Abstract
Vaccine adjuvants have been reported to induce both mucosal and systemic immunity when applied to mucosal surfaces and this dual response appears important for protection against certain pathogens. Despite the potential advantages, however, no mucosal adjuvants are currently approved for human use. Evaluating compounds as mucosal adjuvants is a slow and costly process due to the need for lengthy animal immunogenicity studies. We have constructed a library of 112 intranasal adjuvant candidate formulations consisting of oil-in-water nanoemulsions that contain various cationic and nonionic surfactants. To facilitate adjuvant development we first evaluated this library in a series of high-throughput, in vitro assays for activities associated with innate and adaptive immune activation in vivo. These in vitro assays screened for the ability of the adjuvant to bind to mucin, induce cytotoxicity, facilitate antigen uptake in epithelial and dendritic cells, and activate cellular pathways. We then sought to determine how these parameters related to adjuvant activity in vivo. While the in vitro assays alone were not enough to predict the in vivo adjuvant activity completely, several interesting relationships were found with immune responses in mice. Furthermore, by varying the physicochemical properties of the surfactant components (charge, surfactant polar head size and hydrophobicity) and the surfactant blend ratio of the formulations, the strength and type of the immune response generated (TH1, TH2, TH17) could be modulated. These findings suggest the possibility of using high-throughput screens to aid in the design of custom adjuvants with unique immunological profiles to match specific mucosal vaccine applications.
Highlights
Vaccines are a fundamental and important means of protection against pathogens
A series of NEs were produced using the cationic surfactant cetylpyridinium chloride (CPC) in combination with various nonionic surfactants, as our prior work demonstrated strong adjuvant activity for a CPC/ Tween80 formulation that was dependent on the presence of CPC [8, 11, 13]
Other series of NEs were made with different cationic surfactants including benzalkonium chloride (BAC), cetrimonium chloride/bromide (CTAC/CTAB), stearalkonium chloride (SAC), benzethonium chloride (BEC), and dioctadecyl dimethyl ammonium chloride/ bromide (DODAC/DODAB). (Fig 1A)
Summary
The mucosal route of vaccination can offer a number of advantages over intramuscular (IM) and subcutaneous administration, such as the potential to induce broader immune responses (including cellular, mucosal and systemic immunity) as opposed to the antibody responses that predominate with most parenteral vaccines [1,2,3,4] For this reason, there is an evolving consensus that mucosal vaccines will be necessary for effective prophylaxis against pathogens whose path of entry is through mucosal surfaces. As mucosal immune surfaces exhibit significant crosstalk, induction of an immune response at one mucosal site has been shown to elicit protective immunity at distant mucosal surfaces as well, making mucosal vaccines promising candidates for prophylaxis against sexually transmitted diseases [1, 5, 6] These surfaces, such as the nasal mucosa, present a high density of immune cells which are accessible [6]. The lack of in vitro assays that can predict in vivo immunogenicity makes mucosal vaccine evaluation burdensome, as it necessitates lengthy immunization studies with large numbers of animals
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