Conjugation of protein to immunostimulatory DNA results in a rapid, long‐lasting and potent induction of cell‐mediated and humoral immunity

Tighe, Helen; Takabayashi, Kenji; Schwartz, David H.; Marsden, Robin; Beck, Lucinda; Corbeil, Jacques; Richman, Douglas D.; Eiden, Joseph; Spiegelberg, Hans L.

doi:10.1002/1521-4141(200007)30:7<1939::aid-immu1939>3.0.co;2-#

Cited by 147 publications

(97 citation statements)

References 26 publications

(38 reference statements)

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“…The interaction of TLR9 with CpG motifs initiates a cascade of events resulting in the activation of B cells and secretion of T helper (Th)1-type cytokines and chemokines [3]. In animal studies, CpG immunostimulation was more efficient if the CpG ODN is chemically coupled to the antigen [4] suggesting that simultaneous activation of a cell by both antigen and CpG is required for optimal effect.…”

Section: Introductionsupporting

confidence: 84%

“…In humans, CPG 7909 has substantially boosted antibody response with Hepatitis B Surface Antigen [17,18] and with AMA1 (Mullen et al, unpublished) and MSP1 42 (Martin et al, unpublished) when these antigens were formulated with alum, but not with the un-adjuvanted influenza vaccine [19]. The mouse data presented in this paper are consistent with these human studies, and both are consistent with studies that show a substantial enhancement of antibody production with CpG covalently linked to the antigen [20].…”

Section: Discussionmentioning

confidence: 99%

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Enhanced antibody production in mice to the malaria antigen AMA1 by CPG 7909 requires physical association of CpG and antigen

Mullen

Aebig

Dobrescu

et al. 2007

Vaccine

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CpG oligodeoxynucleotides are potent immunostimulants. In this study, CPG 7909 was formulated with the recombinant Plasmodium falciparum protein AMA1-C1 adsorbed to Alhydrogel (aluminum hydroxide) and used to immunize mice. Mice receiving free CPG 7909 in a separate same site injection to the AMA1-C1/Alhydrogel had the same antibody responses as mice receiving AMA1-C1/Alhydrogel alone. For mice immunized with CPG 7909 bound to the AMA1-C1/Alhydrogel formulation, there was a bell shaped CPG 7909 dose response curve with the highest antibody response co-incident with the concentration of CPG 7909 that saturated binding to the Alhydrogel. At a higher CPG 7909 dose where 74% was unbound, there was no enhancement of response over AMA1-C1/Alhydrogel alone. Our results suggest that the adjuvant effects of CpGs are optimal when adsorbed to Alhydrogel and highlight the need for careful characterization of the vaccine formulation.

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Section: Introductionsupporting

confidence: 84%

Section: Discussionmentioning

confidence: 99%

Enhanced antibody production in mice to the malaria antigen AMA1 by CPG 7909 requires physical association of CpG and antigen

Mullen

Aebig

Dobrescu

et al. 2007

Vaccine

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“…17). Thus, oligodeoxynucleotides containing CpG motifs that bind to TLR9 exhibit immunostimulatory activities and have been used as powerful vehicles and adjuvants for the induction of cellular and humoral immune responses (31). In mice, TLR9 is expressed on all major DC subtypes (32).…”

Section: Discussionmentioning

confidence: 99%

The Extra Domain A from Fibronectin Targets Antigens to TLR4-Expressing Cells and Induces Cytotoxic T Cell Responses In Vivo

Lasarte

Casares

Gorraiz

et al. 2007

The Journal of Immunology

115

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Vaccination strategies based on the in vivo targeting of Ags to dendritic cells (DCs) are needed to improve the induction of specific T cell immunity against tumors and infectious agents. In this study, we have used a recombinant protein encompassing the extra domain A from fibronectin (EDA), an endogenous ligand for TLR4, to deliver Ags to TLR4-expressing DC. The purified EDA protein was shown to bind to TLR4-expressing HEK293 cells and to activate the TLR4 signaling pathway. EDA also stimulated the production by DC of proinflammatory cytokines such as IL-12 or TNF-α and induced their maturation in vitro and in vivo. A fusion protein between EDA and a cytotoxic T cell epitope from OVA efficiently presented this epitope to specific T cells and induced the in vivo activation of a strong and specific CTL response. Moreover, a fusion protein containing EDA and the full OVA also improved OVA presentation by DC and induced CTL responses in vivo. These EDA recombinant proteins protected mice from a challenge with tumor cells expressing OVA. These results strongly suggest that the fibronectin extra domain A may serve as a suitable Ag carrier for the development of antiviral or antitumoral vaccines.

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“…On the contrary, CpG presented onto the surface of cationic microspheres was able to augment the antibody response and it was suggested due to a certain effect of surface nature in B cells engagement [28,32]. CpG administration [24,25,42,54]. So far, the absence of correlation with the observed antibodies production could be due to the direct effect of CpG oligonucleotide in B cells.…”

Section: Discussionmentioning

confidence: 99%

Co-encapsulation of an antigen and CpG oligonucleotides into PLGA microparticles by TROMS technology

Román

Irache

Gómez

et al. 2008

European Journal of Pharmaceutics and Biopharmaceutics

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Conjugation of protein to immunostimulatory DNA results in a rapid, long‐lasting and potent induction of cell‐mediated and humoral immunity

Cited by 147 publications

References 26 publications

Enhanced antibody production in mice to the malaria antigen AMA1 by CPG 7909 requires physical association of CpG and antigen

Enhanced antibody production in mice to the malaria antigen AMA1 by CPG 7909 requires physical association of CpG and antigen

The Extra Domain A from Fibronectin Targets Antigens to TLR4-Expressing Cells and Induces Cytotoxic T Cell Responses In Vivo

Co-encapsulation of an antigen and CpG oligonucleotides into PLGA microparticles by TROMS technology

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