Safety and Immunological Outcomes Following Human Inoculation With Nontypeable Haemophilus influenzae

(See the editorial commentary by Barenkamp on pages 717–9.) Haemophilus influenzae is gram-negative bacterium that exclusively colonizes and infects the human host. Nontypeable H. influenzae (NTHi) strains lack an outer capsule and are commensals of the human upper respiratory tract. Between 20% and 80% of healthy children are colonized with NTHi at any one time [1–4], and colonization is a dynamic process, with new strains being acquired and replacing old strains periodically [5]. Although less virulent than encapsulated strains, NTHi can cause upper respiratory tract infection and, less commonly, distal invasive infection [6]. NTHi is the responsible agent in approximately 30%–40% of cases of otitis media in children [7–9] and a frequent cause of sinusitis in healthy adults [10]. Smokers and those with chronic lung disease are at risk for lower respiratory tract infection, including acute exacerbation of bronchitis and pneumonia [11]. Colonization is considered the first step in invasive infection, although specific mechanisms that lead from colonization to invasive disease are incompletely understood. In some cases, intercurrent viral infection may promote invasion [12, 13]. NTHi has become a desirable vaccine target. The pneumococcal vaccine Synflorix uses protein D of H. influenzae conjugated to pneumococcal polysaccharides. This vaccine has been shown to reduce the incidence of H. influenzae–associated otitis media by 31% [14]. NTHi has other outer membrane structure, such as fimbriae, outer membrane proteins (OMPs), and lipooligosaccharide, that play a role in virulence and could be potential vaccine antigens [15–17]. NTHi infections can be induced in animal models but do not occur naturally and do not fully reproduce human colonization and infection [18]. Previous human experimental models of Streptococcus pneumoniae, Neisseria gonorrhoeae, and Haemophilus ducreyi infections have provided useful information regarding pathogenesis and protective immune responses [19–24]. The goal of this study was to develop a safe experimental human model of NTHi nasopharyngeal colonization, using a novel strain of NTHi. Colonization results, safety, reactogenicity, and immunological responses are presented. This model could provide a way to rapidly evaluate the early efficacy of candidate vaccines. Because other bacterial pathogens, such as S. pneumoniae, Neisseria meningitidis, and Bordetella pertussis, initiate similar interactions with their obligate human host by colonization of the upper respiratory tract, this model could also be a mechanism for studying the pathogenesis of respiratory colonization.