Versatile Virus-Like Particle Carrier for Epitope Based Vaccines

Tissot, Alain C.; Renhofa, Regīna; Schmitz, Nicole; Cielēns, Indulis; Meijerink, Edwin; Ose, Velta; Jennings, Gary T.; Saudan, Philippe; Pumpens, Paul; Bachmann, Martin F.

doi:10.1371/journal.pone.0009809

Cited by 173 publications

(129 citation statements)

References 40 publications

Supporting

Mentioning

122

Contrasting

Order By: Relevance

“…The generation of M2e-AP205 has been described previously [31]. Briefly, the cDNA encoding the influenza M2 protein ectodomain consensus sequence (SLLTEVETPIRNEWGCRCNDSSD) was fused via a linker sequence (GSGG) to the N-terminus of the viral capsid protein of the RNA-phage AP205.…”

Section: Generation Of M2e-ap205 Particles and Vaccine Designmentioning

confidence: 99%

“…This vaccine consists of the extracellular domain of M2 (M2e) fused to the N-terminus of the viral capsid protein of the RNA-bateriophage AP205 (M2e-AP205) and has been previously described to protect mice from a lethal challenge with influenza virus [31]. It is important to note that upon assembly of the M2e-AP205 coat protein fusion protein, Escherichia coli RNA is packaged into the VLPs.…”

Section: Inducing Protective M2e Antibodies By Vaccination: Tlr-signamentioning

confidence: 99%

See 1 more Smart Citation

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Schmitz¹,

Beerli²,

Bauer³

et al. 2012

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

A vaccine protecting against all influenza strains is a long-sought goal, particularly for emerging pandemics. As previously shown, vaccines based on the highly conserved extracellular domain of M2 (M2e) may protect against all influenza A strains. Here, we demonstrate that M2e-specific monoclonal antibodies (mAbs) protect mice from a lethal influenza infection. To be protective, antibodies had to be able to bind to Fc receptors and fix complement. Furthermore, mAbs of IgG2c isotype were protective in mice, while antibodies of identical specificity, but of the IgG1 isotype, failed to prevent disease. These findings readily translated into vaccine design. A vaccine targeting M2 in the absence of a toll-like receptor (TLR) 7 ligand primarily induced IgG1, whilst the same vaccine linked to a TLR7 ligand yielded high levels of IgG2c antibodies. Although both vaccines protected mice from a lethal challenge, mice treated with the vaccine containing a TLR7 ligand showed significantly lower morbidity. In accordance with these findings, vaccination of TLR7 -/-mice with a vaccine containing a TLR7 ligand did not result in protection from a lethal challenge. Hence, the innate immune system is required to direct isotype switching toward the more protective IgG2a/c antibodies.Keywords: Antibodies r Immunotherapy r Toll like receptors r Vaccination r Virology IntroductionInfection with influenza virus is a major cause of morbidity as well as mortality throughout the world. Influenza virus is a very dynamic pseudo species and constantly avoids immunity at the population level by accumulating mutations in the hemagglutinin (HA) and neuraminidase molecules in a process called genetic drift. In addition, in a rare process called genetic shift, human influenza viruses may reassort with avian or swine influenza viruses [1]. Since under these circumstances, the virus hits an essentially naive population, the epidemic may become a pandemic with potentially millions of people infected and killed by the virus.Correspondence: Dr. Martin F. Bachmann e-mail: martin.bachmann@me.com Induction of protective immunity against influenza virus, not affected by genetic drift or shift, is therefore a major goal in vaccine development [2,3]. T cells are usually more cross-reactive than antibodies [4][5][6] and additionally recognize more conserved, virus-internal proteins [7,8]. Induction of broadly reactive T cells by vaccination may therefore be a potential avenue to follow [9,10]. This, however, may be a difficult task, since protective T-cell responses are usually short lived in mice [11] and humans [12], and it has not been possible so far to induce long-lived T-cell mediated immunity by vaccination. An alternative approach represents the induction of protective antibody responses directed against conserved viral structures. The extracellular domain of M2 (M2e) is a candidate for such a vaccine. M2e is highly conserved in all influenza A strains and has hardly changed over the last 90 years [13,14]. Although the recently emerged pandemic influ...

show abstract

Section: Generation Of M2e-ap205 Particles and Vaccine Designmentioning

confidence: 99%

Section: Inducing Protective M2e Antibodies By Vaccination: Tlr-signamentioning

confidence: 99%

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Schmitz¹,

Beerli²,

Bauer³

et al. 2012

Eur J Immunol

Self Cite

View full text Add to dashboard Cite

show abstract

“…However, many VLPs in development still require the coadministration of adjuvants to be fully effective (17,18). VLPs can easily be engineered to express foreign epitopes using genetic fusion or chemical conjugation (19)(20)(21). At present, there are two vaccines used in humans derived from VLPs: The hepatitis B virus vaccine and the human papillomavirus vaccine.…”

mentioning

confidence: 99%

Nanoparticle Adjuvant Sensing by TLR7 Enhances CD8+ T Cell–Mediated Protection from Listeria Monocytogenes Infection

