Animals immunized i.d. with gp140-adsorbed NP enhanced serum IgG production after a single prime, and this effect was comparable Buparlisib molecular weight or better than that induced by Alum. Surprisingly, CpGB co-adsorbed to NP with either TT or gp140 did not enhance antibody production further
(data not shown). Alum salts are well known strong parenteral adjuvants which are components of an array of licensed human vaccines [8]. However, to date they have not been successfully used for mucosal vaccination. Reactogenicity of Alum salts is an important characteristic of their adjuvanticity. Their mechanism of action has been associated with induction of local uric acid crystals [33] and inflammasome activation with release of IL-1β by macrophages and DC [34] and [35]. Such reactogenicity is deemed too potent for mucosal use [36]. We do not know
the mechanism of in vivo enhancement of humoral responses by gp140-adsorbed NP but since find protocol NP alone showed little if any reactogenicity in the skin of mice when compared to that induced by Alum, the mechanism of action may be highly different to that of Alum salts. The efficient cell internalization of NP and their subsequent localization within the endolysosome compartment in the absence of co-stimulatory molecule up-regulation and cytokine/chemokine production by DC clearly suggest a different mechanism. Thus, the lack of Alum-type reactogenicity of NP makes them good potential candidates for mucosal immunization. This may be particularly important where potential inflammation and edema have been associated with induction of Bell’s palsy [37]. Although no adverse effects were observed on nasal administration of YC-NaMA NP in mice, further experiments will be required to confirm the safety of these NP after intranasal application in humans, in particular the assessment of the effect of surfactants on the nasal olfactory and respiratory epithelia.
Nevertheless, the amount of NaMA, a naturally occurring fatty acid in human nasal fluid [28], used in this formulation was very low (0.025%), and as such the likelihood for toxicity is considered to be small. We immunized mice with gp140-adsorbed YC-NaMA using different nearly routes of immunization, including nasal, vaginal and rectal. The responses to gp140 via vaginal and rectal mucosal compartments were weak or null (data not shown). Reasons for this unresponsiveness in these mucosas may include physical properties of mucus (pore size and rheological factors) [38], and/or their paucity of follicle associated epithelium when compared to nasal associated lymphoid tissue (NALT). Nasal immunization, in contrast, potently induced both systemic and mucosal humoral immune responses. Intranasal immunization has been described as an effective route to induce systemic and mucosal immune responses to Ag, in particular in the urogenital tract, with scarce if any induction in the gut [39] and [40].
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