A respiratory syncytial virus (RSV) F protein nanoparticle vaccine focuses antibody responses to a conserved neutralization domain

2020 ◽  
Vol 5 (47) ◽  
pp. eaba6466 ◽  
Author(s):  
Kurt A. Swanson ◽  
Jennifer N. Rainho-Tomko ◽  
Zachary P. Williams ◽  
Lilibeth Lanza ◽  
Michael Peredelchuk ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Viral Infection ◽  
Rational Design ◽  
Nonhuman Primates ◽  
Antibody Responses ◽  
F Protein ◽  
Syncytial Virus ◽  
Neutralizing Epitopes

A stabilized form of the respiratory syncytial virus (RSV) fusion (F) protein has been explored as a vaccine to prevent viral infection because it presents several potent neutralizing epitopes. Here, we used a structure-based rational design to optimize antigen presentation and focus antibody (Ab) responses to key epitopes on the pre-fusion (pre-F) protein. This protein was fused to ferritin nanoparticles (pre-F-NP) and modified with glycans to mask nonneutralizing or poorly neutralizing epitopes to further focus the Ab response. The multimeric pre-F-NP elicited durable pre-F–specific Abs in nonhuman primates (NHPs) after >150 days and elicited potent neutralizing Ab (NAb) responses in mice and NHPs in vivo, as well as in human cells evaluated in the in vitro MIMIC system. This optimized pre-F-NP stimulated a more potent Ab response than a representative pre-F trimer, DS-Cav1. Collectively, this pre-F vaccine increased the generation of NAbs targeting the desired pre-F conformation, an attribute that facilitates the development of an effective RSV vaccine.

Monoclonal antibody based in vitro potency assay as a predictor of antigenic integrity and in vivo immunogenicity of a Respiratory Syncytial Virus post-fusion F-protein based vaccine

Vaccine ◽  
2018 ◽  
Vol 36 (12) ◽  
pp. 1673-1680
Author(s):  
Matieyendou Didier Djagbare ◽  
Li Yu ◽  
Arun Parupudi ◽  
Jenny Sun ◽  
Melissa L. Coughlin ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Respiratory Syncytial Virus ◽  
Potency Assay ◽  
F Protein ◽  
Syncytial Virus

scholarly journals In Silico Prediction of Multi-Epitopes Vaccine from the Fusion F Protein Against Respiratory Syncytial Virus

2020 ◽  
Vol 5 (2) ◽  
Keyword(s):  
T Cells ◽  
Respiratory Syncytial Virus ◽  
The Elderly ◽  
Population Coverage ◽  
Mhc I ◽  
F Protein ◽  
Mhc Ii ◽  
Syncytial Virus

Respiratory Syncytial Virus (RSV) is the major cause of the lower respiratory tract illness (RTI) in the elderly and in immunocompromised patients and children under 5 years of age. The disease causes deaths of approximately 500 infants each year. Conventional vaccine against the disease demonstrated immunological pitfalls to enhance T-helper responses and developed non-neutralising antibodies. This study aimed to predict epitopes from the fusion F protein of SRV that elicit the immune system and acted as safer efficacious vaccine. A total of 199 strains of RSV were retrieved from the NCBI database. The immune epitope database analysis resources (IEDB) were used for epitopes prediction against B and T cells. The population coverage was also calculated for the proposed epitopes against the whole world. Only two epitopes (441-YVSNK-445 and 440-DYVS-443) successfully passed all B cell prediction tools and demonstrated higher score in Emini and Kolaskar and tongaonker software. Thus were proposed as B cells epitopes. For T cells, a total of 177 epitopes were found to interact with MHC-I alleles. Among them four epitopes (53-YTSVITIEL-61; 250-YMLTNSELL-258, 198-YIDKQLLPI-206, and 450-VSVGNTLYY-458) were proposed since they interacted with the highest number of alleles and the best binding affinity to MHC-1 alleles. Moreover, a total of 397 core epitopes were found to interact with MHC-П alleles. However, the best four core proposed epitopes that interacted with higher number of MHC-II alleles were 217-IETVIEFQQ-226; 250-YMLTNSELL-258; 477-FYDPLVFPS-485 and 505-FIRKSDELL-513. Strikingly the epitope 250-YMLTNSELL-258 successfully interacted with both MHC-1and MHC-П alleles. The population coverage was 48.61% and 99.64% for MHC-I and MHC-II epitopes, respectively, and 100% for all T cells epitopes. Taken together ten epitopes successfully proposed as vaccine candidate against RSV. In vivo and in vitro clinical trials studies are required to elucidate the effectiveness of these epitopes as vaccine.