Lebel

Daudelin

Chartrand

et al. 2014

The Journal of Immunology

View full text Add to dashboard Cite

Developing new adjuvants and vaccination strategies is of paramount importance to successfully fight against many life-threatening infectious diseases and cancer. Very few adjuvants are currently authorized for human use, and these mainly stimulate a humoral response. However, specific Abs are not sufficient to confer protection against persisting infections or cancer. Therefore, development of adjuvants and immunomodulators able to enhance cell-mediated immune responses represents a major medical need. We recently showed that papaya mosaic virus nanoparticles (PapMV), self-assembled from the coat protein of a plant virus and a noncoding ssRNA molecule, are highly immunogenic in mice. PapMV can be used either as a vaccine delivery platform, through fusion of various epitopes to the coat protein or as adjuvant to enhance humoral immune responses against coadministered Ags or vaccines. However, the mechanisms that confer these immunomodulatory properties to PapMV and its ability to enhance T cell vaccines remain unknown. Using immunization studies in mice, we demonstrate in this paper that PapMV represents a novel TLR7 agonist with strong immunostimulatory properties. More importantly, pretreatment with PapMV significantly improves effector and memory CD8+ T cell responses generated through dendritic cell vaccination increasing protection against a Listeria monocytogenes challenge.

show abstract

“…Studies in modular VLPs presume that it is nearly impossible for a peptide antigen element to assume its conformational integrity when it is presented on a modular VLP (Jennings and Bachmann 2007, Tissot et al 2010. Until now, presentation of a peptide antigen element on a modular VLP and the impact of display strategy for presentation of the antigen element on the quality of the resulting antibodies are not fully understood.…”

Section: Virus-like Particles (Vlps)mentioning

confidence: 99%

“…Thus, in order to obtain antibodies that cross-react with the native antigen protein, the epitope peptides need to maintain conformational integrity (Purcell et al 2007, Purcell et al 2003). The quality of antibodies has been shown to resemble the protection efficacy of the antibodies (Alvarez et al 2010 A higher antibody quality indicates a higher potential of protection efficacy, thus a high quality of antibodies is desirable.Studies in modular VLPs presume that it is nearly impossible for a peptide antigen element to assume its conformational integrity when it is presented on a modular VLP (Jennings and Bachmann 2007, Tissot et al 2010. Until now, presentation of a peptide antigen element on a modular VLP and the impact of display strategy for presentation of the antigen element on the quality of the resulting antibodies are not fully understood.…”

mentioning

confidence: 99%

Engineering of virus-like particles for alternative vaccine candidate targeting a hypervariable peptide antigen element

Anggraeni¹

View full text Add to dashboard Cite

A promising alternative to replace the current egg-or cell culture-based technology for vaccine production from live viruses is virus-like particle (VLP) technology based on a microbial platform. VLPs are macromolecular assemblies of viral capsid proteins, which have been shown to tolerate insertion of antigen modules via genetic recombinant technology, yielding modular VLPs. Many studies on modular VLPs presume that when a peptide antigen element is taken out from the intact proteins and then modularised on VLPs, it is unable to fold into its native structure. However, until now, presentation of a peptide antigen element on a VLP and the impact of the display strategy to present the antigen element on the quality of the resulting antibodies (i.e. the ability of the antibodies to recognise the intact protein) are not fully understood. This thesis aims to understand the underlying fundamentals regarding modularisation of peptide antigen elements on VLPs for induction of high-quality antibodies. A hypervariable receptor-binding domain, Helix 190 (H190), from the hemagglutinin protein of influenza A virus was used as a model for modularisation on VLPs from murine polyomavirus (MuPyV) VP1 protein. Four major findings are presented. Firstly, two display strategies, i.e. arraying of H190 in tandem repeats and the use of helix promoter elements, were shown to display H190 in its immunogenic form equally. However, modularisation using tandem repeat display induced antibodies of a higher quality than modularisation using helix promoter elements.Secondly, the quality of antibodies induced by the tandem repeat display bearing two copies of H190 was optimum, thus no significant improvement was observed following the use of adjuvant or increasing the copy number of H190. Additionally, the increase in the copy number of H190 was shown to reduce the assembly capability and solubility of modular VP1 in an environment that was optimised for wild-type VP1. Thirdly, this thesis shows the novel finding in the use of flanking ionic elements to stabilise VLP precursors, termed as capsomeres, bearing two copies of H190 containing a hydrophobic stretch, which caused aggregation. Fourthly, the first steps towards obtaining the atomic crystal structure of presented H190 on a modular protein were performed, i.e. a mild and satisfactory laboratory process was developed to achieve high-purity modular VP1 capsomeres, unattainable using previously established expression and purification process of wild-type MuPyV VP1. This thesis shows a step forward towards understanding the presentation of a peptide antigen element on a VLP that enables induction of highquality antibodies, and towards VLP engineering to manipulate the aggregation and solubility of modular VP1. VLP technology based on a microbial platform presented here is iii a potentially safe and effective alternative vaccine candidate that targets a hypervariable peptide antigen element. The speed of the microbial platform allows a rapid response to the hypervariability of the pe...

show abstract

Versatile Virus-Like Particle Carrier for Epitope Based Vaccines

Cited by 173 publications

References 40 publications

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Universal vaccine against influenza virus: Linking TLR signaling to anti‐viral protection

Nanoparticle Adjuvant Sensing by TLR7 Enhances CD8+ T Cell–Mediated Protection from Listeria Monocytogenes Infection

Engineering of virus-like particles for alternative vaccine candidate targeting a hypervariable peptide antigen element

Contact Info

Product

Resources

About