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.
Highlights
Respiratory syncytial virus (RSV), consisting of A and B subtype, is a major causative agent of severe lower respiratory tract disease in infants, young children, and the elderly worldwide
We examined whether immunization of mice with recombinantly modified G protein core fragment (Gcf), deficient in CD4+ T cell epitope, could offer protection against RSV infection while eliminating RSV G glycoprotein (RSVG)-mediated lung immunopathology
We immunized mice with the recombinant wild type Gcf derived from RSV A2, recombinant RSV A2 Gcf with its CD4+ T cell epitope replaced with the corresponding a.a. sequence from RSV B Gcf (AGcf/BCD4), recombinant RSV B Gcf with its CD4+ T cell epitope replaced with the corresponding a.a. sequence from RSV A2 Gcf (BGcf/ACD4), recombinant wild type Gcf derived from RSV B1, Formalin-inactivated RSV (FI-RSV), or CT adjuvant alone
Summary
Respiratory syncytial virus (RSV), consisting of A and B subtype, is a major causative agent of severe lower respiratory tract disease in infants, young children, and the elderly worldwide. FI-RSV caused enhanced respiratory disease hallmarked by pulmonary eosinophilia and predominant Th2 type cytokine response following subsequent RSV infection in individuals who received this vaccine [1,2]. BBG2Na, a subunit vaccine candidate, has shown to elicit immune response in small and large animals and been evaluated in human clinical trials [5,6,7]. Mice vaccinated with rVVG developed enhanced lung disease accompanied by pulmonary eosinophilia following intranasal RSV infection [9,10,11]. Further studies have suggested the induction of Th2-biased CD4+ T cell response concomitant with the secretion of excess Th2 cytokines as the cause of rVVG immunization leading to the enhanced lung disease [9,12,13]
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
