Intranasal c-di-GMP-adjuvanted plant-derived H5 influenza vaccine induces multifunctional Th1 CD4+ cells and strong mucosal and systemic antibody responses in mice

Madhun, Abdullah Sami; Haaheim, Lars R.; Nøstbakken, Jane Kristin; Ebensen, Thomas; Chichester, Jessica A.; Yusibov, Vidadi; Guzmán, Carlos A.; Cox, Rebecca Jane

doi:10.1016/j.vaccine.2011.04.094

Cited by 87 publications

(91 citation statements)

References 51 publications

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“…We have recently shown that IN administration of the plant-derived HA/cd-i-GMP vaccine induced strong humoral and cellular immune responses, including a balanced Th1/Th2 cytokine and antibody responses and high frequencies of multifunctional Th1 CD4 C T cells. 11 Taken together, our findings suggest that an effective cellular response may at least in part explain the high levels of protection observed in ferrets despite the low titers of serum HI antibodies.…”

Section: Discussionsupporting

confidence: 55%

“…8 ) and several studies have identified its potential as an adjuvant for mucosal and systemic vaccination. [9][10][11][12] We have previously demonstrated immunostimulatory properties of c-di-GMP when used as a mucosal influenza vaccine adjuvant in mice. 11,12 IN or sublingual administration of c-di-GMP adjuvanted influenza vaccines was shown to induce strong homologous and cross reactive mucosal and systemic humoral immune responses, with a balanced Th1/Th2 profile and high frequencies of multifunctional Th1 CD4…”

Section: Introductionmentioning

confidence: 99%

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Intranasal vaccination with a plant-derived H5 HA vaccine protects mice and ferrets against highly pathogenic avian influenza virus challenge

Major

Chichester

Pathirana

et al. 2015

Human Vaccines & Immunotherapeutics

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Highly pathogenic avian influenza H5N1 infection remains a public health threat and vaccination is the best measure of limiting the impact of a potential pandemic. Mucosal vaccines have the advantage of eliciting immune responses at the site of viral entry, thereby preventing infection as well as further viral transmission. In this study, we assessed the protective efficacy of hemagglutinin (HA) from the A/Indonesia/05/05 (H5N1) strain of influenza virus that was produced by transient expression in plants. The plant-derived vaccine, in combination with the mucosal adjuvant (3,5)-cyclic dimeric guanylic acid (c-di-GMP) was used for intranasal immunization of mice and ferrets, before challenge with a lethal dose of the A/Indonesia/05/05 (H5N1) virus. Mice vaccinated with 15g or 5g of adjuvanted HA survived the viral challenge, while all control mice died within 10 d of challenge. Vaccinated animals elicited serum hemagglutination inhibition, IgG and IgA antibody titers. In the ferret challenge study, all animals vaccinated with the adjuvanted plant vaccine survived the lethal viral challenge, while 50% of the control animals died. In both the mouse and ferret models, the vaccinated animals were better protected from weight loss and body temperature changes associated with H5N1 infection compared with the non-vaccinated controls. Furthermore, the systemic spread of the virus was lower in the vaccinated animals compared with the controls. Results presented here suggest that the plant-produced HA-based influenza vaccine adjuvanted with c-di-GMP is a promising vaccine/adjuvant combination for the development of new mucosal influenza vaccines

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Section: Discussionsupporting

confidence: 55%

Section: Introductionmentioning

confidence: 99%

Intranasal vaccination with a plant-derived H5 HA vaccine protects mice and ferrets against highly pathogenic avian influenza virus challenge

Major

Chichester

Pathirana

et al. 2015

Human Vaccines & Immunotherapeutics

Self Cite

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“…Such a proposal was included in several patent applications by David Karaolis, two of which were granted in 2009, as U.S. patents 7,569,555 and 7,592,326 (418). The ability of c-di-GMP to work as a mucosal adjuvant was recently used for intranasal and sublingual administration of live attenuated vaccines of influenza H5N1 virus (419,420).…”

Section: Cyclic Di-gmp As An Immunomodulatormentioning

confidence: 99%

Cyclic di-GMP: the First 25 Years of a Universal Bacterial Second Messenger

Römling

Galperin

Gomelsky

2013

Microbiol Mol Biol Rev

1,474

1,698

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SUMMARY Twenty-five years have passed since the discovery of cyclic dimeric (3′→5′) GMP (cyclic di-GMP or c-di-GMP). From the relative obscurity of an allosteric activator of a bacterial cellulose synthase, c-di-GMP has emerged as one of the most common and important bacterial second messengers. Cyclic di-GMP has been shown to regulate biofilm formation, motility, virulence, the cell cycle, differentiation, and other processes. Most c-di-GMP-dependent signaling pathways control the ability of bacteria to interact with abiotic surfaces or with other bacterial and eukaryotic cells. Cyclic di-GMP plays key roles in lifestyle changes of many bacteria, including transition from the motile to the sessile state, which aids in the establishment of multicellular biofilm communities, and from the virulent state in acute infections to the less virulent but more resilient state characteristic of chronic infectious diseases. From a practical standpoint, modulating c-di-GMP signaling pathways in bacteria could represent a new way of controlling formation and dispersal of biofilms in medical and industrial settings. Cyclic di-GMP participates in interkingdom signaling. It is recognized by mammalian immune systems as a uniquely bacterial molecule and therefore is considered a promising vaccine adjuvant. The purpose of this review is not to overview the whole body of data in the burgeoning field of c-di-GMP-dependent signaling. Instead, we provide a historic perspective on the development of the field, emphasize common trends, and illustrate them with the best available examples. We also identify unresolved questions and highlight new directions in c-di-GMP research that will give us a deeper understanding of this truly universal bacterial second messenger.

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“…Coincident with increased delivery to LNs, nanoparticle delivery of cdGMP blocked dissemination of cdGMP into the systemic circulation ( Figure 1A). dose of cdGMP administered with hemagglutinin protein as a clinically relevant influenza antigen was completely ineffective as a parenteral vaccine (19). Similarly, cdGMP administered s.c. with HIV pseudovirions was also ineffective at adjuvanting humoral responses against the HIV Env protein (20).…”

Section: Cd8αmentioning

confidence: 99%