA sensitization (Bphs). Here we show, by using inbred strains of mice, F1hybrids, and segregating populations, that, unlike Bphs, PTX-induced 5-HT sensitivity (Bpss) and BDK sensitivity (Bpbs) are recessive traits and are separately controlled by multiple loci unlinked to 5-HT and BDK receptors, respectively. Furthermore, we found that PTX sensitizes mice to HA independently of Toll-like receptor 4, a purported receptor for PTX, and that the VAAS properties of PTX are not dependent upon endothelial caveolae or endothelial nitric oxide synthase. Finally, by using mice deficient in individual Gαi/oG-protein subunits, we demonstrate that Gαi1and Gαi3are the criticalin vivotargets of ADP-ribosylation underlying VAAS elicited by PTX exposure.

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Characterization of Individual Human Antibodies That Bind Pertussis Toxin Stimulated by Acellular Immunization

Infection and Immunity ◽

10.1128/iai.00004-18 ◽

2018 ◽

Vol 86 (6) ◽

pp. e00004-18 ◽

Cited By ~ 5

Author(s):

Edith Acquaye-Seedah ◽

Elizabeth E. Reczek ◽

Hugh H. Russell ◽

Andrea M. DiVenere ◽

Sara O. Sandman ◽

...

Keyword(s):

Pertussis Toxin ◽

Protective Antigen ◽

Whooping Cough ◽

Structural Explanation ◽

Booster Immunization ◽

Human Antibodies ◽

B Subunit ◽

Individual Human

ABSTRACTDespite high vaccination rates, the incidence of whooping cough has steadily been increasing in developing countries for several decades. The current acellular pertussis (aP) vaccines all include the major protective antigen pertussis toxin (PTx) and are safer, but they appear to be less protective than infection or older, whole-cell vaccines. To better understand the attributes of individual antibodies stimulated by aP, we isolated plasmablast clones recognizing PTx after booster immunization of two donors. Five unique antibody sequences recognizing native PTx were recovered and expressed as recombinant human IgG1 antibodies. The antibodies all bind different epitopes on the PTx S1 subunit, B oligomer, or S1-B subunit interface, and just one clone neutralized PTx in anin vitroassay. To better understand the epitopes bound by the nonneutralizing S1-subunit antibodies, comprehensive mutagenesis with yeast display provided a detailed map of the epitope recognized by antibodies A8 and E12. Residue R76 is required for antibody A8 binding and is present on the S1 surface but is only partially exposed in the holotoxin, providing a structural explanation for A8's inability to neutralize holotoxin. The B-subunit-specific antibody D8 inhibited PTx binding to a model receptor and neutralized PTxin vitroas well as in anin vivoleukocytosis assay. This is the first study, to our knowledge, to identify individual human antibodies stimulated by the acellular pertussis vaccine and demonstrates the feasibility of using these approaches to address outstanding issues in pertussis vaccinology, including mechanisms of accelerated waning of protective immunity despite repeated aP immunization.

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