Cotton rats previously inoculated with formalin-inactivated RSV were challenged intranasally with live RSV in an attempt to experimentally induce an enhancement of RSV disease similar to that observed following administration of formalin-inactivated RSV vaccine to that observed following administration of formalin-inactivated RSV vaccine to infants 20 years ago. Within 24 hours after infection with RSV cotton rats developed pulmonary lesions that reached a maximum by the fourth day. Histologically the lesions resembled an experimental pulmonary Arthus reaction, although adoptive transfer experiments were not successful in confirming this mechanism. An action of formalin on RSV appears to be responsible for this effect, because live virus or virus heated in the absence of formalin did not induce enhanced immunopathology. Selected epitopes on the F and/or G RSV surface glycoproteins that are involved in inucing neutralizing antibodies were modified so as to reduce or ablate their antigenicity. However, other epitopes on the F and/or G glycoproteins are not ablated by formalin because cotton rats inoculated parenterally with formalin-inactivated vi;rus developed a high level of F and G antibodies measurable by ELISA. At this time the effect of formalin on RSV cannot be localized to either the F or G glycoprotein of RSV. Although the site(s) at which formalin acts to produce its disease enhancing effect has not been identified it is clear formalin-treaated RSV stimulates an unbalanced immune response in which an unusually large proportion of antibodies are directed against non-protective epitopes on RSV F and/or G. Consequently, effective resistance is not provided and the stage is set for an accelerated immune response to non-protective antigenic sites when infection occurs. Whether an accelerated immune response to non-protective epitopes plays a major role in enhancement remains to be determined.
