Immunization with PCEP microparticles containing pertussis toxoid, CpG ODN and a synthetic innate defense regulator peptide induces protective immunity against pertussis

Garlapati, Srinivas; Eng, Nelson F.; Kiros, Tadele G.; Kindrachuk, Jason; Mutwiri, George; Hancock, Robert E. W.; Halperin, Scott A.; Potter, Andrew; Babiuk, Lorne A.; Gerdts, Volker

doi:10.1016/j.vaccine.2011.07.009

Cited by 59 publications

(43 citation statements)

References 26 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Anti-infective peptides IDR-1 and IDR-1002 confer in vivo protection against bacterial infections through modulation of innate immune responses, including the regulation of chemokine/cytokine responses and recruitment of monocytes to the site of infection [3,4]. Likewise, IDR-1018 and IDR-HH2 also demonstrate the ability to modulate the host cytokine/chemokine environment [26,27], while both IDR-1002 and IDR-HH2 promote adjuvant activity in formulation [5,6]. We sought to determine whether the ability to promote monocyte adhesion to fibronectin demonstrated by IDR-1002 was shared with other IDR peptides as well.…”

Section: Resultsmentioning

confidence: 99%

“…While a common feature of IDR peptides is their ability to enhance cellular infiltration to sites of infection, mechanistic studies to date have focused on the indirect stimulation of chemotaxis, through the stimulation of chemokine production, rather than any direct effects on cellular motility. In this study, we identified a mechanism by which synthetic peptide IDR-1002 directly enhances monocyte migration, a hallmark effect in IDR-mediated protection against bacterial infection [3,4] and its deployment in adjuvant formulations [5,6]. Specifically, we demonstrated that IDR-1002 enhanced monocyte migration towards chemokines through a fibronectin matrix by strengthening the interaction between monocytes and this substrate.…”

Section: Discussionmentioning

confidence: 99%

“…It has also been developed and outlicensed as a component of an adjuvant formulation, comprising IDR-1002, CpG oligonucleotide and polyphosphazene. In this adjuvant formulation, which enables effective single-dose vaccines against pertussis, its primary role is to enhance recruitment of immune cells [5,6]. Although IDR peptides demonstrate potent anti-infective and adjuvant properties, our limited understanding regarding the mechanisms by which IDR peptides modulate immunity represents an obstacle in their development as clinical therapeutic agents.…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthetic Immunomodulatory Peptide IDR-1002 Enhances Monocyte Migration and Adhesion on Fibronectin

Madera

Hancock²

2012

J Innate Immun

Self Cite

View full text Add to dashboard Cite

Regulation of the immune system by immunomodulatory agents, such as the synthetic innate defense regulator (IDR) peptides, has been proposed as a potential strategy to strengthen host immune responses against infection. IDR peptides confer protection in vivo against a range of bacterial infections and have been developed as components of single-dose vaccine adjuvants due to their ability to modulate innate immunity, correlating with an increased recruitment of monocytes to sites of infection or immunization. However, the mechanisms by which IDR peptides augment monocyte recruitment remain poorly defined. Anti-infective peptide IDR-1002 was demonstrated here to lack direct monocyte chemoattractive activity yet enhance, by up to 5-fold, the ability of human monocytes to migrate on fibronectin towards chemokines. This effect correlated with an increased adhesion of monocytes and THP-1 cells to fibronectin by IDR-1002 and other IDR peptides and the adhesion of THP-1 cells to fibronectin occurred in a β₁-integrin-dependent manner, corresponding with an increased activation of β₁-integrins and the phosphoinositide 3-kinase (PI3K)-Akt pathway. PI3K- and Akt-specific inhibitors abrogated IDR-1002-induced adhesion and activation of β₁-integrins, whereas p38 and MEK1 inhibitors did not affect, or moderately inhibited, adhesion, respectively. Furthermore, IDR-1002 enhancement of monocyte migration towards chemokines and activation of β₁-integrins was abrogated in the presence of PI3K- and Akt-specific inhibitors. In summary, IDR-1002 enhanced monocyte migration on fibronectin through promotion of β₁-integrin-mediated interactions regulated by the PI3K-Akt pathway, revealing a mechanism by which IDR-1002 promotes monocyte recruitment.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthetic Immunomodulatory Peptide IDR-1002 Enhances Monocyte Migration and Adhesion on Fibronectin

Madera

Hancock²

2012

J Innate Immun

Self Cite

View full text Add to dashboard Cite

show abstract

“…In fact, HDP-based peptides have been shown to enhance vaccination efficiency in several in vivo models, in which the vaccination mixture contains synthetic DNA (43)(44)(45)(46)(47). Although little is known about the effects of these specific HDPs on DNA-induced immune activation, it is possible that part of their efficacy comes from increasing the proinflammatory DNA-induced immune response.…”

