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: 4.65). 12/2008; 83(2):748-56. DOI: 10.1128/JVI.01811-08
Source: PubMed

ABSTRACT 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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    ABSTRACT: Porcine circovirus-2 (PCV-2) is primarily transmitted through mucosa, thus the mucosal immunity may constitute an essential feature of vaccination strategies against PCV-2 infection. Mucosal immunity elicited by recombinant replication-deficient adenovirus expressing the major epitopes of PCV-2 capsid protein (rAd/Cap/518) via intranasal (i.n.), intramuscular (i.m.) or oral routes in mice were evaluated. Immunization with rAd/Cap/518 via i.n. route induced higher titers of IgA in saliva, bronchoalveolar and intestinal lavage fluid compared with those immunized via i.m. route. The proportions of CD3+, CD3+CD4+ and CD3+CD8+ T cells were significantly increased in mice immunized with rAd/Cap/518 via i.n. route compared with the control group. Higher levels of IFN-γ were detected in the spleen and mesenteric lymph nodes of mice immunized with rAd/Cap/518 via i.n. route compared with other groups, yet IL-4 was not detected in any group. Real-time PCR analysis confirmed viral DNA loads in the i.m. or i.n. immunization group was lower than that seen in the rAd immunization. These results indicate that i.n. administration of rAd/Cap/518 can elicit humoral and Th1-type cellular protective immunity in both systemic and mucosal immune compartments in mice, representing a promising mucosal vaccine candidate against PCV-2.
    Veterinary Immunology and Immunopathology 04/2013; DOI:10.1016/j.vetimm.2013.03.015 · 1.75 Impact Factor
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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.
    Journal of veterinary science (Suwŏn-si, Korea) 03/2014; 15(3). DOI:10.4142/jvs.2014.15.3.399 · 1.14 Impact Factor
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    ABSTRACT: BACKGROUND: Replication-competent virus vector vaccines might have advantages compared with non-replicating vector vaccines. We tested the safety and immunogenicity of an oral adenovirus serotype 4 vector vaccine candidate (Ad4-H5-Vtn) expressing the haemagglutinin from an avian influenza A H5N1 virus. METHODS: We did this phase 1 study at four sites in the USA. We used a computer-generated randomisation list (block size eight, stratified by site) to assign healthy volunteers aged 18-40 years to receive one of five doses of Ad4-H5-Vtn (10(7) viral particles [VP], 10(8) VP, 10(9) VP, 10(10) VP, 10(11) VP) or placebo (3:1). Vaccine or placebo was given on three occasions, about 56 days apart. Participants, investigators, and study-site personnel were masked to assignment throughout the study. Subsequently, volunteers received a boost dose with 90 μg of an inactivated parenteral H5N1 vaccine. Primary immunogenicity endpoints were seroconversion by haemagglutination-inhibition (HAI), defined as a four-times rise compared with baseline titre, and HAI geometric mean titre (GMT). We solicited symptoms of reactogenicity daily for 7 days after each vaccination and recorded symptoms that persisted beyond 7 days as adverse events. Primary analysis was per protocol. This trial is registered with, number NCT01006798. FINDINGS: We enrolled 166 participants (125 vaccine; 41 placebo) between Oct 19, 2009, and Sept 9, 2010. HAI responses were low: 13 of 123 vaccinees (11%, 95% CI 6-17) and three of 41 placebo recipients (7%, 2-20) seroconverted. HAI GMT was 6 (95% CI 5-7) for vaccinees, and 5 (5-6) for placebo recipients. However, when inactivated H5N1 vaccine became available, one H5N1 boost was offered to all participants. In this substudy, HAI seroconversion occurred in 19 of 19 participants in the 10(11) VP cohort (100%; 95% CI 82-100) and eight of 22 placebo recipients (36%; 17-59); 17 of 19 participants in the 10(11) VP cohort (89%; 67-99) achieved seroprotection compared with four of 22 placebo recipients (18%; 5-40); GMT was 135 (89-205) with 10(11) VP, compared with 13 (7-21) with placebo. The cumulative frequency of abdominal pain, diarrhoea, and nasal congestion after all three vaccinations was significantly higher in vaccinees than placebo recipients (21 [16·8%] of 125 vs one [2·4%] of 41, p=0·017; 24 [19·2%] of 125 vs two [4·9%] of 41, p=0·027; 41 [32·8%] of 125 vs six [14·6%] of 41, p=0·028; respectively). No serious treatment-related adverse events occurred. INTERPRETATION: Oral Ad4 vector priming might enhance the efficacy of poorly immunogenic vaccines such as H5N1. FUNDING: Wellcome Trust Foundation, PaxVax.
    The Lancet Infectious Diseases 01/2013; 13(3). DOI:10.1016/S1473-3099(12)70345-6 · 19.45 Impact Factor


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May 31, 2014