Passive immunization with human anti-protein D antibodies induced by polysaccharide protein D conjugates protects chinchillas against otitis media after intranasal challenge with Haemophilus influenzae

Novotny, Laura A.; Jurcisek, Joseph A.; Godfroid, Fabrice; Poolman, Jan; Denoël, Philippe; Bakaletz, Lauren O.

doi:10.1016/j.vaccine.2006.03.021

Cited by 48 publications

(50 citation statements)

References 55 publications

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“…At this early time point relative to bacterial challenge, NTHI was detected within all lavage fluids ( Fig. 3) and at concentrations that were both highly comparable among cohorts as well as to levels in published reports using this chinchilla superinfection model (mean for all animals, 3.7 ϫ 10 3 Ϯ 1 ϫ 10 3 CFU of NTHI per ml of nasopharyngeal lavage fluid) (25)(26)(27). There was no statistically significant difference in relative bacterial loads among cohorts (P ϭ 0.54); therefore, the potential to develop experimental OM was comparable among all animals, with the only discriminator being the specific vaccine formulation administered prior to NTHI challenge.…”

Section: Figsupporting

confidence: 76%

“…reports and further confirmed the reproducible nature of disease induction in this outbred, mixed-sex experimental animal model of viral-bacterial coinfection (23,(25)(26)(27).…”

Section: Figsupporting

confidence: 71%

“…To achieve this goal, we used an experimental model that more closely mimics the polymicrobial nature and kinetics of disease reported for children, in whom an upper respiratory tract viral infection precedes the development of bacterial OM (22,23). This animal model is robust and reproducible and is shown to be predictive of a pediatric clinical trial outcome (25,28). Moreover, it has shown utility to test preclinically the robustness of various vaccine candidates in a polymicrobial disease model system (25-27, 29, 30).…”

Section: Discussionmentioning

confidence: 99%

“…The incidence of experimental OM was determined by video otoscopy and tympanometry via use of an established metric to indicate relative signs of inflammation and presence of middle ear fluid behind the tympanic membrane (25). Four days after NTHI challenge, 31% of middle ears (5/16 ears) in the cohort immunized with dmLT alone had evidence of middle ear fluid, with a peak incidence of disease of 88% (14/16 ears) that occurred between days 12 and 15 ( Fig.…”

Section: Figmentioning

confidence: 99%

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Transcutaneous Immunization with a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model

Novotny

Clements

Goodman

2017

Clin Vaccine Immunol

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Otitis media (OM) is a common pediatric disease, and nontypeable Haemophilus influenzae (NTHI) is the predominant pathogen in chronic OM, recurrent OM, and OM associated with treatment failure. OM is also a polymicrobial disease, wherein an upper respiratory tract viral infection predisposes to ascension of NTHI from the nasopharynx, the site of colonization, to the normally sterile middle ear, resulting in disease. Using a clinically relevant viral-bacterial coinfection model of NTHIinduced OM, we performed transcutaneous immunization (TCI) via a band-aid delivery system to administer each of three promising NTHI vaccine candidates derived from bacterial adhesive proteins and biofilm mediators: recombinant soluble PilA (rsPilA), chimV4, and integration host factor. Each immunogen was admixed with the adjuvant LT(R192G/L211A), a double mutant of Escherichia coli heat-labile enterotoxin, and assessed for relative ability to prevent the onset of experimental OM. For each cohort, the presence of circulating immunogen-specific antibody-secreting cells and serum antibody was confirmed prior to intranasal NTHI challenge. After bacterial challenge, blinded video otoscopy and tympanometry revealed a significant reduction in the proportion of animals with signs of OM compared to levels in animals receiving adjuvant only, with an overall vaccine efficacy of 64 to 77%. These data are the first to demonstrate the efficacy afforded by TCI with a band-aid vaccine delivery system in a clinically relevant polymicrobial model of OM. The simplicity of TCI with a band-aid and the significant efficacy observed here hold great promise for reducing the global burden of OM in the pediatric population.KEYWORDS IHF, biofilms, chimV4, nontypeable Haemophilus influenzae, rsPilA T ranscutaneous immunization (TCI) is a noninvasive strategy to induce an immune response by engagement of the numerous antigen-presenting cells within the dermis and epidermis (1, 2). This regime results in both systemic and mucosal immune responses, important outcomes as the mucosae serve as critical defensive barriers to antigenic insult and bacterial disease (3, 4). TCI is needle free, which is expected to aid in patient compliance, to limit risks associated with both administration and waste, and to reduce costs related to formulation and delivery (5). Thus, TCI promises to facilitate greater vaccine distribution.Otitis media (OM) is a disease of the uppermost respiratory tract mucosa and is one of the most common bacterial diseases of childhood due to a multifactorial combination of anatomical, immunological, and environmental factors (6). OM is also a polymicrobial disease caused by one or more of several bacterial species that typically reside within the human nasopharynx. The ability of nontypeable Haemophilus influenzae (NTHI), Streptococcus pneumoniae, and Moraxella catarrhalis to ascend from the nasopharynx through the Eustachian tube and gain access to the normally sterile middle ear space is facilitated by perturbation of the physical and inn...

