scholarly journals Vaccinia virus-based vaccines confer protective immunity against SARS-CoV-2 virus in Syrian hamsters

2021 ◽  
Author(s):  
Rakesh Kulkarni ◽  
Wen-Ching Chen ◽  
Ying Lee ◽  
Chi-Fei Kao ◽  
Shiu-Lok Hu ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Respiratory Illness ◽  
Cold Chain ◽  
Infection Model ◽  
Recombinant Vaccines ◽  
Viral Spread ◽  
Severe Respiratory Illness

COVID-19 in humans is caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that belongs to the beta family of coronaviruses. SARS-CoV-2 causes severe respiratory illness in 10-15% of infected individuals and mortality in 2-3%. Vaccines are urgently needed to prevent infection and to contain viral spread. Although several mRNA- and adenovirus-based vaccines are highly effective, their dependence on the cold chain transportation makes global vaccination a difficult task. In this context, a stable lyophilized vaccine may present certain advantages. Accordingly, establishing additional vaccine platforms remains vital to tackle SARS-CoV-2 and any future variants that may arise. Vaccinia virus (VACV) has been used to eradicate smallpox disease, and several attenuated viral strains with enhanced safety for human applications have been developed. We have generated two candidate SARS-CoV-2 vaccines based on two vaccinia viral strains, MVA and v-NY, that express full-length SARS-CoV-2 spike protein. Whereas MVA is growth-restricted in mammalian cells, the v-NY strain is replication-competent. We demonstrate that both candidate recombinant vaccines induce high titers of neutralizing antibodies in C57BL/6 mice vaccinated according to prime-boost regimens. Furthermore, our vaccination regimens generated TH1-biased immune responses in mice. Most importantly, prime-boost vaccination of a Syrian hamster infection model with MVA-S and v-NY-S protected the hamsters against SARS-CoV-2 infection, supporting that these two vaccines are promising candidates for future development. Finally, our vaccination regimens generated neutralizing antibodies that partially cross-neutralized SARS-CoV-2 variants of concern.

scholarly journals Vaccinia virus-based vaccines confer protective immunity against SARS-CoV-2 virus in Syrian hamsters

PLoS ONE ◽  
2021 ◽  
Vol 16 (9) ◽  
pp. e0257191
Author(s):  
Rakesh Kulkarni ◽  
Wen-Ching Chen ◽  
Ying Lee ◽  
Chi-Fei Kao ◽  
Shiu-Lok Hu ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Respiratory Illness ◽  
Cold Chain ◽  
Infection Model ◽  
Recombinant Vaccines ◽  
Viral Spread ◽  
Severe Respiratory Illness

COVID-19 in humans is caused by Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) that belongs to the beta family of coronaviruses. SARS-CoV-2 causes severe respiratory illness in 10–15% of infected individuals and mortality in 2–3%. Vaccines are urgently needed to prevent infection and to contain viral spread. Although several mRNA- and adenovirus-based vaccines are highly effective, their dependence on the “cold chain” transportation makes global vaccination a difficult task. In this context, a stable lyophilized vaccine may present certain advantages. Accordingly, establishing additional vaccine platforms remains vital to tackle SARS-CoV-2 and any future variants that may arise. Vaccinia virus (VACV) has been used to eradicate smallpox disease, and several attenuated viral strains with enhanced safety for human applications have been developed. We have generated two candidate SARS-CoV-2 vaccines based on two vaccinia viral strains, MVA and v-NY, that express full-length SARS-CoV-2 spike protein. Whereas MVA is growth-restricted in mammalian cells, the v-NY strain is replication-competent. We demonstrate that both candidate recombinant vaccines induce high titers of neutralizing antibodies in C57BL/6 mice vaccinated according to prime-boost regimens. Furthermore, our vaccination regimens generated TH1-biased immune responses in mice. Most importantly, prime-boost vaccination of a Syrian hamster infection model with MVA-S and v-NY-S protected the hamsters against SARS-CoV-2 infection, supporting that these two vaccines are promising candidates for future development. Finally, our vaccination regimens generated neutralizing antibodies that partially cross-neutralized SARS-CoV-2 variants of concern.

