Safety and Immunological Outcomes Following Human Inoculation With Nontypeable Haemophilus influenzae

Patricia L WINOKUR; Kathryn CHALONER; Gary V DOERN; Jennifer FERREIRA; Michael A APICELLA

doi:10.1093/infdis/jit238

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Safety and Immunological Outcomes Following Human Inoculation With Nontypeable Haemophilus influenzae

Journal article

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Safety and Immunological Outcomes Following Human Inoculation With Nontypeable Haemophilus influenzae

Patricia L WINOKUR, Kathryn CHALONER, Gary V DOERN, Jennifer FERREIRA and Michael A APICELLA

The Journal of infectious diseases, Vol.208(5), pp.728-738

2013

DOI: 10.1093/infdis/jit238

PMCID: PMC3733507

PMID: 23715660

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Abstract

Background: Nontypeable Haemophilus influenzae (NTHi) exclusively infects humans, causing significant numbers of upper respiratory tract infections. The goal of this study was to develop a safe experimental human model of NTHi nasopharyngeal colonization. Methods: A novel streptomycin-resistant strain of NTHi was developed, and 15 subjects were inoculated in an adaptive-design phase I trial to rapidly identify colonizing doses of NTHi. Bayesian analysis was used to estimate the human colonizing dose 50 and 90 (HCD50 and HCD90, respectively). Side effects and immunological responses to whole-cell sialylated NTHi were measured. Results: Nine subjects were colonized and tolerated colonization well. Immunological analyses demonstrated that 7 colonized subjects and 0 noncolonized subjects had a 4-fold rise in serum levels of immunoglobulin A, immunoglobulin M, or immunoglobulin G. Preexisting immunity to whole-cell NTHi did not predict success or failure of colonization. Conclusions: The statistical design incorporated a slow escalation to higher dose levels. HCD50 and HCD90 Bayesian estimates were identified as approximately 2000 and 150 000 colony-forming units, respectively; credible interval estimates were broad. This study provides a potential platform for early proof of concept studies for NTHi vaccines, as well as a way to evaluate bacterial factors associated with colonization. Keywords: Bayesian analysis; Haemophilus influenzae; adaptive design; nasopharyngeal colonization; respiratory pathogens; upper respiratory tract.

Infectious Diseases

Microbiology

Bacteriology

Fundamental and applied biological sciences. Psychology

Miscellaneous

Biological and medical sciences

Medical sciences

Details

Title: Subtitle: Safety and Immunological Outcomes Following Human Inoculation With Nontypeable Haemophilus influenzae
Creators: Patricia L WINOKUR - Department of Internal Medicine, University of Iowa, Iowa City, United States
Kathryn CHALONER - Department of Biostatistics, University of Iowa, Iowa City, United States
Gary V DOERN - Department of Pathology, University of Iowa, Iowa City, United States
Jennifer FERREIRA - EMMES Corporation, Rockville, Maryland, United States
Michael A APICELLA - Department of Microbiology, University of Iowa, Iowa City, United States
Resource Type: Journal article
Publication Details: The Journal of infectious diseases, Vol.208(5), pp.728-738
DOI: 10.1093/infdis/jit238
PMID: 23715660
PMCID: PMC3733507
NLM abbreviation: J Infect Dis
ISSN: 0022-1899
eISSN: 1537-6613
Publisher: Oxford University Press
Language: English
Date published: 2013
Academic Unit: Microbiology and Immunology; Infectious Diseases; Epidemiology; Pathology; Medicine Administration; Internal Medicine
Record Identifier: 9984094625802771

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