Delivery of Human Immunodeficiency Virus Vaccine Vectors to the Intestine Induces Enhanced Mucosal Cellular Immunity

Abstract

Effective vaccines for human immunodeficiency virus type 1 (HIV-1) will likely need to stimulate protective immunity in the intestinal mucosa, where HIV-1 infection causes severe CD4 ؉ T-cell depletion. While replication-competent recombinant adenovirus (rAd) vectors can stimulate adenovirus-specific mucosal immunity after replication, oral delivery of replication-defective rAd vectors encoding specific immunogens has proven challenging. In this study, we have systematically identified barriers to effective gut delivery of rAd vectors and identified sites and strategies to induce potent cellular and humoral immunity. Vector-mediated gene transfer by rAd5 was susceptible to low-pH buffer, gastric and pancreatic proteases, and extracellular mucins. Using ex vivo organ explants, we found that transduction with rAd5 was highest in the ileum and colon among all intestinal segments. Transgene expression was 100-fold higher after direct surgical introduction into the ileum than after oral gavage, with rAd5 showing greater potency than the rAd35 or the rAd41 vector. A single immunization of rAd5 encoding HIV-1 gp140B to the ileum stimulated potent CD8؉ T-cell responses in the intestinal and systemic compartments, and these responses were further enhanced by intramuscular rAd5 boosting. These studies suggest that induction of primary immune responses by rAd5 gut immunization and subsequent systemic boosting elicits potent antigen-specific gut mucosal responses.

Route of Adenovirus-Based HIV-1 Vaccine Delivery Impacts the Phenotype and Trafficking of Vaccine-Elicited CD8 + T Lymphocytes

“…1A), whereas previous studies have shown that higher volumes of intranasal instillation mediate passage of the instillate to the lower respiratory tract (39). Some studies have also surgically or chemically manipulated mucosal surfaces (44,46), which could lead to persistent inflammation at the site of antigen delivery and alter the dynamics of antigen uptake and presen- Using adoptive transfer studies, we assessed the initial priming and trafficking patterns of antigen-specific CD8 ϩ T lymphocytes following immunization. I.m.…”

“…Previous studies have suggested that mucosal rAd vector immunization can efficiently prime for a boosted mucosal recall response (23,44). We therefore evaluated the extent to which i.n.…”

Gene-Based Vaccination with a Mismatched Envelope Protects against Simian Immunodeficiency Virus Infection in Nonhuman Primates

“…Recombinant adenovirus type 5 (rAd5) vectors are replication-defective E1-, E3-, and E4-deleted human Ads. rAd28 vectors are E1-and E3-deleted replication-defective vectors, and all have been previously described (44). DNA plasmids have been extensively described and used in clinical trials (8,9).…”

Induction of Intestinal Immunity by Mucosal Vaccines As a Means of Controlling HIV Infection

“…One such concern is the delivery of the immunogens through the stomach, which can serve as a natural barrier to proper vaccination due to its acidic and proteolytic environment, as well as the small intestines due to the presence of pancreatic proteases and mucins. 76 To counteract vaccine degradation, sodium bicarbonate solution intake can be used prior to vaccination in order to neutralize gastric acid. 77 Alternatively, enteric-coated capsules have been developed to utilize the digestive tract's pH gradient, releasing the viral vector only after it has passed through the highly acidic and proteolytic environment of the stomach and has reached an environment where it can induce both humoral and cellular intestinal immunity.…”