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Section: Figsupporting

confidence: 76%

“…reports and further confirmed the reproducible nature of disease induction in this outbred, mixed-sex experimental animal model of viral-bacterial coinfection (23,(25)(26)(27).…”

Section: Figsupporting

confidence: 71%

Section: Discussionmentioning

confidence: 99%

Section: Figmentioning

confidence: 99%

See 2 more Smart Citations

Transcutaneous Immunization with a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model

Novotny

Clements

Goodman

2017

Clin Vaccine Immunol

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“…A chinchilla model of human OM has long been used to investigate the role of NTHI in OM. This animal model of disease has been successfully used to develop candidate vaccines aimed to prevent NTHI-mediated OM (for example, (17)(18)(19)). In addition, mutational studies have identified NTHI gene products essential in bacterial pathogenesis (for example, (20 -23)).…”

mentioning

confidence: 99%

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Harrison

Dubois

John-Williams

et al. 2016

Molecular & Cellular Proteomics

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A thorough understanding of the molecular details of the interactions between bacteria and host are critical to ultimately prevent disease. Recent technological advances allow simultaneous analysis of host and bacterial protein and metabolic profiles from a single small tissue sample to provide insight into pathogenesis. We used the chinchilla model of human otitis media to determine, for the first time, the most expansive delineation of global changes in protein and metabolite profiles during an experimentally induced disease. After 48 h of infection with nontypeable Haemophilus influenzae, middle ear tissue lysates were analyzed by high-resolution quantitative two-dimensional liquid chromatography-tandem mass spectrometry. Dynamic changes in 105 chinchilla proteins and 66 metabolites define the early proteomic and metabolomic signature of otitis media. Our studies indicate that establishment of disease coincides with actin morphogenesis, suppression of inflammatory mediators, and bacterial aerobic respiration. We validated the observed increase in the actin-remodeling complex, Arp2/3, and experimentally showed a role for Arp2/3 in nontypeable Haemophilus influenzae invasion. Direct inhibition of actin branch morphology altered bacterial invasion into host epithelial cells, and is supportive of our efforts to use the information gathered to modify outcomes of disease. The twenty-eight nontypeable Haemophilus influenzae proteins identified participate in carbohydrate and amino acid metabolism, redox homeostasis, and include cell wall-associated metabolic proteins. Quantitative characterization of the molecular signatures of infection will redefine our understanding of host response driven developmental changes during pathogenesis. These data represent the first comprehensive study of host protein and metabolite profiles in vivo in response to infection and show the feasibility of extensive characterization of host protein profiles during disease. Identification of novel protein targets and metabolic biomarkers will advance development of therapeutic and diagnostic options for treatment of disease. Molecular & Cellular Proteomics 15: 10.1074/mcp.M115.052498, 1117-1138, 2016.Our current understanding of the global changes that occur during infection is primarily based upon transcriptional profiles of either the host or the bacteria. However, a significant component of disease progression is dependent upon posttranscriptional processes. Recent advances in the application of two-dimensional tandem mass spectrometry have dramatically increased sensitivity to allow simultaneous analyses of multiple molecules from very small biological samples. In this study, we report the comprehensive proteomic and metabolomic profiling of middle ear tissues using samples that are smaller than those typically obtained from a human biopsy. Proteomic and metabolomic analyses of samples as small as biopsies will revolutionize the elucidation of the mechanisms From the

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Current and future prospects for a vaccine for nontypeable Haemophilus influenzae

Murphy

2009

Curr Infect Dis Rep

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Nontypeable Haemophilus influenzae is an important human respiratory tract pathogen that causes about 30% of otitis media in infants and children. This proportion is increasing as a result of pneumococcal conjugate vaccines. Because of the morbidity associated with otitis media, a strong rationale exists to develop strategies to prevent these infections. A challenge to developing a vaccine for nontypeable H. influenzae is the antigenic heterogeneity of several major surface antigens and the genetic heterogeneity among strains. Several research groups have identified conserved surface proteins and tested them as putative vaccines. A recent clinical trial with protein D, a conserved surface antigen, demonstrated partial efficacy in preventing H. influenzae otitis media. This important result provides a proof of principle for developing a vaccine to prevent otitis media caused by nontypeable H. influenzae. Several vaccine antigens for nontypeable H. influenzae are in development.

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Passive immunization with human anti-protein D antibodies induced by polysaccharide protein D conjugates protects chinchillas against otitis media after intranasal challenge with Haemophilus influenzae

Cited by 48 publications

References 55 publications

Transcutaneous Immunization with a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model

Transcutaneous Immunization with a Band-Aid Prevents Experimental Otitis Media in a Polymicrobial Model

Comprehensive Proteomic and Metabolomic Signatures of Nontypeable Haemophilus influenzae-Induced Acute Otitis Media Reveal Bacterial Aerobic Respiration in an Immunosuppressed Environment

Current and future prospects for a vaccine for nontypeable Haemophilus influenzae

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