scholarly journals Nonglycosylated G-Protein Vaccine Protects against Homologous and Heterologous Respiratory Syncytial Virus (RSV) Challenge, while Glycosylated G Enhances RSV Lung Pathology and Cytokine Levels

2015 ◽  
Vol 89 (16) ◽  
pp. 8193-8205 ◽  
Author(s):  
Sandra Fuentes ◽  
Elizabeth M. Coyle ◽  
Hana Golding ◽  
Surender Khurana
Keyword(s):  
Respiratory Syncytial Virus ◽  
G Protein ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Protective Efficacy ◽  
Lung Pathology ◽  
Content Type ◽  
Viral Loads ◽  
Syncytial Virus

ABSTRACTNew efforts are under way to develop a vaccine against respiratory syncytial virus (RSV) that will provide protective immunity without the potential for vaccine-associated disease enhancement such as that observed in infants following vaccination with formalin-inactivated RSV vaccine. In addition to the F fusion protein, the G attachment surface protein is a target for neutralizing antibodies and thus represents an important vaccine candidate. However, glycosylated G protein expressed in mammalian cells has been shown to induce pulmonary eosinophilia upon RSV infection in a mouse model. In the current study, we evaluated in parallel the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain (amino acids 67 to 298) expressed inEscherichia coli(REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model. Vaccination with REG generated neutralizing antibodies against RSV A2 in 7/11 BALB/c mice, while RMG did not elicit neutralizing antibodies. Total serum binding antibodies against the recombinant proteins (both REG and RMG) were measured by surface plasmon resonance (SPR) and were found to be >10-fold higher for REG- than for RMG-vaccinated animals. Reduction of lung viral loads to undetectable levels after homologous (RSV-A2) and heterologous (RSV-B1) viral challenge was observed in 7/8 animals vaccinated with REG but not in RMG-vaccinated animals. Furthermore, enhanced lung pathology and elevated Th2 cytokines/chemokines were observed exclusively in animals vaccinated with RMG (but not in those vaccinated with REG or phosphate-buffered saline [PBS]) after homologous or heterologous RSV challenge. This study suggests that bacterially produced unglycosylated G protein could be developed alone or as a component of a protective vaccine against RSV disease.IMPORTANCENew efforts are under way to develop vaccines against RSV that will provide protective immunity without the potential for disease enhancement. The G attachment protein represents an important candidate for inclusion in an effective RSV vaccine. In the current study, we evaluated the safety and protective efficacy of the RSV A2 recombinant unglycosylated G protein ectodomain produced inE. coli(REG) and those of glycosylated G produced in mammalian cells (RMG) in a mouse RSV challenge model (strains A2 and B1). The unglycosylated G generated high protective immunity and no lung pathology, even in animals that lacked anti-RSV neutralizing antibodies prior to RSV challenge. Control of viral loads correlated with antibody binding to the G protein. In contrast, the glycosylated G protein provided poor protection and enhanced lung pathology after RSV challenge. Therefore, bacterially produced unglycosylated G protein holds promise as an economical approach to a protective vaccine against RSV.

scholarly journals Differential Antigen Requirements for Protection against Systemic and Intranasal Vaccinia Virus Challenges in Mice

2008 ◽  
Vol 82 (14) ◽  
pp. 6829-6837 ◽  
Author(s):  
David R. Kaufman ◽  
Jaap Goudsmit ◽  
Lennart Holterman ◽  
Bonnie A. Ewald ◽  
Matthew Denholtz ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Recombinant Adenovirus ◽  
Protective Efficacy ◽  
Postexposure Prophylaxis ◽  
Virus Challenge ◽  
Protective Antigens ◽  
A Subunit ◽  
Potential Strategy

