Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy

A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Viral Immunology, Vaccines, and Antivirals".

Deadline for manuscript submissions: closed (30 November 2019) | Viewed by 35064

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Guest Editor
Department of Microbiology and Immunology, Taipei Medical University, Taipei, Taiwan
Interests: molecular virology; viral entry; antivirals; viral oncolytics
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Members of the Morbillivirus genus are enveloped negative-strand RNA viruses that include a number of highly contagious pathogens important to humans and animals. They are known to be transmitted via the respiratory route and cause febrile diseases that can be fatal. Despite the availability of attenuated vaccines against several members, these viruses remain responsible for significant morbidity and mortality in their natural hosts worldwide. The development of molecular biology techniques over the past decades has helped increase the understanding of morbillivirus pathogenesis and explore the possibility to engineer their genomes as viral vectors. Specifically, recent advances have observed the potential use of recombinant morbilliviruses as platforms for novel vaccine development and oncolytic virotherapy against cancers. Continuous research will likely provide further insights into the disease control of morbilliviruses and explore vaccine and therapeutic applications of their genetic vectors.

Dr. Liang-Tzung Lin
Guest Editor

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Keywords

  • Morbilliviruses
  • recombinant genome
  • viral vector
  • vaccine development
  • oncolytic virotherapy

Published Papers (8 papers)

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Editorial

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2 pages, 152 KiB  
Editorial
Special Issue “Recent Advances in Morbillivirus Vaccine Development and Oncolytic Virotherapy”
by Liang-Tzung Lin
Viruses 2020, 12(3), 341; https://doi.org/10.3390/v12030341 - 20 Mar 2020
Viewed by 1990
Abstract
Members of the Morbillivirus genus are enveloped, negative-strand RNA viruses that include a number of highly contagious pathogens important to humans and animals [...] Full article

