Development of safe and effective RSV vaccine by modified CD4 epitope in G protein core fragment (Gcf)

PLoS One. 2014 Apr 15;9(4):e94269. doi: 10.1371/journal.pone.0094269. eCollection 2014.

Abstract

Respiratory syncytial virus (RSV) is a major cause of respiratory tract infection in infants and young children worldwide, but currently no safe and effective vaccine is available. The RSV G glycoprotein (RSVG), a major attachment protein, is an important target for the induction of protective immune responses during RSV infection. However, it has been thought that a CD4+ T cell epitope (a.a. 183-195) within RSVG is associated with pathogenic pulmonary eosinophilia. To develop safe and effective RSV vaccine using RSV G protein core fragment (Gcf), several Gcf variants resulting from modification to CD4+ T cell epitope were constructed. Mice were immunized with each variant Gcf, and the levels of RSV-specific serum IgG were measured. At day 4 post-challenge with RSV subtype A or B, lung viral titers and pulmonary eosinophilia were determined and changes in body weight were monitored. With wild type Gcf derived from RSV A2 (wtAGcf), although RSV A subtype-specific immune responses were induced, vaccine-enhanced disease characterized by excessive pulmonary eosinophil recruitment and body weight loss were evident, whereas wtGcf from RSV B1 (wtBGcf) induced RSV B subtype-specific immune responses without the signs of vaccine-enhanced disease. Mice immunized with Th-mGcf, a fusion protein consisting CD4+ T cell epitope from RSV F (F51-66) conjugated to mGcf that contains alanine substitutions at a.a. position 185 and 188, showed higher levels of RSV-specific IgG response than mice immunized with mGcf. Both wtAGcf and Th-mGcf provided complete protection against RSV A2 and partial protection against RSV B. Importantly, mice immunized with Th-mGcf did not develop vaccine-enhanced disease following RSV challenge. Immunization of Th-mGcf provided protection against RSV infection without the symptom of vaccine-enhanced disease. Our study provides a novel strategy to develop a safe and effective mucosal RSV vaccine by manipulating the CD4+ T cell epitope within RSV G protein.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CD4-Positive T-Lymphocytes / immunology*
  • Epitopes, T-Lymphocyte / immunology*
  • Female
  • Mice
  • Respiratory Syncytial Virus Vaccines / adverse effects
  • Respiratory Syncytial Virus Vaccines / immunology*
  • Safety*
  • Viral Fusion Proteins / chemistry*
  • Viral Fusion Proteins / immunology*

Substances

  • Epitopes, T-Lymphocyte
  • G glycoprotein, Respiratory syncytial virus
  • Respiratory Syncytial Virus Vaccines
  • Viral Fusion Proteins

Grants and funding

This work was supported by Top Brand Project grant from Korea Research Council of Fundamental Science and Technology and KRIBB Initiative program (KGM0821113) and the National Research Foundation of Korea Grant funded by the Korean Government (2013K1A2A1058638). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.