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Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae.

Novotny LA, Clements JD, Bakaletz LO - Mucosal Immunol (2011)

Bottom Line: Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone.Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls.These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM.

View Article: PubMed Central - PubMed

Affiliation: The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Center for Microbial Pathogenesis and The Ohio State University College of Medicine, Columbus, Ohio, USA.

ABSTRACT
We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM. Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone. Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls. These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM.

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Related in: MedlinePlus

Mean nontypeable Haemophilus influenzae (NTHI) biomass scores for each bulla after transcutaneous immunization (TCI) following a therapeutic regimen, based on blinded evaluation and ranked on a 0 to 4+ scale of relative residual biomass. *Statistically significant compared with receipt of dmLT alone (P<0.05). Receipt of LB1, rsPilA, or chimV4, admixed with dmLT, resulted in significantly enhanced resolution of NTHI biofilms established within the middle ear space. dmLT, double mutant of E. coli heat-labile enterotoxin; rsPilA, recombinant soluble PilA.
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fig4: Mean nontypeable Haemophilus influenzae (NTHI) biomass scores for each bulla after transcutaneous immunization (TCI) following a therapeutic regimen, based on blinded evaluation and ranked on a 0 to 4+ scale of relative residual biomass. *Statistically significant compared with receipt of dmLT alone (P<0.05). Receipt of LB1, rsPilA, or chimV4, admixed with dmLT, resulted in significantly enhanced resolution of NTHI biofilms established within the middle ear space. dmLT, double mutant of E. coli heat-labile enterotoxin; rsPilA, recombinant soluble PilA.

Mentions: To examine the therapeutic potential of TCI with the NTHI OMP P5- and Tfp-directed immunogens, we now first challenged chinchillas by direct inoculation of the middle ear with NTHI strain 86-028NP and allowed a robust biofilm to form in the middle ear space. Previous work has established that when using this protocol within 4 days after direct challenge, 83–100% of all middle ears develop a biomass that occupies approximately 75–100% of the middle ear space. Thus, after these biomasses were established, animals were immunized by TCI to determine if the resulting antibodies could resolve these structures. At 1 week after receipt of the second dose, each middle ear was blindly ranked based on a 0 to 4+ scale of relative biomass, wherein a score of 0 indicated that no biomass was detected within the middle ear space and 4.0+ designated that 75–100% of the middle ear space was filled with biomass. The average biomass score for the cohort that received dmLT alone was 2.8, which indicated that approximately 50–75% of the middle ear space was filled with biomass (Figure 4). In contrast, use of the therapeutic immunization regimen with LB1, rsPilA, or chimV4, alone or delivered with dmLT, resulted in a significantly reduced biomass (P<0.05). The average biomass score after receipt of LB1 or rsPilA, alone or with dmLT, was between 0.9 and 1.2, and thus 75% of the biomass had resolved after TCI. Receipt of chimV4 alone or with dmLT resulted in greater reduction in the relative biomass scores to 0.6 and 0.3, respectively. Based on relative biomass score alone, the addition of dmLT did not appear to significantly influence the outcome achieved in immunized animals. Nonetheless, overall, therapeutic immunization with the OMP P5- and Tfp-targeted immunogens elicited an immune response that resulted in a significant reduction in biomass within the middle ear.


Transcutaneous immunization as preventative and therapeutic regimens to protect against experimental otitis media due to nontypeable Haemophilus influenzae.

Novotny LA, Clements JD, Bakaletz LO - Mucosal Immunol (2011)

Mean nontypeable Haemophilus influenzae (NTHI) biomass scores for each bulla after transcutaneous immunization (TCI) following a therapeutic regimen, based on blinded evaluation and ranked on a 0 to 4+ scale of relative residual biomass. *Statistically significant compared with receipt of dmLT alone (P<0.05). Receipt of LB1, rsPilA, or chimV4, admixed with dmLT, resulted in significantly enhanced resolution of NTHI biofilms established within the middle ear space. dmLT, double mutant of E. coli heat-labile enterotoxin; rsPilA, recombinant soluble PilA.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3118858&req=5

fig4: Mean nontypeable Haemophilus influenzae (NTHI) biomass scores for each bulla after transcutaneous immunization (TCI) following a therapeutic regimen, based on blinded evaluation and ranked on a 0 to 4+ scale of relative residual biomass. *Statistically significant compared with receipt of dmLT alone (P<0.05). Receipt of LB1, rsPilA, or chimV4, admixed with dmLT, resulted in significantly enhanced resolution of NTHI biofilms established within the middle ear space. dmLT, double mutant of E. coli heat-labile enterotoxin; rsPilA, recombinant soluble PilA.
Mentions: To examine the therapeutic potential of TCI with the NTHI OMP P5- and Tfp-directed immunogens, we now first challenged chinchillas by direct inoculation of the middle ear with NTHI strain 86-028NP and allowed a robust biofilm to form in the middle ear space. Previous work has established that when using this protocol within 4 days after direct challenge, 83–100% of all middle ears develop a biomass that occupies approximately 75–100% of the middle ear space. Thus, after these biomasses were established, animals were immunized by TCI to determine if the resulting antibodies could resolve these structures. At 1 week after receipt of the second dose, each middle ear was blindly ranked based on a 0 to 4+ scale of relative biomass, wherein a score of 0 indicated that no biomass was detected within the middle ear space and 4.0+ designated that 75–100% of the middle ear space was filled with biomass. The average biomass score for the cohort that received dmLT alone was 2.8, which indicated that approximately 50–75% of the middle ear space was filled with biomass (Figure 4). In contrast, use of the therapeutic immunization regimen with LB1, rsPilA, or chimV4, alone or delivered with dmLT, resulted in a significantly reduced biomass (P<0.05). The average biomass score after receipt of LB1 or rsPilA, alone or with dmLT, was between 0.9 and 1.2, and thus 75% of the biomass had resolved after TCI. Receipt of chimV4 alone or with dmLT resulted in greater reduction in the relative biomass scores to 0.6 and 0.3, respectively. Based on relative biomass score alone, the addition of dmLT did not appear to significantly influence the outcome achieved in immunized animals. Nonetheless, overall, therapeutic immunization with the OMP P5- and Tfp-targeted immunogens elicited an immune response that resulted in a significant reduction in biomass within the middle ear.

Bottom Line: Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone.Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls.These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM.

View Article: PubMed Central - PubMed

Affiliation: The Research Institute at Nationwide Children's Hospital, Department of Pediatrics, Center for Microbial Pathogenesis and The Ohio State University College of Medicine, Columbus, Ohio, USA.

ABSTRACT
We have developed three nontypeable Haemophilus influenzae (NTHI) adhesin-derived immunogens that are significantly efficacious against experimental otitis media (OM) due to NTHI when delivered parenterally. We now expanded our preventative immunization strategies to include transcutaneous immunization (TCI) as a less invasive, but potentially equally efficacious, regimen to prevent OM due to NTHI. Additionally, we examined the potential of TCI as a therapeutic immunization regimen to resolve ongoing experimental OM. Preventative immunization with NTHI outer membrane protein (OMP) P5- and type IV pilus-targeted immunogens, delivered with the adjuvant LT(R192G-L211A), induced significantly earlier clearance of NTHI from the nasopharynges and middle ears of challenged chinchillas compared with receipt of immunogen or adjuvant alone. Moreover, therapeutic immunization resulted in significant resolution of established NTHI biofilms from the middle ear space of animals compared with controls. These data advocate TCI with the adhesin-directed immunogens as an efficacious regimen for prevention and resolution of experimental NTHI-induced OM.

Show MeSH
Related in: MedlinePlus