Brief History and Characterization of Enhanced Respiratory Syncytial Virus Disease

ABSTRACTIn 1967, infants and toddlers immunized with a formalin-inactivated vaccine against respiratory syncytial virus (RSV) experienced an enhanced form of RSV disease characterized by high fever, bronchopneumonia, and wheezing when they became infected with wild-type virus in the community. Hospitalizations were frequent, and two immunized toddlers died upon infection with wild-type RSV. The enhanced disease was initially characterized as a “peribronchiolar monocytic infiltration with some excess in eosinophils.” Decades of research defined enhanced RSV disease (ERD) as the result of immunization with antigens not processed in the cytoplasm, resulting in a nonprotective antibody response and CD4+T helper priming in the absence of cytotoxic T lymphocytes. This response to vaccination led to a pathogenic Th2 memory response with eosinophil and immune complex deposition in the lungs after RSV infection. In recent years, the field of RSV experienced significant changes. Numerous vaccine candidates with novel designs and formulations are approaching clinical trials, defying our previous understanding of favorable parameters for ERD. This review provides a succinct analysis of these parameters and explores criteria for assessing the risk of ERD in new vaccine candidates.

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Recombinant Respiratory Syncytial Virus (RSV) Bearing a Set of Mutations from Cold-Passaged RSV Is Attenuated in Chimpanzees

Journal of Virology ◽

10.1128/jvi.72.5.4467-4471.1998 ◽

1998 ◽

Vol 72 (5) ◽

pp. 4467-4471 ◽

Cited By ~ 62

Author(s):

Stephen S. Whitehead ◽

Katalin Juhasz ◽

Cai-Yen Firestone ◽

Peter L. Collins ◽

Brian R. Murphy

Keyword(s):

Respiratory Syncytial Virus ◽

Recombinant Virus ◽

Wild Type Strain ◽

Nucleotide Sequence Analysis ◽

Missense Mutations ◽

Wild Type ◽

Vaccine Candidates ◽

Rsv Infection ◽

Syncytial Virus

ABSTRACT A set of five missense mutations previously identified by nucleotide sequence analysis of subgroup A cold-passaged (cp) respiratory syncytial virus (RSV) has been introduced into a recombinant wild-type strain of RSV. This recombinant virus, designated rA2cp, appears to replicate less efficiently in the upper and lower respiratory tracts of seronegative chimpanzees than either biologically derived or recombinant wild-type RSV. Infection with rA2cp also resulted in significantly less rhinorrhea and cough than infection with wild-type RSV. These findings confirm the role of thecp mutations in attenuation of RSV and identify their usefulness for inclusion in future live attenuated recombinant RSV vaccine candidates.

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

Virologica Sinica ◽

10.1007/s12250-021-00345-3 ◽

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.

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Fcγ Receptor IIa (FCGR2A) Polymorphism Is Associated With Severe Respiratory Syncytial Virus Disease in Argentinian Infants

Frontiers in Cellular and Infection Microbiology ◽

10.3389/fcimb.2020.607348 ◽

2020 ◽

Vol 10 ◽

Author(s):

María Pía Holgado ◽

Silvina Raiden ◽

Inés Sananez ◽

Vanesa Seery ◽

Leonardo De Lillo ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Virus Disease ◽

Severe Disease ◽

Critical Role ◽

Fcγ Receptor ◽

Factors Associated ◽

Severe Group ◽

Rsv Infection ◽

Syncytial Virus ◽

The Relationship

BackgroundMost patients with respiratory syncytial virus (RSV) infection requiring hospitalization have no risk factors for severe disease. Genetic variation in the receptor for the Fc portion of IgG (FcγR) determines their affinity for IgG subclasses driving innate and adaptive antiviral immunity. We investigated the relationship between FcγRIIa-H131R polymorphism and RSV disease.MethodsBlood samples were collected from 182 infants ≤24-month-old (50 uninfected, 114 RSV-infected with moderate course and 18 suffering severe disease). FcγRIIa-H131R SNP genotypic frequencies (HH, HR, RR) and anti-RSV IgG1, IgG2 and IgG3 levels were studied.ResultsGenotypic frequencies for FcγRIIa-H131R SNP were comparable between uninfected and RSV-infected infants. In contrast, we found a significant higher frequency of HH genotype in severe RSV-infected children compared to moderate patients. Among severe group, HH infants presented more factors associated to severity than HR or RR patients did. Furthermore, compared to moderate RSV-infected infants, severe patients showed higher levels of anti-RSV IgG1 and IgG3.ConclusionsWe found an association between an FcγRIIa (H131) polymorphism and severe RSV disease, which points towards a critical role for interactions between FcγRs and immune complexes in RSV pathogenesis. This genetic factor could also predict the worse outcome and identify those infants at risk during hospitalization.

