Physicochemical characterization and biological activity of synthetic TLR4 agonist formulations

Anderson, Ryan C.; Fox, Christopher B.; Dutill, Timothy S.; Shaverdian, Narek; Evers, Tara; Poshusta, Garrett R.; Chesko, James; Coler, Rhea N.; Friede, Martin; Reed, Steven G.; Vedvick, Thomas S.

doi:10.1016/j.colsurfb.2009.08.022

Cited by 100 publications

(86 citation statements)

References 41 publications

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“…EM005 is an oil-in-water stable emulsion containing a lipid A-like synthetic compound (2,6). Lipid A is a component of lipopolysaccharide, which is responsible for the toxicity associated with gram-negative bacteria.…”

Section: Resultsmentioning

confidence: 99%

Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

et al. 2009

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We have identified new malaria vaccine candidates through the combination of bioinformatics prediction of stable protein domains in the Plasmodium falciparum genome, chemical synthesis of polypeptides, in vitro biological functional assays, and association of an antigen-specific antibody response with protection against clinical malaria.Within the predicted open reading frame of P. falciparum hypothetical protein PFF0165c, several segments with low hydrophobic amino acid content, which are likely to be intrinsically unstructured, were identified. The synthetic peptide corresponding to one such segment (P27A) was well recognized by sera and peripheral blood mononuclear cells of adults living in different regions where malaria is endemic. High antibody titers were induced in different strains of mice and in rabbits immunized with the polypeptide formulated with different adjuvants. These antibodies recognized native epitopes in P. falciparum-infected erythrocytes, formed distinct bands in Western blots, and were inhibitory in an in vitro antibody-dependent cellular inhibition parasite-growth assay. The immunological properties of P27A, together with its low polymorphism and association with clinical protection from malaria in humans, warrant its further development as a malaria vaccine candidate.

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Section: Resultsmentioning

confidence: 99%

Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

et al. 2009

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“…GLA is a synthetic and therefore homogeneous variant of the TLR4 agonist lipid A, formulated in a stable oil-in-water emulsion (SE) (36). Strong Th1 immune responses induced by protein antigens in combination with GLA-SE have been observed in mouse models of tuberculosis (37), leishmaniasis (38), and influenza (39).…”

mentioning

confidence: 99%

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

et al. 2013

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؉ T cell responses. Finally, protective immunity was also induced using the Toll-like receptor 4 agonist glucopyranosyl lipid adjuvantstable emulsion (GLA-SE) as the adjuvant, which also correlated with high antibody titers yet CD4 ؉ T cell immunity that was significantly less potent than that with poly(I·C)LC. Overall, these data suggest that full-length CS proteins and poly(I·C)LC or GLA-SE offer a simple vaccine formulation to be used alone or in combination with other vaccines for preventing malaria infection. Malaria infection with Plasmodium falciparum causes more than 600,000 deaths annually as well as significant morbidity worldwide (1). A range of efforts to control and treat malaria include public health measures such as insecticide-treated bed nets, indoor residual spraying, and widespread usage of antimalarial drugs. Despite the impact of these approaches, the most cost-effective solution to prevent infection and to ultimately control the malaria endemic is to develop a vaccine.Currently, the most advanced vaccine tested in humans against P. falciparum infection is RTS,S, which targets the circumsporozoite (CS) protein (CSP), the major and most abundant antigen expressed on the surfaces of infectious sporozoites. RTS,S given with the AS01 adjuvant (RTS,S/AS01) shows ϳ30% protection against clinical disease and severe malaria (2, 3). Thus, while these first results in phase III trials with RTS,S/AS01 are encouraging, there may be additional approaches for further optimizing the breadth, potency, and duration of immunity against the CSP using different immunogens or more-potent adjuvants. In terms of antigen design, RTS,S is comprised of a truncated form of CSP containing the central repeat region, NANP, which is a target for antibody-mediated neutralization, as well as CD8 ϩ and CD4 ϩ T cell epitopes at the C-terminal end. This truncated CS protein is then fused to the hepatitis B virus surface antigen, creating an immunogenic particle. Therefore, using a more-full-length CSP, including the N-terminal end and the R1 region of CSP as well as the minor repeat region (NVDP), might favor broader antibody responses than against the NANP repeat region alone (4-8). Moreover, a full-length CSP may provide additional T cell epitopes, leading to increased breadth of cellular immunity, which could also enhance protection. Another approach is to enhance the humoral and cellular immune responses by altering the type of adjuvant given with the full-length-CSP-based protein vaccine.Early studies in mice showed that protection was associated with high antibody titers (9-11). The next generation of malaria vaccines combined CSP with more-potent adjuvants, like Pseu-

