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Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection.

Zhu Q, Talton J, Zhang G, Cunningham T, Wang Z, Waters RC, Kirk J, Eppler B, Klinman DM, Sui Y, Gagnon S, Belyakov IM, Mumper RJ, Berzofsky JA - Nat. Med. (2012)

Bottom Line: Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract.Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system.Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA; Department of Oncology, Air Force General Hospital, Beijing, China.

ABSTRACT
Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms. Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sites in animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but this route is clinically impractical. Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viral challenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.

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Orally delivered FS30D-coated PLGA nanoparticle protein vaccine confers antibody-mediated resistance to virus infection in the rectal or vaginal tract. FS30D-coated PLGA containing antigen proteins A33 and L1 and TLR ligands (ProtAg+TLRL) was administered orally with a two-week interval. (a) Serum and local IgA (top) and IgG (bottom) antibodies against both A33 and L1 (together) measured at three weeks after the last immunization. Both FS30D/PLGA/ProtAg+TLRL p.o. and ProtAg+TLRL i.c.r. groups have significantly higher antibody titers than the other groups (P < 0.02). **P < 0.01 and ***P < 0.001 indicate difference (for both sites) from each of the bars without asterisks. Results from two independent experiments (n = 10 per group). (b) Disease course of the mice after challenge with WR by the i.c.r. (4×107 PFU) or i.vag. (1×107 PFU) route three weeks after the last immunization. **P < 0.02, ***P < 0.001 indicate the differences between the FS30D/PLGA/ProtAg+TLRL and unimmunized groups in weight loss (n = 10 14 per group). §, 75% mortality; ¶, 50% mortality.
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Figure 4: Orally delivered FS30D-coated PLGA nanoparticle protein vaccine confers antibody-mediated resistance to virus infection in the rectal or vaginal tract. FS30D-coated PLGA containing antigen proteins A33 and L1 and TLR ligands (ProtAg+TLRL) was administered orally with a two-week interval. (a) Serum and local IgA (top) and IgG (bottom) antibodies against both A33 and L1 (together) measured at three weeks after the last immunization. Both FS30D/PLGA/ProtAg+TLRL p.o. and ProtAg+TLRL i.c.r. groups have significantly higher antibody titers than the other groups (P < 0.02). **P < 0.01 and ***P < 0.001 indicate difference (for both sites) from each of the bars without asterisks. Results from two independent experiments (n = 10 per group). (b) Disease course of the mice after challenge with WR by the i.c.r. (4×107 PFU) or i.vag. (1×107 PFU) route three weeks after the last immunization. **P < 0.02, ***P < 0.001 indicate the differences between the FS30D/PLGA/ProtAg+TLRL and unimmunized groups in weight loss (n = 10 14 per group). §, 75% mortality; ¶, 50% mortality.

Mentions: The ability of PLGA nanoparticles containing the above vaccine components to induce antibody responses was assessed by immunization through either the i.c.r. or s.c. routes (Supplementary Fig. 10a), and the results further showed that CD4+ T cells were also activated by such a vaccine regimen (Supplementary Fig. 10b). We therefore constructed FS30D-coated PLGA/A33+L1+TLRL vaccine microparticles and administered them orally. Vaccinia-specific IgA and IgG antibody responses were significantly induced in both the large intestine (tested in tissue homogenates) and vaginal tracts (tested in vaginal washes) (Fig. 4a). Further, orally immunized mice resisted the WR virus challenge by either the rectal or vaginal route (Fig. 4b) as determined by weight loss and by 0 vs 75% or 50% mortality, respectively. Therefore, the FS30D-coated PLGA vaccine system can also be used to induce antibody-mediated mucosal protection at both mucosal transmission sites.


Large intestine-targeted, nanoparticle-releasing oral vaccine to control genitorectal viral infection.

