Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE+GLA) adjuvant

Treanor, John J.; Essink, Brandon; Hull, Steven G.; Reed, Steven G.; Izikson, Ruvim; Patriarca, P.; Goldenthal, Karen L.; Kohberger, Robert; Dunkle, Lisa M.

doi:10.1016/j.vaccine.2013.08.064

Cited by 78 publications

(50 citation statements)

References 26 publications

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“…Topical R848 has been used in a phase I clinical trial for a cancer vaccine [31], and boosted responses to injected influenza vaccine when delivered topically in a clinical trial [32]. The addition of GLA led to substantially improved antibody responses to haemagglutinin in a clinical study [33]. Poly I:C has been used safely with live attenuated influenza vaccine, but there was no antigen alone control, so it is hard to determine whether it boosted responses [34].…”

Section: Discussionmentioning

confidence: 99%

The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling

et al. 2017

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Toll like receptor (TLR) ligands are important adjuvant candidates, causing antigen presenting cells to release inflammatory mediators, leading to the recruitment and activation of other leukocytes. The aim of this study was to define the response of human blood derived dendritic cells and macrophages to three TLR ligands acting singly or in combination, Poly I:C (TLR3), GLA (TLR4) and R848 (TLR7/8). Combinations of TLR agonists have been shown to have a synergistic effect on individual cytokines, here we look at the global inflammatory response measuring both cytokines and chemokines. Using a custom Luminex assay we saw dose responses in several mediators including CCL3 (MIP1α), IL-1α, IL-1β, IL-12, CXCL10 (IP-10) and IL-6, all of which were significantly increased by the combination of R848 and GLA, even when low dose GLA was added. The synergistic effect was inhibited by specific MAP kinase inhibitors blocking the kinases p38 and JNK but not MEK1. Combining TLR adjuvants also had a synergistic effect on cytokine responses in human mucosal tissue explants. From this we conclude that the combination of R848 and GLA potentiates the inflammatory profile of antigen presenting cells. Since the pattern of inflammatory mediators released can alter the quality and quantity of the adaptive immune response to vaccination, this study informs vaccine adjuvant design.

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Section: Discussionmentioning

confidence: 99%

The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling

et al. 2017

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“…Note that the GLA-LSQ adjuvant is currently under development for use in clinical trials. Two completed clinical studies of pre-erythrocytic vaccines containing GLA-SE have demonstrated that GLA-SE is safe and well-tolerated [54], [55], and there are multiple ongoing clinical studies using GLA-SE as adjuvant for malaria and other vaccines. In view of its pre-clinical performance with the rCSP and its safety profile, we plan to proceed with this adjuvant in combination with rCSP in the initial clinical trial.…”

Section: Discussionmentioning

confidence: 99%

A Full-Length Plasmodium falciparum Recombinant Circumsporozoite Protein Expressed by Pseudomonas fluorescens Platform as a Malaria Vaccine Candidate

Noe

Espinosa

et al. 2014

PLoS ONE

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The circumsporozoite protein (CSP) of Plasmodium falciparum is a major surface protein, which forms a dense coat on the sporozoite's surface. Preclinical research on CSP and clinical evaluation of a CSP fragment-based RTS, S/AS01 vaccine have demonstrated a modest degree of protection against P. falciparum, mediated in part by humoral immunity and in part by cell-mediated immunity. Given the partial protective efficacy of the RTS, S/AS01 vaccine in a recent Phase 3 trial, further improvement of CSP-based vaccines is crucial. In this report, we describe the preclinical development of a full-length, recombinant CSP (rCSP)-based vaccine candidate against P. falciparum malaria suitable for current Good Manufacturing Practice (cGMP) production. Utilizing a novel high-throughput Pseudomonas fluorescens expression platform, we demonstrated greater efficacy of full-length rCSP as compared to N-terminally truncated versions, rapidly down-selected a promising lead vaccine candidate, and developed a high-yield purification process to express immunologically active, intact antigen for clinical trial material production. The rCSP, when formulated with various adjuvants, induced antigen-specific antibody responses as measured by enzyme-linked immunosorbent assay (ELISA) and immunofluorescence assay (IFA), as well as CD4+ T-cell responses as determined by ELISpot. The adjuvanted rCSP vaccine conferred protection in mice when challenged with transgenic P. berghei sporozoites containing the P. falciparum repeat region of CSP. Furthermore, heterologous prime/boost regimens with adjuvanted rCSP and an adenovirus type 35-vectored CSP (Ad35CS) showed modest improvements in eliciting CSP-specific T-cell responses and anti-malarial protection, depending on the order of vaccine delivery. Collectively, these data support the importance of further clinical development of adjuvanted rCSP, either as a stand-alone product or as one of the components in a heterologous prime/boost strategy, ultimately acting as an effective vaccine candidate for the mitigation of P. falciparum-induced malaria.

