Genetically Thermo-Stabilised, Immunogenic Poliovirus Empty Capsids; a Strategy for Non-replicating Vaccines

Fox, Helen; Knowlson, Sarah; Minor, Philip D.; Macadam, Andrew

doi:10.1371/journal.ppat.1006117

Cited by 48 publications

(69 citation statements)

References 20 publications

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“…Although the PV57␦ VLPs used here were shown to have stability superior to that of the wt when produced in a mammalian system, the stabilization did not extend to particles expressed in yeast, possibly for the reasons outlined above. However, in preliminary experiments using the thermostable mutants previously characterized by Fox et al (18,20,49), we have shown Pichia to be capable of efficiently producing D antigen. Therefore, we believe that this system has the potential to produce a VLP vaccine not only for a polio-free world but also as a model system for enterovirus VLP vaccine production.…”

Section: Discussionmentioning

confidence: 67%

Comparative Molecular Biology Approaches for the Production of Poliovirus Virus-Like Particles Using Pichia pastoris

Sherry

Grehan

Snowden

et al. 2020

mSphere

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For enteroviruses such as poliovirus (PV), empty capsids, which are antigenically indistinguishable from mature virions, are produced naturally during viral infection. The production of such capsids recombinantly, in heterologous systems such as yeast, have great potential as virus-like particle (VLP) vaccine candidates. Here, using PV as an exemplar, we show the production of VLPs in Pichia pastoris by coexpression of the structural precursor protein P1 and the viral protease 3CD. The level of expression of the potentially cytotoxic protease relative to that of the P1 precursor was modulated by three different approaches: expression of the P1 precursor and protease from different transcription units, separation of the P1 and protease proteins using the Thosea asigna virus (TaV) 2A translation interruption sequence, or separation of the P1 and protease-coding sequences by an internal ribosome entry site sequence from Rhopalosiphum padi virus (RhPV). We also investigate the antigenicity of VLPs containing previously characterized mutations when produced in Pichia. Finally, using transmission electron microscopy and two-dimensional classification, we show that Pichia-derived VLPs exhibited the classical icosahedral capsid structure displayed by enteroviruses. IMPORTANCE Although the current poliovirus immunization program has been extremely successful in reducing the number of cases of paralytic polio worldwide, now more cases are caused by vaccine-derived polioviruses than by wild poliovirus. Switching to inactivated poliovirus vaccines will reduce this over time; however, their production requires the growth of large amounts of virus. This biosafety concern can be addressed by producing just the virus capsid. The capsid serves to protect the genetic material, which causes disease when introduced into a cell. Therefore, empty capsids (virus-like particles [VLPs]), which lack the viral RNA genome, are safe both to make and to use. We exploit yeast as a versatile model expression system to produce VLPs, and here we specifically highlight the potential of this system to supply next-generation poliovirus vaccines to secure a polio-free world for the future.

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Section: Discussionmentioning

confidence: 67%

Comparative Molecular Biology Approaches for the Production of Poliovirus Virus-Like Particles Using Pichia pastoris

Sherry

Grehan

Snowden

et al. 2020

mSphere

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“…One is the development of an inactivated vaccine based on nonpathogenic poliovirus strains; the other, more ambitious, is focused on making purified VLP-based vaccines, which would not include a poliovirus propagation step at any stage of production. While both approaches address the safety concerns that drive up the cost of manufacturing the original IPV, which relies on the propagation of large quantities of pathogenic poliovirus strains, they both include tedious purification processes and face significant problems of stabilizing labile poliovirus epitopes required for the induction of protective neutralizing antibodies (22,47,48). Moreover, the nonreplicating vaccines are deficient in the induction of the mucosal immune response, which is critical for the interruption of poliovirus transmission.…”

Section: Discussionmentioning

confidence: 99%

“…Poliovirus VLPs are unstable and easily convert from a protective D-antigen to an inactivated C-or H-antigen conformation, which does not induce neutralizing antibodies (21). Even if the antigenic stability of VLPs can be increased by introducing mutations into the capsid protein sequence (22), purified VLPs are incapable of inducing a mucosal immune response, just like the original IPV, and scaling up the experimental systems of VLP production and purification to the industrial level may represent a formidable challenge.…”