ABSTRACT The development of a subunit vaccine for smallpox represents a potential strategy to avoid the safety concerns associated with replication-competent vaccinia virus. Preclinical studies to date with subunit smallpox vaccine candidates, however, have been limited by incomplete information regarding protective antigens and the requirement for multiple boost immunizations to afford protective immunity. Here we explore the protective efficacy of replication-incompetent, recombinant adenovirus serotype 35 (rAd35) vectors expressing the vaccinia virus intracellular mature virion (IMV) antigens A27L and L1R and extracellular enveloped virion (EEV) antigens A33R and B5R in a murine vaccinia virus challenge model. A single immunization with the rAd35-L1R vector effectively protected mice against a lethal systemic vaccinia virus challenge. The rAd35-L1R vector also proved more efficacious than the combination of four rAd35 vectors expressing A27L, L1R, A33R, and B5R. Moreover, serum containing L1R-specific neutralizing antibodies afforded postexposure prophylaxis after systemic vaccinia virus infection. In contrast, the combination of rAd35-L1R and rAd35-B5R vectors was required to protect mice against a lethal intranasal vaccinia virus challenge, suggesting that both IMV- and EEV-specific immune responses are important following intranasal infection. Taken together, these data demonstrate that different protective antigens are required based on the route of vaccinia virus challenge. These studies also suggest that rAd vectors warrant further assessment as candidate subunit smallpox vaccines.

scholarly journals Attenuation of Vaccinia Virus

Acta Naturae ◽  
2015 ◽  
Vol 7 (4) ◽  
pp. 113-121 ◽  
Author(s):  
S. N. Yakubitskiy ◽  
I. V. Kolosova ◽  
R. A. Maksyutov ◽  
S. N. Shchelkunov
Keyword(s):  
Vaccinia Virus ◽  
Vaccine Strain ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Virulence Genes ◽  
Binding Protein ◽  
Smallpox Vaccination ◽  
Lethal Challenge ◽  
Mammalian Cell Cultures ◽  
Genes Encoding

Since 1980, in the post-smallpox vaccination era the human population has become increasingly susceptible compared to a generation ago to not only the variola (smallpox) virus, but also other zoonotic orthopoxviruses. The need for safer vaccines against orthopoxviruses is even greater now. The Lister vaccine strain (LIVP) of vaccinia virus was used as a parental virus for generating a recombinant 1421ABJCN clone defective in five virulence genes encoding hemagglutinin (A56R), the IFN--binding protein (B8R), thymidine kinase (J2R), the complement-binding protein (C3L), and the Bcl-2-like inhibitor of apoptosis (N1L). We found that disruption of these loci does not affect replication in mammalian cell cultures. The isogenic recombinant strain 1421ABJCN exhibits a reduced inflammatory response and attenuated neurovirulence relative to LIVP. Virus titers of 1421ABJCN were 3 lg lower versus the parent VACV LIVP when administered by the intracerebral route in new-born mice. In a subcutaneous mouse model, 1421ABJCN displayed levels of VACV-neutralizing antibodies comparable to those of LIVP and conferred protective immunity against lethal challenge by the ectromelia virus. The VACV mutant holds promise as a safe live vaccine strain for preventing smallpox and other orthopoxvirus infections.

scholarly journals Recombinant Modified Vaccinia Virus Ankara Expressing the Spike Glycoprotein of Severe Acute Respiratory Syndrome Coronavirus Induces Protective Neutralizing Antibodies Primarily Targeting the Receptor Binding Region

2005 ◽  
Vol 79 (5) ◽  
pp. 2678-2688 ◽  
Author(s):  
Zhiwei Chen ◽  
Linqi Zhang ◽  
Chuan Qin ◽  
Lei Ba ◽  
Christopher E. Yi ◽  
...  
Keyword(s):  
Severe Acute Respiratory Syndrome ◽  
Vaccinia Virus ◽  
Receptor Binding ◽  
Mammalian Cells ◽  
Neutralizing Antibodies ◽  
Binding Region ◽  
Major Mechanism ◽  
Modified Vaccinia Virus Ankara ◽  
Viral Vaccine ◽  
Receptor Binding Region

