Oral Vaccine Delivery: Can it Protect Against Non-mucosal Pathogens?

Lina Wang; Ross L Coppel

Disclosures

Expert Rev Vaccines. 2008;7(6):729-738. 

In This Article

Expert Commentary

There are considerable theoretical advantages of oral delivery compared with systemic delivery; however, there are a number of significant hurdles to be overcome before we can reliably deliver a safe and effective oral vaccine. A minority of vaccines that are licensed for human use are administered orally, including polio, cholera, typhoid, rotavirus and adenovirus vaccines.[3,79] The adenovirus vaccine is currently restricted to military personnel, although it may find more widespread use as vector carrying vaccine antigens for HIV and malaria, notwithstanding recent poor results in HIV trials.[80,81] The first licensed rotavirus vaccine, a tetravalent rhesus-based rotavirus vaccine (RRV-TV; Rota-Shield™), was withdrawn from the market shortly after its approval owing to an unusual incidence of intussusceptions. A new pentavalent rotavirus vaccine (PRV, RotaTeq™) was licensed in 2006 and its safety is currently under postmarketing monitoring.[82] Nevertheless, several other oral vaccines are at various stages of clinical testing.[1] All of these oral vaccines are designed to prevent diseases contracted through mucosal surfaces and are composed of either live-attenuated viruses/bacteria or killed whole cells. By contrast, there has been relatively little progress in the clinical development of subunit oral vaccines, particularly for non-mucosally transmitted pathogens. In this article, we have provided evidence that oral immunization is an alternative that is worthy of study and optimization in order to prevent infections transmitted through non-mucosal routes, such as malaria, Japanese encephalitis and hepatitis B. For infections that are endemic in resource-poor developing countries, oral administration would greatly enhance wi-despread vaccine deployment.

For effective oral immunization, vaccine antigens must be protected from the proteolytic environment of the gut, efficiently taken up by cells of the GALT and an appropriate immune response must be induced. The availability of a range of novel delivery systems, as well as the development of mucosal adjuvants, has provided potential for the future development of subunit oral vaccines. The mucosal immune system is a complex system, generating a large amount of sIgA, as well as systemic immunoglobulins and cell-mediated immune responses.[79] sIgA is unlikely to have much value in immunity to non-mucosal pathogens and we do not understand the mechanisms that favor IgG over IgA when the antigen is introduced mucosally. The nature of the immune response required varies from infection to infection and we have little knowledge of how we may vary presentation in terms of the physical nature of the antigen, adjuvant, dosing and regimen to encourage the desired response. The relative weighting of humoral responses compared with cell-mediated responses is likely to be important and, depending on the protective mechanism of a vaccine antigen, either Th1 or Th2 type responses may be desirable. A detailed understanding of the mechanisms of oral immunization is critical for the design of effective oral vaccines; however, as for vaccines in general, such understanding has remained elusive and vaccine formulation still remains largely empirical.

A major concern regarding oral delivery is the possibility of inducing oral tolerance, whereby oral delivery of an antigen would prevent systemic responses on subsequent exposure to the same antigen.[83] Such oral tolerance has been extensively studied in animal models including mice, rats and guinea pigs. Other species appear to be less prone to the development of systemic nonresponsiveness.[84] Although tolerance is the default response of the intestinal immune system, studies showed that it does not occur every time the antigen is fed, but depends on a multitude of factors, such as the nature, size and dose of the antigen, coadministration of adjuvant and host-specific factors.[83] Thus, the potential for an oral vaccine to induce oral tolerance will need to be assessed carefully by trials.

For attenuated live vectors, there is an inherent danger that live vaccines may revert back to virulence or retain sufficient virulence to become pathogenic in immunocompromised individuals, particularly if the attenuated organisms survive long enough to pass from person to person. A significant proportion of the world's population, particularly those in some African countries, show levels of immunosupression due to HIV infection; thus, special caution is required when devising and performing a clinical trial to test a new attenuated organism vaccine in these populations. In addition, more information is required regarding the efficiency of such vaccines in populations with significant levels of pre-existing immunity to the carrier.

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