Respiratory syncytial virus (RSV) is the leading cause of lower respiratory tract infections among infants and young children. The development of a vaccine for RSV has been hindered because of the serious reactions which followed natural infection in trials of a formalin- inactivated RSV (FI-RSV) vaccine in children. Subsequent studies suggested that FI-RSV potentiated the immune response to RSV. The use of rodent models for the safety testing of RSV vaccines has proved controversial. The proposed research will develop a nonhuman primate model of RSV infection and vaccine immunopotentiation in both infant and adult rhesus monkeys. The following mechanism of immunopotentiation is proposed. After immunization with FI-RSV there were responses to viral proteins which were not usually recognized after RSV infection, as shown in Preliminary Studies. In addition, the cellular immune responses were likely different from those that follow a natural RSV infection. Upon subsequent infection these immune responses, coupled with replicating virus in the lungs, are proposed to have resulted in an exaggerated response. We will test three hypotheses: i) Vaccination with FI-RSV stimulates an immune response with prominent reactivity to the internal and matrix proteins of RSV, ii) FI-RSV vaccination stimulates a Th2 type CD4+ T cell response which differs from that following RSV infection, iii) Young animals are more susceptible than older animals to the disease enhancing effect of FI-RSV.
Specific Aim 1. Compare the susceptibility of infant and young adult rhesus monkeys to i) RSV infection and to ii) enhanced pulmonary histopathology when RSV infection occurs after immunization with FI-RSV. We will characterize the clinical, viral, and histopathological features of RSV infection in naive and FI-RSV immunized infant and adult rhesus monkeys.
Specific Aim 2. Compare the immunological parameters following i) infection with RSV and ii) immunization with FI-RSV followed by RSV infection in rhesus monkeys. The immunological evaluation will include measuring systemic and mucosal humoral and cellular immune responses. There is a critical need for the establishment of reliable and well- defined models for the in vivo testing of RSV vaccines. The proposed studies will characterize a nonhuman primate model that offers many unique advantages for the study of human disease, including the similarities in the ontogeny of the immune system in monkeys and humans and the ability to use human reagents for the characterization of immune responses. These studies will extend our understanding of RSV vaccine immunopotentiation and provide a well characterized in vivo model for future studies of RSV vaccines and pathogenesis.
