Natural orthopoxvirus outbreaks such as
vaccinia,
cowpox, cattlepox and buffalopox continue to cause morbidity in the human population. Monkeypox virus remains a significant agent of morbidity and mortality in Africa. Furthermore, monkeypox virus's broad host-range and expanding environs make it of particular concern as an emerging human pathogen. Monkeypox virus and variola virus (the etiological agent of
smallpox) are both potential agents of bioterrorism. The first line response to orthopoxvirus disease is through vaccination with first-generation and second-generation
vaccines, such as Dryvax and
ACAM2000. Although these
vaccines provide excellent protection, their widespread use is impeded by the high level of adverse events associated with vaccination using live, attenuated virus. It is possible that
vaccines could be used in combination with
antiviral drugs to reduce the incidence and severity of
vaccine-associated adverse events, or as a preventive in individuals with uncertain exposure status or
contraindication to vaccination. We have used the intranasal
mousepox (
ectromelia) model to evaluate the efficacy of vaccination with Dryvax or
ACAM2000 in conjunction with treatment using the broad spectrum
antiviral,
brincidofovir (BCV,
CMX001). We found that co-treatment with BCV reduced the severity of vaccination-associated lesion development. Although the immune response to vaccination was quantifiably attenuated, vaccination combined with BCV treatment did not alter the development of full protective immunity, even when administered two days following
ectromelia challenge. Studies with a non-replicating
vaccine,
ACAM3000 (MVA), confirmed that BCV's mechanism of attenuating the immune response following vaccination with live virus was, as expected, by limiting viral replication and not through inhibition of the immune system. These studies suggest that, in the setting of post-exposure prophylaxis, co-administration of BCV with vaccination should be considered a first response to a
smallpox emergency in subjects of uncertain exposure status or as a means of reduction of the incidence and severity of
vaccine-associated adverse events.