Research

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17 pages, 2193 KiB  
Article
Measles Vaccines Designed for Enhanced CD8+ T Cell Activation
by Elena Busch, Kristina D. Kubon, Johanna K. M. Mayer, Gemma Pidelaserra-Martí, Jessica Albert, Birgit Hoyler, Johannes P. W. Heidbuechel, Kyle B. Stephenson, Brian D. Lichty, Wolfram Osen, Stefan B. Eichmüller, Dirk Jäger, Guy Ungerechts and Christine E. Engeland
Viruses 2020, 12(2), 242; https://doi.org/10.3390/v12020242 - 21 Feb 2020
Cited by 14 | Viewed by 4964
Abstract
Priming and activation of CD8+ T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics [...] Read more.
Priming and activation of CD8+ T cell responses is crucial to achieve anti-viral and anti-tumor immunity. Live attenuated measles vaccine strains have been used successfully for immunization for decades and are currently investigated in trials of oncolytic virotherapy. The available reverse genetics systems allow for insertion of additional genes, including heterologous antigens. Here, we designed recombinant measles vaccine vectors for priming and activation of antigen-specific CD8+ T cells. For proof-of-concept, we used cytotoxic T lymphocyte (CTL) lines specific for the melanoma-associated differentiation antigen tyrosinase-related protein-2 (TRP-2), or the model antigen chicken ovalbumin (OVA), respectively. We generated recombinant measles vaccine vectors with TRP-2 and OVA epitope cassette variants for expression of the full-length antigen or the respective immunodominant CD8+ epitope, with additional variants mediating secretion or proteasomal degradation of the epitope. We show that these recombinant measles virus vectors mediate varying levels of MHC class I (MHC-I)-restricted epitope presentation, leading to activation of cognate CTLs, as indicated by secretion of interferon-gamma (IFNγ) in vitro. Importantly, the recombinant OVA vaccines also mediate priming of naïve OT-I CD8+ T cells by dendritic cells. While all vaccine variants can prime and activate cognate T cells, IFNγ release was enhanced using a secreted epitope variant and a variant with epitope strings targeted to the proteasome. The principles presented in this study will facilitate the design of recombinant vaccines to elicit CD8+ responses against pathogens and tumor antigens. Full article
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21 pages, 3612 KiB  
Article
Oxidative Stress in Canine Histiocytic Sarcoma Cells Induced by an Infection with Canine Distemper Virus Led to a Dysregulation of HIF-1α Downstream Pathway Resulting in a Reduced Expression of VEGF-B In Vitro
by Federico Armando, Matteo Gambini, Attilio Corradi, Chiara Giudice, Vanessa Maria Pfankuche, Graham Brogden, Friederike Attig, Maren von Köckritz-Blickwede, Wolfgang Baumgärtner and Christina Puff
Viruses 2020, 12(2), 200; https://doi.org/10.3390/v12020200 - 11 Feb 2020
Cited by 14 | Viewed by 3792
Abstract
Histiocytic sarcomas represent malignant tumors which require new treatment strategies. Canine distemper virus (CDV) is a promising candidate due to its oncolytic features reported in a canine histiocytic sarcoma cell line (DH82 cells). Interestingly, the underlying mechanism might include a dysregulation of angiogenesis. [...] Read more.
Histiocytic sarcomas represent malignant tumors which require new treatment strategies. Canine distemper virus (CDV) is a promising candidate due to its oncolytic features reported in a canine histiocytic sarcoma cell line (DH82 cells). Interestingly, the underlying mechanism might include a dysregulation of angiogenesis. Based on these findings, the aim of the present study was to investigate the impact of a persistent CDV-infection on oxidative stress mediated changes in the expression of hypoxia-inducible factor (HIF)-1α and its angiogenic downstream pathway in DH82 cells in vitro. Microarray data analysis, immunofluorescence for 8-hydroxyguanosine, superoxide dismutase 2 and catalase, and flow cytometry for oxidative burst displayed an increased oxidative stress in persistently CDV-infected DH82 cells (DH82Ond pi) compared to controls. The HIF-1α expression in DH82Ond pi increased, as demonstrated by Western blot, and showed an unexpected, often sub-membranous distribution, as shown by immunofluorescence and immunoelectron microscopy. Furthermore, microarray data analysis and immunofluorescence confirmed a reduced expression of VEGF-B in DH82Ond pi compared to controls. In summary, these results suggest a reduced activation of the HIF-1α angiogenic downstream pathway in DH82Ond pi cells in vitro, most likely due to an excessive, unusually localized, and non-functional expression of HIF-1α triggered by a CDV-induced increased oxidative stress. Full article
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23 pages, 6799 KiB  
Article
The Susceptibility of Human Melanoma Cells to Infection with the Leningrad-16 Vaccine Strain of Measles Virus
by Yulia Ammour, Oxana Ryabaya, Yulia Shchetinina, Elena Prokofeva, Marina Gavrilova, Dmitry Khochenkov, Denis Vorobyev, Evgeny Faizuloev, Igor Shohin, Vitaly V. Zverev, Oxana Svitich and Tatiana Nasedkina
Viruses 2020, 12(2), 173; https://doi.org/10.3390/v12020173 - 4 Feb 2020
Cited by 13 | Viewed by 3080
Abstract
Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human [...] Read more.
Oncolytic viruses, including live attenuated measles virus (MV) vaccine strains, have recently been shown as promising therapeutic agents against human malignancies. In this study, the oncolytic potential of the attenuated vaccine strain Leningrad-16 (L-16) of MV was evaluated in a panel of human metastatic melanoma cell lines. The L-16 measles virus was shown to replicate within melanoma cells mediating direct cell killing of tumor cells, although all melanoma cell lines varied in regard to their ability to respond to L-16 MV infection, as revealed by the different pattern of the Interferon Stimulated Gene expression, cytokine release and mechanisms of cell death. Furthermore, the statistically significant L-16 measles virus related tumor growth inhibition was demonstrated in a melanoma xenograft model. Therefore, L-16 MV represents an appealing oncolytic platform for target delivery of therapeutic genes along with other attenuated measles virus strains. Full article