ABSTRACT Immunization with a killed or inactivated viral vaccine provides significant protection in animals against challenge with certain corresponding pathogenic coronaviruses (CoVs). However, the promise of this approach in humans is hampered by serious concerns over the risk of leaking live severe acute respiratory syndrome (SARS) viruses. In this study, we generated a SARS vaccine candidate by using the live-attenuated modified vaccinia virus Ankara (MVA) as a vector. The full-length SARS-CoV envelope Spike (S) glycoprotein gene was introduced into the deletion III region of the MVA genome. The newly generated recombinant MVA, ADS-MVA, is replication incompetent in mammalian cells and highly immunogenic in terms of inducing potent neutralizing antibodies in mice, rabbits, and monkeys. After two intramuscular vaccinations with ADS-MVA alone, the 50% inhibitory concentration in serum was achieved with reciprocal sera dilutions of more than 1,000- to 10,000-fold in these animals. Using fragmented S genes as immunogens, we also mapped a neutralizing epitope in the region of N-terminal 400 to 600 amino acids of the S glycoprotein (S400-600), which overlaps with the angiotensin-converting enzyme 2 (ACE2) receptor-binding region (RBR; S318-510). Moreover, using a recombinant soluble RBR-Fc protein, we were able to absorb and remove the majority of the neutralizing antibodies despite observing that the full S protein tends to induce a broader spectrum of neutralizing activities in comparison with fragmented S proteins. Our data suggest that a major mechanism for neutralizing SARS-CoV likely occurs through blocking the interaction between virus and the cellular receptor ACE2. In addition, ADS-MVA induced potent immune responses which very likely protected Chinese rhesus monkeys from pathogenic SARS-CoV challenge.

scholarly journals A single dose, BCG-adjuvanted SARS-CoV-2 vaccine induces Th1-polarized immunity and high-titre neutralizing antibodies in mice

2020 ◽  
Author(s):  
Claudio Counoupas ◽  
Alberto O. Stella ◽  
Nayan D. Bhattacharyya ◽  
Alice Grey ◽  
Karishma Patel ◽  
...  
Keyword(s):  
Single Dose ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Candidate ◽  
Rapid Development ◽  
Population Level ◽  
High Titre ◽  
Spike Protein ◽  
Cold Chain ◽  
Igg Antibody

AbstractNext-generation vaccines that are safe, effective and with equitable access globally are required to prevent SARS-CoV-2 transmission at a population level. One strategy that has gained significant interest is to ‘repurpose’ existing licensed vaccines for use against COVID-19. In this report, we have exploited the immunostimulatory properties of bacille Calmette-Guérin (BCG), the vaccine for tuberculosis, to develop a SARS-CoV-2-specific and highly immunogenic vaccine candidate. Combination of BCG with a stabilized, trimeric form of the SARS-CoV-2 spike antigen promoted rapid development of virus-specific IgG antibodies in the sera of vaccinated mice, which could be further augmented by the addition of alum. This vaccine formulation, termed BCG:CoVac, induced a Th1-biased response both in terms of IgG antibody subclass and cytokine release by vaccine-specific CD4+ and CD8+ T cells. A single dose of BCG:CoVac was sufficient to induce high-titre SARS-CoV-2 neutralizing antibodies (NAbs) that were detectable as early as 2 weeks post-vaccination; NAb levels were greater than that seen in the sera of SARS-CoV-2-infected individuals. Boosting of BCG:CoVac-primed mice with a heterologous vaccine combination (spike protein plus alum) could further increase SARS-CoV-2 spike protein-specific antibody response. BCG:CoVac would be broadly applicable for all populations susceptible to SARS-CoV-2 infection and in particular could be readily incorporated into current vaccine schedules in countries where BCG is currently used.ImportanceEffective distribution of vaccine to low- and middle-income countries is critical for the control of the COVID-19 pandemic. To achieve this, vaccines must offer effective protective immunity yet should be cheap to manufacture and meet cold chain management requirements. This study describes a unique COVID-19 vaccine candidate, termed BCG:CoVac, that when delivered as a single dose induces potent SARS-CoV-2 specific immunity in mice, particularly through generation of high-titre, anti-viral neutralising antibodies. BCG:CoVac is built on safe and well-characterised vaccine components: 1) the BCG vaccine, used for control of tuberculosis since 1921 which also has remarkable ‘off target’ effects, protecting children and the elderly against diverse respiratory viral infections; 2) Alhydrogel adjuvant (Alum), a low cost, globally accessible vaccine adjuvant with an excellent safety record in humans (part of >20 licensed human vaccines and in use >70 years); 3) Stabilized, trimeric SARS-CoV-2 spike protein, which stimulates immune specificity for COVID-19. Further assessment in humans will determine if BCG:CoVac can impart protective immunity against not only SARS-CoV-2, but also other respiratory infections where BCG has known efficacy.

