Mucosal vaccine delivery: is M cell-targeted delivery effective in the mucosal lumen?

A priori, it would seem logical to use targeted delivery to enhance the effectiveness of a mucosal vaccine. This notion is based in part on observations that selective capture of microbes by M cell surface receptors can help drive transport of antigen into lymphoid tissues and induce protective mucosal immune responses such as secretory IgA. However, the basic receptor capture principle alone might not be sufficient to drive mucosal vaccines to clinical practice; indeed, synthetic mucosal vaccines have not yet become part of the mainstream vaccine armamentarium. Therefore, it may be appropriate to re-examine the criteria for evaluating mucosal vaccine delivery and the strategies used for developing effective delivery systems. Taking into account the dynamics of the mucosal lumen, additional approaches may be incorporated into existing vaccine development strategies. Here, we consider the potential for examining forces such as long-range electrostatic interactions. It is estimated that most infectious diseases enter the body through mucosal routes, so the development of effective mucosal vaccines is an important medical goal. Vaccines against mucosal pathogens fall into two general categories. The first category is live attenuated organisms, such as attenuated poliovirus, rotavirus, or cold-adapted influenza, or attenuated bacteria such as Salmonella typhi. The induction of immunity is dependent on the ability of the live organism to resemble pathogenic infection, and trigger protective immunity. In the case of mucosal infections, this immune response includes both T cell responses as well as serum IgG and mucosal IgA. This discussion will focus mainly on mucosal IgA responses; a fuller discussion of mucosal vaccine induction of cellular immunity is published elsewhere [1]. While live attenuated vaccines are useful, they are not easily developed for all mucosal pathogens, so a second category includes killed microbes, extracts, and recombinant forms of microbial antigens. For example, killed versions of influenza and polio, and purified Salmonella typhi polysaccharide have been in use for decades. However, in contrast to live attenuated vaccines that are given orally, these killed or extracted forms of vaccines are injected into non-mucosal tissues (e.g., intramuscular). While this avoids the potential risks of administering live potentially pathogenic microbes, it also has the disadvantage that it mainly induces a central IgG immune response and no mucosal immunity. That is, while serum IgG can provide some protection, it is not as potent at mucosal surfaces as secretory IgA. Thus, there remains a need for a mucosal vaccination technology that can effectively induce protective mucosal immunity. Mucosal lymphoid tissues such as intestinal Peyer’s patches and tonsils are sites for the induction and development of mucosal immunity, especially secretory IgA [2-5]. So it would seem that the best strategy for mucosal immunization would be to target the delivery of vaccine antigens to these lymphoid tissues [6,7]. The entry route to these tissues is known to be through the specialized epithelial M cells, which can capture large (1 to 10 micron) particles and transcytose them to the underlying lymphoid tissues where antigen presenting cells pick up the delivered package and trigger the sequence of events leading to mucosal immune responses.