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Eosinophils contribute to innate antiviral immunity and promote clearance of respiratory syncytial virus

Blood ◽

10.1182/blood-2007-01-071340 ◽

2007 ◽

Vol 110 (5) ◽

pp. 1578-1586 ◽

Cited By ~ 156

Author(s):

Simon Phipps ◽

Chuan En Lam ◽

Suresh Mahalingam ◽

Matthew Newhouse ◽

Ruben Ramirez ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Host Defense ◽

No Production ◽

Wild Type ◽

Interleukin 5 ◽

Virus Clearance ◽

Lung Dysfunction ◽

Rsv Infection ◽

Syncytial Virus

AbstractEosinophils are recruited to the lungs in response to respiratory syncytial virus (RSV) infection; however, their role in promoting antiviral host defense remains unclear. Here, we demonstrate that eosinophils express TLRs that recognize viral nucleic acids, are activated and degranulate after single-stranded RNA (ssRNA) stimulation of the TLR-7–MyD88 pathway, and provide host defense against RSV that is MyD88 dependent. In contrast to wild-type mice, virus clearance from lung tissue was more rapid in hypereosinophilic (interleukin-5 transgenic) mice. Transfer of wild-type but not MyD88-deficient eosinophils to the lungs of RSV-infected wild-type mice accelerated virus clearance and inhibited the development of airways hyperreactivity. Similar responses were observed when infected recipient mice were MyD88 deficient. Eosinophils isolated from infected hypereosinophilic MyD88-sufficient but not MyD88-deficient mice expressed greater amounts of IFN regulatory factor (IRF)–7 and eosinophil-associated ribonucleases EAR-1 and EAR-2. Hypereosinophilia in the airways of infected mice also correlated with increased expression of IRF-7, IFN-β, and NOS-2, and inhibition of NO production with the NOS-2 inhibitor L-NMA partially reversed the accelerated virus clearance promoted by eosinophils. Collectively, our results demonstrate that eosinophils can protect against RSV in vivo, as they promote virus clearance and may thus limit virus-induced lung dysfunction.

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T-HELPER CYTOKINE RESPONSE IN INFANTS WITH EARLY RESPIRATORY SYNCYTIAL VIRUS(RSV) INFECTION. ▴ 1104

Pediatric Research ◽

10.1203/00006450-199604001-01126 ◽

1996 ◽

Vol 39 ◽

pp. 186-186

Author(s):

Debra A Tristram ◽

Kathy Xi ◽

Ezzat Assian ◽

Robert C Welliver

Keyword(s):

Respiratory Syncytial Virus ◽

Cytokine Response ◽

T Helper ◽

Rsv Infection ◽

Syncytial Virus

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Toll-like receptor 4-mediated respiratory syncytial virus disease and lung transcriptomics in differentially susceptible inbred mouse strains

Physiological Genomics ◽

10.1152/physiolgenomics.00101.2019 ◽

2019 ◽

Vol 51 (12) ◽

pp. 630-643 ◽

Cited By ~ 1

Author(s):

Jacqui Marzec ◽

Hye-Youn Cho ◽

Monica High ◽

Zachary R. McCaw ◽

Fernando Polack ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Virus Disease ◽

Inbred Mouse ◽

Dominant Negative ◽

Epidermal Differentiation ◽

Mouse Strains ◽

Toll Like Receptor ◽

Wild Type ◽

Toll Like Receptor 4 ◽

Syncytial Virus

Respiratory syncytial virus (RSV) causes severe lower respiratory tract disease in infants, young children, and susceptible adults. The pathogenesis of RSV disease is not fully understood, although toll-like receptor 4 (TLR4)-related innate immune response is known to play a role. The present study was designed to determine TLR4-mediated disease phenotypes and lung transcriptomics and to elucidate transcriptional mechanisms underlying differential RSV susceptibility in inbred strains of mice. Dominant negative Tlr4 mutant (C3H/HeJ, HeJ, Tlr4Lps-d) and its wild-type (C3H/HeOuJ, OuJ, Tlr4Lps-n) mice and five genetically diverse, differentially responsive strains bearing the wild-type Tlr4Lps-n allele were infected with RSV. Bronchoalveolar lavage, histopathology, and genome-wide transcriptomics were used to characterize the pulmonary response to RSV. RSV-induced lung neutrophilia [1 day postinfection (pi)], epithelial proliferation (1 day pi), and lymphocytic infiltration (5 days pi) were significantly lower in HeJ compared with OuJ mice. Pulmonary RSV expression was also significantly suppressed in HeJ than in OuJ. Upregulation of immune/inflammatory ( Cxcl3, Saa1) and heat shock protein ( Hspa1a, Hsph1) genes was characteristic of OuJ mice, while cell cycle and cell death/survival genes were modulated in HeJ mice following RSV infection. Strain-specific transcriptomics suggested virus-responsive ( Oasl1, Irg1, Mx1) and epidermal differentiation complex ( Krt4, Lce3a) genes may contribute to TLR4-independent defense against RSV in resistant strains including C57BL/6J. The data indicate that TLR4 contributes to pulmonary RSV pathogenesis and activation of cellular immunity, the inflammasome complex, and vascular damage underlies it. Distinct transcriptomics in differentially responsive Tlr4-wild-type strains provide new insights into the mechanism of RSV disease and potential therapeutic targets.