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“…Glucopyranosyl lipid adjuvant (GLA) is a formulated form of the synthetic TLR4 agonist PHAD (Avanti Polar Lipids), which is analogous to the detoxified LPS derivative monophosphoryl lipid A (MPL), a component of the human papillomavirus vaccine Cervarix (9). Experimental vaccines containing GLA demonstrate enhanced immunogenicity in a variety of disease models (8), and in the context of influenza, GLA formulated in a stable emulsion (GLA-SE) improved Fluzone-dependent antibody titers in mice and nonhuman primates, relative to an emulsion alone (10)(11)(12)(13). Given the critical importance of immunological priming for pandemic vaccine preparedness, we set out to test whether adjuvanting a recombinant H5 antigen with GLA-SE would broaden protective immunity against H5N1.…”

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Adjuvant solution for pandemic influenza vaccine production

Clegg

Roque

Hoeven

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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Extensive preparation is underway to mitigate the next pandemic influenza outbreak. New vaccine technologies intended to supplant egg-based production methods are being developed, with recombinant hemagglutinin (rHA) as the most advanced program for preventing seasonal and avian H5N1 Influenza. Increased efforts are being focused on adjuvants that can broaden vaccine immunogenicity against emerging viruses and maximize vaccine supply on a worldwide scale. Here, we test protection against avian flu by using H5N1-derived rHA and GLA-SE, a two-part adjuvant system containing glucopyranosyl lipid adjuvant (GLA), a formulated synthetic Toll-like receptor 4 agonist, and a stable emulsion (SE) of oil in water, which is similar to the best-in-class adjuvants being developed for pandemic flu. Notably, a single submicrogram dose of rH5 adjuvanted with GLA-SE protects mice and ferrets against a high titer challenge with H5N1 virus. GLA-SE, relative to emulsion alone, accelerated induction of the primary immune response and broadened its durability against heterosubtypic H5N1 virus challenge. Mechanistically, GLA-SE augments protection via induction of a Th1-mediated antibody response. Innate signaling pathways that amplify priming of Th1 CD4 T cells will likely improve vaccine performance against future outbreaks of lethal pandemic flu.

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Physicochemical characterization and biological activity of synthetic TLR4 agonist formulations

Cited by 100 publications

References 41 publications

Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice

Adjuvant solution for pandemic influenza vaccine production

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Physicochemical characterization and biological activity of synthetic TLR4 agonist formulations

Cited by 100 publications

References 41 publications

Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

Vaccine Potentials of an Intrinsically Unstructured Fragment Derived from the Blood Stage-Associated Plasmodium falciparum Protein PFF0165c

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4+T Cell Immunity and Protection in Mice

Adjuvant solution for pandemic influenza vaccine production

Contact Info

Product

Resources

About

Full-Length Plasmodium falciparum Circumsporozoite Protein Administered with Long-Chain Poly(I·C) or the Toll-Like Receptor 4 Agonist Glucopyranosyl Lipid Adjuvant-Stable Emulsion Elicits Potent Antibody and CD4⁺T Cell Immunity and Protection in Mice