Commentary
Oral vaccination in man using antigens in particles: current status

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Abstract

Over 30 publications suggest that antigens given orally to mice in biocompatible microspheres stimulate an immune response and, in some cases, can give rise to protective immunity. Of those responses in mice that have been reproduced, confirmation in large animal models and in Phase 1 studies has not resulted. Particles containing antigens given orally and mixed with soluble adjuvants like cholera toxin have generally not produced any better data in mice than that seen with mixed solutions of unprotected antigens and adjuvants. Peyer’s patch M cell targeting of antigens in particles remains however a relatively untested hypothesis. While binding and uptake of M cell-targeted latex particles and stable liposomes by mouse M cells has been clearly shown using the mouse M cell-specific lectin, Ulex europaeus 1 (UEA-1), a direct relationship between M cell particle uptake and immune outcome remains illusive. Some studies have produced increased serum antibodies from UEA-1- and cholera toxin B (CTB)-coated liposomes containing antigens. Other groups are currently working on developing novel human M cell ligands for attachment to stable particles for oral delivery. Use of untargeted antigen-containing particles with adjuvants administered by the nasal route remains an alternative option.

Introduction

Intuitively, oral vaccination using antigens in particles appears to have a sound scientific rationale based on the protection of an antigen from exposure to gastric acid, bile and pancreatic secretions. At the same time, advantage is taken of the inherent inclination of intestinal Peyer’s patch (PP) M cells to take up particulates as part of its duty as a sentinel in the triggering of mucosal immunity against enteric pathogens (reviewed in Krahenbuhl and Neutra, 2000). Yet much controversy exists in respect of how stable particles really need to be, of how long the antigen needs to be encapsulated in the gastrointestinal tract, and as to whether M cells really take up more than just a few particles in vivo. Importantly, due to the lack of particle data on human tissue there is difficulty in relating particle uptake data in mice to man. Even if we accept the assertion that mouse oral immune data with antigens in particles has predictive merit, we are still faced with difficulties since even in the majority of successful mouse oral studies to date, the doses of antigen are still too high and the immune outcomes too low. It is possible that adjuvants or even targeting ligands (reviewed in Clark et al., 2000) might address the latter, but to date, results using adjuvants in various formats with particles have been quite poor. PP targeting work to discover new human M cell ligands is at an early research stage but appears promising.

Section snippets

Particle uptake by the intestinal Peyer’s patches

Estimates of particle uptake ability and capacity by PP M cells have been plagued by lack of standardisation of methodology. These include experimental variations in the intestinal loop model used in different species, in the numbers of particles used, and in the calculations of binding to PP and of uptake into the draining lymphatics (reviewed in Delie, 1998). Particle absorption values as high as 30% were detected in the early to mid-1990s using mainly polystyrene polymer. Recent use of lower

Of mice and men

Despite numerous papers over the past 15 years suggesting that antigens in particles can give immune responses in mice when given orally, it should be pointed out that much of this data was achieved with model stable proteins such as ovalbumen or bovine serum albumen. These antigens are atypical and have limited predictive value. Studies with real antigens require complicated neutralising antibody or challenge assays in order to show that any immunity generated is functional. A review by

Adjuvants for oral vaccination

A common and very reproducible experiment is to give a solution of tetanus toxoid (TTx) with a potent mucosal adjuvant, cholera toxin (CT), to bicarbonate-pretreated mice by the oral route (Jackson et al., 1993). Invariably, antibody titres are seen to both agents, albeit at high doses of TTx and at toxic doses of CT. The responses to TTx given orally with CT do not compare well, however, with those seen to TTx solution by the s.c. route at 1/100 the dose of TTx. In man, when the urease antigen

Human M cell targeting

M cell targeting using a ligand–particle construct has many technical hurdles to overcome to prove the scientific concept even in mice. Firstly, demonstration that the mouse M cell specific lectin, UEA-1, can confer a genuine enhanced immune outcome from a targeted particle containing a fluorescently-tagged antigen would be helpful. Secondly, it needs to be shown if the immune response is directly related to the amount of particles seen in M cells from selected mice from the same immunisation

Commercialisation reality

In the event of a targeted vaccine particle working in man, a major technical advance would have been demonstrated, combining the best of pharmaceutical technology, molecular biology, M cell knowledge and immunology. However, this is not enough to carry a product to commercialisation. There are additional process steps required for a reproducible and safe formulation. Since the product would be multicomponent, containing at least one antigen and a targeting agent, the assays for quality control

Conclusions

Many hard lessons have been learned over the past 15 years by those working with non-living vaccines administered by the oral route, and especially with particle formulations. Overall, there is not much evidence that antigens in particles can induce adequate protective immune responses compared to antigens in solution, bearing in mind some of the pitfalls described. Recent confocal measurements in single cells suggest that particle uptake by M cells may be a less frequent event than previously

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