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“…A major issue that has arisen previously in designing a Pfs25-based vaccine is the need for a strong yet human-use-compatible adjuvant to overcome the inherent lack of antigenicity of Pfs25; in a phase I clinical trial, erythema nodosum associated with the Montanide ISA 51 oil-in-water adjuvant was observed in a small number of subjects, which led to cessation of that vaccine formulation (21). New adjuvants based on squalene-oil-in-water emulsion in the context of a nontoxic lipid A-like moiety, glucopyranosyl lipid A (GLA), have been developed in extensive animal/in vitro experimentation (22)(23)(24)(25) and used in human experimentation (26), and they have been demonstrated to have the desired effects of low reactogenicity, induction of high levels of effector antibodies, and optimized affinity maturation.…”

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confidence: 99%

Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes

Patra

Carter

et al. 2015

Infect Immun

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A vaccine to prevent the transmission of malaria parasites from infected humans to mosquitoes is an important component for the elimination of malaria in the 21st century, yet it remains neglected as a priority of malaria vaccine development. The lead candidate for Plasmodium falciparum transmission-blocking vaccine development, Pfs25, is a sexual stage surface protein that has been produced for vaccine testing in a variety of heterologous expression systems. Any realistic malaria vaccine will need to optimize proper folding balanced against cost of production, yield, and potentially reactogenic contaminants. Here Chlamydomonas reinhardtii microalga-produced recombinant Pfs25 protein was formulated with four different human-compatible adjuvants (alum, Toll-like receptor 4 [TLR-4] agonist glucopyranosal lipid A [GLA] plus alum, squalene-oil-in-water emulsion, and GLA plus squalene-oil-in-water emulsion) and compared for their ability to induce malaria transmission-blocking antibodies. Alga-produced recombinant Pfs25 plus GLA plus squalene-oil-in-water adjuvant induced the highest titer and avidity in IgG antibodies, measured using alga-produced recombinant Pfs25 as the enzyme-linked immunosorbent assay (ELISA) antigen. These antibodies specifically reacted with the surface of P. falciparum macrogametes and zygotes and effectively prevented parasites from developing within the mosquito vector in standard membrane feeding assays. Alga-produced Pfs25 in combination with a human-compatible adjuvant composed of a TLR-4 agonist in a squalene-oil-in-water emulsion is an attractive new vaccine candidate that merits head-to-head comparison with other modalities of vaccine production and administration.A vaccine to prevent gametocytemic humans from infecting mosquitoes by inducing antibodies against sexual stage Plasmodium antigens, termed a transmission-blocking vaccine (TBV), was first demonstrated experimentally as proof of principle using a chicken model of Plasmodium gallinaceum more than 30 years ago (1, 2). TBV development has been stated to be a key priority toward achieving the global goals of malaria control and elimination (3, 4), yet it lags behind other malaria vaccine development despite candidate proteins such as Pfs25 being deeply studied as a TBV. Pfs25, the first molecularly cloned Plasmodium sexual stage protein, was identified more than 25 years ago and remains a lead TBV candidate (5, 6). Parasite-produced Pfs25 contains 4 epidermal growth factor (EGF)-like domains and is not glycosylated, which makes it biotechnologically challenging to produce the properly folded, conformationally correct recombinant protein(s) required for the induction of effective transmission-blocking antibodies (7-9). Heterologous expression systems used to produce Pfs25 as a recombinant subunit immunogen include Escherichia coli (10), Saccharomyces cerevisiae (11), Pichia pastoris (7, 12), baculovirus (13), Nicotiana benthamiana (14), Triticum vulgare (wheat germ) extract (6,15,16), and most recently, the chloroplast of the mic...

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Evaluation of safety and immunogenicity of recombinant influenza hemagglutinin (H5/Indonesia/05/2005) formulated with and without a stable oil-in-water emulsion containing glucopyranosyl-lipid A (SE+GLA) adjuvant

Cited by 78 publications

References 26 publications

The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling

The synergistic effects of combining TLR ligand based adjuvants on the cytokine response are dependent upon p38/JNK signalling

A Full-Length Plasmodium falciparum Recombinant Circumsporozoite Protein Expressed by Pseudomonas fluorescens Platform as a Malaria Vaccine Candidate

Alga-Produced Malaria Transmission-Blocking Vaccine Candidate Pfs25 Formulated with a Human Use-Compatible Potent Adjuvant Induces High-Affinity Antibodies That Block Plasmodium falciparum Infection of Mosquitoes

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