Adenovirus type 5 with modified hexons induces robust transgene‐specific immune responses in mice with pre‐existing immunity against adenovirus type 5

Abe, Shinya; Okuda, Kenji; Ura, Takehiro; Kondo, Asami; Yoshida, Atsushi; Yoshizaki, Shinji; Mizuguchi, Hiroyuki; Klinman, Dennis M.; Shimada, Masaru

doi:10.1002/jgm.1332

Cited by 46 publications

(50 citation statements)

References 49 publications

(63 reference statements)

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“…This conclusion was corroborated by the fact that when anti-P. yoelii CS antibody was used to neutralize rAd in vitro, it neutralized equally both HVR1-and HVR5-modified rAds, suggesting that an epitope present in HVR5 can also be a target of neutralizing antibody, albeit to a lesser degree. The observation of HVR5 being the possible target of neutralizing antibody in addition to HVR1 is not contradictory to the study by Roberts et al, which reported that replacement of all HVRs with those of Ad48 was necessary to completely circumvent preexisting immunity to Ad5 (20), or to the study by Abe et al, which showed that HVR5 modification could also circumvent preexisting anti-Ad5 immunity, although they never compared the effect of HVR5 modification with that of HVR1 modification (29). In our study, the percentage of neutralizing antibody against HVR1 within all neutralizing antibodies seems to differ among human sera, and this variation could arise from the difference in immunogenicity of HVRs among individuals.…”

Section: Figurementioning

confidence: 62%

Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

Shiratsuchi

Rai²,

Krause³

et al. 2010

J. Clin. Invest.

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Although adenovirus (Ad) has been regarded as an excellent vaccine vector, there are 2 major drawbacks to using this platform: (a) Ad-based vaccines induce a relatively weak humoral response against encoded transgenes, and (b) preexisting immunity to Ad is highly prevalent among the general population. To overcome these obstacles, we constructed an Ad-based malaria vaccine by inserting a B cell epitope derived from a Plasmodium yoelii circumsporozoite (

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Section: Figurementioning

confidence: 62%

Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

Shiratsuchi

Rai²,

Krause³

et al. 2010

J. Clin. Invest.

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“…However, the relative importances of the seven individual HVRs as NAb epitopes remain incompletely understood, and recent studies have suggested that Ad5 NAb responses may actually be focused primarily on one specific HVR, such as HVR1 or HVR5 (1,15). In this study, we characterized the contribution of individual hexon HVRs as Ad5 NAb epitopes.…”

mentioning

confidence: 97%

“…We previously reported that replacing all seven hexon HVRs in Ad5 with those from a rare human adenovirus serotype, Ad48, resulted in a chimeric vector, Ad5HVR48 (1)(2)(3)(4)(5)(6)(7), that evaded the majority of preexisting Ad5 immunity in preclinical studies in mice and rhesus monkeys (13). However, the relative importances of the seven individual HVRs as NAb epitopes remain incompletely understood, and recent studies have suggested that Ad5 NAb responses may actually be focused primarily on one specific HVR, such as HVR1 or HVR5 (1,15).…”

mentioning

confidence: 99%

Adenovirus Serotype 5-Specific Neutralizing Antibodies Target Multiple Hexon Hypervariable Regions

Bradley

Maxfield

Lynch

et al. 2012

J Virol

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The immunogenicity of adenovirus serotype 5 (Ad5) vectors has been shown to be suppressed by neutralizing antibodies (NAbs) directed primarily against the hexon hypervariable regions (HVRs). We previously reported that replacing all seven HVRs with those from the rare serotype virus Ad48 resulted in a chimeric Ad5HVR48(1-7) vector that largely evaded preexisting Ad5 immunity in mice and rhesus monkeys. In this study, we evaluated the extent to which Ad5-specific NAbs are directed against various HVRs. We constructed partial HVR-chimeric Ad5 vectors with only a subset of HVRs exchanged, and we utilized these vectors in both NAb assays and murine immunogenicity studies with and without baseline Ad5 immunity. Our results demonstrate that Ad5-specific NAbs target multiple HVRs, suggesting that replacing all HVRs is required to optimize evasion of anti-Ad5 immunity. These data have important implications for the development of novel vectors for both vaccines and gene therapy.

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“…Several approaches have therefore been developed to circumvent pre-existing anti-Ad5 immunity and/or to facilitate the induction of potent adaptive immune responses by Ad-based vaccines in general. These approaches include the use of novel Ad5-based platforms (15,16), modification of Ad5 structure (17), and the development of alternative serotype (human-or chimpanzeederived) adenovirus-based vectors (18).…”

mentioning

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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Adenovirus type 5 with modified hexons induces robust transgene‐specific immune responses in mice with pre‐existing immunity against adenovirus type 5

Abstract: These data demonstrate that Ad5 vector with hexon modification reduce their sensitivity to pre-existing anti-Ad immunity and improve their clinical utility.

Cited by 46 publications

References 49 publications

Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

Replacing adenoviral vector HVR1 with a malaria B cell epitope improves immunogenicity and circumvents preexisting immunity to adenovirus in mice

Adenovirus Serotype 5-Specific Neutralizing Antibodies Target Multiple Hexon Hypervariable Regions

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

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