scholarly journals Evaluation of the Safety and Immune Efficacy of Recombinant Human Respiratory Syncytial Virus Strain Long Live Attenuated Vaccine Candidates

2021 ◽  
Author(s):  
Li-Nan Wang ◽  
Xiang-Lei Peng ◽  
Min Xu ◽  
Yuan-Bo Zheng ◽  
Yue-Ying Jiao ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Gene Deletion ◽  
Human Respiratory Syncytial Virus ◽  
Temperature Sensitive ◽  
T7 Promoter ◽  
Vaccine Candidates ◽  
Rsv Infection ◽  
Syncytial Virus

AbstractHuman respiratory syncytial virus (RSV) infection is the leading cause of lower respiratory tract illness (LRTI), and no vaccine against LRTI has proven to be safe and effective in infants. Our study assessed attenuated recombinant RSVs as vaccine candidates to prevent RSV infection in mice. The constructed recombinant plasmids harbored (5′ to 3′) a T7 promoter, hammerhead ribozyme, RSV Long strain antigenomic cDNA with cold-passaged (cp) mutations or cp combined with temperature-sensitive attenuated mutations from the A2 strain (A2cpts) or further combined with SH gene deletion (A2cptsΔSH), HDV ribozyme (δ), and a T7 terminator. These vectors were subsequently co-transfected with four helper plasmids encoding N, P, L, and M2-1 viral proteins into BHK/T7-9 cells, and the recovered viruses were then passaged in Vero cells. The rescued recombinant RSVs (rRSVs) were named rRSV-Long/A2cp, rRSV-Long/A2cpts, and rRSV-Long/A2cptsΔSH, respectively, and stably passaged in vitro, without reversion to wild type (wt) at sites containing introduced mutations or deletion. Although rRSV-Long/A2cpts and rRSV-Long/A2cptsΔSH displayed  temperature-sensitive (ts) phenotype in vitro and in vivo, all rRSVs were significantly attenuated in vivo. Furthermore, BALB/c mice immunized with rRSVs produced Th1-biased immune response, resisted wtRSV infection, and were free from enhanced respiratory disease. We showed that the combination of ΔSH with attenuation (att) mutations of cpts contributed to improving att phenotype, efficacy, and gene stability of rRSV. By successfully introducing att mutations and SH gene deletion into the RSV Long parent and producing three rRSV strains, we have laid an important foundation for the development of RSV live attenuated vaccines.

scholarly journals Inhibitory Effect of Sargassum fusiforme and Its Components on Replication of Respiratory Syncytial Virus In Vitro and In Vivo

Viruses ◽  
2021 ◽  
Vol 13 (4) ◽  
pp. 548
Author(s):  
Kiramage Chathuranga ◽  
Asela Weerawardhana ◽  
Niranjan Dodantenna ◽  
Lakmal Ranathunga ◽  
Won-Kyung Cho ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Antiviral Agent ◽  
Active Components ◽  
Sargassum Fusiforme ◽  
Antiviral Effects ◽  
Improve Life Expectancy ◽  
Rsv Infection ◽  
Syncytial Virus

Sargassum fusiforme, a plant used as a medicine and food, is regarded as a marine vegetable and health supplement to improve life expectancy. Here, we demonstrate that S. fusiforme extract (SFE) has antiviral effects against respiratory syncytial virus (RSV) in vitro and in vivo mouse model. Treatment of HEp2 cells with a non-cytotoxic concentration of SFE significantly reduced RSV replication, RSV-induced cell death, RSV gene transcription, RSV protein synthesis, and syncytium formation. Moreover, oral inoculation of SFE significantly improved RSV clearance from the lungs of BALB/c mice. Interestingly, the phenolic compounds eicosane, docosane, and tetracosane were identified as active components of SFE. Treatment with a non-cytotoxic concentration of these three components elicited similar antiviral effects against RSV infection as SFE in vitro. Together, these results suggest that SFE and its potential components are a promising natural antiviral agent candidate against RSV infection.

