Three CpG oligodeoxynucleotide classes differentially enhance antigen-specific humoral and cellular immune responses in mice

Liu, Ying; Luo, Xing; Yang, Chi; Yu, San-Ke; Xu, Hui

doi:10.1016/j.vaccine.2011.05.087

Cited by 25 publications

(26 citation statements)

References 26 publications

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“…In the current study, the three types of optimal human CpG motifs were used as built-in adjuvants to enhance the immunostimulatory activity. More importantly, we investigated the effects of modifying plasmid vectors with these three distinct types of optimal human-specific CpG motifs in a mouse model with the aim of improving the immunogenicity of DNA vaccines for human use.Our results indicate that modification of plasmid backbone with the three major types of human CpG motifs improved the immunostimulatory activity on human PBMCs in vitro as previously studies [10,13,21,28] and resulted in enhanced β-Gal-specific humoral and cell-mediated immune responses in vivo. At the same time, we investigated whether the expression of β-Gal was directly affected by the four CpG-modified plasmids.…”

supporting

confidence: 83%

“…On the one hand, these differences may be largely attributed to the different immunostimulatory activities of the three types of human CpG motifs proved in this study (Fig. 1) or as previously reported [10,13,31]. Certain or different numbers of CpG motifs in DNA vectors have been shown to induce different or opposing effects on immune responses in previous studies [9,17].…”

supporting

confidence: 68%

“…In addition, the CpGC adjuvant was the most efficient among them in enhancing PA4-specific humoral, cell-mediated, and protective immune responses to the DNA vaccines due to not only strong B-cell activation but also to that of pDCs and NK cells [14,22,23]. Therefore, the CpGA and CpGC modifications promoted the DNA vaccines via Th cell immune responses to produce IgG and/or IgG2a antibodies against both AHc and PA4 antigens, which translated into strong protective effects against BoNT/A and A16R, respectively.It is worth noting that very distinct effects of plasmid backbone modifications with certain or several types of human CpG motifs were also observed on the immunogenicity of conventional DNA vaccines and DNA replicon vaccines encoding AHc or PA4 in vivo, which were different from the in vitro effects [10,13,14,22,31]. Our results and other studies also found different effects for CpG motifs in plasmid backbone as compared with ODNs in vivo or in vitro.…”

contrasting

confidence: 49%

“…Therefore, any attempts to modulate and augment immunogenicity of DNA vaccines must directly evaluate the in vivo effect of CpG-modified plasmids rather than that depending on the effects of CpG ODNs or in vitro observations. Such differential effects of CpG motifs have been observed between in vivo and in vitro studies or between CpGs as built-in adjuvants and CpG-ODNs [10,13,21,28,31].Aside from the reasons above, distinct effects of CpG motifs may depend on other factors, including certain antigens/pathogens and DNA vectors. Some studies as well as the present study showed that antigen-specific humoral and cellular immunity can be increased by CpG modification of DNA plasmids [9,20,21,30,32].…”

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confidence: 99%

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Three types of humanCpG motifs differentially modulate and augment immunogenicity of nonviral and viral repliconDNA vaccines as built‐in adjuvants

Li²,

Ma³

et al. 2012

Eur J Immunol

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Naked DNA vaccines given by intramuscular injection are efficient in mouse models, but they require improvement for human use. As the immunogenicity of DNA vaccines depends, to a large extent, on the presence of CpG motifs as built-in adjuvants, we addressed this issue by inserting three types of human CpG motifs (A-type, B-type, and C-type) into the backbone of nonviral DNA and viral DNA replicon vectors with distinct immunostimulatory activities on human PBMCs. The adjuvant effects of CpG modifications in DNA vaccines expressing three types of antigens (β-Gal, AHc, or PA4) were then characterized in mice and found to significantly enhance antigen-specific humoral and cell-mediated immune responses. The three types of CpG motifs also differentially affected and modulated immune responses and protective potency against botulinum neurotoxin serotype A and Bacillus anthracis A16R challenge. Taken together, these results demonstrate that insertion of human CpG motifs can differentially modulate the immunogenicity of nonviral DNA vaccines as well as viral DNA replicon vaccines. Our study provides not only a better understanding of the in vivo activities of CpG motif adjuvants but implications for the rational design of such motifs as built-in adjuvants for DNA vectors targeting specific antigens.Keywords: adjuvant · CpG · DNA vaccine · Immunogenicity · Replicon vector Additional supporting information may be found in the online version of this article at the publisher's web-site IntroductionPrevious studies have proved that DNA immunization can elicit antigen-specific humoral and cell-mediated immune responses and provide effective protective immunity against a variety of pathogens in various animal models [1,2]. However, the potency of naked DNA vaccines produced in nonhuman primates and humans is usually lower than that in the small animals used in these models [1]. Additionally, early DNA vaccines did not Correspondence: Dr. Zhi-Wei Sun e-mail: szwyhhh@yahoo.com.cn afford sufficient immunogenicity in human clinical studies. Therefore, the efficacy of DNA vaccines must be modulated and augmented to enable this technology to be successfully applied to human clinical trials. A number of strategies have been investigated to increase the immunogenicity of DNA vaccines over the last few years, including adjuvants, alterations in the codon bias, cytokines, chemokines, CpG, electroporation, liposomes, microparticles, and heterologous prime/boost immunization [2][3][4][5][6]. * These authors contributed equally to this work. The levels of IL-6 and IFN-γ in the culture supernatants of human PBMCs cultured with the indicated (C) CpG-modified nonviral DNA plasmids or (D) viral DNA replicon plasmids were determined by ELISA. Data are represented as mean + SD of n = 6 samples and are from one experiment representative of two experiments performed. Statistical significance over the control unmodified plasmids and media was determined by ANOVA test ( * P < 0.05; ** P < 0.01; *** P < 0.001).Previous studies have shown that the ef...

