Protollin™: a novel adjuvant for intranasal vaccines

Jones, Trevor O.; Cyr, Sonya; Allard, Francine; Bellerose, Nathalie; Lowell, George H.; Burt, David S.

doi:10.1016/j.vaccine.2004.03.035

Cited by 41 publications

(24 citation statements)

References 26 publications

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“…Liposomes have been shown to enhance the uptake of CpG ODN (16-mer) by immune cells in spleen and lymph nodes [440] and DC maturation by these adjuvants [438]. Other combinations include MPA/trehalose dicorynomycolate for a protein vaccine [445], chi-tosan/LTK63 (a nontoxic E. coli enterotoxin mutant) for DT-conjugated group C meningococcal polysaccharide antigen [446], chitosan/muramyl di-peptide (MDP) for Helicobacter pylori urease [230], PLG microparticles/ MF59 for recombinant protein antigens [447], PLGA particles/LPS for West Nile encephalitis [291], proteosome/LPS for influenza virus [448], QS-21 combinations with a variety of adjuvants for KLH-conjugated peptide vaccine [237], and FML (a glycoprotein complex) combinations with a variety of adjuvants for visceral leishmaniasis (VL) [449]. More complex adjuvant systems (3 adjuvant components) have also been tried.…”

Section: Adjuvant Combinationsmentioning

confidence: 99%

Selection of Adjuvants for Enhanced Vaccine Potency

Wang¹,

Singh²

2011

WJV

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Section: Adjuvant Combinationsmentioning

confidence: 99%

Selection of Adjuvants for Enhanced Vaccine Potency

Wang¹,

Singh²

2011

WJV

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“…To investigate the effect of nasal vaccination with GA in a mouse model of AD, we treated animals with nasal GA alone or together with a mucosal adjuvant. For the latter, we used a proteosomebased mucosal adjuvant comprising purified outer membrane proteins of Neisseria meningitides and LPS (IVX-908; Protollin; ID Biomedical Corp.) that has been used safely in both humans (22) and mice (30,31). APP-Tg mice received 4 nasal treatments the first week and then were boosted on a weekly basis for the next 5 weeks, after which neuropathological analysis was performed.…”

Section: Figurementioning

confidence: 99%

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Frenkel¹,

Maron²,

Burt³

et al. 2005

J. Clin. Invest.

159

115

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Amyloid β-peptide (Aβ) appears to play a key pathogenic role in Alzheimer disease (AD). Immune therapy in mouse models of AD via Aβ immunization or passive administration of Aβ antibodies markedly reduces Aβ levels and reverses behavioral impairment. However, a human trial of Aβ immunization led to meningoencephalitis in some patients and was discontinued. Here we show that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans plus glatiramer acetate, an FDA-approved synthetic copolymer used to treat multiple sclerosis, potently decreases Aβ plaques in an AD mouse model. This effect did not require the presence of antibody, as it was observed in B cell-deficient (Ig m-null) mice. Vaccinated animals developed activated microglia that colocalized with Aβ fibrils, and the extent of microglial activation correlated strongly with the decrease in Aβ fibrils. Activation of microglia and clearing of Aβ occurred with the adjuvant alone, although to a lesser degree. Our results identify a novel approach to immune therapy for AD that involves clearing of Aβ through the utilization of compounds that have been safely tested on or are currently in use in humans. IntroductionAlzheimer disease (AD) is the most common form of senile dementia, affecting more than 18 million people worldwide. With increased life expectancy, this number is expected to rise in the future. AD is characterized by widespread functional disturbance of the human brain. The classical neuropathological features are senile plaques, neurofibrillary tangles composed of paired helical filaments, and dystrophic neuritis. Compact senile plaques composed of amyloid β-peptide (Aβ) fibrils are associated with pathological changes in the surrounding brain neurons that lead to their death. Aβ appears to play a key pathogenic role in AD (1), and studies have connected the Aβ plaque with formation of intracellular tau tangles, another neurotoxic feature of AD (2, 3).A body of work has accumulated demonstrating that anti-Aβ antibodies are effective in clearance of amyloid deposits in vitro and in amyloid precursor protein-Tg (APP-Tg) mice (4-10). Solomon et al. showed in vitro that anti-Aβ antibodies can lead to disaggregation of Aβ fibrils, restoring Aβ solubility and thus prevent neurotoxic effects on cell lines (11, 12). Schenk et al. then demonstrated that parenteral immunization of APP-Tg mice with synthetic Aβ in complete Freund adjuvant (CFA) markedly decreased the number and density of Aβ deposits in the brain, with concomitant

