title: A novel highly reproducible and lethal nonhuman primate model for orthopox virus infection.
abstract: The intentional re-introduction of Variola virus (VARV), the agent of smallpox, into the human population is of great concern due its bio-terroristic potential. Moreover, zoonotic infections with Cowpox (CPXV) and Monkeypox virus (MPXV) cause severe diseases in humans. Smallpox vaccines presently available can have severe adverse effects that are no longer acceptable. The efficacy and safety of new vaccines and antiviral drugs for use in humans can only be demonstrated in animal models. The existing nonhuman primate models, using VARV and MPXV, need very high viral doses that have to be applied intravenously or intratracheally to induce a lethal infection in macaques. To overcome these drawbacks, the infectivity and pathogenicity of a particular CPXV was evaluated in the common marmoset (Callithrix jacchus).A CPXV named calpox virus was isolated from a lethal orthopox virus (OPV) outbreak in New World monkeys. We demonstrated that marmosets infected with calpox virus, not only via the intravenous but also the intranasal route, reproducibly develop symptoms resembling smallpox in humans. Infected animals died within 1-3 days after onset of symptoms, even when very low infectious viral doses of 5x10(2) pfu were applied intranasally. Infectious virus was demonstrated in blood, saliva and all organs analyzed.We present the first characterization of a new OPV infection model inducing a disease in common marmosets comparable to smallpox in humans. Intranasal virus inoculation mimicking the natural route of smallpox infection led to reproducible infection. In vivo titration resulted in an MID(50) (minimal monkey infectious dose 50%) of 8.3x10(2) pfu of calpox virus which is approximately 10,000-fold lower than MPXV and VARV doses applied in the macaque models. Therefore, the calpox virus/marmoset model is a suitable nonhuman primate model for the validation of vaccines and antiviral drugs. Furthermore, this model can help study mechanisms of OPV pathogenesis.
authors.affiliation: Robert Koch-Institut, Berlin, Germany.
authors.forename: Marit
authors.initials: M
authors.lastname: Kramski
authors.forename: Kerstin
authors.initials: K
authors.lastname: Mätz-Rensing
authors.forename: Christiane
authors.initials: C
authors.lastname: Stahl-Hennig
authors.forename: Franz-Josef
authors.initials: FJ
authors.lastname: Kaup
authors.forename: Andreas
authors.initials: A
authors.lastname: Nitsche
authors.forename: Georg
authors.initials: G
authors.lastname: Pauli
authors.forename: Heinz
authors.initials: H
authors.lastname: Ellerbrok
mesh_terms: D000818:Animals; D002144:Callithrix; D015608:Cowpox virus; D004195:Disease Models, Animal; D018155:Orthopoxvirus / Q000472:pathogenicity*; D011213:Poxviridae Infections; D012900:Smallpox Vaccine; D015996:Survival Rate
chemical_list: D012900:Smallpox Vaccine
references.citation: PLoS One. 2009 Sep 03;4(9):e6883
references.pmid: 19727399
references.citation: Virology. 1995 Jan 10;206(1):136-47
references.pmid: 7831769
references.citation: J Virol. 2008 Mar;82(6):3054-60
references.pmid: 18094181
references.citation: Curr Opin Infect Dis. 2004 Apr;17(2):81-9
references.pmid: 15021045
references.citation: Vet Pathol. 2006 Mar;43(2):212-8
references.pmid: 16537943
references.citation: Antiviral Res. 2003 Jan;57(1-2):41-52
references.pmid: 12615302
references.citation: J Infect Dis. 1987 Aug;156(2):293-8
