A bivalent outer membrane vesicle-based intranasal vaccine to prevent infection of periodontopathic bacteria

Ryoma Nakao; Satoru Hirayama; Takehiro Yamaguchi; Hidenobu Senpuku; Hideki Hasegawa; Tadaki Suzuki; Yukihiro Akeda; Makoto Ohnishi

doi:10.1016/j.vaccine.2023.05.058

A bivalent outer membrane vesicle-based intranasal vaccine to prevent infection of periodontopathic bacteria

Vaccine. 2023 Jul 5;41(30):4369-4383. doi: 10.1016/j.vaccine.2023.05.058. Epub 2023 Jun 9.

Authors

Ryoma Nakao¹, Satoru Hirayama², Takehiro Yamaguchi³, Hidenobu Senpuku⁴, Hideki Hasegawa⁵, Tadaki Suzuki⁶, Yukihiro Akeda³, Makoto Ohnishi³

Affiliations

¹ Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan. Electronic address: ryoma73@niid.go.jp.
² Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Division of Microbiology and Infectious Diseases, Niigata University Graduate School of Medical and Dental Sciences, Niigata 951-8514, Japan.
³ Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.
⁴ Department of Bacteriology I, National Institute of Infectious Diseases, Tokyo 162-8640, Japan; Department of Microbiology and Immunology, School of Dentistry at Matsudo, Nihon University, Chiba 271-8587, Japan.
⁵ Department of Influenza Virus Research Center, National Institute of Infectious Diseases, Tokyo 208-0011, Japan.
⁶ Department of Pathology, National Institute of Infectious Diseases, Tokyo 162-8640, Japan.

PMID: 37302966
DOI: 10.1016/j.vaccine.2023.05.058

Abstract

Periodontal disease has become a serious public health problem, not only causing tooth loss, but also inducing chronic disorders of extra-oral organs. The present study assessed an intranasal vaccine strategy to prevent periodontal disease using outer membrane vesicles (OMVs) of two major periodontopathic bacteria, Porphyromonas gingivalis (Pg) and Aggregatibacter actinomycetemcomitans (Aa). We compared the morphology, composition, and immune activity between OMVs of Pg strain ATCC 33277 and Aa strain Y4. Aa OMVs had a smoother surface and stronger lipid A activity compared to Pg OMVs. The in vitro immune activity elicited by Aa OMVs in macrophage-like cells was remarkably stronger than that of Pg OMVs. Intranasal immunization of mice with Aa OMVs alone resulted in robust, humoral immune responses in blood and saliva. Despites the intrinsically low mucosal immunogenicity of Pg OMVs alone, using Aa OMVs as a mucosal adjuvant strongly enhanced Pg-specific immune responses, resulting in both serum IgG and salivary IgA, both of which aggregated Pg and Aa cells. Furthermore, Aa OMVs were found to be a more potent mucosal adjuvant than Poly(I:C) in the context of enhancing the production of Pg-specific IgG (especially IgG2a) and IgA. In addition, in a randomized, blinded study, mice oral challenged with Pg and Aa after intranasal immunization with Pg OMVs and Aa OMVs had significantly decreased numbers of both microorganisms compared to mock-immunized mice. Furthermore, in an intracerebral injection mouse model, there were no serious adverse effects on the brain even after administrating a dose of OMVs as same as that used for intranasal administration. Taken together, the bivalent OMV intranasal vaccine may be effective in preventing colonization of periodontopathic bacteria in the oral cavity and related systemic disorders associated with periodontal diseases.

Keywords: Aggregatibacter actinomycetemcomitans; Outer membrane vesicles (OMVs); Periodontal disease; Porphyromonas gingivalis; Vaccines.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adjuvants, Immunologic
Administration, Intranasal
Animals
Antibodies, Bacterial
Immunoglobulin A
Immunoglobulin G
Mice
Periodontal Diseases*
Porphyromonas gingivalis
Vaccines, Combined

Substances

Vaccines, Combined
Adjuvants, Immunologic
Immunoglobulin G
Immunoglobulin A
Antibodies, Bacterial