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Immune profiles provide insights into respiratory syncytial virus disease severity in young children

Science Translational Medicine ◽

10.1126/scitranslmed.aaw0268 ◽

2020 ◽

Vol 12 (540) ◽

pp. eaaw0268 ◽

Cited By ~ 7

Author(s):

Santtu Heinonen ◽

Victoria M. Velazquez ◽

Fang Ye ◽

Sara Mertz ◽

Santiago Acero-Bedoya ◽

...

Keyword(s):

Respiratory Syncytial Virus ◽

Disease Severity ◽

Virus Disease ◽

Severe Disease ◽

Mild Disease ◽

Hla Dr ◽

Increased Risk ◽

Determining Factors ◽

Rsv Infection ◽

Syncytial Virus

Respiratory syncytial virus (RSV) is associated with major morbidity in infants, although most cases result in mild disease. The pathogenesis of the disease is incompletely understood, especially the determining factors of disease severity. A better characterization of these factors may help with development of RSV vaccines and antivirals. Hence, identification of a “safe and protective” immunoprofile induced by natural RSV infection could be used as a as a surrogate of ideal vaccine-elicited responses in future clinical trials. In this study, we integrated blood transcriptional and cell immune profiling, RSV loads, and clinical data to identify factors associated with a mild disease phenotype in a cohort of 190 children <2 years of age. Children with mild disease (outpatients) showed higher RSV loads, greater induction of interferon (IFN) and plasma cell genes, and decreased expression of inflammation and neutrophil genes versus children with severe disease (inpatients). Additionally, only infants with severe disease had increased numbers of HLA-DRlow monocytes, not present in outpatients. Multivariable analyses confirmed that IFN overexpression was associated with decreased odds of hospitalization, whereas increased numbers of HLA-DRlow monocytes were associated with increased risk of hospitalization. These findings suggest that robust innate immune responses are associated with mild RSV infection in infants.

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Characterization of a Novel Respiratory Syncytial Virus-Specific Human Cytotoxic T-Lymphocyte Epitope

Journal of Virology ◽

10.1128/jvi.74.16.7694-7697.2000 ◽

2000 ◽

Vol 74 (16) ◽

pp. 7694-7697 ◽

Cited By ~ 41

Author(s):

Philip J. R. Goulder ◽

Franziska Lechner ◽

Paul Klenerman ◽

Kenneth McIntosh ◽

Bruce D. Walker

Keyword(s):

T Cells ◽

Respiratory Syncytial Virus ◽

T Lymphocyte ◽

Cytotoxic T Lymphocyte ◽

Rsv Infection ◽

Syncytial Virus ◽

Restricted Epitope

ABSTRACT Respiratory syncytial virus (RSV) infection is a major cause of morbidity in childhood worldwide. The first human RSV-specific cytotoxic T-lymphocyte epitope to be defined is described. This HLA B7-restricted epitope in nucleoprotein (NP) was detectable in four healthy, B7-positive adult subjects using B7-RSV-NP tetrameric complexes to stain CD8+ T cells.

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The Immunogenicity and Safety of Rsv Vaccines in Development: A Systematic Review

10.20944/preprints202005.0477.v1 ◽

2020 ◽

Author(s):

Jing Shan

Keyword(s):

Systematic Review ◽

Clinical Trials ◽

Respiratory Syncytial Virus ◽

Pregnant Women ◽

Vaccine Candidate ◽

Controlled Vocabulary ◽

Acute Lower Respiratory Infection ◽

Vaccine Candidates ◽

Rsv Infection ◽

Syncytial Virus

Background: Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory infection globally. There are vaccines in pipeline to prevent it but a systematic review on immunogenicity and safety of vaccine is lacking. Methods: This systematic review of RSV vaccine clinical trials was undertaken using 4 databases. Searches were conducted using both controlled vocabulary terms such as ‘Respiratory Syncytial Virus, Human’, ‘Respiratory Syncytial Virus Infections’, ‘Respiratory Syncytial Virus Vaccines’, ‘Immunization’, ‘Immunization Programs’ and ‘Vaccines’ and corresponding text word terms. The searches for published papers were limited to clinical trials published from January 2000 to August 6th, 2018. RSV infection case was defined as RSV associated medically attended acute respiratory illness (MAARI) or RSV infection by serologically-confirmed test (Western Blot) during the RSV surveillance period. We calculated the relative risk of each vaccine trial with RSV infection case. Results: Of 4395 publications, 24 were included and data were extracted covering 4 major types of RSV vaccine candidates, these being live-attenuated/chimeric (n=9), recombinant-vector (n=10), subunit (n=1) and nanoparticle vaccines (n=4). For RSV infection cases, 7 trials were involved and none of them showed a vaccine-related increased MAARI during RSV surveillance season. Conclusion: LID ∆M2-2, MEDI M2-2, and RSVcps2 (live-attenuated) were considered the most promising vaccine candidates in infant and children. In the elderly, a nanoparticle F vaccine candidate was considered as a potential effective vaccine. Although no promising vaccine was identified from pregnant-women test, RSV F-024 subunit vaccine candidate and an RSV F nanoparticle vaccine showed encouraging results in healthy non-pregnant women.

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