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Human metapneumovirus: enhanced pulmonary disease in cotton rats immunized with formalin-inactivated virus vaccine
Kevin C Yim1, Rose P Cragin, Marina S Boukhvalova
1Virion Systems, Inc., 9610 Medical Center Drive, Suite 100, Rockville, MD 20850, United States. kevinyim@virionsystems.com
Abstract:
Cotton rats (Sigmodon hispidus) are susceptible to the recently discovered human metapneumovirus (hMPV), an agent closely related to human respiratory syncytial virus. Since certain respiratory syncytial virus vaccines can induce enhanced disease upon viral challenge, we have done similar experiments with hMPV in cotton rats. Young adult cotton rats were vaccinated with a formalin-inactivated preparation of hMPV strain C-85473, or with a mock preparation of the vaccine on day 0 and again on day 28. All animals were challenged intranasally on day 49 with 10(7) TCID50 of the same hMPV strain. Animals were sacrificed on days 4, 7, and 10 post-challenge and lungs were removed for viral quantitation, histopathology, and cytokine mRNA expression analysis (interferon-gamma (IFN-gamma) and interleukin-4 (IL-4)). Although the vaccinated animals showed almost complete protection from viral replication in the lungs (<10(2.0) TCID50 per gram), there was a dramatic increase in the lung pathology, particularly the interstitial pneumonitis and alveolitis with elevated serum neutralizing antibody titer prior to challenge. Cytokine profiles were distinctive from those observed during primary infection and re-infection. The data raise safety concerns for hMPV vaccine preparations.
Insights
Cotton rats vaccinated with an inactivated human metapneumovirus (hMPV) vaccine showed protection from viral replication but experienced enhanced lung pathology. This suggests potential safety concerns for hMPV vaccine development.
Area of Science:
- Virology
- Immunology
- Vaccinology
Background:
- Human metapneumovirus (hMPV) is a respiratory virus related to human respiratory syncytial virus (hRSV).
- Some hRSV vaccines have demonstrated enhanced disease upon viral challenge.
- Cotton rats are a susceptible model for hMPV infection.
Purpose of the Study:
- To investigate the safety and immunogenicity of a formalin-inactivated hMPV vaccine in cotton rats.
- To evaluate vaccine-induced lung pathology and immune responses following hMPV challenge.
Main Methods:
- Cotton rats were vaccinated with inactivated hMPV or a mock preparation.
- Animals were challenged intranasally with live hMPV.
- Lung tissue was analyzed for viral load, histopathology, and cytokine expression (IFN-gamma, IL-4).
Main Results:
- Vaccinated rats exhibited significant protection against viral replication in the lungs.
- Despite viral protection, vaccinated animals showed markedly increased lung pathology, including interstitial pneumonitis and alveolitis.
- Distinct cytokine profiles were observed compared to primary or re-infection.
Conclusions:
- Formalin-inactivated hMPV vaccination in cotton rats leads to enhanced lung pathology despite viral clearance.
- These findings raise safety concerns regarding the development of hMPV vaccines.
- Further research is needed to understand and mitigate vaccine-enhanced disease for hMPV.
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