Controlled human infection with Bordetella pertussis induces asymptomatic, immunising colonisation

Andrew Preston, Hans de Graaf, Muktar Ibrahim, Alison Hill, Diane Gbesemete, Andrew Vaughn, Andrew Gorringe, Anne-Marie Buisman, Saul Faust, Kent Kester, Guy Berbers, Dimitri Diavotopoulos, Robert Read

Research output: Contribution to journalArticle

Abstract

RATIONALE: Bordetella pertussis is one of the leading causes of vaccine preventable death and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infection might be a target of future vaccine strategies but has not been demonstrated to occur.

OBJECTIVE: To demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define microbiological and immunological features of pre-symptomatic infection.

METHODS: Healthy subjects aged 18-45 years with an anti-pertussis toxin IgG concentration of <20 IU/ml were inoculated intranasally with non-attenuated, wild type Bordetella pertussis strain B1917. Safety, colonisation and shedding were monitored over 17 days in an in-patient facility. Colonisation was assessed by culture and qPCR. Azithromycin was administered from day 14. The inoculum dose was escalated aiming to colonise at least 70% of participants. Immunological responses were measured.

RESULTS: 34 participants were challenged in groups of four or five. The dose was gradually escalated from 103 colony forming units (0% colonised) to 105 colony forming units (80% colonised). Minor symptoms were reported in a minority of participants. Azithromycin eradicated colonisation in 48 hours in 88% of colonised individuals. Anti-pertussis toxin IgG seroconversion occurred in nine out of 19 colonised participants and in none of the participants who were not colonised. Nasal wash was a more sensitive method to detect colonisation than pernasal swabs. No shedding of Bordetella pertussis was detected in systematically collected environmental samples.

INTERPRETATION: Bordetella pertussis colonisation can be deliberately induced and leads to a systemic immune response without causing pertussis symptoms.ClinicalTrials.gov:NCT03751514.

Original languageEnglish
Pages (from-to)1-35
Number of pages35
JournalClinical Infectious Diseases
Early online date28 Sep 2019
DOIs
Publication statusPublished - 28 Sep 2019

Keywords

  • Bordetella pertussis
  • human challenge
  • carriage
  • immune response

Cite this

Controlled human infection with Bordetella pertussis induces asymptomatic, immunising colonisation. / Preston, Andrew; de Graaf, Hans; Ibrahim, Muktar; Hill, Alison; Gbesemete, Diane; Vaughn, Andrew; Gorringe, Andrew; Buisman, Anne-Marie; Faust, Saul; Kester, Kent; Berbers, Guy; Diavotopoulos, Dimitri; Read, Robert.

In: Clinical Infectious Diseases, 28.09.2019, p. 1-35.

Research output: Contribution to journalArticle

Preston, A, de Graaf, H, Ibrahim, M, Hill, A, Gbesemete, D, Vaughn, A, Gorringe, A, Buisman, A-M, Faust, S, Kester, K, Berbers, G, Diavotopoulos, D & Read, R 2019, 'Controlled human infection with Bordetella pertussis induces asymptomatic, immunising colonisation', Clinical Infectious Diseases, pp. 1-35. https://doi.org/10.1093/cid/ciz840, https://doi.org/10.1093/cid/ciz840
Preston, Andrew ; de Graaf, Hans ; Ibrahim, Muktar ; Hill, Alison ; Gbesemete, Diane ; Vaughn, Andrew ; Gorringe, Andrew ; Buisman, Anne-Marie ; Faust, Saul ; Kester, Kent ; Berbers, Guy ; Diavotopoulos, Dimitri ; Read, Robert. / Controlled human infection with Bordetella pertussis induces asymptomatic, immunising colonisation. In: Clinical Infectious Diseases. 2019 ; pp. 1-35.
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abstract = "RATIONALE: Bordetella pertussis is one of the leading causes of vaccine preventable death and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infection might be a target of future vaccine strategies but has not been demonstrated to occur.OBJECTIVE: To demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define microbiological and immunological features of pre-symptomatic infection.METHODS: Healthy subjects aged 18-45 years with an anti-pertussis toxin IgG concentration of <20 IU/ml were inoculated intranasally with non-attenuated, wild type Bordetella pertussis strain B1917. Safety, colonisation and shedding were monitored over 17 days in an in-patient facility. Colonisation was assessed by culture and qPCR. Azithromycin was administered from day 14. The inoculum dose was escalated aiming to colonise at least 70{\%} of participants. Immunological responses were measured.RESULTS: 34 participants were challenged in groups of four or five. The dose was gradually escalated from 103 colony forming units (0{\%} colonised) to 105 colony forming units (80{\%} colonised). Minor symptoms were reported in a minority of participants. Azithromycin eradicated colonisation in 48 hours in 88{\%} of colonised individuals. Anti-pertussis toxin IgG seroconversion occurred in nine out of 19 colonised participants and in none of the participants who were not colonised. Nasal wash was a more sensitive method to detect colonisation than pernasal swabs. No shedding of Bordetella pertussis was detected in systematically collected environmental samples.INTERPRETATION: Bordetella pertussis colonisation can be deliberately induced and leads to a systemic immune response without causing pertussis symptoms.ClinicalTrials.gov:NCT03751514.",
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AU - Preston, Andrew

