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

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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Immunogenicity of Heterologous Prime-Boost Regimens Involving Recombinant Adenovirus Serotype 11 (Ad11) and Ad35 Vaccine Vectors in the Presence of Anti-Ad5 Immunity

Journal of Virology ◽

10.1128/jvi.79.15.9694-9701.2005 ◽

2005 ◽

Vol 79 (15) ◽

pp. 9694-9701 ◽

Cited By ~ 122

Author(s):

Angelique A. C. Lemckert ◽

Shawn M. Sumida ◽

Lennart Holterman ◽

Ronald Vogels ◽

Diana M. Truitt ◽

...

Keyword(s):

Immune Responses ◽

Recombinant Adenovirus ◽

Human Populations ◽

Vaccine Vectors ◽

Adenovirus Serotype ◽

Immunodeficiency Virus ◽

High Prevalence ◽

Boost Vaccine ◽

Serotype 5 ◽

Cellular Immune

ABSTRACT The high prevalence of preexisting immunity to adenovirus serotype 5 (Ad5) in human populations will likely limit the immunogenicity and clinical utility of recombinant Ad5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 and other pathogens. A potential solution to this problem is to utilize rAd vaccine vectors derived from rare Ad serotypes such as Ad35 and Ad11. We have previously reported that rAd35 vectors were immunogenic in the presence of anti-Ad5 immunity, but the immunogenicity of heterologous rAd prime-boost regimens and the extent that cross-reactive anti-vector immunity may limit this approach have not been fully explored. Here we assess the immunogenicity of heterologous vaccine regimens involving rAd5, rAd35, and novel rAd11 vectors expressing simian immunodeficiency virus Gag in mice both with and without anti-Ad5 immunity. Heterologous rAd prime-boost regimens proved significantly more immunogenic than homologous regimens, as expected. Importantly, all regimens that included rAd5 were markedly suppressed by anti-Ad5 immunity. In contrast, rAd35-rAd11 and rAd11-rAd35 regimens elicited high-frequency immune responses both in the presence and in the absence of anti-Ad5 immunity, although we also detected clear cross-reactive Ad35/Ad11-specific humoral and cellular immune responses. Nevertheless, these data suggest the potential utility of heterologous rAd prime-boost vaccine regimens using vectors derived from rare human Ad serotypes.

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Immunogenicity of Recombinant Fiber-Chimeric Adenovirus Serotype 35 Vector-Based Vaccines in Mice and Rhesus Monkeys

Journal of Virology ◽

10.1128/jvi.79.22.14161-14168.2005 ◽

2005 ◽

Vol 79 (22) ◽

pp. 14161-14168 ◽

Cited By ~ 72

Author(s):

Anjali Nanda ◽

Diana M. Lynch ◽

Jaap Goudsmit ◽

Angelique A. C. Lemckert ◽

Bonnie A. Ewald ◽

...

Keyword(s):

Rhesus Monkeys ◽

In Vivo Studies ◽

Preclinical Studies ◽

Adenovirus Serotype ◽

Immunodeficiency Virus ◽

Serotype 5 ◽

Fiber Proteins ◽

Hiv 1

ABSTRACT Preexisting immunity to adenovirus serotype 5 (Ad5) has been shown to suppress the immunogenicity of recombinant Ad5 (rAd5) vector-based vaccines for human immunodeficiency virus type 1 (HIV-1) in both preclinical studies and clinical trials. A potential solution to this problem is to utilize rAd vectors derived from rare Ad serotypes, such as Ad35. However, rAd35 vectors have appeared less immunogenic than rAd5 vectors in preclinical studies to date. In this study, we explore the hypothesis that the differences in immunogenicity between rAd5 and rAd35 vectors may be due in part to differences between the fiber proteins of these viruses. We constructed capsid chimeric rAd35 vectors containing the Ad5 fiber knob (rAd35k5) and compared the immunogenicities of rAd5, rAd35k5, and rAd35 vectors expressing simian immunodeficiency virus Gag and HIV-1 Env in mice and rhesus monkeys. In vitro studies demonstrated that rAd35k5 vectors utilized the Ad5 receptor CAR rather than the Ad35 receptor CD46. In vivo studies showed that rAd35k5 vectors were more immunogenic than rAd35 vectors in both mice and rhesus monkeys. These data suggest that the Ad5 fiber knob contributes substantially to the immunogenicity of rAd vectors. Moreover, these studies demonstrate that capsid chimeric rAd vectors can be constructed to combine beneficial immunologic and serologic properties of different Ad serotypes.