scholarly journals Shifting immunodominance pattern of two cytotoxic T-lymphocyte epitopes in the F glycoprotein of the Long strain of respiratory syncytial virus

2004 ◽  
Vol 85 (11) ◽  
pp. 3229-3238 ◽  
Author(s):  
Carolina Johnstone ◽  
Patricia de León ◽  
Francisco Medina ◽  
José A. Melero ◽  
Blanca García-Barreno ◽  
...  
Keyword(s):  
Respiratory Syncytial Virus ◽  
Vaccinia Virus ◽  
T Lymphocyte ◽  
Cytotoxic T Lymphocyte ◽  
Recombinant Vaccinia Virus ◽  
Recombinant Vaccinia ◽  
F Protein ◽  
Syncytial Virus ◽  
Lymphocyte Responses

Human respiratory syncytial virus (RSV) is a major cause of respiratory infection in children and in the elderly. The RSV fusion (F) glycoprotein has long been recognized as a vaccine candidate as it elicits cytotoxic T-lymphocyte (CTL) and antibody responses. Two murine H-2Kd-restricted CTL epitopes (F85–93 and F92–106) are known in the F protein of the A2 strain of RSV. F-specific CTL lines using BCH4 fibroblasts that are persistently infected with the Long strain of human RSV as stimulators were generated, and it was found that in this strain only the F85–93 epitope is conserved. Motif based epitope prediction programs and an F2 chain deleted F protein encoded in a recombinant vaccinia virus enabled identification of a new epitope in the Long strain, F249–258, which is presented by Kd as a 9-mer (TYMLTNSEL) or a 10-mer (TYMLTNSELL) peptide. The results suggest that the 10-mer might be a naturally processed endogenous Kd ligand. The CD8+ T-lymphocyte responses to epitopes F85–93 and F249–258 present in the F protein of RSV Long were found to be strongly skewed to F85–93 in in vitro multispecific CTL lines and in vivo during a secondary response to a recombinant vaccinia virus that expresses the entire F protein. However, no hierarchy in CD8+ T-lymphocyte responses to F85–93 and F249–258 epitopes was observed in vivo during a primary response.

scholarly journals In Vitro and In Vivo Fitness of Respiratory Syncytial Virus Monoclonal Antibody Escape Mutants

2006 ◽  
Vol 80 (23) ◽  
pp. 11651-11657 ◽  
Author(s):  
Xiaodong Zhao ◽  
Enmei Liu ◽  
Fu-Ping Chen ◽  
Wayne M. Sullender
Keyword(s):  
Cell Culture ◽  
Monoclonal Antibody ◽  
Respiratory Syncytial Virus ◽  
Viral Population ◽  
Nucleotide Substitutions ◽  
Cotton Rats ◽  
Syncytial Virus ◽  
In Vivo Growth

ABSTRACT Respiratory syncytial virus (RSV) is the only infectious disease for which a monoclonal antibody (MAb) is used in humans. Palivizumab (PZ) is a humanized murine MAb to the F protein of RSV. PZ-resistant viruses appear after in vitro and in vivo growth of RSV in the presence of PZ. Fitness for replication could be a determinant of the likelihood of dissemination of resistant viruses. We assessed the fitness of two PZ-resistant viruses (F212 and MP4). F212 grew less well in cell culture than the parent A2 virus and was predicted to be less fit than A2. Equal amounts of F212 and A2 were mixed and passaged in cell culture. F212 disappeared from the viral population, indicating it was less fit than the A2 virus. The MP4 virus grew as well as A2 in culture and in cotton rats. A2/MP4 virus input ratios of 1:1, 10:1, 100:1, and 1,000:1 were compared in competitive replication. For all input ratios except 1,000:1, the MP4 virus became dominant, supplanting the A2 virus. The MP4 virus also dominated the A2 virus during growth in cotton rats. Thus, the mutant MP4 virus was more fit than A2 virus in both in vitro and in vivo competitive replication. Whether this fitness difference was due to the identified nucleotide substitutions in the F gene or to mutations elsewhere in the genome is unknown. Understanding the mechanisms by which mutant virus fitness increased or decreased could prove useful for consideration in attenuated vaccine design efforts.