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supporting

confidence: 83%

supporting

confidence: 68%

contrasting

confidence: 49%

mentioning

confidence: 99%

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Three types of humanCpG motifs differentially modulate and augment immunogenicity of nonviral and viral repliconDNA vaccines as built‐in adjuvants

Li²,

Ma³

et al. 2012

Eur J Immunol

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“…The enhanced immune responses induced by CpG ODNs provide protective immunity in several infectious disease models. For example, reduced bacterial burden was detected in mice immunized with CpG ODN and ovalbumin (OVA) coadministered intramuscularly when challenged with Listeria monocytogenes expressing the CTL epitope of OVA [257][258][259][260][261][262][263][264] (designated Lm-OVA) 10 days postimmunization (6).Also,intramuscularcoinjectionofrecombinant Toxoplasma gondii protein with CpG ODN as an adjuvant induces a Th1-biased humoral response demonstrated by an increased IgG2a to IgG1 antibody ratio and increased protection against oral T. gondii infection in a mouse model (7). In a human clinical trial, intramuscular delivery of CpG 7909 induced robust specific antibody response to a commercial hepatitis B vaccine (Engerix-B) (8).…”

Section: Nfectious Diseases Are the Leading Cause Of Illness In Hummentioning

confidence: 99%

Topical CpG Adjuvantation of a Protein-Based Vaccine Induces Protective Immunity to Listeria monocytogenes

Cheng

Wee

Kollmann

et al. 2014

Clin. Vaccine Immunol.

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Combinations of various CpG motifs cloned into plasmid backbone modulate and enhance protective immunity of viral replicon DNA anthrax vaccines

Yu¹,

Ma²,

Xu³

et al. 2014

Med Microbiol Immunol

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DNA vaccines are generally weak stimulators of the immune system. Fortunately, their efficacy can be improved using a viral replicon vector or by the addition of immunostimulatory CpG motifs, although the design of these engineered DNA vectors requires optimization. Our results clearly suggest that multiple copies of three types of CpG motifs or combinations of various types of CpG motifs cloned into a viral replicon vector backbone with strong immunostimulatory activities on human PBMC are efficient adjuvants for these DNA vaccines to modulate and enhance protective immunity against anthrax, although modifications with these different CpG forms in vivo elicited inconsistent immune response profiles. Modification with more copies of CpG motifs elicited more potent adjuvant effects leading to the generation of enhanced immunity, which indicated a CpG motif dose-dependent enhancement of antigen-specific immune responses. Notably, the enhanced and/or synchronous adjuvant effects were observed in modification with combinations of two different types of CpG motifs, which provides not only a contribution to the knowledge base on the adjuvant activities of CpG motifs combinations but also implications for the rational design of optimal DNA vaccines with combinations of CpG motifs as "built-in" adjuvants. We describe an efficient strategy to design and optimize DNA vaccines by the addition of combined immunostimulatory CpG motifs in a viral replicon DNA plasmid to produce strong immune responses, which indicates that the CpG-modified viral replicon DNA plasmid may be desirable for use as vector of DNA vaccines.

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Three CpG oligodeoxynucleotide classes differentially enhance antigen-specific humoral and cellular immune responses in mice

Cited by 25 publications

References 26 publications

Three types of humanCpG motifs differentially modulate and augment immunogenicity of nonviral and viral repliconDNA vaccines as built‐in adjuvants

Three types of humanCpG motifs differentially modulate and augment immunogenicity of nonviral and viral repliconDNA vaccines as built‐in adjuvants

Topical CpG Adjuvantation of a Protein-Based Vaccine Induces Protective Immunity to Listeria monocytogenes

Combinations of various CpG motifs cloned into plasmid backbone modulate and enhance protective immunity of viral replicon DNA anthrax vaccines

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