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21 pages, 2834 KiB  
Article
Immunological Effects and Viral Gene Expression Determine the Efficacy of Oncolytic Measles Vaccines Encoding IL-12 or IL-15 Agonists
by Paul S. Backhaus, Rūta Veinalde, Laura Hartmann, Jessica E. Dunder, Lara M. Jeworowski, Jessica Albert, Birgit Hoyler, Tanja Poth, Dirk Jäger, Guy Ungerechts and Christine E. Engeland
Viruses 2019, 11(10), 914; https://doi.org/10.3390/v11100914 - 3 Oct 2019
Cited by 37 | Viewed by 4372
Abstract
Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in [...] Read more.
Tumor-targeted immunomodulation using oncolytic viral vectors is currently being investigated as a promising strategy in cancer therapy. In a previous study, we showed that a measles virus Schwarz vaccine strain (MeVac) vector encoding an interleukin-12 fusion protein (FmIL-12) is an effective immunotherapy in the MC38cea murine colon adenocarcinoma model. We hypothesized that MeVac encoding interleukin-15 may mediate enhanced T and NK cell responses and thus increase the therapeutic efficacy, especially in NK cell-controlled tumors. Therefore, we generated MeVac vectors encoding an interleukin-15 superagonist, FmIL-15. Replication and oncolytic capacity, transgene expression, and functionality of MeVac FmIL-15 vectors were validated in vitro. Effects on the tumor immune landscape and therapeutic efficacy of both FmIL-12 and FmIL-15 vectors were studied in the MC38cea and B16hCD46 tumor models. Treatment with MeVac FmIL-15 increased T and NK cell infiltration in both models. However, MeVac FmIL-12 showed more robust viral gene expression and immune activation, resulting in superior anti-tumor efficacy. Based on these results, MeVac encoding a human IL-12 fusion protein was developed for future clinical translation. Full article
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16 pages, 1545 KiB  
Article
Forced Degradation Studies to Identify Critical Process Parameters for the Purification of Infectious Measles Virus
by Daniel Loewe, Julian Häussler, Tanja A. Grein, Hauke Dieken, Tobias Weidner, Denise Salzig and Peter Czermak
Viruses 2019, 11(8), 725; https://doi.org/10.3390/v11080725 - 7 Aug 2019
Cited by 21 | Viewed by 5818
Abstract
Oncolytic measles virus (MV) is a promising treatment for cancer but titers of up to 1011 infectious particles per dose are needed for therapeutic efficacy, which requires an efficient, robust, and scalable production process. MV is highly sensitive to process conditions, and [...] Read more.
Oncolytic measles virus (MV) is a promising treatment for cancer but titers of up to 1011 infectious particles per dose are needed for therapeutic efficacy, which requires an efficient, robust, and scalable production process. MV is highly sensitive to process conditions, and a substantial fraction of the virus is lost during current purification processes. We therefore conducted forced degradation studies under thermal, pH, chemical, and mechanical stress to determine critical process parameters. We found that MV remained stable following up to five freeze–thaw cycles, but was inactivated during short-term incubation (< 2 h) at temperatures exceeding 35 °C. The infectivity of MV declined at pH < 7, but was not influenced by different buffer systems or the ionic strength/osmolality, except high concentrations of CaCl2 and MgSO4. We observed low shear sensitivity (dependent on the flow rate) caused by the use of a peristaltic pump. For tangential flow filtration, the highest recovery of MV was at a shear rate of ~5700 s−1. Our results confirm that the application of forced degradation studies is important to identify critical process parameters for MV purification. This will be helpful during the early stages of process development, ensuring the recovery of high titers of active MV particles after purification. Full article
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22 pages, 3520 KiB  
Article
Starvation-Induced Differential Virotherapy Using an Oncolytic Measles Vaccine Virus
by Gabriel Scheubeck, Susanne Berchtold, Irina Smirnow, Andrea Schenk, Julia Beil and Ulrich M. Lauer
Viruses 2019, 11(7), 614; https://doi.org/10.3390/v11070614 - 5 Jul 2019
Cited by 9 | Viewed by 3404
Abstract
Starvation sensitizes tumor cells to chemotherapy while protecting normal cells at the same time, a phenomenon defined as differential stress resistance. In this study, we analyzed if starvation would also increase the oncolytic potential of an oncolytic measles vaccine virus (MeV-GFP) while protecting [...] Read more.
Starvation sensitizes tumor cells to chemotherapy while protecting normal cells at the same time, a phenomenon defined as differential stress resistance. In this study, we analyzed if starvation would also increase the oncolytic potential of an oncolytic measles vaccine virus (MeV-GFP) while protecting normal cells against off-target lysis. Human colorectal carcinoma (CRC) cell lines as well as human normal colon cell lines were subjected to various starvation regimes and infected with MeV-GFP. The applied fasting regimes were either short-term (24 h pre-infection) or long-term (24 h pre- plus 96 h post-infection). Cell-killing features of (i) virotherapy, (ii) starvation, as well as (iii) the combination of both were analyzed by cell viability assays and virus growth curves. Remarkably, while long-term low-serum, standard glucose starvation potentiated the efficacy of MeV-mediated cell killing in CRC cells, it was found to be decreased in normal colon cells. Interestingly, viral replication of MeV-GFP in CRC cells was decreased in long-term-starved cells and increased after short-term low-glucose, low-serum starvation. In conclusion, starvation-based virotherapy has the potential to differentially enhance MeV-mediated oncolysis in the context of CRC cancer patients while protecting normal colon cells from unwanted off-target effects. Full article
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Review

