title: Safety and immunological outcomes following human inoculation with nontypeable Haemophilus influenzae.
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.
authors.affiliation: Department of Internal Medicine, Division of Infectious Diseases, University of Iowa, 200 Hawkins Dr, Iowa City,IA 52242, USA. patricia-winokur@uiowa.edu
authors.forename: Patricia L
authors.initials: PL
authors.lastname: Winokur
authors.forename: Kathryn
authors.initials: K
authors.lastname: Chaloner
authors.forename: Gary V
authors.initials: GV
authors.lastname: Doern
authors.forename: Jennifer
authors.initials: J
authors.lastname: Ferreira
authors.forename: Michael A
authors.initials: MA
authors.lastname: Apicella
mesh_terms: D000293:Adolescent; D000328:Adult; D002353:Carrier State / Q000276:immunology* / Q000473:pathology*; D005260:Female; D006192:Haemophilus Infections / Q000276:immunology* / Q000473:pathology*; D006193:Haemophilus influenzae / Q000254:growth & development* / Q000276:immunology*; D006805:Human Experimentation; D006801:Humans; D008297:Male; D008962:Models, Theoretical; D055815:Young Adult
keywords: Bayesian analysis; Haemophilus influenzae; adaptive design; nasopharyngeal colonization; respiratory pathogens; upper respiratory tract