Abstract
BackgroundIn an event of a smallpox outbreak in humans, the window for efficacious treatment by vaccination with vaccinia viruses (VACV) is believed to be limited to the first few days post-exposure (p.e.). We recently demonstrated in a mouse model for human smallpox, that active immunization 2–3 days p.e. with either VACV-Lister or modified VACV Ankara (MVA) vaccines, can rescue animals from lethal challenge of ectromelia virus (ECTV), the causative agent of mousepox. The present study was carried out in order to determine whether a single dose of the anti-viral cidofovir (CDV), administered at different times and doses p.e. either alone or in conjunction with active vaccination, can rescue ECTV infected mice.MethodsAnimals were infected intranasally with ECTV, treated on different days with various single CDV doses and monitored for morbidity, mortality and humoral response. In addition, in order to determine the influence of CDV on the immune response following vaccination, both the "clinical take”, IFN-gamma and IgG Ab levels in the serum were evaluated as well as the ability of the mice to withstand a lethal challenge of ECTV. Finally the efficacy of a combined treatment regime of CDV and vaccination p.e. was determined.ResultsA single p.e. CDV treatment is sufficient for protection depending on the initiation time and dose (2.5 – 100 mg/kg) of treatment. Solid protection was achieved by a low dose (5 mg/kg) CDV treatment even if given at day 6 p.e., approximately 4 days before death of the control infected untreated mice (mean time to death (MTTD) 10.2). At the same time point complete protection was achieved by single treatment with higher doses of CDV (25 or 100 mg/kg). Irrespective of treatment dose, all surviving animals developed a protective immune response even when the CDV treatment was initiated one day p.e.. After seven days post treatment with the highest dose (100 mg/kg), virus was still detected in some organs (e.g. lung and liver) yet all animals survived, suggesting that efficacious single CDV treatment requires a potent immune system. The combination of CDV and vaccination provided no additional protection over CDV alone. Yet, combining CDV and vaccination maintained vaccination efficacy.ConclusionsAltogether, our data substantiate the feasibility of single post-exposure antiviral treatment to face orthopoxvirus infection.
Highlights
Smallpox, a human disease caused by variola virus (VARV), was associated throughout the history with pandemics involving profound illness and mortality
Infection of mice with Ectromelia virus (ECTV), the causative agent of the highly virulent and contagious mousepox disease, is considered today as one of the most relevant small animal models for smallpox. This is mainly due to the facts that a) like VARV the human pathogen, ectromelia virus (ECTV) is a natural mouse pathogen, b) it has a low respiratory lethal dose (1–100 plaque forming units), c) the disease duration in the mouse (7–12 days) is accelerated compared to human smallpox (18–22 days) but still on a time scale that better simulates smallpox disease in humans than other animal models, and d) both viruses can be detected in respiratory gases during pre-exanthem period and induce rash [7,9,10,11,12]
Post-exposure treatment with a single dose of cidofovir In order to evaluate the efficacy of single dose treatment, an established mouse model of ECTV infection was used [7]
Summary
A human disease caused by variola virus (VARV), was associated throughout the history with pandemics involving profound illness and mortality. The feasibility of therapeutic p.e. vaccination was reevaluated in various animal models for various lethal orthopoxviruses using conventional and new generation vaccines [6,7,8] These studies highlighted the importance of adequate animal models and a relevant virus which could simulate the long incubation period in humans and allow for the development of productive immune response p.e. Infection of mice with Ectromelia virus (ECTV), the causative agent of the highly virulent and contagious mousepox disease, is considered today as one of the most relevant small animal models for smallpox. We recently demonstrated in a mouse model for human smallpox, that active immunization 2–3 days p.e. with either VACV-Lister or modified VACV Ankara (MVA) vaccines, can rescue animals from lethal challenge of ectromelia virus (ECTV), the causative agent of mousepox. The present study was carried out in order to determine whether a single dose of the anti-viral cidofovir (CDV), administered at different times and doses p.e. either alone or in conjunction with active vaccination, can rescue ECTV infected mice
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