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20 pages, 5190 KiB  
Review
Viral Pathogenesis, Recombinant Vaccines, and Oncolytic Virotherapy: Applications of the Canine Distemper Virus Reverse Genetics System
by Jianjun Zhao, Yanrong Ren, Jie Chen, Jiasan Zheng and Dongbo Sun
Viruses 2020, 12(3), 339; https://doi.org/10.3390/v12030339 - 20 Mar 2020
Cited by 9 | Viewed by 6949
Abstract
Canine distemper virus (CDV) is a highly contagious pathogen transmissible to a broad range of terrestrial and aquatic carnivores. Despite the availability of attenuated vaccines against CDV, the virus remains responsible for outbreaks of canine distemper (CD) with significant morbidity and mortality in [...] Read more.
Canine distemper virus (CDV) is a highly contagious pathogen transmissible to a broad range of terrestrial and aquatic carnivores. Despite the availability of attenuated vaccines against CDV, the virus remains responsible for outbreaks of canine distemper (CD) with significant morbidity and mortality in domesticated and wild carnivores worldwide. CDV uses the signaling lymphocytic activation molecule (SLAM, or CD150) and nectin-4 (PVRL4) as entry receptors, well-known tumor-associated markers for several lymphadenomas and adenocarcinomas, which are also responsible for the lysis of tumor cells and apparent tumor regression. Thus, CDV vaccine strains have emerged as a promising platform of oncolytic viruses for use in animal cancer therapy. Recent advances have revealed that use of the CDV reverse genetic system (RGS) has helped increase the understanding of viral pathogenesis and explore the development of recombinant CDV vaccines. In addition, genetic engineering of CDV based on RGS approaches also has the potential of enhancing oncolytic activity and selectively targeting tumors. Here, we reviewed the host tropism and pathogenesis of CDV, and current development of recombinant CDV-based vaccines as well as their use as oncolytic viruses against cancers. Full article
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