scholarly journals Attenuated infection by a Pteropine orthoreovirus isolated from an Egyptian fruit bat in Zambia

2021 ◽  
Vol 15 (9) ◽  
pp. e0009768
Author(s):  
Hayato Harima ◽  
Michihito Sasaki ◽  
Yasuko Orba ◽  
Kosuke Okuya ◽  
Yongjin Qiu ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Phylogenetic Analyses ◽  
Respiratory Illness ◽  
Replication Capacity ◽  
Fruit Bats ◽  
Rt Pcr ◽  
Fruit Bat ◽  
Eidolon Helvum ◽  
Severe Respiratory Illness ◽  
Generation Sequencing

Background Pteropine orthoreovirus (PRV) is an emerging bat-borne zoonotic virus that causes severe respiratory illness in humans. Although PRVs have been identified in fruit bats and humans in Australia and Asia, little is known about the prevalence of PRV infection in Africa. Therefore, this study performed an PRV surveillance in fruit bats in Zambia. Methods Egyptian fruit bats (Rousettus aegyptiacus, n = 47) and straw-colored fruit bats (Eidolon helvum, n = 33) captured in Zambia in 2017–2018 were screened for PRV infection using RT-PCR and serum neutralization tests. The complete genome sequence of an isolated PRV strain was determined by next generation sequencing and subjected to BLAST and phylogenetic analyses. Replication capacity and pathogenicity of the strain were investigated using Vero E6 cell cultures and BALB/c mice, respectively. Results An PRV strain, tentatively named Nachunsulwe-57, was isolated from one Egyptian fruit bat. Serological assays demonstrated that 98% of sera (69/70) collected from Egyptian fruit bats (n = 37) and straw-colored fruit bats (n = 33) had neutralizing antibodies against PRV. Genetic analyses revealed that all 10 genome segments of Nachunsulwe-57 were closely related to a bat-derived Kasama strain found in Uganda. Nachunsulwe-57 showed less efficiency in viral growth and lower pathogenicity in mice than another PRV strain, Miyazaki-Bali/2007, isolated from a patient. Conclusions A high proportion of Egyptian fruit bats and straw-colored fruit bats were found to be seropositive to PRV in Zambia. Importantly, a new PRV strain (Nachunsulwe-57) was isolated from an Egyptian fruit bat in Zambia, which had relatively weak pathogenicity in mice. Taken together, our findings provide new epidemiological insights about PRV infection in bats and indicate the first isolation of an PRV strain that may have low pathogenicity to humans.

scholarly journals Protective Immunity in Macaques Vaccinated with a Modified Vaccinia Virus Ankara-Based Measles Virus Vaccine in the Presence of Passively Acquired Antibodies

2000 ◽  
Vol 74 (9) ◽  
pp. 4236-4243 ◽  
Author(s):  
Koert J. Stittelaar ◽  
Linda S. Wyatt ◽  
Rik L. de Swart ◽  
Helma W. Vos ◽  
Jan Groen ◽  
...  
Keyword(s):  
Vaccinia Virus ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Measles Virus ◽  
Wild Type ◽  
Live Attenuated Vaccine ◽  
Cell Responses ◽  
Modified Vaccinia Virus Ankara ◽  
Current Vaccine ◽  
Induced Immunity

