Adjuvants for human vaccines

Alving, Carl R.; Peachman, Kristina K.; Rao, Mangala; Reed, Steven G.

doi:10.1016/j.coi.2012.03.008

Cited by 196 publications

(153 citation statements)

References 47 publications

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“…In addition to its high immunogenicity for T cells, the sequence of rPfMSP8 (⌬Asn/Asp) is highly conserved among P. falciparum isolates, effectively eliminating the problem associated with the strain specificity of T cell responses. While our efforts have focused on improving immunogenicity through vaccine design, other efforts in the field have enjoyed recent success in developing and testing new, potent adjuvants for use in human subjects (64,65). We are excited about the possibility of further enhancing the immunogenicity of rPfMSP1/8 with the use of adjuvants other than Quil A.…”

Section: Discussionmentioning

confidence: 99%

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

et al. 2013

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The C-terminal 19-kDa domain of Plasmodium falciparum merozoite surface protein 1 (PfMSP1 19 ) is an established target of protective antibodies. However, clinical trials of PfMSP1 42 , a leading blood-stage vaccine candidate which contains the protective epitopes of PfMSP1 19 , revealed suboptimal immunogenicity and efficacy. Based on proof-of-concept studies in the Plasmodium yoelii murine model, we produced a chimeric vaccine antigen containing recombinant PfMSP1 19 (rPfMSP1 19 ) fused to the N terminus of P. falciparum merozoite surface protein 8 that lacked its low-complexity Asn/Asp-rich domain, rPfMSP8 (⌬Asn/ Asp). Immunization of mice with the chimeric rPfMSP1/8 vaccine elicited strong T cell responses to conserved epitopes associated with the rPfMSP8 (⌬Asn/Asp) fusion partner. While specific for PfMSP8, this T cell response was adequate to provide help for the production of high titers of antibodies to both PfMSP1 19 and rPfMSP8 (⌬Asn/Asp) components. This occurred with formulations adjuvanted with either Quil A or with Montanide ISA 720 plus CpG oligodeoxynucleotide (ODN) and was observed in both inbred and outbred strains of mice. PfMSP1/8-induced antibodies were highly reactive with two major alleles of PfMSP1 19 (FVO and 3D7). Of particular interest, immunization with PfMSP1/8 elicited higher titers of PfMSP1 19 -specific antibodies than a combined formulation of rPfMSP1 42 and rPfMSP8 (⌬Asn/Asp). As a measure of functionality, PfMSP1/8-specific rabbit IgG was shown to potently inhibit the in vitro growth of blood-stage parasites of the FVO and 3D7 strains of P. falciparum. These data support the further testing and evaluation of this chimeric PfMSP1/8 antigen as a component of a multivalent vaccine for P. falciparum malaria.

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Section: Discussionmentioning

confidence: 99%

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

et al. 2013

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“…Activation of a cellular PRR triggers a specific response (36). This response is not limited to the direct inhibition of the pathogen but also participates in the generation of a protective adaptive immune response; in fact, many vaccine adjuvants take advantage of this phenomenon (e.g., pIC is a MDA5/TLR3 agonist [37], AS03 activates TLR4 [38], and CpG is recognized by TLR9 [39]). To maximize the effect of a viral vaccine, theoretically we should match the vaccine with an adjuvant that activates the appropriate PRR for that virus, i.e., mimics the natural infection.…”

Section: Discussionmentioning

confidence: 99%

A Sendai Virus-Derived RNA Agonist of RIG-I as a Virus Vaccine Adjuvant

Martínez-Gil

Goff

Hai

et al. 2013

J Virol

110

115

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The innate immune system is responsible for recognizing invading pathogens and initiating a protective response. In particular, the retinoic acid-inducible gene 1 protein (RIG-I) participates in the recognition of single-and double-stranded RNA viruses. RIG-I activation leads to the production of an appropriate cytokine and chemokine cocktail that stimulates an antiviral state and drives the adaptive immune system toward an efficient and specific response against the ongoing infection. One of the best-characterized natural RIG-I agonists is the defective interfering (DI) RNA produced by Sendai virus strain Cantell. This 546-nucleotide RNA is a well-known activator of the innate immune system and an extremely potent inducer of type I interferon. We designed an in vitro-transcribed RNA that retains the type I interferon stimulatory properties, and the RIG-I affinity of the Sendai virus produced DI RNA both in vitro and in vivo. This in vitro-synthesized RNA is capable of enhancing the production of antiinfluenza virus hemagglutinin (HA)-specific IgG after intramuscular or intranasal coadministration with inactivated H1N1 2009 pandemic vaccine. Furthermore, our adjuvant is equally effective at increasing the efficiency of an influenza A/Puerto Rico/8/34 virus inactivated vaccine as a poly(I·C)-or a squalene-based adjuvant. Our in vitro-transcribed DI RNA represents an excellent tool for the study of RIG-I agonists as vaccine adjuvants and a starting point in the development of such a vaccine.

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“…Vaccine adjuvants are capable of enhancing immunogenicity of antigens either through exerting immunostimulatory effects or by altering the process of antigen delivery. Major categories of adjuvants include killed bacteria, bacterial components, aluminum salt, oil-based emulsions, polysaccharides, and liposomes [1][2][3][4][5]. Aluminum salt (Alum) is one of the most common adjuvants approved for human use, but its use is limited by suboptimal immunostimulatory capacity and difficulties in preparation and handling [6].…”

Section: Introductionmentioning

confidence: 99%

Co-Delivery of Imiquimod and Plasmid DNA via an Amphiphilic pH-Responsive Star Polymer that Forms Unimolecular Micelles in Water

Lin

Yao

et al. 2016

Polymers

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Dual functional unimolecular micelles based on a pH-responsive amphiphilic star polymer β-CD-(PLA-b-PDMAEMA-b-PEtOxMA) 21 have been developed for the co-delivery of imiquimod and plasmid DNA to dendritic cells. The star polymer with well-defined triblock arms was synthesized by combining activator regenerated by electron-transfer atom-transfer radical polymerization with ring-opening polymerization. Dissipative particle dynamics simulation showed that core-mesophere-shell-type unimolecular micelles could be formed. Imiquimod-loaded micelles had a drug loading of 1.6 wt % and a larger average size (28 nm) than blank micelles (19 nm). The release of imiquimod in vitro was accelerated at the mildly acidic endolysosomal pH (5.0) in comparison to physiologic pH (7.4). Compared with blank micelles, a higher N:P ratio was required for imiquimod-loaded micelles to fully condense DNA into micelleplexes averaging 200-400 nm in size. In comparison to blank micelleplexes, imiquimod-loaded micelleplexes of the same N:P ratio displayed similar or slightly higher efficiency of gene transfection in a mouse dendritic cell line (DC2.4) without cytotoxicity. These results suggest that such pH-responsive unimolecular micelles formed by the well-defined amphiphilic star polymer may serve as promising nano-scale carriers for combined delivery of hydrophobic immunostimulatory drugs (such as imiquimod) and plasmid DNA with potential application in gene-based immunotherapy.

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Adjuvants for human vaccines

Cited by 196 publications

References 47 publications

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

A Chimeric Plasmodium falciparum Merozoite Surface Protein Vaccine Induces High Titers of Parasite Growth Inhibitory Antibodies

A Sendai Virus-Derived RNA Agonist of RIG-I as a Virus Vaccine Adjuvant

Co-Delivery of Imiquimod and Plasmid DNA via an Amphiphilic pH-Responsive Star Polymer that Forms Unimolecular Micelles in Water

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