Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors

Appledorn, Daniel M.; McBride, Aaron J.; Seregin, Sergey S.; Scott, Jeannine M.; Schuldt, Nathaniel J.; Kiang, Anne; Godbehere, Sarah; Amalfitano, Andrea

doi:10.1038/gt.2008.114

Cited by 64 publications

(99 citation statements)

References 49 publications

(90 reference statements)

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“…Previous reports have characterized innate cytokine profiles of Ad vectors in mice (3,4,53) and in vitro (2,18,19,20,29,36,52). For example, several studies have reported that Ad35 induces higher levels of the costimulatory markers CD80 and CD40 and interferons than does Ad5 in vitro in human DC (29) as well as higher levels of IL-10 and reduced proliferation in T cells cocultured with DCs (2).…”

Section: Discussionmentioning

confidence: 99%

Vaccination with Adenovirus Serotypes 35, 26, and 48 Elicits Higher Levels of Innate Cytokine Responses than Adenovirus Serotype 5 in Rhesus Monkeys

Teigler

Iampietro

Barouch

2012

J Virol

109

126

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Adenovirus (Ad) vaccine vectors have proven highly immunogenic in multiple experimental models, but the innate immune responses induced by these vectors remain poorly characterized. Here we report innate cytokine responses to 5 different Ad vectors in 26 rhesus monkeys. Vaccination with adenovirus serotype 35 (Ad35), Ad26, and Ad48 induced substantially higher levels of antiviral (gamma interferon [IFN-γ], 10-kDa gamma interferon-induced protein [IP-10]) and proinflammatory (interleukin 1 receptor antagonist [IL-1RA], IL-6) cytokines than vaccination with Ad5 on day 1 following immunization.In vitrostudies with capsid chimeric vectors and receptor-blocking monoclonal antibodies suggested that fiber-receptor interactions, as well as other capsid components, were critical for triggering these innate responses. Moreover, multiple cell populations, including dendritic cells, monocytes/macrophages, and T lymphocytes, contributed to these innate cytokine profiles. These data demonstrate that Ad35, Ad26, and Ad48, which utilize CD46 as their primary cellular receptor, induce significantly greater innate cytokine responses than Ad5, which uses the coxsackievirus and adenovirus receptor (CAR). These differences in innate triggering result in markedly different immunologic milieus for the subsequent generation of adaptive immune responses by these vaccine vectors.

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Section: Discussionmentioning

confidence: 99%

Vaccination with Adenovirus Serotypes 35, 26, and 48 Elicits Higher Levels of Innate Cytokine Responses than Adenovirus Serotype 5 in Rhesus Monkeys

Teigler

Iampietro

Barouch

2012

J Virol

109

126

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“…The Ad5-GFP, Ad5-null, Ad5-HIV/Gag, and Ad5-EAT-2 viruses were purified as previously described (19,24). The rAd5-EAT-2(R31Q) vector is identical to the rAd5-EAT-2 virus, except it additionally contains an arginine 31 to glutamine (EAT-2-R31Q) mutation in the EAT-2 SH2 domain constructed as follows.…”

Section: Vector Constructionmentioning

confidence: 99%

Vaccines Expressing the Innate Immune Modulator EAT-2 Elicit Potent Effector Memory T Lymphocyte Responses despite Pre-Existing Vaccine Immunity