scholarly journals Exacerbation of Influenza A Virus Disease Severity by Respiratory Syncytial Virus Co-Infection in a Mouse Model

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1630 ◽  
Author(s):  
Junu A. George ◽  
Shaikha H. AlShamsi ◽  
Maryam H. Alhammadi ◽  
Ahmed R. Alsuwaidi
Keyword(s):  
T Cells ◽  
Respiratory Syncytial Virus ◽  
Influenza A Virus ◽  
Influenza A ◽  
Immune Cell ◽  
Virus Disease ◽  
Viral Loads ◽  
Syncytial Virus

Influenza A virus (IAV) and respiratory syncytial virus (RSV) are leading causes of childhood infections. RSV and influenza are competitive in vitro. In this study, the in vivo effects of RSV and IAV co-infection were investigated. Mice were intranasally inoculated with RSV, with IAV, or with both viruses (RSV+IAV and IAV+RSV) administered sequentially, 24 h apart. On days 3 and 7 post-infection, lung tissues were processed for viral loads and immune cell populations. Lung functions were also evaluated. Mortality was observed only in the IAV+RSV group (50% of mice did not survive beyond 7 days). On day 3, the viral loads in single-infected and co-infected mice were not significantly different. However, on day 7, the IAV titer was much higher in the IAV+RSV group, and the RSV viral load was reduced. CD4 T cells were reduced in all groups on day 7 except in single-infected mice. CD8 T cells were higher in all experimental groups except the RSV-alone group. Increased airway resistance and reduced thoracic compliance were demonstrated in both co-infected groups. This model indicates that, among all the infection types we studied, infection with IAV followed by RSV is associated with the highest IAV viral loads and the most morbidity and mortality.

scholarly journals Assessing Uncertainty in A2 Respiratory Syncytial Virus Viral Dynamics

2015 ◽  
Vol 2015 ◽  
pp. 1-9 ◽  
Author(s):  
Gilberto González-Parra ◽  
Hana M. Dobrovolny
Keyword(s):  
Respiratory Syncytial Virus ◽  
Human Subjects ◽  
Respiratory Illness ◽  
The United States ◽  
Viral Kinetics ◽  
Phase Duration ◽  
Syncytial Virus ◽  
Parameter Values

Respiratory syncytial virus (RSV) is the most common cause of bronchiolitis and pneumonia in children younger than 1 year of age in the United States. Moreover, RSV is being recognized more often as a significant cause of respiratory illness in older adults. Although RSV has been studied both clinically and in vitro, a quantitative understanding of the infection dynamics is still lacking. In this paper, we study the effect of uncertainty in the main parameters of a viral kinetics model of RSV. We first characterize the RSV replication cycle and extract parameter values by fitting the mathematical model to in vivo data from eight human subjects. We then use Monte Carlo numerical simulations to determine how uncertainty in the parameter values will affect model predictions. We find that uncertainty in the infection rate, eclipse phase duration, and infectious lifespan most affect the predicted dynamics of RSV. This study provides the first estimate of in vivo RSV infection parameters, helping to quantify RSV dynamics. Our assessment of the effect of uncertainty will help guide future experimental design to obtain more precise parameter values.

scholarly journals Induction of high-mobility group Box-1 in vitro and in vivo by respiratory syncytial virus

2018 ◽  
Vol 83 (5) ◽  
pp. 1049-1056 ◽  
Author(s):  
Sara Manti ◽  
Terri J Harford ◽  
Carmelo Salpietro ◽  
Fariba Rezaee ◽  
Giovanni Piedimonte
Keyword(s):  
Respiratory Syncytial Virus ◽  
High Mobility ◽  
High Mobility Group ◽  
Syncytial Virus
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