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

Abstract

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 [18F]-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 [18F]-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.

Delivery strategies to enhance oral vaccination against enteric infections

“…A novel nanogel technology developed by Kiyono and colleagues enables the persistence of vaccine material in the nasal passage after administration, ensuring adequate antigen exposure [249,250]. This system has recently been evaluated in a non-human primate model where intra-nasal administration of pneumococcal surface protein A in nanogel led to robust mucosal and systemic immune responses and provided protection from Streptococcus pneumoniae challenge [251]. While, there are no published data on the efficacy of the nanogel by the oral route, its application as an oral delivery strategy has been patented [252].…”

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

“…32 , 33 When cCHP–PspA nanogel was nasally administered 3 times at 1-week intervals to mice, antigen-specific IgG levels were significantly elevated in the serum and bronchial fluids, and antigen-specific SIgA levels were increased in nasal fluids. In contrast, administration of PspA antigen alone failed to induce any antigen-specific antibodies.…”

“…33 When a cCHP–PspA nanogel was nasally administered to rhesus macaques 5 times at 2-week intervals, serum levels of PspA-specific IgG were significantly elevated and then gradually decreased over a period of 8 months. In addition, the production of PspA-specific SIgA was induced in both nasal washes and bronchoalveolar lavage fluids and then decreased in the same manner as did PspA-specific IgG in the serum.…”

“…Furthermore, the cCHP–PspA nanogel induced PspA-specific antibodies with neutralizing activity against S. pneumoniae . 33 In a positron emission tomography (PET) study combined with MR imaging to monitor the deposition and fate of vaccine antigens in the nasal cavity, nasally administered 18 F-labeled PspA ( 18 F-PspA) showed prolonged retention in the nasal epithelium (that is, for as long as 6 hours), compared with PspA antigen alone (Fig. 2).…”

“…Therefore, cCHP–PspA nanogel exhibits promising characteristics of a safe and effective nasal vaccine candidate for the prevention and control of pneumonia. 33

10.1080/21645515.2018.1461298-F0002Figure 2.Distribution of nasally administered 18 F-labeled PspA, a surface protein of S. pneumoniae, in cCHP nanogels or PBS by positron emission tomography and magnetic resonance imaging. No deposition of 18 F-labeled PspA in olfactory bulb and brain as indicated with arrows.

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