Vaccine 33 (2015) 2399–2405 Contents lists available at ScienceDirect Vaccine j our na l ho me page: www.elsevier.com/locate/vaccine Review Advances and challenges in mucosal adjuvant technology Daniel Newsted a , Firouzeh Fallahi b , Ashkan Golshani c , Ali Azizi d,e,* a Department of Biochemistry and Biomedical Sciences, McMaster University, 1280 Main St W, Hamilton, ON, Canada b Health Canada, 2301 Midland Ave, Toronto, ON, Canada c Department of Biology, Carleton University, 1125 Colonel by Drive, Ottawa, ON, Canada d Department of Pathology and Laboratory Medicine, University of Ottawa, 451 Smyth Rd, Ottawa, ON, Canada e Department of Biotechnology, University of Ontario Institute of Technology, Toronto, ON, Canada a r t i c l e i n f o Article history: Received 10 December 2014 Received in revised form 17 March 2015 Accepted 26 March 2015 Available online 10 April 2015 Keywords: Adjuvants Nanoparticles Mucosal vaccines Immune response a b s t r a c t Adjuvants play attractive roles in enhancement of immune response during vaccination; however, due to several challenges, only a limited number of adjuvants are licensed by health authorities. The lack of an effective mucosal adjuvant is even more significant as none of the licensed adjuvants revealed a strong enhancement in immune system after mucosal administration. Over the past two decades, several mucosal adjuvants have been developed to deliver antigens to the target cells in the mucosal immune system and increase specific immune responses. However, the safety and efficacy of these adjuvants for testing in human trials is still an important issue, requiring further study. In this article, we briefly review the challenges associated with most common mucosal adjuvants and discuss potential strategies for targeting the mucosal immune system. © 2015 Elsevier Ltd. All rights reserved. 1. Introduction The mucosal immune system appears to be the major target of most human pathogens [1–3]. Therefore, a specific, robust pre- existing immune response in mucosal compartments might be able to prevent infection. However, conflicting views regarding the mechanisms of protection at mucosal sites attests to our lack of knowledge in understanding the human mucosal immune sys- tem [3,4]. Another major obstacle in the development of mucosal vaccines is that antigens applied to mucosal membranes gener- ally induce relatively weak immune responses [3,4]. To generate robust immune responses, a potent mucosal adjuvant and/or deliv- ery system is required. Adjuvants modulate the immune response by promoting the prolonged release of antigens, targeting APCs, and directing the immune response towards a Th1 or Th2 response. Therefore the incorporation of an appropriate adjuvant in vaccine formulations will assist in stronger induction of a protective immu- nity [4,5]. The ability of an adjuvant to accomplish its task depends on its structure and physiochemical properties in relation to cell recep- tors and the type of antigen. Genes of mucosal adjuvants include protein toxins, recombinant protein subunits, and nucleic acids * Corresponding author at: University of Ottawa, Department of Pathology and Laboratory Medicine, 46 Colonnade Rd, Toronto, Canada M2K 0A8. Tel.: +1 416 508 5846. E-mail addresses: aazizi@uottawa.ca, aliazizi555@yahoo.ca (A. Azizi). among others, each with the potential to augment the efficacy of mucosal vaccines [4,6]. Mucosal adjuvants can be divided into two classes (immunostimulators and vehicle delivery systems). Immunostimulatory adjuvants (e.g. LT, CT, TLR ligands, cytokines) are able to activate innate immunity directly, while vehicle delivery systems (e.g. virus-like particles, liposomes, and archeosomes) pro- tect antigens from harsh condition and target M-cells in mucosal surfaces [7]. The mucosal administration route, target, and human clinical testing (phase I, II, and III trials) of the described adjuvants are presented in Table 1. Several studies have highlighted potential candidate adjuvants that have demonstrated utility in stimulating a mucosal immune response. The majority of adjuvants licensed by the FDA were alum- based; however, the tendency of alum for depot formation and its low immunogenicity convinced health authorities to approve the use of other safe adjuvants [8]. The failure of the classical adjuvants in the induction of the desired mucosal immune response drives the development of new carriers that will safely deliver a selected antigen and/or induce a specific immune response. The follow- ing sections discuss current studies that assess promising mucosal adjuvants for the development of effective mucosal vaccines. 2. Immunostimulator adjuvants 2.1. LT and CT The Escherichia coli heat labile enterotoxin (LT) and the cholera toxin (CT) have been investigated as possible vaccine adjuvants http://dx.doi.org/10.1016/j.vaccine.2015.03.096 0264-410X/© 2015 Elsevier Ltd. All rights reserved.