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

• Published in: PloS one 2014-04, Vol.9 (4), p.e94269
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Agricultural biotechnology; Agriculture; Alanine; Animals; Antigenic determinants; Biology and Life Sciences; Blood diseases; Body weight; Body weight loss; CD4 antigen; CD4-Positive T-Lymphocytes - immunology; Children; Cytokines; Eosinophilia; Epitopes; Epitopes, T-Lymphocyte - immunology; Female; Fusion protein; Genetic aspects; Glycoproteins; Immune response; Immunization; Immunoglobulin G; Immunoglobulins; Infants; Infections; Laboratories; Life sciences; Lung diseases; Lymphocytes; Lymphocytes T; Medicine and Health Sciences; Mice; Mucosa; Pharmaceutical sciences; Physiological aspects; Proteins; Research and Analysis Methods; Respiratory syncytial virus; Respiratory Syncytial Virus Vaccines - adverse effects; Respiratory Syncytial Virus Vaccines - immunology; Respiratory tract; Respiratory tract diseases; Safety; Studies; Vaccines; Viral Fusion Proteins - chemistry; Viral Fusion Proteins - immunology; Viral vaccines; Viruses
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0094269

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.