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confidence: 99%

Newcastle Disease Virus-Based Vectored Vaccine against Poliomyelitis

Viktorova

Khattar

Kouiavskaia

et al. 2018

J Virol

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The poliovirus eradication initiative has spawned global immunization infrastructure and dramatically decreased the prevalence of the disease, yet the original virus eradication goal has not been met. The suboptimal properties of the existing vaccines are among the major reasons why the program has repeatedly missed eradication deadlines. Oral live poliovirus vaccine (OPV), while affordable and effective, occasionally causes the disease in the primary recipients, and the attenuated viruses rapidly regain virulence and can cause poliomyelitis outbreaks. Inactivated poliovirus vaccine (IPV) is safe but expensive and does not induce the mucosal immunity necessary to interrupt virus transmission. While the need for a better vaccine is widely recognized, current efforts are focused largely on improvements to the OPV or IPV, which are still beset by the fundamental drawbacks of the original products. Here we demonstrate a different design of an antipoliovirus vaccine based on production of virus-like particles (VLPs). The poliovirus capsid protein precursor, together with a protease required for its processing, are expressed from a Newcastle disease virus (NDV) vector, a negative-strand RNA virus with mucosal tropism. In this system, poliovirus VLPs are produced in the cells of vaccine recipients and are presented to their immune systems in the context of active replication of NDV, which serves as a natural adjuvant. Intranasal administration of the vectored vaccine to guinea pigs induced strong neutralizing systemic and mucosal antibody responses. Thus, the vectored poliovirus vaccine combines the affordability and efficiency of a live vaccine with absolute safety, since no full-length poliovirus genome is present at any stage of the vaccine life cycle. A new, safe, and effective vaccine against poliovirus is urgently needed not only to complete the eradication of the virus but also to be used in the future to prevent possible virus reemergence in a postpolio world. Currently, new formulations of the oral vaccine, as well as improvements to the inactivated vaccine, are being explored. In this study, we designed a viral vector with mucosal tropism that expresses poliovirus capsid proteins. Thus, poliovirus VLPs are produced , in the cells of a vaccine recipient, and are presented to the immune system in the context of vector virus replication, stimulating the development of systemic and mucosal immune responses. Such an approach allows the development of an affordable and safe vaccine that does not rely on the full-length poliovirus genome at any stage.

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“…Furthermore, hyper-attenuated S19 poliovirus strains unable to replicate in humans have been developed at NIBSC [56] and will be used as seeds for IPV production [57] as well as reagents for essential assays requiring the use of live poliovirus that will now be possible to carry out at lower containment levels, such as neutralization assays for seroprevalence studies or characterization of immunoglobulin preparations for medical use [58]. In addition, NIBSC in collaboration with the Universities of Leeds and Oxford and the John Innes Center (JIC) in the UK has made considerable progress in the research and development of non-infectious vaccine-like particles to be used as vaccines in the post-eradication era [53,59].…”

Section: Poliovirus and Other Enterovirusesmentioning

confidence: 99%

Commonly setting biological standards in rare diseases

O’Connor¹,

Buckland

Almond

et al. 2019

Expert Opinion on Orphan Drugs

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Introduction: Standardization is important across the life cycle of medicinal products, supporting the diagnosis, treatment, and prevention of a wide range of diseases. For rare diseases, standardization is even more important, as patient groups are small, presenting significant challenges in the design, conduct, analysis, and interpretation of clinical studies. It is here that standardization institutions, including the UK's National Institute for Biological Standards and Control (NIBSC), can have a key role. Areas covered: A considerable proportion of NIBSC's work supports the better understanding, diagnosis, treatment, and prevention of rare diseases. NIBSC is also part of the UK's Medicines and Health care products Regulatory Agency (MHRA), creating an agency that is uniquely placed to combine scientific and regulatory expertize for the benefit of public health. This review provides an overview of NIBSC's work in rare diseases and highlights the positive impact of the work of standardization institutions in this field. Expert opinion: Standardization in product development is key for patients with rare diseases. The work of standardization institutions is increasingly being recognized as crucial for supporting scientific and clinical advancements, and early and collaborative interactions can provide drug developers with the necessary expertize, when standards matter most.

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Genetically Thermo-Stabilised, Immunogenic Poliovirus Empty Capsids; a Strategy for Non-replicating Vaccines

Cited by 48 publications

References 20 publications

Comparative Molecular Biology Approaches for the Production of Poliovirus Virus-Like Particles Using Pichia pastoris

Comparative Molecular Biology Approaches for the Production of Poliovirus Virus-Like Particles Using Pichia pastoris

Newcastle Disease Virus-Based Vectored Vaccine against Poliomyelitis

Commonly setting biological standards in rare diseases

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