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Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule

View Article: PubMed Central - PubMed

ABSTRACT

There are several benefits of oral immunization including the ability to elicit mucosal immune responses that may protect against pathogens that invade through a mucosal surface. Our understanding of human immune biology is hampered by the difficulty in isolating mucosal cells from humans, and the fact that animal models may or may not completely mirror human intestinal immunobiology. In this human pharmacodynamic study, a novel adenovirus vector-based platform expressing influenza hemagglutinin was explored. We used radio-controlled capsules to deliver the vaccine to either the jejunum or the ileum. The resulting immune responses induced by immunization at each of the intestinal sites were investigated. Both intestinal sites were capable of inducing mucosal and systemic immune responses to influenza hemagglutinin, but ileum delivery induced higher numbers of antibody secreting cells of IgG and IgA isotypes, increased mucosal homing B cells, and higher number of vaccine responders. Overall, these data provided substantial insights into human mucosal inductive sites, and aided in the design and selection of indications that could be used with this oral vaccine platform.

No MeSH data available.


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(A) The proportion of β7(high) as a percentage of CD19+B cells in PBMCs are shown days 0 and 7 following vaccination in either the jejunum or ileum (**p = 0.0024 for the jejunum-targeted group and p = 0.0034 for the ileum-targeted group at day0 and day7, Wilcoxon test of paired t test). Each icon represents an individual subject. Bars represent the median of β7(high) CD19+B cells. The red arrow indicates a subject that was analyzed for FACS data in Figs 5 and 6. (B) Samples of CD19 versus β7 staining are shown on day 0 and day 7 PBMCs. (C) Both β7(intermediate) and β7(negative) CD19+B cells expressed α4 integrin (blue line). The negative control (FMO) is shown in orange. CD19+β7(high) cells have high expression of α4 integrin (red line). (D) On day7 following vaccination, β7(high) B cells in PBMCs express CD27(high) and CD27(lintermediate). (E) Gating on β7(high) and β7(negative) B cells, surface IgA and IgG expression are shown. (F) β7(high) IgA + B cells show CCR9 expression compared to β7(negative) B cells. Population 1: day 7 β7(high) CD19+B cells, population 2: day 7 β7(intermediate) CD19+B cells, population 3: β7(negative) CD19+B cells.
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f5: (A) The proportion of β7(high) as a percentage of CD19+B cells in PBMCs are shown days 0 and 7 following vaccination in either the jejunum or ileum (**p = 0.0024 for the jejunum-targeted group and p = 0.0034 for the ileum-targeted group at day0 and day7, Wilcoxon test of paired t test). Each icon represents an individual subject. Bars represent the median of β7(high) CD19+B cells. The red arrow indicates a subject that was analyzed for FACS data in Figs 5 and 6. (B) Samples of CD19 versus β7 staining are shown on day 0 and day 7 PBMCs. (C) Both β7(intermediate) and β7(negative) CD19+B cells expressed α4 integrin (blue line). The negative control (FMO) is shown in orange. CD19+β7(high) cells have high expression of α4 integrin (red line). (D) On day7 following vaccination, β7(high) B cells in PBMCs express CD27(high) and CD27(lintermediate). (E) Gating on β7(high) and β7(negative) B cells, surface IgA and IgG expression are shown. (F) β7(high) IgA + B cells show CCR9 expression compared to β7(negative) B cells. Population 1: day 7 β7(high) CD19+B cells, population 2: day 7 β7(intermediate) CD19+B cells, population 3: β7(negative) CD19+B cells.

Mentions: We found a marked increase in β7(high) CD19 + B cells (population 1) post vaccination in 21 out of 24 subjects (Fig. 5A). In the jejunum-targeted group, medians of 1.56% of β7(high) B cells (95 CI: 1.2–2.4) on day 0 and 2.91% of β7(high) B cells (95 CI: 2.2–4.3) on day 7 were observed. In the ileum-targeted group, medians of 1.84% of β7(high) B cells (95 CI: 1.4–2.3) on day 0 and 4.98% of β7(high) B cells (95 CI: 1.5–9.3) on day 7 were observed. Although the response was not significantly different between the two groups (two way ANOVA), a trend showing a higher induction of β7(high) B cells in the ileum group was observed on day 7. Ten and eleven subjects (out of 12 each) showed increases in β7(high) B cells after vaccination in the jejunum and ileum targeted groups, respectively. Flow cytometry is show with a representative subject, and used throughout the flow analysis in Figs 5 and 6, and marked in Fig. 5A with a red arrow. The representative subject is shown for β7 versus CD19 at days 0 and 7 to demonstrate the emergence of the β7(high) population post immunization (Fig. 5B). β7(intermediate and negative) B cells (population 2 and 3) expressed α4 integrin (Fig. 5C, blue line) and the corresponding β7(high) B cells expressed high levels of α4 integrin (Fig. 5C, red line), suggesting rAd oral delivery generated α4(high)β7(high) gut homing B cells.


