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

Lina Wang; Ross L Coppel


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

In This Article

Oral Vaccines Against Other Non-mucosal Diseases

Japanese encephalitis virus (JEV) is transmitted by mosquitoes and is responsible for an acute infection of the CNS resulting in encephalitis. A mouse brain-derived, formalin-inactivated vaccine is available for immunization against JEV but it has several limitations in terms of high cost of production and risk of allergic reaction. Attempts are being made to develop an improved vaccine using recombinant DNA technology.[66] Oral immunization of mice with live JEV was shown to induce a brisk and protective immune response, suggesting the possibility of developing an oral vaccine against JEV.[67] Rauthan et al. showed that a recombinant JEV envelope protein, synthesized in E. coli, induced high-level antigen-specific anti-JEV antibodies when administered orally to mice with CpG as an adjuvant.[68] These antibodies, however, failed to neutralize JEV activity in vitro and the immunization did not protect the mice against lethal JEV challenge.[68] The authors suggested that the denatured state of the recombinant protein, which contains 12 cysteine residues, was responsible for its failure, as the same protein failed to induce virus-neutralizing antibodies by intramuscular immunization. Since the native JEV envelope protein is the major target of virus-neutralizing antibodies, and protection against JEV is mainly antibody dependent, further work is necessary to use a correctly folded protein to evaluate its efficiency as an oral vaccine. Perhaps, production as a secreted protein by transgenic plants would solve problems of conformation. In a murine model of virus-induced encephalitis, Zanin et al. reported that a prime-boost regimen of recombinant envelope protein delivered orally with saponin following DNA vaccination produced antibody levels that partially protected mice against viral encephalitis.[69] These studies support the concept of using oral vaccination against a viral infection of the CNS and, with further development, this strategy could improve the management of endemic encephalitis, especially in resource-poor regions.

Hepatitis B infection is a major health problem worldwide, causing progressive liver cirrhosis, hepatocellular necrosis and cancer. An effective and safe vaccine is currently available, which comprises purified hepatitis B surface antigen (HBsAg), but the costs of production, distribution and delivery have been too high for widespread administration in many developing countries. The problem of cost can be overcome by subsidy of the price by charitable organizations to allow mass-immunization programs, but this may not be a sustainable solution in the longer term. Although HBV can be transmitted by sexual contact (mucosal route), the infection is mainly transmitted by exposure to contaminated blood or via maternal transmission. Protection against HBV is known to be antibody mediated and a serum antibody response to HBsAg exceeding 10 mIU/ml is indicative of protection in humans.[70]

There has been considerable work toward the development of an oral vaccine against hepatitis B, including the use of live vectors expressing HBsAg[71] and encapsulation of HBsAg in biodegradable microparticles.[25,72] Several research groups have focused on transgenic plants expressing HBsAg for oral vaccine production and delivery. The protein was first expressed in tobacco leaves in early 1992[73] and, since then, its expression has been demonstrated in a variety of plants with optimization of the expression systems giving increased yields.[70] Successful induction of HBV-specific serum antibodies has been reported in several studies by feeding mice with HBsAg-expressing plant materials;[74,75,76] however, all these studies included CT as an adjuvant, which is not feasible for human use. Two studies have taken the plant-expressed HBsAg into small-scale clinical trials without the use of an adjuvant.[77,78] In the first trial, two out of three human volunteers who ingested transgenic lettuce leaves developed serum antibody responses at levels considered to be protective.[77] In the second larger study, a double-blind, placebo-controlled clinical trial was performed to evaluate the immunogenicity of HBsAg expressed in potatoes and delivered orally to previously vaccinated individuals.[78] After volunteers ate uncooked potatoes, HBsAg-specific serum antibodies increased in ten out of 16 volunteers who ate three doses of transgenic potatoes, in nine out of 17 volunteers who ate two doses of transgenic potatoes and in none of the volunteers who ate nontransgenic potatoes. The transgenic potatoes were tolerated similarly to nontransgenic control potatoes. These results are promising, support the further development of oral hepatitis B vaccines produced and delivered in plants.


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