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Oral Delivery of a Novel Recombinant Streptococcus mitis Vector Elicits Robust Vaccine Antigen-Specific Oral Mucosal and Systemic Antibody Responses and T Cell Tolerance.

Xie E, Kotha A, Biaco T, Sedani N, Zou J, Stashenko P, Duncan MJ, Campos-Neto A, Cayabyab MJ - PLoS ONE (2015)

Bottom Line: Oral vaccination led to the efficient and persistent bacterial colonization of the mouth and the induction of both salivary and systemic antibody responses.Interestingly, persistently colonized animals developed antigen-specific systemic T cell tolerance.Based on these findings we propose the use of rS. mitis vaccine vector for the induction of mucosal antibodies that will prevent the penetration of the mucosa by pathogens such as HIV.

View Article: PubMed Central - PubMed

Affiliation: Global Infectious Disease Research Center and the Department of Immunology and Infectious Diseases, The Forsyth Institute, 245 First Street, Cambridge, Massachusetts, United States of America.

ABSTRACT
The pioneer human oral commensal bacterium Streptococcus mitis has unique biologic features that make it an attractive mucosal vaccine or therapeutic delivery vector. S. mitis is safe as a natural persistent colonizer of the mouth, throat and nasopharynx and the oral commensal bacterium is capable of inducing mucosal antibody responses. A recombinant S. mitis (rS. mitis) that stably expresses HIV envelope protein was generated and tested in the germ-free mouse model to evaluate the potential usefulness of this vector as a mucosal vaccine against HIV. Oral vaccination led to the efficient and persistent bacterial colonization of the mouth and the induction of both salivary and systemic antibody responses. Interestingly, persistently colonized animals developed antigen-specific systemic T cell tolerance. Based on these findings we propose the use of rS. mitis vaccine vector for the induction of mucosal antibodies that will prevent the penetration of the mucosa by pathogens such as HIV. Moreover, the first demonstration of rS. mitis having the ability to elicit T cell tolerance suggest the potential use of rS. mitis as an immunotherapeutic vector to treat inflammatory, allergic and autoimmune diseases.

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Related in: MedlinePlus

Recombinant S. mitis induces mucosal and systemic antibody responses.Germ-free Balb/c mice were inoculated orally with 109 cfu rS. mitis expressing HIV Env gp120 (Smitis HIV Env), rS. mitis containing an integrated Ermr gene without Env gp120 (Smitis), or PBS (Non-Immunized). Following immunization, the presence of IgA, IgG1, and IgG2a antibodies specific to the HIV Env gp120 protein (HIV Ag) or S. mitis lysate antigens (S. mitis Ag) was measured by ELISA in the saliva (A) and serum (B) of mice. The mean optical density (OD) (±SEM) values of the undiluted samples from 3 mice/group at various timepoints post-immunization are shown. The saliva and serum antibody dilution factor was 1:3 or indicated otherwise.
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pone.0143422.g005: Recombinant S. mitis induces mucosal and systemic antibody responses.Germ-free Balb/c mice were inoculated orally with 109 cfu rS. mitis expressing HIV Env gp120 (Smitis HIV Env), rS. mitis containing an integrated Ermr gene without Env gp120 (Smitis), or PBS (Non-Immunized). Following immunization, the presence of IgA, IgG1, and IgG2a antibodies specific to the HIV Env gp120 protein (HIV Ag) or S. mitis lysate antigens (S. mitis Ag) was measured by ELISA in the saliva (A) and serum (B) of mice. The mean optical density (OD) (±SEM) values of the undiluted samples from 3 mice/group at various timepoints post-immunization are shown. The saliva and serum antibody dilution factor was 1:3 or indicated otherwise.

Mentions: Infants, children and adults colonized by S. mitis develop salivary antibodies to the pioneer bacterium [7, 22], and therefore we determined whether the vaccinated germ-free mice also develop antibody responses to rS. mitis. Salivary IgA specific to HIV Env protein as well as S. mitis lysate antigens were initially detected three weeks post-inoculation and the antibody responses increased concomitant with S. mitis persistence in the oral cavity (Figs 4A and 5A). The amount of HIV-specific salivary IgA in rS. mitis HIV Env-vaccinated mice was significantly higher than in control S. mitis-vaccinated or in non-immunized mice on day 22, 45, 60 and 70 (p < 0.05 at each timepoint). As expected, on those same days, similar amounts of S. mitis antigen-specific salivary IgA were found in either rS. mitis HIV Env or control S. mitis-immunized mice, which were both significantly higher than in non-immunized mice (p < 0.05 at each timepoint). Salivary IgG1 and IgG2a antibodies specific to rS. mitis were undetectable.