Aldhamen

Seregin

Schuldt

et al. 2012

The Journal of Immunology

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The mixed results from recent vaccine clinical trials targeting HIV-1 justify the need to enhance the potency of HIV-1 vaccine platforms in general. Use of first-generation recombinant adenovirus serotype 5 (rAd5) platforms failed to protect vaccinees from HIV-1 infection. One hypothesis is that the rAd5-based vaccine failed due to the presence of pre-existing Ad5 immunity in many vaccines. We recently confirmed that EAT-2–expressing rAd5 vectors uniquely activate the innate immune system and improve cellular immune responses against rAd5-expressed Ags, inclusive of HIV/Gag. In this study, we report that use of the rAd5-EAT-2 vaccine can also induce potent cellular immune responses to HIV-1 Ags despite the presence of Ad5-specific immunity. Compared to controls expressing a mutant SH2 domain form of EAT-2, Ad5 immune mice vaccinated with an rAd5-wild-type EAT-2 HIV/Gag-specific vaccine formulation significantly facilitated the induction of several arms of the innate immune system. These responses positively correlated with an improved ability of the vaccine to induce stronger effector memory T cell-biased, cellular immune responses to a coexpressed Ag despite pre-existing anti-Ad5 immunity. Moreover, inclusion of EAT-2 in the vaccine mixture improves the generation of polyfunctional cytolytic CD8+ T cell responses as characterized by enhanced production of IFN-γ, TNF-α, cytotoxic degranulation, and increased in vivo cytolytic activity. These data suggest a new approach whereby inclusion of EAT-2 expression in stringent human vaccination applications can provide a more effective vaccine against HIV-1 specifically in Ad5 immune subjects.

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“…The Ad-GFP virus was purified as previously described (22). The open reading frame of EAT-2 gene (GenBank Accession no.…”

Section: Vector Constructionmentioning

confidence: 99%

Expression of the SLAM Family of Receptors Adapter EAT-2 as a Novel Strategy for Enhancing Beneficial Immune Responses to Vaccine Antigens

Aldhamen

Appledorn

Seregin

et al. 2011

The Journal of Immunology

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Recent studies have shown that activation of the signaling lymphocytic activation molecule (SLAM) family of receptors plays an important role in several aspects of immune regulation. However, translation of this knowledge into a useful clinical application has not been undertaken. One important area where SLAM-mediated immune regulation may have keen importance is in the field of vaccinology. Because SLAM signaling plays such a critical role in the innate and adaptive immunity, we endeavored to develop a strategy to improve the efficacy of vaccines by incorporation of proteins known to be important in SLAM-mediated signaling. In this study, we hypothesized that coexpression of the SLAM adapter EWS-FLI1–activated transcript 2 (EAT-2) along with a pathogen-derived Ag would facilitate induction of beneficial innate immune responses, resulting in improved induction of Ag-specific adaptive immune responses. To test this hypothesis, we used rAd5 vector-based vaccines expressing murine EAT-2, or the HIV-1–derived Ag Gag. Compared with appropriate controls, rAd5 vectors expressing EAT-2 facilitated bystander activation of NK, NKT, B, and T cells early after their administration into animals. EAT-2 overexpression also augments the expression of APC (macrophages and dendritic cells) surface markers. Indeed, this multitiered activation of the innate immune system by vaccine-mediated EAT-2 expression enhanced the induction of Ag-specific cellular immune responses. Because both mice and humans express highly conserved EAT-2 adapters, our results suggest that human vaccination strategies that specifically facilitate SLAM signaling may improve vaccine potency when targeting HIV Ags specifically, as well as numerous other vaccine targets in general.

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Complex interactions with several arms of the complement system dictate innate and humoral immunity to adenoviral vectors

Cited by 64 publications

References 49 publications

Vaccination with Adenovirus Serotypes 35, 26, and 48 Elicits Higher Levels of Innate Cytokine Responses than Adenovirus Serotype 5 in Rhesus Monkeys

Vaccination with Adenovirus Serotypes 35, 26, and 48 Elicits Higher Levels of Innate Cytokine Responses than Adenovirus Serotype 5 in Rhesus Monkeys

Vaccines Expressing the Innate Immune Modulator EAT-2 Elicit Potent Effector Memory T Lymphocyte Responses despite Pre-Existing Vaccine Immunity

Expression of the SLAM Family of Receptors Adapter EAT-2 as a Novel Strategy for Enhancing Beneficial Immune Responses to Vaccine Antigens

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