ABSTRACT Recombinant modified vaccinia virus Ankara (MVA), encoding the measles virus (MV) fusion (F) and hemagglutinin (H) (MVA-FH) glycoproteins, was evaluated in an MV vaccination-challenge model with macaques. Animals were vaccinated twice in the absence or presence of passively transferred MV-neutralizing macaque antibodies and challenged 1 year later intratracheally with wild-type MV. After the second vaccination with MVA-FH, all the animals developed MV-neutralizing antibodies and MV-specific T-cell responses. Although MVA-FH was slightly less effective in inducing MV-neutralizing antibodies in the absence of passively transferred antibodies than the currently used live attenuated vaccine, it proved to be more effective in the presence of such antibodies. All vaccinated animals were effectively protected from the challenge infection. These data suggest that MVA-FH should be further tested as an alternative to the current vaccine for infants with maternally acquired MV-neutralizing antibodies and for adults with waning vaccine-induced immunity.

scholarly journals Hepatitis C Virus Vaccine Research: Time to Put Up or Shut Up

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1596
Author(s):  
Alex S. Hartlage ◽  
Amit Kapoor
Keyword(s):  
Hepatitis C Virus ◽  
Hepatitis C ◽  
Neutralizing Antibodies ◽  
Protective Immunity ◽  
Vaccine Development ◽  
Human Infection ◽  
Infection Model ◽  
Vaccine Trials ◽  
Viral Vaccine ◽  
Chronic Hcv

Unless urgently needed to prevent a pandemic, the development of a viral vaccine should follow a rigorous scientific approach. Each vaccine candidate should be designed considering the in-depth knowledge of protective immunity, followed by preclinical studies to assess immunogenicity and safety, and lastly, the evaluation of selected vaccines in human clinical trials. The recently concluded first phase II clinical trial of a human hepatitis C virus (HCV) vaccine followed this approach. Still, despite promising preclinical results, it failed to protect against chronic infection, raising grave concerns about our understanding of protective immunity. This setback, combined with the lack of HCV animal models and availability of new highly effective antivirals, has fueled ongoing discussions of using a controlled human infection model (CHIM) to test new HCV vaccine candidates. Before taking on such an approach, however, we must carefully weigh all the ethical and health consequences of human infection in the absence of a complete understanding of HCV immunity and pathogenesis. We know that there are significant gaps in our knowledge of adaptive immunity necessary to prevent chronic HCV infection. This review discusses our current understanding of HCV immunity and the critical gaps that should be filled before embarking upon new HCV vaccine trials. We discuss the importance of T cells, neutralizing antibodies, and HCV genetic diversity. We address if and how the animal HCV-like viruses can be used for conceptualizing effective HCV vaccines and what we have learned so far from these HCV surrogates. Finally, we propose a logical but narrow path forward for HCV vaccine development.

scholarly journals Protective Efficacy of Recombinant Modified Vaccinia Virus Ankara Delivering Middle East Respiratory Syndrome Coronavirus Spike Glycoprotein

2015 ◽  
Vol 89 (16) ◽  
pp. 8651-8656 ◽  
Author(s):  
Asisa Volz ◽  
Alexandra Kupke ◽  
Fei Song ◽  
Sylvia Jany ◽  
Robert Fux ◽  
...  
Keyword(s):  
Middle East ◽  
Vaccinia Virus ◽  
Neutralizing Antibodies ◽  
Protective Efficacy ◽  
Challenge Infection ◽  
Middle East Respiratory Syndrome ◽  
Infection Model ◽  
Safety And Efficacy ◽  
Dipeptidyl Peptidase 4 ◽  
Modified Vaccinia Virus Ankara

Middle East respiratory syndrome coronavirus (MERS-CoV) causes severe respiratory disease in humans. We tested a recombinant modified vaccinia virus Ankara (MVA) vaccine expressing full-length MERS-CoV spike (S) glycoprotein by immunizing BALB/c mice with either intramuscular or subcutaneous regimens. In all cases, MVA-MERS-S induced MERS-CoV-specific CD8+T cells and virus-neutralizing antibodies. Vaccinated mice were protected against MERS-CoV challenge infection after transduction with the human dipeptidyl peptidase 4 receptor. This MERS-CoV infection model demonstrates the safety and efficacy of the candidate vaccine.

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