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. 2015 Jun 9;33(25):2881-6.
doi: 10.1016/j.vaccine.2015.04.080. Epub 2015 May 2.

Oral delivery of wafers made from HBsAg-expressing maize germ induces long-term immunological systemic and mucosal responses

Celine A Hayden  1 , Maria E Fischer  1 , Bryan L Andrews  1 , Hayley C Chilton  1 , Debra D Turner  2 , John H Walker  3 , Ian R Tizard  2 , John A Howard  4
Affiliations

Oral delivery of wafers made from HBsAg-expressing maize germ induces long-term immunological systemic and mucosal responses

Celine A Hayden et al. Vaccine. .

Abstract

Background: The hepatitis B surface antigen (HBsAg) has been administered over the last 20 years as a parenteral vaccine against the hepatitis B virus (HBV). Despite high seroconversion rates, chronic infection rates are still high worldwide. Orally delivered vaccines provide a practical alternative to injected vaccines, potentially helping poorly responding populations and providing a viable alternative for populations in remote locations. Anamnestic responses are vital to establishing the efficacy of a given vaccine and have been assessed in this study using a plant-based oral delivery platform expressing HBsAg.

Methods: Long-term immunological memory was assessed in mice injected with a primary dose of Recombivax and boosted with orally-delivered HBsAg wafers, control wafers, or parenterally-delivered commercial vaccine (Recombivax).

Results: Mice boosted with HBsAg orally-administered wafers displayed sharp increases in mucosal IgA titers in fecal material and steep increases in serum IgA, whereas mice boosted with Recombivax showed no detectable levels of IgA in either fecal or serum samples following four boosting treatments. Long-term memory in the orally-treated mice was evidenced by sustained fecal IgA, and serum IgA, IgG, and mIU/mL over one year, while Recombivax-treated mice displayed sustained serum IgG and mIU/mL. Furthermore, sharp increases in these same antibodies were induced after re-boosting at 47 and 50 weeks post-primary injection.

Conclusions: Orally-delivered vaccines can provide long-term immune responses mucosally and systemically. For sexually-transmitted diseases that can be acquired at mucosal surfaces, such as HBV, an oral delivery platform may provide added protection over a conventional parenterally administered vaccine.

Keywords: Anamnestic response; Bioencapsulation; Immunogenicity; Long-term immune memory; Maize oral vaccine; Mucosal; Plant vaccine; Subunit vaccine; Supercritical fluid extraction.

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Figures

Figure 1
Figure 1
Fecal IgA response to oral and injected boosting doses of HBsAg. Mice were injected with 0.25μg of Recombivax® on day 0 and boosted by HBsAg wafer (HB oral), control wafer (Control), or by Recombivax® injection (RBX). A 500-fold dilution of fecal pellets was used and arithmetic mean O.D. for each treatment group was plotted relative to weeks post-primary injection (ppi). Black arrows indicate boosting on weeks 13, 15, 47, and 50 ppi. Different lower-case letters represent significantly different responses (p<0.0001).
Figure 2
Figure 2
Serum IgA mean titers in mice boosted with oral versus injected vaccine. A 250-fold dilution of samples was used and the arithmetic mean O.D. for each treatment group was plotted relative to weeks post-primary injection (ppi). The white arrow indicates primary injection at week 0, and black arrows indicate boosting on weeks 13, 15, 47, and 50 ppi. Different lower-case letters represent significantly different responses (p<0.0001). Abbreviations are as in Figure 1.
Figure 3
Figure 3
Serum IgG geometric mean titers as determined by ELISA. A white arrow indicates primary injection of 0.25μg Recombivax® on day 0. Black arrows indicate initiation of oral HBsAg, Recombivax®, or control boosting. Different lower-case letters represent significantly different responses (p<0.0001). Abbreviations are as in Figure 1.
Figure 4
Figure 4
Total serum Ig response, as determined by the WHO 2nd International Standard. Titers of mice boosted with control germ, HBsAg germ (HB oral), or Recombivax (RBX) were normalized to pre-boost titers (mIU/mL at week n/ mIU/mL at week 13) and geometric means calculated for each treatment group. Different lower-case letters represent significantly different responses at the terminal bleed (p=0.0005).
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