Intranasal DNA Vaccine for Protection against Respiratory Infectious Diseases: The Delivery Perspectives

Xu, Yingying; Yuen, Pak-Wai; Lam, Jenny Ka-Wing

Enterotoxins are protein exotoxin released by pathogens that infect the gut. Enterotoxin-based mucosal adjuvants are the most potent and well-established strategy for the induction of both mucosal and systemic immunity to co-administered protein antigens [180] . Heat-labile enterotoxin (LT) from E. coli and cholera enterotoxin (CT) are very potent adjuvants but they are too toxic to be used in human. Therefore, detoxified mutants of enterotoxins have been produced by site-directed mutagenesis and they are extensively investigated as adjuvants for mucosal vaccine including intranasal vaccine. Intranasal antigen immunization with LT mutant adjuvants can provide effective protection against infectious diseases in animals [181] [182] [183] [184] [185] . It is suggested that the LT mutant adjuvants could induce potent cytotoxic T lymphocyte responses. The mechanism of action is believed to arise from enhanced permeation of antigens across epithelial barriers and a marked increase in antigen presentation by APCs [66] . Mutants of CT have also showed strong adjuvant activity [73, 186, 187] , and could retain good adjuvant function when administered intranasally [73] . It is expected that LT mutants and CT mutants have similar mechanisms of adjuvant activities [58] . The major concern with the intranasal administration of mutant LT or CT is that these toxin derivatives may gain access into the central nervous system through the olfactory nerve. It has been reported that both native and mutant LT used as adjuvants were associated with the development of Bell's palsy following intranasal delivery in humans [70, 71, 188] . The risk of enterotoxin as mucosal adjuvant for intranasal administration is already discussed in Section 3.4. Lipopolysaccharides (LPS) are the major component of the outer membrane of Gram-negative bacteria, and could elicit strong immune response. However, they are also highly toxic. In order to make them safe and suitable as vaccine adjuvants, LPS derivatives are produced to reduce the endotoxic effect but to retain their immunostimulatory function. Monophosphoryl lipid A (MPL) is one example of LPS derivative that is investigated as vaccine adjuvant. MPL is prepared by removal of a phosphate and fatty acid group from the lipid A of Salmonella minnesola. MPL is thought to interact with Toll-like receptor 4 (TLR-4) on APCs. It has been demonstrated that MPL could activate macrophages, increase their cytokine secretion and hence immune response [216] [217] [218] [219] [220] . Regarding safety, MPL appears to retain the immunogenic activity of LPS but with significantly reduced toxicity [221] . MPL has been extensively evaluated in the clinic as adjuvants for various diseases including infectious diseases with an acceptable profile of adverse effects [182] . MPL has been used successfully as a mucosal adjuvant when formulated with liposomes or virosomes for intranasal administration in animals [222] [223] [224] .