A role for immune complexes in enhanced respiratory syncytial virus disease

Abstract

Respiratory syncytial virus (RSV) is the leading cause of bronchiolitis and viral pneumonia in infants and young children. Administration of a formalin inactivated vaccine against RSV to children in the 1960s resulted in increased morbidity and mortality in vaccine recipients who subsequently contracted RSV. This incident precluded development of subunit RSV vaccines for infants for over 30 years, because the mechanism of illness was never clarified. An RSV vaccine for infants is still not available. Here, we demonstrate that enhanced RSV disease is mediated by immune complexes and abrogated in complement component C3 and B cell-deficient mice but not in controls. Further, we show correlation with the enhanced disease observed in children by providing evidence of complement activation in postmortem lung sections from children with enhanced RSV disease.

Figure 1.

Pulmonary histopathology 7 d after RSV challenge in mice that had received the indicated preimmunization (10×). Hematoxylin and eosin (A); immunofluorescence staining for C3 (FITC; B), IgG (rhodamine; C) and colocalization of C3 and IgG (D).

Figure 2.

AHR 7 d after RSV challenge in previously immunized BALB/c mice. AHR to acetylcholine challenge is defined by the time-integrated rise in peak airway pressure. Results are means ± SEM (error bars) of 7–10 animals per group and are representative of two independent experiments. *P < 0.05 compared with placebo, RSV, and FIPIV. **P < 0.05 compared with placebo, RSV, and FIPIV. * vs. **: P = 0.29.

Figure 3.

Hematoxylin and eosin stained pulmonary sections of C3 ET (+/+) and deficient (−/−) mice preimmunized with FIRSV and challenged with RSV.

Figure 4.

AHR 7 d after RSV challenge previously immunized with FIRSV. (A) B6129F2 WT (C3^+/+) and C3 deficient (C3^−/−),*: P < 0.001; and (B) C57BL/10 (B^+/+) and B10 μMT (B^−/−) mice, **: P = 0.009. AHR to acetylcholine challenge is defined by the time-integrated rise in peak airway pressure. Results are means ± SEM (error bars) of 9–12 animals per group and are representative of three independent experiments.

Figure 5.

Deposition of C4d in pulmonary tissue of both patients (1 and 2) who died of ERD in 1967 and control patient (control). Immunohistochemistry staining for C4d (A) and preimmune rabbit sera (B) (reference 18).