Induction of Mucosal IgA-Mediated Protective Immunity Against Nontypeable Haemophilus influenzae Infection by a
Rika Nakahashi-Ouchida1,2,3, Hiromi Mori1,3, Yoshikazu Yuki1,3,4
1Division of Mucosal Vaccines, International Research and Development Center for Mucosal Vaccines, The Institute of Medical Science, The University of Tokyo, Tokyo, Japan.
Insights
A novel nasal vaccine using the P6 antigen (cCHP-P6) effectively prevents nontypeable Haemophilus influenzae (NTHi) infections. This vaccine induces protective antibodies, inhibiting biofilm formation and reducing NTHi colonization in the respiratory tract.
Area of Science:
- Immunology
- Vaccinology
- Microbiology
Background:
- Nontypeable Haemophilus influenzae (NTHi) is a significant pathogen causing otitis media in children, with no current vaccine.
- NTHi colonization and biofilm formation in the upper respiratory tract lead to recurrent infections.
- A nasal vaccine inducing secretory IgA to prevent NTHi biofilms is highly desirable.
Purpose of the Study:
- To develop and evaluate a cationic cholesteryl pullulan-based (cCHP) nanogel nasal vaccine containing the conserved NTHi surface antigen P6 (cCHP-P6).
- To assess the vaccine's ability to induce protective mucosal immunity against NTHi.
Main Methods:
- Development of a cCHP nanogel vaccine incorporating the NTHi P6 antigen.
- Nasal immunization of mice with cCHP-P6.
- Measurement of P6-specific IgA in mucosal fluids (nasal and middle ear washes).
- Assessment of NTHi binding, biofilm inhibition, and protection against intranasal NTHi challenge.
- Evaluation of vaccine-induced IgA against clinical NTHi isolates and in an in vitro human nasal epithelial model.
Main Results:
- Nasal immunization with cCHP-P6 successfully induced P6-specific IgA in mucosal fluids.
- The induced IgA directly bound to NTHi via P6, inhibiting biofilm formation.
- cCHP-P6 vaccination protected mice against NTHi challenge by reducing nasal colonization.
- Vaccine-induced IgA demonstrated efficacy against diverse NTHi clinical isolates and inhibited bacterial attachment in vitro.
Conclusions:
- The cCHP-P6 nanogel nasal vaccine is a promising candidate for preventing NTHi-induced infectious diseases.
- The vaccine effectively induces protective mucosal immunity in the airway.
- Potential applications include preventing otitis media, sinusitis, and pneumonia caused by NTHi.
Abstract:
Nontypeable Haemophilus influenzae (NTHi) strains form a major group of pathogenic bacteria that colonizes the nasopharynx and causes otitis media in young children. At present, there is no licensed vaccine for NTHi. Because NTHi colonizes the upper respiratory tract and forms biofilms that cause subsequent infectious events, a nasal vaccine that induces NTHi-specific secretory IgA capable of preventing biofilm formation in the respiratory tract is desirable. Here, we developed a cationic cholesteryl pullulan-based (cCHP nanogel) nasal vaccine containing the NTHi surface antigen P6 (cCHP-P6) as a universal vaccine antigen, because P6 expression is conserved among 90% of NTHi strains. Nasal immunization of mice with cCHP-P6 effectively induced P6-specific IgA in mucosal fluids, including nasal and middle ear washes. The vaccine-induced P6-specific IgA showed direct binding to the NTHi via the surface P6 proteins, resulting in the inhibition of NTHi biofilm formation. cCHP-P6 nasal vaccine thus protected mice from intranasal NTHi challenge by reducing NTHi colonization of nasal tissues and eventually eliminated the bacteria. In addition, the vaccine-induced IgA bound to different NTHi clinical isolates from patients with otitis media and inhibited NTHi attachment in a three-dimensional in vitro model of the human nasal epithelial surface. Therefore, the cCHP-P6 nanogel nasal vaccine induced effective protection in the airway mucosa, making it a strong vaccine candidate for preventing NTHi-induced infectious diseases, such as otitis media, sinusitis, and pneumonia.
