Development of Safe and Effective RSV Vaccine by Modified CD4 Epitope in G Protein Core Fragment (Gcf)

Cheon, In Su; Shim, Byoung-Shik; Park, Sung-Moo; Choi, Youngjoo; Jang, Ji Eun; Jung, Dae Im; Kim, Jae-Ouk; Chang, Jun; Yun, Cheol‐Heui; Song, Man Ki

doi:10.1371/journal.pone.0094269

Cited by 9 publications

(13 citation statements)

References 36 publications

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“…Both IFN-γ- and IL-17A-expressing cells were significantly fewer following RSV B G peptide stimulation (Fig 5B) as compared to those seen following RSV A2 G peptide stimulation after RSV A challenge (Fig 4B). These results indicate that a.a. residues 183–195 of the RSV B G protein do not play roles as CD4 + T-cell epitopes, as previously reported [29]. Consequently, CD4 T-cell responses for the RSV B subtype were not found in our study.…”

Section: Resultssupporting

confidence: 71%

“…It was previously shown that a.a. residues 183–195 of GcfA functions as a CD4 T-cell epitope that is necessary for induction of a strong antibody response, while the same region of GcfB lacks T-cell epitope functionality and induces a relatively weak antibody response [29]. Thus, we reasoned that fusion of the GcfA sequence to the GcfB sequence might simultaneously provoke T-cell activity against both GcfA and GcfB, and thus, that immunization with the GcfAB fusion antigen might induce strong humoral responses against both subtypes.…”

Section: Resultsmentioning

confidence: 99%

“…We previously demonstrated that GcfA or GcfB-immune mice vaccinated via mucosal routes induced subtype-specific humoral immune responses involving serum IgG and mucosal IgA antibodies [28, 29]. Because GcfAB is composed of two RSV subtype G central domains, we expected to induce humoral immunity against both RSV subtypes in GcfAB-immune mice.…”

Section: Discussionmentioning

confidence: 99%

“…We designed a recombinant fusion protein, GcfAB, using the pET-21d-GcfA and pET-21d-GcfB expression plasmid, which have been previously described [28, 29]. The coding sequence of the RSV B G protein from amino acid residues 131–230 of the RSV B1 subtype was amplified with the forward primer () and the reverse primer () by PCR using the pET-21d-GcfB expression plasmid as the template.…”

Section: Methodsmentioning

confidence: 99%

“…Immunization with the Gcf subunit vaccine, which consists of the RSV G core fragment (a.a 131–230) and CT as an adjuvant, also induced humoral immune responses, especially when administered intranasally; intranasal administration induced a greater mucosal IgA response than did intramuscular injection [28]. Furthermore, sublingual immunization with wtBGcf, which consists of the G core fragment (a.a. 131–230) from RSV B1, elicited RSV B G-specific humoral antibody responses without inducing eosinophil recruitment upon RSV B subtype infection [29]. …”

Section: Introductionmentioning

confidence: 99%

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Universal vaccine against respiratory syncytial virus A and B subtypes

Lee¹,

Chang²

2017

PLoS ONE

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Respiratory syncytial virus (RSV) is a major cause of acute lower respiratory tract infection in infants, young children, and the elderly. Two subtypes of RSV, A and B, circulate alternately at 1-2-year intervals during epidemics. The attachment glycoprotein (G protein) of RSV is one of the major targets for immune responses. In this study, we generated a recombinant fusion protein, GcfAB, which consists of the central regions (a.a. residues 131–230) of the G proteins of both RSV A (A2 strain) and B (B1 strain) subtypes, and investigated immunogenicity, protective efficacy, and immunopathology. We immunized mice with GcfAB plus cholera toxin as a mucosal adjuvant via intranasal (IN) or sublingual (SL) routes. The IN group showed higher levels of RSV G-specific antibody responses, including serum IgG and mucosal IgA, compared with the SL group. On the contrary, more vigorous RSV G-specific CD4+ T-cell responses were elicited in the SL group than in the IN group after RSV-A but not RSV-B viral challenge. Furthermore, the SL group showed more pulmonary eosinophil recruitment and body weight loss than did the IN group after RSV-A challenge. Both IN and SL immunization with GcfAB provided potential protection against both subtypes of infections. Together, these results suggest that vaccination with GcfAB via an IN route could be a universal vaccine regimen preventing both RSV A and B infections.

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Section: Resultssupporting

confidence: 71%

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Universal vaccine against respiratory syncytial virus A and B subtypes

Lee¹,

Chang²

2017

PLoS ONE

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Respiratory syncytial virus F and G protein core fragments fused to HBsAg-binding protein (SBP) induce a Th1-dominant immune response without vaccine-enhanced disease

Khan

Ahmad

Zhang

et al. 2018

International Immunology

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The induction of a dominant Th2-type response is the main cause of harmful inflammation in respiratory syncytial virus (RSV) vaccine trials. A balanced Th1 versus Th2 immune response is needed for a safe and effective RSV vaccine. In this study, we evaluated the potential of a recombinant protein SBP-FG as a vaccine candidate with the main focus on shifting the harmful Th2 response to a Th1 response. SBP-FG consists of epitopes from RSV fusion (F) and attachment (G) proteins conjugated to the N-terminus of HBsAg-binding protein (SBP). SBP-FG induced significantly stronger immune responses assessed at the level of total IgG, IgA and neutralizing antibodies as compared with formalin-inactivated RSV (FI-RSV) and live RSV. Analysis of IgG isotypes, lung cytokines and T helper cells showed that SBP-FG induced a dominant Th1-type response. Further, SBP-FG immunized mice showed significantly reduced lung eosinophilia, reduced viral multiplication in lungs after challenge infection and provided protection against RSV infection. These results suggest that SBP-FG can be developed into a safe and effective vaccine against RSV. However, more studies are required to further evaluate SBP-FG as a potent vaccine candidate against RSV.

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Analysis of Human RSV Immunity at the Molecular Level: Learning from the Past and Present

et al. 2015

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Human RSV is one of the most prevalent viral pathogens of early childhood for which no vaccine is available. Herein we provide an analysis of RSV epitope data to examine its application to vaccine design and development. Our objective was to provide an overview of antigenic coverage, identify critical antibody and T cell determinants, and then analyze the cumulative RSV epitope data from the standpoint of functional responses using a combinational approach to characterize antigenic structure and epitope location. A review of the cumulative data revealed, not surprisingly, that the vast majority of epitopes have been defined for the two major surface antigens, F and G. Antibody and T cell determinants have been reported from multiple hosts, including those from human subjects following natural infection, however human data represent a minority of the data. A structural analysis of the major surface antigen, F, showed that the majority of epitopes defined for functional antibodies (neutralizing and/or protective) were either shown to bind pre-F or to be accessible in both pre- and post-F forms. This finding may have has implications for on-going vaccine design and development. These interpretations are in agreement with previous work and can be applied in the larger context of functional epitopes on the F protein. It is our hope that this work will provide the basis for further RSV-specific epitope discovery and investigation into the nature of antigen conformation in immunogenicity.

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Development of Safe and Effective RSV Vaccine by Modified CD4 Epitope in G Protein Core Fragment (Gcf)

Cited by 9 publications

References 36 publications

Universal vaccine against respiratory syncytial virus A and B subtypes

Universal vaccine against respiratory syncytial virus A and B subtypes

Respiratory syncytial virus F and G protein core fragments fused to HBsAg-binding protein (SBP) induce a Th1-dominant immune response without vaccine-enhanced disease

Analysis of Human RSV Immunity at the Molecular Level: Learning from the Past and Present

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