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Faculty Opinions recommendation of Vaccination with adenovirus serotypes 35, 26, and 48 elicits higher levels of innate cytokine responses than adenovirus serotype 5 in rhesus monkeys.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.717953702.793459313 ◽

2012 ◽

Author(s):

Willy Bogers ◽

Petra Mooij

Keyword(s):

Rhesus Monkeys ◽

Adenovirus Serotype ◽

Cytokine Responses ◽

Serotype 5

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IL-36 signaling amplifies Th1 responses by enhancing proliferation and Th1 polarization of naive CD4+ T cells

Blood ◽

10.1182/blood-2012-06-439026 ◽

2012 ◽

Vol 120 (17) ◽

pp. 3478-3487 ◽

Cited By ~ 123

Author(s):

Solenne Vigne ◽

Gaby Palmer ◽

Praxedis Martin ◽

Céline Lamacchia ◽

Deborah Strebel ◽

...

Keyword(s):

T Cells ◽

Immune Responses ◽

Cd4 T Cells ◽

Interleukin 1 ◽

Th1 Cell ◽

Critical Function ◽

Mediators Of Inflammation ◽

Th1 Polarization

AbstractThe interleukin-1 (IL-1) superfamily of cytokines comprises a set of pivotal mediators of inflammation. Among them, the action of IL-36 cytokines in immune responses has remained elusive. In a recent study, we demonstrated a direct effect of IL-36 on immune cells. Here we show that, among T cells, the IL-36 receptor is predominantly expressed on naive CD4+ T cells and that IL-36 cytokines act directly on naive T cells by enhancing both cell proliferation and IL-2 secretion. IL-36β acts in synergy with IL-12 to promote Th1 polarization and IL-36 signaling is also involved in mediating Th1 immune responses to Bacillus Calmette-Guerin infection in vivo. Our findings point toward a critical function of IL-36 in the priming of Th1 cell responses in vitro, and in adaptive immunity in a model of mycobacterial infection in vivo.

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Intramuscular Delivery of Adenovirus Serotype 5 Vector Expressing Humanized Protective Antigen Induces Rapid Protection against Anthrax That May Bypass Intranasally Originated Preexisting Adenovirus Immunity

Clinical and Vaccine Immunology ◽

10.1128/cvi.00560-13 ◽

2013 ◽

Vol 21 (2) ◽

pp. 156-164 ◽

Cited By ~ 6

Author(s):

Shipo Wu ◽

Zhe Zhang ◽

Rui Yu ◽

Jun Zhang ◽

Ying Liu ◽

...

Keyword(s):

Immune Responses ◽

Intramuscular Injection ◽

Protective Antigen ◽

Lethal Dose ◽

Adenovirus Serotype ◽

Cellular Immune Responses ◽

Intramuscular Inoculation ◽

Serotype 5 ◽

Cellular Immune ◽

Induced Immunity

ABSTRACTDeveloping an effective anthrax vaccine that can induce a rapid and sustained immune response is a priority for the prevention of bioterrorism-associated anthrax infection. Here, we developed a recombinant replication-deficient adenovirus serotype 5-based vaccine expressing the humanized protective antigen (Ad5-PAopt). A single intramuscular injection of Ad5-PAopt resulted in rapid and robust humoral and cellular immune responses in Fisher 344 rats. Animals intramuscularly inoculated with a single dose of 108infectious units of Ad5-PAopt achieved 100% protection from challenge with 10 times the 50% lethal dose (LD50) of anthrax lethal toxin 7 days after vaccination. Although preexisting intranasally induced immunity to Ad5 slightly weakened the humoral and cellular immune responses to Ad5-PAopt via intramuscular inoculation, 100% protection was achieved 15 days after vaccination in Fisher 344 rats. The protective efficacy conferred by intramuscular vaccination in the presence of preexisting intranasally induced immunity was significantly better than that of intranasal delivery of Ad5-PAopt and intramuscular injection with recombinant PA and aluminum adjuvant without preexisting immunity. As natural Ad5 infection often occurs via the mucosal route, the work here largely illuminates that intramuscular inoculation with Ad5-PAopt can overcome the negative effects of immunity induced by prior adenovirus infection and represents an efficient approach for protecting against emerging anthrax.

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Helminth infection is associated with dampened cytokine responses to viral and bacterial stimulations in Tsimane hunter-horticulturalists

10.1101/2021.09.29.462428 ◽

2021 ◽

Author(s):

India Schneider-Crease ◽

Aaron D. Blackwell ◽

Thomas S. Kraft ◽

Melissa Emery Thompson ◽

Ivan Maldonado Suarez ◽

...

Keyword(s):