Section: Discussionmentioning

confidence: 99%

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

Coorens

Dijk

Bikker

et al. 2015

The Journal of Immunology

View full text Add to dashboard Cite

Cathelicidins are essential in the protection against invading pathogens through both their direct antimicrobial activity and their immunomodulatory functions. Although cathelicidins are known to modulate activation by several TLR ligands, little is known about their influence on DNA-induced macrophage activation. In this study, we explored the effects of cathelicidins on DNA-induced activation of chicken macrophages and elucidated the intracellular processes underlying these effects. Our results show that chicken cathelicidin (CATH)-2 strongly enhances DNA-induced activation of both chicken and mammalian macrophages because of enhanced endocytosis of DNA–CATH-2 complexes. After endocytosis, DNA is liberated from the complex because of proteolytic breakdown of CATH-2, after which TLR21 is activated. This leads to increased cytokine expression and NO production. Through the interaction with DNA, CATH-2 can play an important role in modulating the immune response at sites of infection. These observations underline the importance of cathelicidins in sensing bacterial products and regulating immune responses.

show abstract

“…4,21 The primary aim of pertussis immunisation is to protect young infants against severe Despite the well-established pertussis immunisation programs in Australia and overseas, infants younger than six months of age continue to be at highest risk of severe outcomes. 10,86,89,[103][104][105][106] In the future, new pertussis vaccines may be able to provide earlier and longer lasting protection by utilising live attenuated B. pertussis strains, novel soluble or micro-particle vaccine formulations, improved adjuvants, or mucosal delivery, [107][108][109] however as these novel vaccines may still be many years away, other strategies need to be considered to protect young infants. 10,61,103,105 The "cocoon" strategy, which attempts to protect newborn infants by immunising their close contacts, such as parents and other caregivers, has been proposed as a possible solution.…”

Section: Immunisation Strategies and Coveragementioning

confidence: 99%

The diagnosis and epidemiology of pertussis in Australia

Kaczmarek¹

View full text Add to dashboard Cite

Pertussis, more commonly known as whooping cough, is one of the most common vaccine-preventable infections reported in Australia. In the last decade, pertussis incidence has increased in Australia and overseas, with large sustained epidemics occurring most notably in developed countries. Australia had a pertussis epidemic between 2009 and 2012, which peaked during 2011 with 38,602 notified cases. The role of improved diagnostic methods, particularly the use of polymerase chain reaction (PCR) testing, has been hypothesised to have led to improved case ascertainment and superior detection of disease activity. This Thesis is comprised of five distinct studies contributing to the investigation of this hypothesis.In Australia, the incidence of pertussis is predominantly monitored using notification data, with the case definition for notifications heavily reliant on laboratory confirmation. By analysing pertussis notifications between 1991 and 2013 by diagnostic test method, I was able to demonstrate that PCR quickly replaced all other laboratory methods for pertussis diagnosis from 2005 onwards, with the exception of persisting serology use in a proportion of adolescents and adults. In addition, a change in the age distribution of notifications was observed over time, with increasing pertussis incidence among older children and adolescents.As notification data can be biased by changes in testing practices, awareness, and definitions, my next study investigated pertussis testing trends in the general practice (GP, primary care) setting between 2000 and 2011 using data from the Bettering the Evaluation And Care of Health (BEACH) program. Among a stable set of GP encounters for respiratory illness, it was observed that the likelihood of individuals being tested for pertussis in 2010-2011 was seven times higher compared to ten years earlier. These findings, at least in part, suggest that notifications have been amplified due to increased testing.To gather more information about the contribution of increased testing to the pertussis epidemic, the incidence of severe pertussis cases admitted to intensive care units (ICUs) was reviewed, as the ICU setting is less likely to be biased by changes in diagnostic This Thesis makes an important and original contribution to understanding the recent resurgence of pertussis in Australia and overseas by addressing gaps in knowledge about changes in diagnostic testing. Although a true increase in pertussis incidence occurred in Australia, increasing PCR diagnosis allowed better case detection across all age groups and healthcare settings. Greater understanding of pertussis epidemiology as a result of PCR diagnosis should ultimately improve pertussis immunisation and control programs, through better identification of at-risk groups.iv

show abstract

Immunization with PCEP microparticles containing pertussis toxoid, CpG ODN and a synthetic innate defense regulator peptide induces protective immunity against pertussis

Cited by 59 publications

References 26 publications

Synthetic Immunomodulatory Peptide IDR-1002 Enhances Monocyte Migration and Adhesion on Fibronectin

Synthetic Immunomodulatory Peptide IDR-1002 Enhances Monocyte Migration and Adhesion on Fibronectin

Importance of Endosomal Cathelicidin Degradation To Enhance DNA-Induced Chicken Macrophage Activation

The diagnosis and epidemiology of pertussis in Australia

Contact Info

Product

Resources

About