Safety and Immunological Outcomes Following Human Inoculation with Nontypeable Haemophilus Influenzae

Publication Type
Journal Article
Year of Publication
2013
Authors
Winokur, PL; Chaloner, K; Doem, GV; Ferreira, J; Apicella, MA
Secondary
J Infect Dis
Volume
208
Start Page
728
Pagination
728-738
Date Published
09/2013
Keywords
adaptive design; Bayesian analysis; Haemophilus influenzae; nasopharyngeal colonization; respiratory pathogens; upper respiratory tract
ISBN
1537-6613
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.