title: Co-administration of the broad-spectrum antiviral, brincidofovir (CMX001), with smallpox vaccine does not compromise vaccine protection in mice challenged with ectromelia virus.
abstract: 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.
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Parker
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, United States.
authors.forename: Ryan
authors.initials: R
authors.lastname: Crump
authors.affiliation: Chimerix Inc., 2505 Meridian Parkway, Suite 340, Durham, NC 27713, United States.
authors.forename: Scott
authors.initials: S
authors.lastname: Foster
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, United States.
authors.forename: Hollyce
authors.initials: H
authors.lastname: Hartzler
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, United States.
authors.forename: Ed
authors.initials: E
authors.lastname: Hembrador
authors.affiliation: Chimerix Inc., 2505 Meridian Parkway, Suite 340, Durham, NC 27713, United States.
authors.forename: E Randall
authors.initials: ER
authors.lastname: Lanier
authors.affiliation: Chimerix Inc., 2505 Meridian Parkway, Suite 340, Durham, NC 27713, United States.
authors.forename: George
authors.initials: G
authors.lastname: Painter
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, United States.
authors.forename: Jill
authors.initials: J
authors.lastname: Schriewer
authors.affiliation: Chimerix Inc., 2505 Meridian Parkway, Suite 340, Durham, NC 27713, United States.
authors.forename: Lawrence C
authors.initials: LC
authors.lastname: Trost
authors.affiliation: Saint Louis University School of Medicine, 1100 S. Grand Blvd., St. Louis, MO 63104, United States. Electronic address: mark.buller@gmail.com.
authors.forename: R Mark
authors.initials: RM
authors.lastname: Buller
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D003596:Cytosine / Q000008:administration & dosage / Q000031:analogs & derivatives*; D004481:Ectromelia virus / Q000276:immunology / Q000502:physiology*; D004482:Ectromelia, Infectious / Q000276:immunology / Q000517:prevention & control* / Q000821:virology; D005260:Female; D006801:Humans; D007109:Immunity; D051379:Mice; D008810:Mice, Inbred C57BL; D063065:Organophosphonates / Q000008:administration & dosage*; D012900:Smallpox Vaccine / Q000008:administration & dosage* / Q000276:immunology; D014611:Vaccination; D014779:Virus Replication
chemical_list: D000998:Antiviral Agents; D063065:Organophosphonates; D012900:Smallpox Vaccine; C525733:brincidofovir; D003596:Cytosine
keywords: ACAM2000; ACAM3000; Cidofovir; Dryvax; MVA; Mousepox