Research paper
Mucosal vaccination: Lung versus nose

https://doi.org/10.1016/j.vetimm.2011.03.004Get rights and content

Abstract

The induction of potent mucosal immune responses able to prevent the establishment of infection at the onset of mucosal pathogen colonisation represents a desirable but challenging goal for vaccine development. Here we compare nasal vaccine delivery with intra-pulmonary vaccination using a sheep lymphatic cannulation model. Our results demonstrate that nasal delivery of a non-infective ISCOMATRIX® influenza vaccine does not induce primary immune responses in the lymph draining the nasal lymph nodes, suggesting that local immune responses in the lymph nodes draining the nasal cavity are relatively weak. However, this mode of delivery can boost existing immunity in the nasal lymph. Using the same adjuvant we were able to induce very potent immune responses in both blood and bronchoalveolar lavage (BAL), following intra-pulmonary delivery of ISCOMATRIX® influenza vaccine, even when very small doses of antigen were employed. Lung delivery could also induce comparable immune responses against other recombinant antigens mixed with ISCOMATRIX® adjuvant and could therefore become a method of choice for the induction of immunity to mucosal pathogens infecting the lower respiratory tract.

Introduction

The majority of important pathogens either enter the host via, or directly infect, mucosal surfaces. These include gastrointestinal pathogens such as Helicobacter pylori, Vibrio cholerae, Escherichia coli; influenza virus in the respiratory tract and Chlamydia trachomatis in the urogenital tract (Holmgren and Czerkinsky, 2005, Holmgren et al., 2003a). The induction of mucosal immune responses able to neutralise such pathogens prior to their establishment within the host (Clements et al., 1986), is one of the most pressing challenges of modern vaccine development. However, while the majority of currently approved vaccines are delivered by injection, subcutaneously delivered vaccines are often very poor at inducing immune responses at mucosal surfaces. As a result it seems logical that mucosal immunity should be pursued by mucosal vaccine delivery. However, mucosal surfaces are generally highly exposed to environmental antigens due to the large surface area combined with regular flow of antigens across these surfaces. Besides pathogen-derived antigens, mucosal surfaces are therefore also exposed to a wide range of benign antigens in food or inhaled air, against which mounting an immune response would be at best a waste of resources and at worst detrimental to the host. Immune responses at mucosal sites are therefore tightly regulated and the induction of mucosal immune responses covering a wide range of mucosal surfaces remains elusive (reviewed in (Meeusen et al., 2004)). This distinction can occur on the basis of the presence of danger signals (Matzinger, 2002) such as pathogen associated molecular patterns (PAMPs) recognised by an ever growing set of pathogen recognition receptors (Iwasaki and Medzhitov, 2010, Medzhitov and Janeway, 2000).

While mucosal surfaces are very diverse both in terms of their nature and relative exposure to pathogens, there are also some suggestions, based primarily on data obtained in mice, that all mucosal surfaces are linked together as part of the “common mucosal immune system” (Iijima et al., 2001). According to this theory, the induction of immune responses at one mucosal site will spread to other mucosal sites. For example immune responses induced in the gut were observed to also affect the mammary gland (Brandtzaeg, 2010). Other studies however, have suggested that the common mucosal immune system is not absolute and that there are important limitations to our ability to induce immune responses at one mucosal site by vaccinating another site (Holmgren et al., 2003b). More recently the term “integrated mucosal immune system” has also been used to indicate that some mucosal sites may be linked, but that mucosal immunity does not necessarily comprise a single system covering all mucosal sites. While the links between immunity at different mucosal sites are not well understood, some of the key mechanisms in the induction of mucosal immunity can be elucidated using large animal models, which have the considerable advantage of providing easy access to all mucosal sites (Hein et al., 2004, Schwartz-Cornil et al., 2006, Yen et al., 2006, Yen et al., 2009). Research of mucosal immunity in large animals may not only be of benefit in the development of better veterinary vaccines, but also is very important for improving vaccination strategies for human infections and disease (Hein and Griebel, 2003). Here we consider what has been learned from studies in sheep about immune induction through nasal and pulmonary vaccination.

Section snippets

Nasal vaccine delivery

There is a large body of evidence showing that nasal vaccination in the mouse induces mucosal immune responses at different sites, particularly with the use of mucosal adjuvants such as cholera toxin or heat-labile enterotoxin from E. coli (Hajishengallis et al., 2005). However, in such small animals it is often difficult to distinguish the immune responses induced by nasal delivery per se, compared to these induced by the swallowing of the vaccine or the inadvertent channelling of the vaccine

Lung vaccine delivery

Pulmonary delivery of pharmacological substances is an attractive option due, at least in part, to the large surface area of the mucosa in the lung (approximately 140 m2 in humans and a similar size in sheep), combined with the thinned mucosal wall in the alveoli, which might allow rapid and efficient uptake of the delivered agent. The drug delivery can be relatively non-invasive with appropriately engineered delivery devices. These devices are readily available for use in humans as demonstrated

Concluding remarks

Even though the induction of mucosal immune responses to prevent and/or cure infection remains a tremendous challenge, it is worthwhile pursuing as it has important implications for the management of both human and animal health. In the course of our investigation in sheep, we developed novel methods to measure antigen in lymph draining from nasal and lung lymphatics and discovered that the amounts of antigen entering the lymphatics associated with the nasal cavity was very low and most likely

Conflict of interest

The authors declare no financial or commercial conflict of interest.

Acknowledgements

This work was supported by grant funding awarded to J.-P. Scheerlinck and P. Sutton from the Australian Research Council and CSL Pty. Ltd.

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