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“…Early proof-of-principal studies with EtpA were conducted using an intranasal route of vaccination with Protollin (14,[17][18][19] or heat-labile toxin (LT) (20). However, because LT is not safe for intranasal vaccination in humans (21,22), and because an LT toxoid will likely be a key component of next-generation vaccines, here we investigated the immunogenicity and protective efficacy …”

mentioning

confidence: 99%

Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin

Luo

Vickers

Fleckenstein

2016

Clin Vaccine Immunol

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c Enterotoxigenic Escherichia coli (ETEC) strains are a common cause of diarrhea. Extraordinary antigenic diversity has prompted a search for conserved antigens to complement canonical approaches to ETEC vaccine development. EtpA, an immunogenic extracellular ETEC adhesin relatively conserved in the ETEC pathovar, has previously been shown to be a protective antigen following intranasal immunization. These studies were undertaken to explore alternative routes of EtpA vaccination that would permit use of a double mutant (R192G L211A) heat-labile toxin (dmLT) adjuvant. Here, oral vaccination with EtpA adjuvanted with dmLT afforded significant protection against small intestinal colonization, and the degree of protection correlated with fecal IgG, IgA, or total fecal antibody responses to EtpA. Sublingual vaccination yielded compartmentalized mucosal immune responses with significant increases in anti-EtpA fecal IgG and IgA, and mice vaccinated via this route were also protected against colonization. In contrast, while intradermal (i.d.) vaccination achieved high levels of both serum and fecal antibodies against both EtpA and dmLT, mice vaccinated via the i.d. route were not protected against subsequent colonization and the avidity of serum IgG and IgA EtpA-specific antibodies was significantly lower after i.d. immunization compared to other routes. Finally, we demonstrate that antiserum from vaccinated mice significantly impairs binding of LT to cognate GM1 receptors and shows near complete neutralization of toxin delivery by ETEC in vitro. Collectively, these data provide further evidence that EtpA could complement future vaccine strategies but also suggest that additional effort will be required to optimize its use as a protective immunogen. Enterotoxigenic Escherichia coli (ETEC) strains are among the most common causes of diarrheal illness in developing countries, where young children are most susceptible (1, 2). In addition, these pathogens are also a common cause of diarrhea in immunologically naive travelers (3) who venture to areas of endemicity where sanitation and clean water remain limited.Given the significant impact of ETEC on global health, a vaccine to prevent these infections is a significant priority (4). However, despite decades of investigative efforts following the discovery of toxin-producing E. coli in patients with clinical illnesses indistinguishable from cholera (5), a vaccine that affords broadbased protection has yet to be developed.All of the ETEC-specific virulence genes described to date are encoded on plasmids. These include the heat-labile and/or heatstable enterotoxins that define this pathovar and the colonization factors (CFs). Most vaccines to date have primarily targeted these colonization factors, which include a broad array of fimbrial as well as afimbrial surface antigens thought to be essential for intestinal colonization and/or heat-labile toxin.Unfortunately, the heterogeneity of CF antigenic structures presents a challenge to development of a broadly protective vaccine. ...

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Protollin™: a novel adjuvant for intranasal vaccines

Cited by 41 publications

References 26 publications

Selection of Adjuvants for Enhanced Vaccine Potency

Selection of Adjuvants for Enhanced Vaccine Potency

Nasal vaccination with a proteosome-based adjuvant and glatiramer acetate clears β-amyloid in a mouse model of Alzheimer disease

Immunogenicity and Protective Efficacy against Enterotoxigenic Escherichia coli Colonization following Intradermal, Sublingual, or Oral Vaccination with EtpA Adhesin

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