AU - de Graaf, Hans

AU - Ibrahim, Muktar

AU - Hill, Alison

AU - Gbesemete, Diane

AU - Vaughn, Andrew

AU - Gorringe, Andrew

AU - Buisman, Anne-Marie

AU - Faust, Saul

AU - Kester, Kent

AU - Berbers, Guy

AU - Diavotopoulos, Dimitri

AU - Read, Robert

N1 - © The Author(s) 2019. Published by Oxford University Press for the Infectious Diseases Society of America.

PY - 2019/9/28

Y1 - 2019/9/28

N2 - RATIONALE: Bordetella pertussis is one of the leading causes of vaccine preventable death and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infection might be a target of future vaccine strategies but has not been demonstrated to occur.OBJECTIVE: To demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define microbiological and immunological features of pre-symptomatic infection.METHODS: Healthy subjects aged 18-45 years with an anti-pertussis toxin IgG concentration of <20 IU/ml were inoculated intranasally with non-attenuated, wild type Bordetella pertussis strain B1917. Safety, colonisation and shedding were monitored over 17 days in an in-patient facility. Colonisation was assessed by culture and qPCR. Azithromycin was administered from day 14. The inoculum dose was escalated aiming to colonise at least 70% of participants. Immunological responses were measured.RESULTS: 34 participants were challenged in groups of four or five. The dose was gradually escalated from 103 colony forming units (0% colonised) to 105 colony forming units (80% colonised). Minor symptoms were reported in a minority of participants. Azithromycin eradicated colonisation in 48 hours in 88% of colonised individuals. Anti-pertussis toxin IgG seroconversion occurred in nine out of 19 colonised participants and in none of the participants who were not colonised. Nasal wash was a more sensitive method to detect colonisation than pernasal swabs. No shedding of Bordetella pertussis was detected in systematically collected environmental samples.INTERPRETATION: Bordetella pertussis colonisation can be deliberately induced and leads to a systemic immune response without causing pertussis symptoms.ClinicalTrials.gov:NCT03751514.

AB - RATIONALE: Bordetella pertussis is one of the leading causes of vaccine preventable death and morbidity globally. Human asymptomatic carriage as a reservoir for community transmission of infection might be a target of future vaccine strategies but has not been demonstrated to occur.OBJECTIVE: To demonstrate that asymptomatic nasopharyngeal carriage of Bordetella pertussis is inducible in humans and to define microbiological and immunological features of pre-symptomatic infection.METHODS: Healthy subjects aged 18-45 years with an anti-pertussis toxin IgG concentration of <20 IU/ml were inoculated intranasally with non-attenuated, wild type Bordetella pertussis strain B1917. Safety, colonisation and shedding were monitored over 17 days in an in-patient facility. Colonisation was assessed by culture and qPCR. Azithromycin was administered from day 14. The inoculum dose was escalated aiming to colonise at least 70% of participants. Immunological responses were measured.RESULTS: 34 participants were challenged in groups of four or five. The dose was gradually escalated from 103 colony forming units (0% colonised) to 105 colony forming units (80% colonised). Minor symptoms were reported in a minority of participants. Azithromycin eradicated colonisation in 48 hours in 88% of colonised individuals. Anti-pertussis toxin IgG seroconversion occurred in nine out of 19 colonised participants and in none of the participants who were not colonised. Nasal wash was a more sensitive method to detect colonisation than pernasal swabs. No shedding of Bordetella pertussis was detected in systematically collected environmental samples.INTERPRETATION: Bordetella pertussis colonisation can be deliberately induced and leads to a systemic immune response without causing pertussis symptoms.ClinicalTrials.gov:NCT03751514.

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KW - human challenge

KW - carriage

KW - immune response

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DO - 10.1093/cid/ciz840

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EP - 35

JO - Clinical Infectious Diseases

JF - Clinical Infectious Diseases

SN - 1058-4838

ER -