167. A Bordetella pertussis Human Challenge Model Induces Immunizing Colonization in the Absence of Symptoms
Session: Oral Abstract Session: Science Relevant to ID
Thursday, October 4, 2018: 11:15 AM
Room: S 157
Background: Bordetella pertussis (Bp) is one of the leading causes of vaccine preventable death and morbidity globally. Over the last 20 years pertussis has resurged worldwide, even in territories with high immunization coverage. To improve vaccine strategies, a greater understanding of human Bp infection and immunity is required. This study aims to develop a safe controlled human Bp infection model and to define natural immune responses against wild type Bp in order to facilitate the development of bioassays and next generation pertussis vaccines.

Methods: In this first-in-human controlled infection model healthy volunteers aged 18-45 years with an anti-pertussis toxin (PT) IgG level of <20 IU/mL were inoculated intranasally with Bp strain B1917. Safety, colonization and shedding were monitored over a 17 day inpatient period. Colonization was assessed by culture and qPCR of nasal washes and nasopharyngeal swabs. Azithromycin eradication therapy was commenced on day 14. The dose of inoculum was escalated to optimize colonization rate, expressed as the percentage of volunteers colonized at any sampling point between day 3 and 14. The immunological response is being assessed at various time-points over one year.

Results: 24 volunteers were challenged in groups of 4-5. The dose was gradually escalated from 103 colony forming units (cfu) to 105 cfu. Colonization rate ranged from 0% (dose 103 cfu) to 80% (105 cfu). Amongst this initial cohort, no significant safety concerns or symptoms attributed to Bp disease were reported. Eradication was achieved by 48 hours in 100% of colonized volunteers. At least four fold rise in anti-PT IgG by day 28 in comparison to baseline was observed in five out of eight volunteers who had >1000 cfu/mL viable Bp in the nasal wash and in one volunteer without detectable colonization. Nasal wash cultures were more sensitive in detecting colonization than nasopharyngeal swab cultures. No shedding of Bp was detected in systematically collected environmental samples.

Conclusion: This is the first study to demonstrate safe deliberate induction of Bp colonization. It shows that asymptomatic Bp colonization occurs, and causes a systemic immune response. The model that we have developed will be a valuable tool to further investigate Bp colonization and vaccine development.

Hans De Graaf, BM1, Muktar Ibrahim, MSc2, Alison Hill, PhD3, Diane Gbesemete, BM2, Andrew Gorringe, PhD4, Dimitri Diavatopoulos, PhD5, Kent Kester, MD6, Guy Berbers, PhD7, Saul Faust, PhD2 and Robert Read, MD, FIDSA8, (1)Faculty of Medicine, Nihr Clinical Research Facility and Nihr Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, NH, United Kingdom, (2)Faculty of Medicine, Nihr Clinical Research Facility and Nihr Biomedical Research Centre, University of Southampton and University Hospital Southampton NHS Foundation Trust, Southampton, United Kingdom, (3)Faculty of Medicine and Institute of Life Science, University of Southampton, Southampton, NH, United Kingdom, (4)Research and Development Institute, Public Health England, Salisbury, United Kingdom, (5)Laboratory of Medical Immunology, Radboud Centre for Infectious Diseases, Radboud University Medical Centre, Nijmegen, Netherlands, (6)Translational Science and Biomarkers, Sanofi Pasteur, Swiftwater, PA, (7)Centre for Infectious Disease Control, National Institute of Public Health and the Environment (RIVM), Bilthoven, Netherlands, (8)Clinical and Experimental Sciences (Faculty of Medicine), University of Southampton and Southampton University Hospital NHS Foundation Trust, Southampton, United Kingdom

Disclosures:

H. De Graaf, None

M. Ibrahim, None

A. Hill, None

D. Gbesemete, None

A. Gorringe, None

D. Diavatopoulos, None

K. Kester, Sanofi: Employee , Salary .

G. Berbers, None

S. Faust, Pfizer, Merck, Sanofi, AstraZeneca/Medimmune: Scientific Advisor , all honoraria paid to institution with no personal payments of any kind .

R. Read, None

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