Oral Delivery of a Novel Recombinant Streptococcus mitis Vector Elicits Robust Vaccine Antigen-Specific Oral Mucosal and Systemic Antibody Responses and T Cell Tolerance.

Xie E, Kotha A, Biaco T, Sedani N, Zou J, Stashenko P, Duncan MJ, Campos-Neto A, Cayabyab MJ - PLoS ONE (2015)

Recombinant S. mitis induces mucosal and systemic antibody responses.Germ-free Balb/c mice were inoculated orally with 109 cfu rS. mitis expressing HIV Env gp120 (Smitis HIV Env), rS. mitis containing an integrated Ermr gene without Env gp120 (Smitis), or PBS (Non-Immunized). Following immunization, the presence of IgA, IgG1, and IgG2a antibodies specific to the HIV Env gp120 protein (HIV Ag) or S. mitis lysate antigens (S. mitis Ag) was measured by ELISA in the saliva (A) and serum (B) of mice. The mean optical density (OD) (±SEM) values of the undiluted samples from 3 mice/group at various timepoints post-immunization are shown. The saliva and serum antibody dilution factor was 1:3 or indicated otherwise.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4664415&req=5

pone.0143422.g005: Recombinant S. mitis induces mucosal and systemic antibody responses.Germ-free Balb/c mice were inoculated orally with 109 cfu rS. mitis expressing HIV Env gp120 (Smitis HIV Env), rS. mitis containing an integrated Ermr gene without Env gp120 (Smitis), or PBS (Non-Immunized). Following immunization, the presence of IgA, IgG1, and IgG2a antibodies specific to the HIV Env gp120 protein (HIV Ag) or S. mitis lysate antigens (S. mitis Ag) was measured by ELISA in the saliva (A) and serum (B) of mice. The mean optical density (OD) (±SEM) values of the undiluted samples from 3 mice/group at various timepoints post-immunization are shown. The saliva and serum antibody dilution factor was 1:3 or indicated otherwise.
Mentions: Infants, children and adults colonized by S. mitis develop salivary antibodies to the pioneer bacterium [7, 22], and therefore we determined whether the vaccinated germ-free mice also develop antibody responses to rS. mitis. Salivary IgA specific to HIV Env protein as well as S. mitis lysate antigens were initially detected three weeks post-inoculation and the antibody responses increased concomitant with S. mitis persistence in the oral cavity (Figs 4A and 5A). The amount of HIV-specific salivary IgA in rS. mitis HIV Env-vaccinated mice was significantly higher than in control S. mitis-vaccinated or in non-immunized mice on day 22, 45, 60 and 70 (p < 0.05 at each timepoint). As expected, on those same days, similar amounts of S. mitis antigen-specific salivary IgA were found in either rS. mitis HIV Env or control S. mitis-immunized mice, which were both significantly higher than in non-immunized mice (p < 0.05 at each timepoint). Salivary IgG1 and IgG2a antibodies specific to rS. mitis were undetectable.

Bottom Line: Oral vaccination led to the efficient and persistent bacterial colonization of the mouth and the induction of both salivary and systemic antibody responses.Interestingly, persistently colonized animals developed antigen-specific systemic T cell tolerance.Based on these findings we propose the use of rS. mitis vaccine vector for the induction of mucosal antibodies that will prevent the penetration of the mucosa by pathogens such as HIV.

View Article: PubMed Central - PubMed

Affiliation: Global Infectious Disease Research Center and the Department of Immunology and Infectious Diseases, The Forsyth Institute, 245 First Street, Cambridge, Massachusetts, United States of America.

ABSTRACT
The pioneer human oral commensal bacterium Streptococcus mitis has unique biologic features that make it an attractive mucosal vaccine or therapeutic delivery vector. S. mitis is safe as a natural persistent colonizer of the mouth, throat and nasopharynx and the oral commensal bacterium is capable of inducing mucosal antibody responses. A recombinant S. mitis (rS. mitis) that stably expresses HIV envelope protein was generated and tested in the germ-free mouse model to evaluate the potential usefulness of this vector as a mucosal vaccine against HIV. Oral vaccination led to the efficient and persistent bacterial colonization of the mouth and the induction of both salivary and systemic antibody responses. Interestingly, persistently colonized animals developed antigen-specific systemic T cell tolerance. Based on these findings we propose the use of rS. mitis vaccine vector for the induction of mucosal antibodies that will prevent the penetration of the mucosa by pathogens such as HIV. Moreover, the first demonstration of rS. mitis having the ability to elicit T cell tolerance suggest the potential use of rS. mitis as an immunotherapeutic vector to treat inflammatory, allergic and autoimmune diseases.

Show MeSH
Related in: MedlinePlus