Zhu Q, Talton J, Zhang G, Cunningham T, Wang Z, Waters RC, Kirk J, Eppler B, Klinman DM, Sui Y, Gagnon S, Belyakov IM, Mumper RJ, Berzofsky JA - Nat. Med. (2012)

Orally delivered FS30D-coated PLGA nanoparticle protein vaccine confers antibody-mediated resistance to virus infection in the rectal or vaginal tract. FS30D-coated PLGA containing antigen proteins A33 and L1 and TLR ligands (ProtAg+TLRL) was administered orally with a two-week interval. (a) Serum and local IgA (top) and IgG (bottom) antibodies against both A33 and L1 (together) measured at three weeks after the last immunization. Both FS30D/PLGA/ProtAg+TLRL p.o. and ProtAg+TLRL i.c.r. groups have significantly higher antibody titers than the other groups (P < 0.02). **P < 0.01 and ***P < 0.001 indicate difference (for both sites) from each of the bars without asterisks. Results from two independent experiments (n = 10 per group). (b) Disease course of the mice after challenge with WR by the i.c.r. (4×107 PFU) or i.vag. (1×107 PFU) route three weeks after the last immunization. **P < 0.02, ***P < 0.001 indicate the differences between the FS30D/PLGA/ProtAg+TLRL and unimmunized groups in weight loss (n = 10 14 per group). §, 75% mortality; ¶, 50% mortality.
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Related In: Results  -  Collection

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getmorefigures.php?uid=PMC3475749&req=5

Figure 4: Orally delivered FS30D-coated PLGA nanoparticle protein vaccine confers antibody-mediated resistance to virus infection in the rectal or vaginal tract. FS30D-coated PLGA containing antigen proteins A33 and L1 and TLR ligands (ProtAg+TLRL) was administered orally with a two-week interval. (a) Serum and local IgA (top) and IgG (bottom) antibodies against both A33 and L1 (together) measured at three weeks after the last immunization. Both FS30D/PLGA/ProtAg+TLRL p.o. and ProtAg+TLRL i.c.r. groups have significantly higher antibody titers than the other groups (P < 0.02). **P < 0.01 and ***P < 0.001 indicate difference (for both sites) from each of the bars without asterisks. Results from two independent experiments (n = 10 per group). (b) Disease course of the mice after challenge with WR by the i.c.r. (4×107 PFU) or i.vag. (1×107 PFU) route three weeks after the last immunization. **P < 0.02, ***P < 0.001 indicate the differences between the FS30D/PLGA/ProtAg+TLRL and unimmunized groups in weight loss (n = 10 14 per group). §, 75% mortality; ¶, 50% mortality.
Mentions: The ability of PLGA nanoparticles containing the above vaccine components to induce antibody responses was assessed by immunization through either the i.c.r. or s.c. routes (Supplementary Fig. 10a), and the results further showed that CD4+ T cells were also activated by such a vaccine regimen (Supplementary Fig. 10b). We therefore constructed FS30D-coated PLGA/A33+L1+TLRL vaccine microparticles and administered them orally. Vaccinia-specific IgA and IgG antibody responses were significantly induced in both the large intestine (tested in tissue homogenates) and vaginal tracts (tested in vaginal washes) (Fig. 4a). Further, orally immunized mice resisted the WR virus challenge by either the rectal or vaginal route (Fig. 4b) as determined by weight loss and by 0 vs 75% or 50% mortality, respectively. Therefore, the FS30D-coated PLGA vaccine system can also be used to induce antibody-mediated mucosal protection at both mucosal transmission sites.

Bottom Line: Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract.Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system.Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.

View Article: PubMed Central - PubMed

Affiliation: Vaccine Branch, Center for Cancer Research, National Cancer Institute, US National Institutes of Health, Bethesda, Maryland, USA; Department of Oncology, Air Force General Hospital, Beijing, China.

ABSTRACT
Both rectal and vaginal mucosal surfaces serve as transmission routes for pathogenic microorganisms. Vaccination through large intestinal mucosa, previously proven protective for both of these mucosal sites in animal studies, can be achieved successfully by direct intracolorectal (i.c.r.) administration, but this route is clinically impractical. Oral vaccine delivery seems preferable but runs the risk of the vaccine's destruction in the upper gastrointestinal tract. Therefore, we designed a large intestine-targeted oral delivery with pH-dependent microparticles containing vaccine nanoparticles, which induced colorectal immunity in mice comparably to colorectal vaccination and protected against rectal and vaginal viral challenge. Conversely, vaccine targeted to the small intestine induced only small intestinal immunity and provided no rectal or vaginal protection, demonstrating functional compartmentalization within the gut mucosal immune system. Therefore, using this oral vaccine delivery system to target the large intestine, but not the small intestine, may represent a feasible new strategy for immune protection of rectal and vaginal mucosa.

Show MeSH
Related in: MedlinePlus