Systemic and mucosal immune responses following oral adenoviral delivery of influenza vaccine to the human intestine by radio controlled capsule
(A) The proportion of β7(high) as a percentage of CD19+B cells in PBMCs are shown days 0 and 7 following vaccination in either the jejunum or ileum (**p = 0.0024 for the jejunum-targeted group and p = 0.0034 for the ileum-targeted group at day0 and day7, Wilcoxon test of paired t test). Each icon represents an individual subject. Bars represent the median of β7(high) CD19+B cells. The red arrow indicates a subject that was analyzed for FACS data in Figs 5 and 6. (B) Samples of CD19 versus β7 staining are shown on day 0 and day 7 PBMCs. (C) Both β7(intermediate) and β7(negative) CD19+B cells expressed α4 integrin (blue line). The negative control (FMO) is shown in orange. CD19+β7(high) cells have high expression of α4 integrin (red line). (D) On day7 following vaccination, β7(high) B cells in PBMCs express CD27(high) and CD27(lintermediate). (E) Gating on β7(high) and β7(negative) B cells, surface IgA and IgG expression are shown. (F) β7(high) IgA + B cells show CCR9 expression compared to β7(negative) B cells. Population 1: day 7 β7(high) CD19+B cells, population 2: day 7 β7(intermediate) CD19+B cells, population 3: β7(negative) CD19+B cells.
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f5: (A) The proportion of β7(high) as a percentage of CD19+B cells in PBMCs are shown days 0 and 7 following vaccination in either the jejunum or ileum (**p = 0.0024 for the jejunum-targeted group and p = 0.0034 for the ileum-targeted group at day0 and day7, Wilcoxon test of paired t test). Each icon represents an individual subject. Bars represent the median of β7(high) CD19+B cells. The red arrow indicates a subject that was analyzed for FACS data in Figs 5 and 6. (B) Samples of CD19 versus β7 staining are shown on day 0 and day 7 PBMCs. (C) Both β7(intermediate) and β7(negative) CD19+B cells expressed α4 integrin (blue line). The negative control (FMO) is shown in orange. CD19+β7(high) cells have high expression of α4 integrin (red line). (D) On day7 following vaccination, β7(high) B cells in PBMCs express CD27(high) and CD27(lintermediate). (E) Gating on β7(high) and β7(negative) B cells, surface IgA and IgG expression are shown. (F) β7(high) IgA + B cells show CCR9 expression compared to β7(negative) B cells. Population 1: day 7 β7(high) CD19+B cells, population 2: day 7 β7(intermediate) CD19+B cells, population 3: β7(negative) CD19+B cells.
Mentions: We found a marked increase in β7(high) CD19 + B cells (population 1) post vaccination in 21 out of 24 subjects (Fig. 5A). In the jejunum-targeted group, medians of 1.56% of β7(high) B cells (95 CI: 1.2–2.4) on day 0 and 2.91% of β7(high) B cells (95 CI: 2.2–4.3) on day 7 were observed. In the ileum-targeted group, medians of 1.84% of β7(high) B cells (95 CI: 1.4–2.3) on day 0 and 4.98% of β7(high) B cells (95 CI: 1.5–9.3) on day 7 were observed. Although the response was not significantly different between the two groups (two way ANOVA), a trend showing a higher induction of β7(high) B cells in the ileum group was observed on day 7. Ten and eleven subjects (out of 12 each) showed increases in β7(high) B cells after vaccination in the jejunum and ileum targeted groups, respectively. Flow cytometry is show with a representative subject, and used throughout the flow analysis in Figs 5 and 6, and marked in Fig. 5A with a red arrow. The representative subject is shown for β7 versus CD19 at days 0 and 7 to demonstrate the emergence of the β7(high) population post immunization (Fig. 5B). β7(intermediate and negative) B cells (population 2 and 3) expressed α4 integrin (Fig. 5C, blue line) and the corresponding β7(high) B cells expressed high levels of α4 integrin (Fig. 5C, red line), suggesting rAd oral delivery generated α4(high)β7(high) gut homing B cells.

View Article: PubMed Central - PubMed

ABSTRACT

There are several benefits of oral immunization including the ability to elicit mucosal immune responses that may protect against pathogens that invade through a mucosal surface. Our understanding of human immune biology is hampered by the difficulty in isolating mucosal cells from humans, and the fact that animal models may or may not completely mirror human intestinal immunobiology. In this human pharmacodynamic study, a novel adenovirus vector-based platform expressing influenza hemagglutinin was explored. We used radio-controlled capsules to deliver the vaccine to either the jejunum or the ileum. The resulting immune responses induced by immunization at each of the intestinal sites were investigated. Both intestinal sites were capable of inducing mucosal and systemic immune responses to influenza hemagglutinin, but ileum delivery induced higher numbers of antibody secreting cells of IgG and IgA isotypes, increased mucosal homing B cells, and higher number of vaccine responders. Overall, these data provided substantial insights into human mucosal inductive sites, and aided in the design and selection of indications that could be used with this oral vaccine platform.

No MeSH data available.


Related in: MedlinePlus