references.pmid: 3036967
references.citation: J Virol. 2005 Oct;79(20):13139-49
references.pmid: 16189015
references.citation: J Virol. 2005 Jun;79(12):7845-51
references.pmid: 15919938
references.citation: J Virol. 2004 May;78(9):4433-43
references.pmid: 15078924
references.citation: Lancet. 2003 May 10;361(9369):1626
references.pmid: 12747889
references.citation: Pharmacol Biochem Behav. 1992 May;42(1):143-53
references.pmid: 1528937
references.citation: Dtsch Arztebl Int. 2009 May;106(19):329-34
references.pmid: 19547733
references.citation: Clin Infect Dis. 2008 May 15;46(10):1555-61
references.pmid: 18419490
references.citation: J Hyg (Lond). 1969 Dec;67(4):609-18
references.pmid: 4982558
references.citation: Epidemiol Infect. 1999 Jun;122(3):455-60
references.pmid: 10459650
references.citation: Future Microbiol. 2007 Feb;2(1):17-34
references.pmid: 17661673
references.citation: J Mol Med (Berl). 1997 Mar;75(3):187-97
references.pmid: 9106075
references.citation: Nat Med. 2005 Jul;11(7):740-7
references.pmid: 15951823
references.citation: Expert Rev Anti Infect Ther. 2006 Apr;4(2):277-89
references.pmid: 16597208
references.citation: Acta Virol. 1976 Oct;20(5):442
references.pmid: 11675
references.citation: J Gen Virol. 2006 Oct;87(Pt 10):2917-2921
references.pmid: 16963750
references.citation: Emerg Infect Dis. 2002 Dec;8(12):1495-6
references.pmid: 12498670
references.citation: Lancet Infect Dis. 2004 Jan;4(1):15-25
references.pmid: 14720564
references.citation: Proc Natl Acad Sci U S A. 1992 Aug 15;89(16):7581-5
references.pmid: 1323844
references.citation: Emerg Infect Dis. 2008 Apr;14(4):670-1
references.pmid: 18394293
references.citation: Br J Dermatol. 1994 Nov;131(5):598-607
references.pmid: 7999588
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15196-200
references.pmid: 15477589
references.citation: Antimicrob Agents Chemother. 2003 Oct;47(10):3275-80
references.pmid: 14506041
references.citation: Eur Neuropsychopharmacol. 2008 May;18(5):383-9
references.pmid: 18222654
references.citation: Clin Med Res. 2003 Apr;1(2):85-6
references.pmid: 15931292
references.citation: Epidemiol Infect. 2000 Jun;124(3):551-62
references.pmid: 10982080
references.citation: Arch Virol. 1986;88(1-2):135-42
references.pmid: 3954598
references.citation: Proc Natl Acad Sci U S A. 2004 Oct 19;101(42):15190-5
references.pmid: 15477590
references.citation: Pediatr Infect Dis J. 1988 Dec;7(12):883-5
references.pmid: 3062564
references.citation: Zentralbl Veterinarmed B. 1991 Aug;38(6):421-31
references.pmid: 1659066
references.citation: N Engl J Med. 2004 Jan 22;350(4):342-50
references.pmid: 14736926
references.citation: Lab Invest. 2001 Dec;81(12):1581-600
references.pmid: 11742030
references.citation: Nature. 2006 Feb 9;439(7077):745-8
references.pmid: 16341204
references.citation: J Virol. 2007 Jun;81(12):6482-90
references.pmid: 17409137
references.citation: Hum Exp Toxicol. 1995 Jan;14(1):146-7
references.pmid: 7748606
references.citation: Antiviral Res. 2000 Sep;47(3):171-7
references.pmid: 10974369
references.citation: Emerg Infect Dis. 2004 Mar;10(3):426-31
references.pmid: 15109408
references.citation: Int J Exp Pathol. 2008 Jun;89(3):171-9
references.pmid: 18460069
references.citation: J Virol. 2006 Jun;80(11):5179-88
references.pmid: 16698998
references.citation: Antiviral Res. 2003 Jan;57(1-2):35-40
references.pmid: 12615301
references.citation: Lancet. 1994 Feb 26;343(8896):543
references.pmid: 7906785