Immunization of Macaques with Formalin-Inactivated Respiratory Syncytial Virus (RSV) Induces Interleukin-13-Associated Hypersensitivity to Subsequent RSV Infection

Abstract

Respiratory syncytial virus (RSV) is a major cause of severe respiratory disease in infants and the elderly. RSV vaccine development has been hampered by results of clinical trials in the 1960s, when formalininactivated whole-RSV preparations adjuvated with alum (FI-RSV) were found to predispose infants for enhanced disease following subsequent natural RSV infection. We have reproduced this apparently immunopathological phenomenon in infant cynomolgus macaques and identified immunological and pathological correlates. Vaccination with FI-RSV induced specific virus-neutralizing antibody responses accompanied by strong lymphoproliferative responses. The vaccine-induced RSV-specific T cells predominantly produced the Th2 cytokines interleukin-13 (IL-13) and IL-5. Intratracheal challenge with a macaque-adapted wild-type RSV 3 months after the third vaccination elicited a hypersensitivity response associated with lung eosinophilia. The challenge resulted in a rapid boosting of IL-13-producing T cells in the FI-RSV-vaccinated animals but not in the FI-measles virus-vaccinated control animals. Two out of seven FI-RSV-vaccinated animals died 12 days after RSV challenge with pulmonary hyperinflation. Surprisingly, the lungs of these two animals did not show overt inflammatory lesions. However, upon vaccination the animals had shown the strongest lymphoproliferative responses associated with the most pronounced Th2 phenotype within their group. We hypothesize that an IL-13-associated asthma-like mechanism resulted in airway hyperreactivity in these animals. This nonhuman primate model will be an important tool to assess the safety of nonreplicating candidate RSV vaccines. Respiratory syncytial virus (RSV) is a member of the familyParamyxoviridae, genus Pneumovirus (3). While associated with relatively mild upper respiratory tract disease in immunocompetent adults, RSV infection is a major cause of severe lower respiratory tract disease in infants, immunocompromised individuals, and the elderly (7). No vaccine against this important pathogen is currently licensed (5). Three major obstacles hamper the development of a safe and effective RSV vaccine. First, the highest RSV-related morbidity and mortality are seen in infants below 6 months of age. A vaccine would therefore have to be effective in the presence of maternally derived RSVspecific virus-neutralizing (VN) antibodies and in children with a relatively immature immune system. Second, natural RSV infection does not induce sustained protective immunity. Therefore, a vaccine should ideally induce a better immune response than natural infection. Both points argue against a classical live attenuated vaccine and favor a subunit vaccine approach. However, development of nonreplicating RSV vaccines has been seriously hampered by a third complication. During vaccine trials in the 1960s, experimental formalin-inactivated whole-RSV (FI-RSV) vaccines were found to predispose infants to enhanced pulmonary disease upon subsequent RSV infection (17). Studies using murine models of RS...

Infant baboons infected with respiratory syncytial virus develop clinical and pathological changes that parallel those of human infants

“…The prolonged duration of signs of lower respiratory tract disease in the infant baboon provides an excellent endpoint to assess the effects of antivirals and vaccines in reducing or preventing RSV-related illness. No other nonhuman primate model has been reported to demonstrate tachypnea or reduced oxygenation following infection with RSV (5,11,17,26,27,30).…”

Kinetics of antiviral CD8 T cell responses during primary and post-vaccination secondary bovine respiratory syncytial virus infection

“…This phenomenon was first observed in a human vaccine trial in the 1960s [4] and was later found to also occur in cattle immunized with formalin-or beta-propriolactone-inactivated bRSV [5,6]. Enhanced disease resulting from immunization with Fl-virus has an immunopathological basis and has now been modeled in hRSV-infected mice [2,[7][8][9] and monkeys [10] and in bRSV-infected cattle [1,[11][12][13]. In mice, immunization with inactivated virus evokes a Th-2 biased CD4 T cell response, which is associated with eosinophilia and clinical symptoms upon challenge [2].…”

The antigenic and genetic variability of bovine respiratory syncytial virus with emphasis on the G protein

“…The underlying mechanism of enhanced disease in FI vaccinated infants a�er subsequent naturally infection is not fully understood. However, the animal model suggests that it was due to strong T-cell priming which predominantly produces Th2 cytokines interleukin-4 (IL-4), IL-5, and IL-13 and induce eosinophilic response (Openshaw et al, 2001;De Swart et al, 2002). Such an unexpected effect of vaccination led to a more detailed study of the immune response to the respiratory syncytial viruses.…”