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Published on: July 6, 2013
Adverse effects of cytomegalovirus vaccination in mice
Abstract:
Studies of live attenuated cytomegalovirus (CMV) vaccine have recently been initiated in man. The possibilities of latent infection and disease resulting from reactivation of vaccine virus are major concerns. Because markers for attenuation of tissue culture-passaged mouse CMV (MCMV) exist, studies of potential adverse effects of vaccination were initiated in mice. Plaque-purified MCMV was passed 12 times in cell culture ("vaccine virus") and shown to be attenuated by virtue of loss of lethality and diminished replication in reticuloendothelial organs of normal mice. Although subcutaneous inoculation of 10(5) plaque-forming units of wild virus was lethal for mice immunosuppressed with antilymphocyte serum (18/18 died), "vaccine MCMV" killed only 3/18 (P < 0.05) and was thus shown to be highly attenuated even in immunosuppressed animals. 4 mo after subcutaneous inoculation of vaccine MCMV, no infectious virus was detectable in the tissues of normal C(3)H mice. However, immunosuppression with anti-lymphocyte serum and cortisone caused MCMV reactivation, dissemination, and wide-spread cytomegalic inclusion disease in 19 of 20 animals. Characterization of the reactivating virus recovered from salivary glands indicated that reversion to virulence had occurred. Thus, vaccine MCMV, although markedly attenuated initially, established latent infection, reactivated after immunosuppression, and reverted to virulence, at least in salivary gland tissue. These data from the murine model substantiate the need for careful surveillance and virologic study of patients given experimental CMV vaccine.
Insights
Live attenuated cytomegalovirus (CMV) vaccine showed initial attenuation in mice but established latent infections. Reactivation under immunosuppression led to virulence reversion, highlighting the need for careful patient monitoring.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Live attenuated cytomegalovirus (CMV) vaccines are under investigation.
- Concerns exist regarding latent infection and disease reactivation from vaccine viruses.
- Mouse CMV (MCMV) offers a model for studying vaccine safety due to known attenuation markers.
Purpose of the Study:
- To assess the safety and potential adverse effects of an experimental live attenuated mouse cytomegalovirus (MCMV) vaccine in a murine model.
- To investigate the potential for latent infection, reactivation, and virulence reversion of the attenuated MCMV vaccine.
Main Methods:
- Plaque-purified MCMV underwent 12 passages in cell culture to create "vaccine virus".
- Attenuation was assessed by comparing lethality and replication in reticuloendothelial organs of normal and immunosuppressed mice (using antilymphocyte serum).
- Latent infection and reactivation were studied 4 months post-inoculation, followed by immunosuppression and viral characterization.
Main Results:
- The "vaccine virus" demonstrated significant attenuation, showing reduced lethality and replication compared to wild-type MCMV, even in immunosuppressed mice.
- Despite initial attenuation, latent MCMV infection was established.
- Immunosuppression (antilymphocyte serum and cortisone) induced MCMV reactivation, dissemination, and cytomegalic inclusion disease.
- Reactivated virus from salivary glands showed reversion to virulence.
Conclusions:
- The experimental live attenuated MCMV vaccine, while initially attenuated, establishes latent infections.
- Reactivation under immunosuppressive conditions can lead to the virus reverting to a virulent form.
- These findings underscore the necessity for rigorous surveillance and virologic monitoring in individuals receiving experimental CMV vaccines.
