Enhanced Induction of Intestinal Cellular Immunity by Oral Priming with Enteric Adenovirus 41 Vectors

Vaccine Research Center, NIAID, National Institutes of Health, Bethesda, Maryland 20892-3005, USA.
Journal of Virology (Impact Factor: 4.44). 12/2008; 83(2):748-56. DOI: 10.1128/JVI.01811-08
Source: PubMed


Human immunodeficiency virus type 1 (HIV-1) infection is characterized by the rapid onset of intestinal T-cell depletion that
initiates the progression to AIDS. The induction of protective immunity in the intestinal mucosa therefore represents a potentially
desirable feature of a preventive AIDS vaccine. In this study, we have evaluated the ability of an enteric adenovirus, recombinant
adenovirus 41 (rAd41), to elicit intestinal and systemic immune responses by different immunization routes, alone or in combination
with rAd5. rAd41 expressing HIV envelope (Env) protein induced cellular immune responses comparable to those of rAd5-based
vectors after either a single intramuscular injection or a DNA prime/rAd boost. Oral priming with rAd41-Env followed by intramuscular
boosting with rAd5-Env stimulated a more potent CD8+ T-cell response in the small intestine than the other immunization regimens. Furthermore, the direct injection of rAd41-Env
into ileum together with intramuscular rAd5-Env boosting increased Env-specific cellular immunity markedly in mucosal as well
as systemic compartments. These data demonstrate that heterologous rAd41 oral or ileal priming with rAd5 intramuscular boosting
elicits enhanced intestinal mucosal cellular immunity and that oral or ileal vector delivery for primary immunization facilitates
the generation of mucosal immunity.

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    • "The supernatants were then collected and stored at -70℃. Splenic lymphocytes were harvested to evaluate cell-mediated immune responses using a nylon mesh screen (Becton, Dickinson and Company, USA) as previously described [21]. Two weeks after challenge, spleens and lungs along with armpit, groin, and mesenteric lymph nodes were collected, grinded and DNA was taken to analyze PCV-2 loads. "
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    ABSTRACT: A recombinant replication-defective adenovirus expressing the major epitopes of Porcine Circovirus-2 (PCV-2) capsid protein (rAd/Cap/518) was previously constructed, and shown to induce mucosal immunity in mice via intranasal immunization. The immune responses induced by intranasal immunization with the combination of rAd/Cap/518 and CpG ODN were evaluated in mice in this study. PCV-2 specific IgG in serum and IgA in saliva, lung and intestinal fluids of the group immunized with rAd/Cap/518 combined with CpG ODN were significantly higher than these immunized with rAd/Cap/518 alone. The frequencies of IL-2 secreting CD4+ T cells and IFN-γ secreting CD8+ T cells were significantly higher in the combined immunization group than these immunized with rAd/Cap/518 alone. The frequencies of CD3+, CD3+CD4+CD8- and CD3+CD4-CD8+ T cells in the combined immunization group were similar to these administered with CpG ODN alone, but significantly higher than those which weren't treated with CpG ODN. PCV-2 load after challenge in the combined immunization group was significantly lower than those in the PBS placebo group and approximately 7-fold lower in the single immunization group. The results indicate rAd/Cap/518 combined with CpG ODN can enhance systemic and local mucosal immunity in mice, representing a promising synergetic mucosal vaccine against PCV-2.
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    • "Depletion of CD8 þ cells by administration of a monoclonal antibody during chronic infection results in a transient increase in plasma viremia, coinciding with the period of depletion of CD8 þ cells (Schmitz et al. 1999). However, the available mAbs directed against CD8a also deplete some NK cells, and depletion of CD8 þ lymphocytes can result in proliferation of CD4 þ T cells, potentially providing additional targets for viral infection and increasing virema via this mechanism (Okoye et al. 2009). Perhaps the clearest evidence of CD8 þ T-cell control of viral replication is provided by evidence of immune escape "
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    ABSTRACT: Nonhuman primate (NHP) disease models for AIDS have made important contributions to the search for effective vaccines for AIDS. Viral diversity, persistence, capacity for immune evasion, and safety considerations have limited development of conventional approaches using killed or attenuated vaccines, necessitating the development of novel approaches. Here we highlight the knowledge gained and lessons learned in testing vaccine concepts in different virus/NHP host combinations. © 2012 Cold Spring Harbor Laboratory Press; all rights reserved.
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    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.
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