Intranasal Immunization With a c-di-GMP-Adjuvanted Acellular Pertussis Vaccine Provides Superior Immunity Against Bordetella pertussis in a Mouse Model

Abstract

Pertussis, caused by the gram-negative bacterium Bordetella pertussis, is a highly contagious respiratory disease. Intranasal vaccination is an ideal strategy to prevent pertussis, as the nasal mucosa represents the first-line barrier to B. pertussis infection. The current intramuscular acellular pertussis (aP) vaccines elicit strong antibody and Th2-biased responses but not necessary cellular and mucosal immunity. Here, we formulated two cyclic dinucleotide (CDN)-adjuvanted aP subunit vaccines, a mammalian 2’,3’-cGAMP-adjuvanted aP vaccine and a bacterial-derived c-di-GMP-adjuvanted aP vaccine, and evaluated their immunogenicity in a mouse model. We found that the aP vaccine alone delivered intranasally (IN) induced moderate systemic and mucosal humoral immunity but weak cellular immunity, whereas the alum-adjuvanted aP vaccine administered intraperitoneally elicited higher Th2 and systemic humoral immune responses but weaker Th1 and Th17 and mucosal immune responses. In contrast, both CDN-adjuvanted aP vaccines administered via the IN route induced robust humoral and cellular immunity systemically and mucosally. Furthermore, the c-di-GMP-adjuvanted aP vaccine generated better antibody production and stronger Th1 and Th17 responses than the 2′,3′-cGAMP-adjuvanted aP vaccine. In addition, following B. pertussis challenge, the group of mice that received IN immunization with the c-di-GMP-adjuvanted aP vaccine showed better protection than all other groups of vaccinated mice, with decreased inflammatory cell infiltration in the lung and reduced bacterial burden in both the upper and lower respiratory tracts. In summary, the c-di-GMP-adjuvanted aP vaccine can elicit a multifaceted potent immune response resulting in robust bacterial clearance in the respiratory tract, which indicates that c-di-GMP can serve as a potential mucosal adjuvant for the pertussis vaccine.

Opposing effects of acellular and whole cell pertussis vaccines onBordetella pertussisbiofilm formation, Siglec-F+ neutrophil recruitment and bacterial clearance in mouse nasal tissues

“…Serological responses to Bp are used to determine vaccine efficacy and protection in humans (33)and animals (13, 34)and are quantified in nasal secretions or nasal lavage. We found that antibodies in the NL were at the limit of detection, with antibodies in the NT significantly (∼1-2 log) increased in wPV immunized mice.…”

Porphyromonas gingivalis induces an inflammatory response via the cGAS-STING signaling pathway in a periodontitis mouse model

“…The flow cytometry procedure was performed according to a previous protocol with minor modifications ( Jiang et al, 2022a ). Procedure details are also provided in the Supplementary material 2.5 .…”

Vaccine Strategies to Elicit Mucosal Immunity

“…Oral mRNA vaccines are also being developed [90]. Several intranasal vaccines that combine protein subunits and adjuvants are being designed and tested against pertussis, tuberculosis, and SARS-CoV-2 [91][92][93][94][95][96]. Outer membrane vesicles, which have previously been used in parenteral meningitis B vaccines, are now being used for intranasal pertussis and SARS-CoV-2 vaccines [97][98][99].…”