Immune Responses ◽

Inflammatory Responses ◽

Remote Communities ◽

Necrosis Factor Alpha ◽

H1n1 Vaccine ◽

Gm Csf ◽

Th2 Cytokine ◽

Cytokine Responses ◽

Macrophage Colony

AbstractBackgroundSoil-transmitted helminth (STH) infections can catalyze immunological changes that affect the response to subsequent infections, particularly those that elicit strong inflammatory responses. As globalization heightens the risk that remote communities with high STH prevalence will encounter novel pathogens, understanding how STHs shape immune responses to these downstream infections becomes increasingly crucial.MethodologyWe worked with Tsimane forager-horticulturalists in the Bolivian Amazon, where STHs are prevalent. We tested whether STHs and eosinophil levels—most likely indicative of infection in this population—are associated with dampened immune responses to in vitro stimulation with H1N1 and lipopolysaccharide (LPS) antigens. Whole blood samples (n = 179) were treated with H1N1 vaccine and LPS and assayed for 13 cytokines (interferon gamma [INF-γ], interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-7, IL-8, IL-10, IL-12p70, IL-13, Granulocyte-macrophage colony-stimulating factor [GM-CSF], and Tumor necrosis factor-alpha [TNF-α]). We evaluated how STHs and eosinophil levels affected cytokine responses and T helper (Th) 1 and Th2-cytokine suite responses to stimulation.ResultsInfection with Ascaris lumbricoides was significantly (p ≤ 0.05) associated with lower response of some cytokines to H1N1 and LPS in women. Eosinophils were significantly negatively associated with some cytokine responses to H1N1 and LPS, with the strongest effects in women, and associated with a reduced Th1- and Th2-cytokine response to H1N1 and LPS in women and men.Conclusions and implicationsWe find that STHs were associated with dampened cytokine responses to certain viral and bacterial antigens, and suggest that this mitigation of host-induced damage may reduce the incidence of cytokine storms in populations with high STH prevalence.

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Inhibition of human erythroid colony-forming units by gamma interferon can be corrected by recombinant human erythropoietin [see comments]

Blood ◽

10.1182/blood.v78.10.2564.2564 ◽

1991 ◽

Vol 78 (10) ◽

pp. 2564-2567 ◽

Cited By ~ 103

Author(s):

RT Jr Means ◽

SB Krantz

Keyword(s):

Chronic Disease ◽

Interleukin 1 ◽

Gamma Interferon ◽

Receptor Expression ◽

Recombinant Erythropoietin ◽

Anemia Of Chronic Disease ◽

Human Erythropoietin ◽

Colony Forming Units

Abstract Tumor necrosis factor (TNF), interleukin-1 (IL-1), and gamma interferon (gamma IFN) inhibit erythropoiesis in vivo and in vitro, and have been implicated in the pathogenesis of the anemia of chronic disease. Anemia in patients with rheumatoid arthritis and in animals exposed chronically to IL-1 and TNF can be corrected by the administration of recombinant erythropoietin (Epo). We exposed highly purified human erythroid colony-forming units (CFU-E) cultured from peripheral blood burst-forming units-erythroid (BFU-E) and unpurified human marrow CFU-E to recombinant human gamma IFN and showed inhibition of colony formation in vitro. This inhibition was reversed by increased concentrations of Epo. The mechanisms by which this effect occurs are unknown at present. Epo may cause a downregulation of gamma IFN receptor expression on CFU-E or, alternatively, gamma IFN may cause a downregulation of Epo receptor expression. A full understanding of these mechanisms awaits a more complete comprehension of the regulation of erythropoiesis; however, the effect of Epo in vitro is similar to its ability to correct the anemia of chronic disease in vivo.

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Use of Adenovirus Serotype 5 Vaccine Vectors in Seropositive, Uncircumcised Men: Safety Lessons from the Step Trial

The Journal of Infectious Diseases ◽

10.1093/infdis/jis737 ◽

2012 ◽

Vol 207 (4) ◽

pp. 689-690 ◽

Cited By ~ 5

Author(s):

T. L. Richie ◽

E. F. Villasante

Keyword(s):

Vaccine Vectors ◽

Adenovirus Serotype ◽

Step Trial ◽

Serotype 5

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Replication-Defective Adenovirus Serotype 5 Vectors Elicit Durable Cellular and Humoral Immune Responses in Nonhuman Primates

Journal of Virology ◽

10.1128/jvi.79.10.6516-6522.2005 ◽

2005 ◽

Vol 79 (10) ◽

pp. 6516-6522 ◽

Cited By ~ 107

Author(s):

Sampa Santra ◽

Michael S. Seaman ◽

Ling Xu ◽

Dan H. Barouch ◽

Carol I. Lord ◽

...

Keyword(s):

Immune Responses ◽

Adenovirus Serotype ◽

Humoral Immune ◽

Humoral Immune Responses ◽

Monkey Model ◽

Immunodeficiency Virus ◽

Serotype 5 ◽

Rapid Generation ◽

Cellular And Humoral Immunity ◽

Replication Defective Adenovirus

ABSTRACT The magnitude and durability of immune responses induced by replication-defective adenovirus serotype 5 (ADV5) vector-based vaccines were evaluated in the simian-human immunodeficiency virus/rhesus monkey model. A single inoculation of recombinant ADV5 vector constructs induced cellular and humoral immunity, but the rapid generation of neutralizing anti-Ad5 antibodies limited the immunity induced by repeated vector administration. The magnitude and durability of the immune responses elicited by these vaccines were greater when they were delivered as boosting immunogens in plasmid DNA-primed monkeys than when they were used as single-modality immunogens. Therefore, administration of ADV5-based vectors in DNA-primed subjects may be a preferred use of this vaccine modality for generating long-term immune protection.

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