Nanogel antigenic protein-delivery system for adjuvant-free intranasal vaccines

Abstract

Nanotechnology is an innovative method of freely controlling nanometre-sized materials. Recent outbreaks of mucosal infectious diseases have increased the demands for development of mucosal vaccines because they induce both systemic and mucosal antigen-specific immune responses. Here we developed an intranasal vaccine-delivery system with a nanometre-sized hydrogel ('nanogel') consisting of a cationic type of cholesteryl-group-bearing pullulan (cCHP). A non-toxic subunit fragment of Clostridium botulinum type-A neurotoxin BoHc/A administered intranasally with cCHP nanogel (cCHP-BoHc/A) continuously adhered to the nasal epithelium and was effectively taken up by mucosal dendritic cells after its release from the cCHP nanogel. Vigorous botulinum-neurotoxin-A-neutralizing serum IgG and secretory IgA antibody responses were induced without co-administration of mucosal adjuvant. Importantly, intranasally administered cCHP-BoHc/A did not accumulate in the olfactory bulbs or brain. Moreover, intranasally immunized tetanus toxoid with cCHP nanogel induced strong tetanus-toxoid-specific systemic and mucosal immune responses. These results indicate that cCHP nanogel can be used as a universal protein-based antigen-delivery vehicle for adjuvant-free intranasal vaccination.

Cationic pullulan nanogel as a safe and effective nasal vaccine delivery system for respiratory infectious diseases

“…11 , 12 In addition, cCHP–BoHc was retained at the nasal mucosa for more than 48 hours after nasal administration, 10 and cCHP–BoHc remained in the nasal mucosa longer than BoHc alone. 10 BoHc antigens were released gradually from the cCHP nanogel, beginning within 1 hour after nasal administration, and antigen release continued over a 12-hour period. 10 …”

“…9 In our studies, recombinant heavy chain from Botulinum type A neurotoxin (BoHc)—a receptor-binding but non-toxin-binding fragment of this neurotoxin—was effectively incorporated into the spherical cCHP particles. 10 Because of the cationic nature of cCHP nanogel, cCHP–BoHc bound electrostatically to the negatively charged mucosal epithelium of the nasal cavity, including the nasopharynx-associated lymphoid tissue, an inductive tissue for the initiation of antigen-specific immune responses. 11 , 12 In addition, cCHP–BoHc was retained at the nasal mucosa for more than 48 hours after nasal administration, 10 and cCHP–BoHc remained in the nasal mucosa longer than BoHc alone.…”

“…10 Because of the cationic nature of cCHP nanogel, cCHP–BoHc bound electrostatically to the negatively charged mucosal epithelium of the nasal cavity, including the nasopharynx-associated lymphoid tissue, an inductive tissue for the initiation of antigen-specific immune responses. 11 , 12 In addition, cCHP–BoHc was retained at the nasal mucosa for more than 48 hours after nasal administration, 10 and cCHP–BoHc remained in the nasal mucosa longer than BoHc alone. 10 BoHc antigens were released gradually from the cCHP nanogel, beginning within 1 hour after nasal administration, and antigen release continued over a 12-hour period.…”

“…10 BoHc antigens were released gradually from the cCHP nanogel, beginning within 1 hour after nasal administration, and antigen release continued over a 12-hour period. 10 …”

“…10 Approximately 40% of the dendritic cell population located below the basement membrane of the nasal epithelium and lamina propria of the nasal cavity acquired BoHc antigen by 6 hours after nasal administration of cCHP–BoHc. 10 In contrast, 2% or fewer dendritic cells engulfed antigen after nasal administration of naked BoHc.…”