Nanogel-based nasal ghrelin vaccine prevents obesity.

Obesity is associated with multiple comorbidities such as cardiovascular diseases and has a huge economic impact on the health-care system. However, the treatment of obesity remains insufficient in terms of efficacy, tolerability, and safety. Here we created a nasal vaccine against obesity for the first time. To avoid the injectable administration-caused pain and skin-related adverse event, we focused on the intranasal route of antigen delivery. We developed a vaccine antigen (ghrelin-PspA (pneumococcal surface protein A)), which is a recombinant fusion protein incorporating ghrelin, a hormone that stimulates food intake and decreases energy expenditure, and PspA, a candidate of pneumococcal vaccine as a carrier protein. Ghrelin-PspA antigen was mixed with cyclic di-GMP adjuvant to enhance the immunogenicity and incorporated within a nanometer-sized hydrogel for the effective antigen delivery. Intranasal immunization with ghrelin-PspA vaccine elicited serum immunoglobulin G antibodies against ghrelin and attenuated body weight gain in diet-induced obesity mice. This obesity-attenuating effect was caused by a decrease in fat accumulation and an increase in energy expenditure that was partially due to an increase in the expression of mitochondrial uncoupling protein 1 in brown adipose tissue. The development of this nasal vaccine provides a new strategy for the prevention and treatment of obesity.

Nanogel-based pneumococcal surface protein A nasal vaccine induces microRNA-associated Th17 cell responses with neutralizing antibodies against Streptococcus pneumoniae in macaques.

We previously established a nanosized nasal vaccine delivery system by using a cationic cholesteryl group-bearing pullulan nanogel (cCHP nanogel), which is a universal protein-based antigen-delivery vehicle for adjuvant-free nasal vaccination. In the present study, we examined the central nervous system safety and efficacy of nasal vaccination with our developed cCHP nanogel containing pneumococcal surface protein A (PspA-nanogel) against pneumococcal infection in nonhuman primates. When [(18)F]-labeled PspA-nanogel was nasally administered to a rhesus macaque (Macaca mulatta), longer-term retention of PspA was noted in the nasal cavity when compared with administration of PspA alone. Of importance, no deposition of [(18)F]-PspA was seen in the olfactory bulbs or brain. Nasal PspA-nanogel vaccination effectively induced PspA-specific serum IgG with protective activity and mucosal secretory IgA (SIgA) Ab responses in cynomolgus macaques (Macaca fascicularis). Nasal PspA-nanogel-induced immune responses were mediated through T-helper (Th) 2 and Th17 cytokine responses concomitantly with marked increases in the levels of miR-181a and miR-326 in the serum and respiratory tract tissues, respectively, of the macaques. These results demonstrate that nasal PspA-nanogel vaccination is a safe and effective strategy for the development of a nasal vaccine for the prevention of pneumonia in humans.