An adenoviral type 5 vector carrying a type 35 fiber as a vaccine vehicle: DC targeting, cross neutralization, and immunogenicity

Ophorst, Olga; Kostense, Stefan; Goudsmit, Jaap; Swart, Rik L. de; Verhaagh, Sandra; Zakhartchouk, Alexander N.; Meijer, Marja van; Sprangers, Mieke; Amerongen, Geert van; Yüksel, Selma; Osterhaus, Albert D. M. E.; Havenga, Menzo

doi:10.1016/j.vaccine.2004.02.011

Cited by 75 publications

(54 citation statements)

References 49 publications

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“…Consistent with this finding, we have previously observed that rAd35f5 vaccine vectors were unable to bypass anti-Ad5 immunity in mice (33). We were unable to evaluate directly the suppressive effects of penton-specific NAbs using our panel of capsid chimeric rAd5/ rAd35 viruses.…”

Section: Discussionsupporting

confidence: 63%

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

Sumida

Truitt

Lemckert

et al. 2005

The Journal of Immunology

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320

276

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The utility of recombinant adenovirus serotype 5 (rAd5) vector-based vaccines for HIV-1 and other pathogens will likely be limited by the high prevalence of pre-existing Ad5-specific neutralizing Abs (NAbs) in human populations. However, the immunodominant targets of Ad5-specific NAbs in humans remain poorly characterized. In this study, we assess the titers and primary determinants of Ad5-specific NAbs in individuals from both the United States and the developing world. Importantly, median Ad5-specific NAb titers were >10-fold higher in sub-Saharan Africa compared with the United States. Moreover, hexon-specific NAb titers were 4- to 10-fold higher than fiber-specific NAb titers in these cohorts by virus neutralization assays using capsid chimeric viruses. We next performed adoptive transfer studies in mice to evaluate the functional capacity of hexon- and fiber-specific NAbs to suppress the immunogenicity of a prototype rAd5-Env vaccine. Hexon-specific NAbs were remarkably efficient at suppressing Env-specific immune responses elicited by the rAd5 vaccine. In contrast, fiber-specific NAbs exerted only minimal suppressive effects on rAd5 vaccine immunogenicity. These data demonstrate that functionally significant Ad5-specific NAbs are directed primarily against the Ad5 hexon protein in both humans and mice. These studies suggest a potential strategy for engineering novel Ad5 vectors to evade dominant Ad5-specific NAbs.

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Section: Discussionsupporting

confidence: 63%

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

Sumida

Truitt

Lemckert

et al. 2005

The Journal of Immunology

Self Cite

320

276

View full text Add to dashboard Cite

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“…This study concluded that pre-existing immunity against Ad5 is not circumvented by Ad5.Fib35. 18 On the other hand, the induced anti-Ad5-neutralizing activity could not diminish the efficiency of an Ad35-based Simian immunodeficiency virus-gag vaccine in mice. 37 Thus, recombinant Ad35 is not affected by the high Ad5 sero prevalence and, in combination with improved transduction of primary glioma cells, may represent a better vector than Ad5.…”

Section: Discussionmentioning

confidence: 96%

“…18 Recent studies have reported that the sero prevalence of human Ad35 is significantly lower than Ad5 in healthy blood donors. 9 However, B-group adenoviruses, including Ad35, have been isolated relatively frequently from immunocompromised patients.…”

Section: Introductionmentioning

confidence: 99%

Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients

et al. 2006

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Clinical trials in malignant glioma have demonstrated excellent safety of recombinant adenovirus type 5 (Ad5) but lack of convincing efficacy. The overall low expression levels of the Coxsackie and Adenovirus receptor and the presence of high anti-Ad5-neutralizing antibody (NAb) titers in the human population are considered detrimental for consistency of clinical results. To identify an adenoviral vector better suited to infect primary glioma cells, we tested a library of fiber-chimeric Ad5-based adenoviral vectors on 12 fresh human glioma cell suspensions. Significantly improved marker gene expression was obtained with several Ad5-chimeric vectors, predominantly vectors carrying fiber molecules derived from B-group viruses (Ad11, Ad16, Ad35 and Ad50). We next tested Ad35 sero prevalence in sera derived from 90 Dutch cancer patients including 30 glioma patients and investigated the transduction efficiency of this vector in glioma cell suspensions. Our results demonstrate that the sero prevalence and the titers of NAb against Ad35 are significantly lower than against Ad5. Also, recombinant Ad35 has significantly increased ability to transfer a gene to primary glioma cells compared to Ad5. We thus conclude that Ad35 represents an interesting candidate vector for gene therapy of malignant glioma.

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“…This clearly limits the value of in vivo studies with Ad5/35 in normal mice. [21][22][23][24][25][26] From other areas of research (in particular, studies with measles virus), a number of CD46 transgenic mouse strains are available. In this study, we used a C57Bl/ 6-based strain that ubiquitously expresses CD46 at levels comparable to humans.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of adenovirus vectors containing serotype 35 fibers for tumor targeting

Gaggar

Paolo

et al. 2006

Cancer Gene Ther

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There is growing evidence from in vitro studies that subgroup B adenoviruses (Ad) can overcome the limitations in safety and tumor transduction efficiency seen with commonly used subgroup C serotype 5-based vectors. In this study, we confirm that the expression level of the B-group Ad receptor, CD46, correlates with the grade of malignancy of cervical cancer in situ. We also demonstrate the in vivo properties of Ad5-based vectors that contain the B-group Ad serotype 35 fiber (Ad5/35) in transgenic mice that express CD46 in a pattern and at a level similar to humans. Upon intravenous and intraperitoneal injection, an Ad5/35 vector did not efficiently transduce normal tissue, but was able to target metastatic or intraperitoneal tumors that express CD46 at levels comparable to human tumors. When an oncolytic Ad5/35-based vector was employed, in both tumor models antitumor effects were observed. Furthermore, injection of Ad5/35 vectors into CD46 transgenic mice caused less innate toxicity than Ad5 vectors. Our data demonstrate that Ad vectors that target CD46 offer advantages over Ad5-based vectors for treatment of cancer.

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An adenoviral type 5 vector carrying a type 35 fiber as a vaccine vehicle: DC targeting, cross neutralization, and immunogenicity

Cited by 75 publications

References 49 publications

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

Neutralizing Antibodies to Adenovirus Serotype 5 Vaccine Vectors Are Directed Primarily against the Adenovirus Hexon Protein

Human adenovirus type 35 vector for gene therapy of brain cancer: improved transduction and bypass of pre-existing anti-vector immunity in cancer patients

Evaluation of adenovirus vectors containing serotype 35 fibers for tumor targeting

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