Induction of secretory immunity and memory at mucosal surfaces

Mucosal epithelia comprise an extensive vulnerable barrier which is reinforced by numerous innate defence mechanisms cooperating intimately with adaptive immunity. Local generation of secretory IgA (SIgA) constitutes the largest humoral immune system of the body. Secretory antibodies function both by performing antigen exclusion at mucosal surfaces and by virus and endotoxin neutralization within epithelial cells without causing tissue damage. SIgA is thus persistently containing commensal bacteria outside the epithelial barrier but can also target invasion of pathogens and penetration of harmful antigens. Resistance to toxin-producing bacteria such as Vibrio cholerae and enterotoxigenic Escherichia coli appears to depend largely on SIgA, and so does herd protection against horizontal faecal-oral spread of enteric pathogens under naive or immunized conditions-with a substantial innate impact both on cross-reactivity and memory. Like natural infections, live mucosal vaccines or adequate combinations of non-replicating vaccines and mucosal adjuvants, give rise not only to SIgA antibodies but also to longstanding serum IgG and IgA responses. However, there is considerably disparity with regard to migration of memory/effector cells from mucosal inductive sites to secretory effector sites and systemic immune organs. Also, although immunological memory is generated after mucosal priming, this may be masked by a self-limiting response protecting the inductive lymphoid tissue in the gut. The intranasal route of vaccine application targeting nasopharynx-associated lymphoid tissue may be more advantageous for certain infections, but only if successful stimulation is achieved without the use of toxic adjuvants that might reach the central nervous system. The degree of protection obtained after mucosal vaccination ranges from reduction of symptoms to complete inhibition of re-infection. In this scenario, it is often difficult to determine the relative importance of SIgA versus serum antibodies, but infection models in knockout mice strongly support the notion that SIgA exerts a decisive role in protection and cross-protection against a variety of infectious agents. Nevertheless, relatively few mucosal vaccines have been approved for human use, and more basic work is needed in vaccine and adjuvant design, including particulate or live-vectored combinations.