Contribution of respiratory syncytial virus G antigenicity to vaccine-enhanced illness and the implications for severe disease during primary respiratory syncytial virus infection.
BACKGROUND
Immunization of BALB/c mice with vaccinia virus expressing the G glycoprotein (vvG) of respiratory syncytial virus (RSV) or with formalin-inactivated alum-precipitated RSV (FI-RSV) predisposes for severe illness, type 2 cytokine production and pulmonary eosinophilia after challenge with live RSV. This similar disease profile has led to the proposal that the presence of the G glycoprotein in the FI-RSV preparation was the immunologic basis for the vaccine-associated enhancement of disease observed in the failed clinical trials of the 1960s. However, processes of disease pathogenesis observed in FI-RSV- and vvG-immunized mice suggest that FI-RSV and vvG immunizations induce immune responses of different compositions and requirements that converge to produce similar disease outcomes upon live virus challenge.


METHODS
The potential role of RSV G present in FI-RSV preparations in increasing postimmunization disease severity was explored in mice.


RESULTS
The absence of RSV G or its immunodominant epitope during FI-RSV immunization does not reduce disease severity after RSV challenge. Furthermore although depletion of V beta 14+ T cells during RSV challenge modulates disease in G-primed mice, minimal impact on disease in FI-RSV-immunized mice is observed.


CONCLUSIONS
FI-RSV vaccine-enhanced illness is not attributable to RSV G. Furthermore formulation of a safe and effective RSV vaccine must ensure RSV antigen production, processing and presentation via the endogenous pathways. Thus gene delivery by vector, by DNA or by live attenuated virus are attractive vaccine approaches.
Johnson
Teresa R
TR
Viral Pathogenesis Laboratory, Vaccine Research Center, National Institute of Allergy and Infectious Disease, National Institutes of Health, Bethesda, MD, USA.
Graham
Barney S
BS
D000818:Animals; D000956:Antigens, Viral / Q000032:analysis*; D004195:Disease Models, Animal; D000939:Epitopes; D005260:Female; D006023:Glycoproteins / Q000276:immunology*; D007109:Immunity / Q000502:physiology*; D007114:Immunization; D015847:Interleukin-4 / Q000032:analysis / Q000276:immunology; D016209:Interleukin-8 / Q000032:analysis / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D011657:Pulmonary Eosinophilia / Q000276:immunology; D018357:Respiratory Syncytial Virus Infections / Q000276:immunology*; D012136:Respiratory Syncytial Viruses / Q000145:classification / Q000276:immunology*; D012680:Sensitivity and Specificity; D012720:Severity of Illness Index; D013373:Substance P / Q000032:analysis / Q000276:immunology; D014765:Viral Vaccines / Q000276:immunology* / Q000494:pharmacology
D000956:Antigens, Viral; D000939:Epitopes; D006023:Glycoproteins; D016209:Interleukin-8; D014765:Viral Vaccines; D015847:Interleukin-4; D013373:Substance P