Safety and Immunogenicity of a Proteosome-
            <i>Shigella flexneri</i>
            2a Lipopolysaccharide Vaccine Administered Intranasally to Healthy Adults

Fries, Louis; Montemarano, Andrew D.; Mallett, Corey P.; Taylor, David N.; Hale, Thomas L.; Lowell, George H.

doi:10.1128/iai.69.7.4545-4553.2001

Cited by 93 publications

(61 citation statements)

References 33 publications

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“…In contrast to the previous study [16], we noticed a trend towards an increase in local nasal signs and symptoms (sneezing, nasal itching, coughing) with increasing vaccine dose among volunteers, a finding that was reported in a prior dose-escalation study of a proteosome-S. flexneri 2a LPS intranasal vaccine [31]. However, similar to the prior Invaplex study, the symptoms were mild, self-limited and well tolerated.…”

Section: Discussioncontrasting

confidence: 55%

“…In the current study, the upper dose (690 g) contained 113 g of LPS in complex with IpaB and IpaC proteins. It would appear that the dose of Invaplex 50 could be increased to attain a more potent immune response given that S. flexneri 2a LPS has been given intranasally in proteosomes at dose amounts of 1.34 mg in a previous clinical trial without serious adverse events [31]. However, a more concentrated Invaplex 50 vaccine would have to be manufactured as the maximum dose (690 g) was given in the current trial due to restrictions on the maximum volume (100 l) delivered by the Dolphin TM device.…”

Section: Discussionmentioning

confidence: 99%

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Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

Riddle¹,

Kaminski²,

Williams³

et al. 2011

Vaccine

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Results: There were no serious adverse events and the majority of adverse events (98%) were mild. Antibody secreting cells (ASC), plasma, and mucosal immune responses to Shigella antigens were detected at all three dose levels with the 690 g dose inducing the highest magnitude and frequency of responses. Vaccination with comparable doses of Invaplex 50 via the Dolphin TM resulted in higher plasma and ASC immune responses as compared to pipette delivery. Conclusion: In this trial the S. flexneri 2a Invaplex 50 vaccine was safe, well-tolerated and induced robust levels of antigen-specific intestinal IgA and ASC responses. The spray device performed well and offered an advantage over pipette intranasal delivery.Published by Elsevier Ltd.

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Section: Discussioncontrasting

confidence: 55%

Section: Discussionmentioning

confidence: 99%

Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

Riddle¹,

Kaminski²,

Williams³

et al. 2011

Vaccine

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“…• Proteosomes (outer membrane vesicles of group B Neisseria meningitidis) to which Shigella sonnei or Shigella flexneri 2a is adsorbed 124 . This vaccine has been administered to humans intranasally.…”

Section: Shigella Vaccine Strategiesmentioning

confidence: 99%

Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

et al. 2007

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More than 50 years of research has yielded numerous Shigella vaccine candidates that have exemplified both the promise of vaccine-induced prevention of shigellosis and the impediments to developing a safe and effective vaccine for widespread use, a goal that has yet to be attained. This Review discusses the most advanced strategies for Shigella vaccine development, the immune responses that are elicited following disease or vaccination, the factors that have accelerated or impeded Shigella vaccine development and our ideas for the way forward.At the end of the 19th century, as epidemics of bacillary dysentery accompanied by high mortality spread across Japan, the young microbiologist Kiyoshi Shiga examined dysenteric stools and isolated a bacterium that was agglutinated by serum from convalescent patients but not from patients with acute disease [1][2][3] (FIG. 1). That bacterium -known today as Shigella dysenteriae 1 -was the first identified member of the genus Shigella. Four Correspondence to M.L. mlevine@medicine.umaryland.edu. Competing interests statement:The authors declare no competing financial interests. Links NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptShigella species (or groups) are now recognized: S. dysenteriae (group A), which has 15 serotypes; Shigella flexneri (group B), which has 14 classical serotypes and subserotypes; Shigella boydii (group C), which has 20 serotypes; and Shigella sonnei (group D), which has single serotype 4 (TABLE 1).There has been resurgent interest in Shigella as a human pathogen, driven by the availability of more precise data on the disease burden 5-8 , emerging antibiotic resistance 9,10 and the fact that mucosally invasive Shigella, which often cause dysentery (gross blood in diarrhoeal stools), are less amenable to the salutary effects of oral rehydration than non-invasive pathogens that cause watery diarrhoea, such as Vibrio cholerae and enterotoxigenic Escherichia coli. The target populations for the use of Shigella vaccines include infants and young children in developing countries (in which the peak incidence occurs at 12-47 months of age and the S. flexneri serotypes predominate) 5-7 .S. dysenteriae 1, which produces Shiga toxin and typically carries R factors that encode resistance to multiple antibodies, waxes and wanes as a cause of epidemic severe disease in the world's least developed countries [11][12][13][14] Few bacterial pathogens have had their pathogenesis or interactions with mammalian tissues elucidated so precisely at the cellular and subcellular levels as Shigella spp. 20,21 Nevertheless, progress in attaining safe and effective Shigella vaccines has faltered. Herein, we review recent and old clinical trials that have evaluated the safety, immunogenicity and efficacy of candidate Shigella vaccines. We relate the bassis for the most popular strategies (BOX 2), the relevance of the different immune responses measured, the factors that have favoured or impeded vaccine development and, most importantly, the less...

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“…During the course of investigating the induction of EAE in APP-Tg mice, we discovered that there was reduction of β amyloid in the brain that occurred independently of anti-Aβ antibodies. These results led to experiments demonstrating that nasal vaccination with a proteosome-based adjuvant that is well tolerated in humans (22) plus glatiramer acetate (GA), an FDAapproved synthetic copolymer used to treat multiple sclerosis (23), potently decreases Αβ plaques in an AD mouse model.…”

Section: Introductionmentioning

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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Safety and Immunogenicity of a Proteosome- Shigella flexneri 2a Lipopolysaccharide Vaccine Administered Intranasally to Healthy Adults

Cited by 93 publications

References 33 publications

Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

Safety and immunogenicity of an intranasal Shigella flexneri 2a Invaplex 50 vaccine

Clinical trials of Shigella vaccines: two steps forward and one step back on a long, hard road

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

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