Division of High-Consequence Pathogens and Pathology




1. DHCPP Molecular Analysis of RNA Viruses Associated with Hemorrhagic Fevers and Hantavirus Pulmonary Syndrome

S. T. Nichol 

With the recent emergence of hantavirus pulmonary syndrome in the United States and the dramatic reemergences of Ebola virus in Africa, a tremendous amount of interest and research activity has been focused on these and related RNA viruses. The molecular biology section of the Special Pathogens Branch has an active program that uses molecular biology approaches to investigate disease outbreaks and to analyze mechanisms of replication, maintenance, and transmission of bunyaviruses, filoviruses, and arenaviruses. Excellent opportunities exist for collaborative studies with other scientists within CDC and also with other U.S. and international collaborators. 

References

Nichol, S. T., C. F. Spiropoulou, S. Morzunov, P. E. Rollin, T.G. Ksiazek, H. Feldmann, A. Sanchez, S. Zaki, J. Childs, and C. J. Peters. 1993. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 262:914-917.

Sanchez, A., S. Trappier, B. W. J. Mahy, C. J. Peters, and S. T. Nichol. 1996. The spike glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing. Proc. Natl. Acad. Sci. USA 93:3602-3607. 


2. DHCPP Discovery and Validation of Molecular Markers of HPV Persistence and Cervical Neoplasia

E. R. Unger

The major HPV-associated public health problem is cervical cancer and cervical cancer precursor lesions (cervical intraepithelial neoplasia [CIN] 2 or 3). Certain types of HPV are recognized as carcinogenic based on their consistent epidemiologic association with cervical cancer and plausible biologic mechanisms. The important public health questions about HPV have shifted from documenting HPV as a risk factor for cervical cancer to translating that knowledge into vaccination strategies to reduce the burden of cervical cancer and cancer precursor lesions. Cervical cancer screening cannot be abandoned as current vaccines do not cover all carcinogenic types.  Current screening methods incorporate HPV testing and are very sensitive but lack specificity.  This results in unnecessary follow-up and procedures in many women.  More efficient screening methods are needed to make vaccination more cost effective.  In collaboration with NCI’s Early Detection Research Network (http://edrn.nci.nih.gov/)¬ we have established a biorepository for cervical cancer biomarker discovery and validation.  Blood, exfoliated cervical cells, and cervical mucous samples are linked to clinical-epidemiological data as well as HPV and cervical disease status.  Studies using protein and gene expression profiling are underway.  Alterations in protein glycosylation as well as DNA methylation and acetylation are being investigated

3. DHCPP Genetic Diversity of Poxviruses and Ecologic Factors for Zoonotic Transmission

D. Carroll, Y. Li, M. Reynolds, Kevin L. Karem, I. Damon  

Poxviruses which affect humans are largely zoonotic infections. The evolutionary pressures on these viruses, via interaction with their host(s) are of considerable interest, and currently under investigation at the CDC Poxvirus Program. The past decade has seen the continued emergence of poxviruses as zoonotic emerging diseases of humans. Monkeypox, cowpox and vaccinia-like viruses have caused outbreaks in Africa, the US, Europe, and South America. The use of molecular techniques and informatics allow for continued phylogenetic and evolutionary analysis. Materials from both primary investigations and laboratory experiments may be used for analysis of the effects of various selective pressures. Genetic relationships can be defined and modeled based on these data. These genetic relationships may also be related to specific zoonotic species that transmit the viruses to other hosts, including humans. Ecology-based models of reservoir habitat and subsequent human disease allow predictive power for future outbreaks. A combination of genetic, ecologic, and epidemiologic information are of high interest for model development.


4. DHCPP Poxvirus Analysis: Understanding Poxvirus Diversity and Host Interactions

V. Olson, I. Damon, K. Karem, M. Reynolds

Orthopoxviruses are large, highly evolved, closely related, viruses that possess the potential to interact with host cells and immune defense responses at many levels. These interactions may be tailored to specific host organisms or alternatively target wider host ranges. Variola (human smallpox virus) is essentially a single host parasite that was historically devastating to unvaccinated human populations and remains a considerable concern as a bioterrorist threat. Monkeypox virus, by contrast, has a wide potential host range, has naturally occurring sylvan host species in Africa, and is of primary concern as a zoonotic agent of human disease. Vaccinia (used successfully as a vaccine to eradicate naturally occurring smallpox) is a virus of uncertain origin that appears to be an example of a virus that has evolved during the long course of the history of passaging for vaccine production. As such, it represents an interesting and important example of ‘artificially’ modified evolution, but which still has the potential to cause serious human disease in persons with incomplete immunity.   The Poxvirus Branch participates in studies of the evolution of these viruses, many of which have multiple, complete genome sequences available, and for which the Branch has one of the most complete collections of viruses (including variola) available for study in the world.   Better understanding virus-host cell interactions and host immunity offers great potential for development of potential infection intervention strategies. Understanding the natural history of monkeypox and the human disease it causes presents interesting and timely challenges for the epidemiology and natural history of orthopoxvirus disease and orthopoxvirus host-reservoirs interactions.

5. DHCPP Genetic Mechanisms of Poxvirus Variation and Attenuation

I. Damon, V. Olson, K. Karem

The effect of proteins expressed by poxviruses through interaction with their host in order to affect disease pathogenesis via evasion or subversion of the immune system is now well recognized. The effects of alterations of these virally encoded proteins may provide insights as to potentially safer vaccines, as well as novel therapeutic targets. Recent work has suggested study of the host-pathogen interactions of the Orthopoxvirus monkeypox may provide new insights as to mechanisms by which orthopoxviruses cause systemic disease. Genetic methods for studying recombinant poxviruses will be desirable, and animal model studies will be established to test hypotheses.

 

6. DHCPP Molluscum Contagiosum Virus

K. Karem, I. Damon

Molluscum contagiosum virus (MCV) is one of the two poxviruses whose sole host is the human; the other, orthopoxvirus variola (the causative agent of smallpox), was declared eradicated in 1980. Unlike orthopoxviruses, MCV causes a benign and self-limiting infection of humans that while concerning, is not life threatening. This virus, although sequenced, has been difficult to study because no tissue culture system exists. It is of ongoing public health concern due to the rate of infection and numerous outpatient visits to physicians and clinics for examination and treatment. Investigations designed to understand the effects of potential therapeutics, evaluation of possible culture systems, and pathogenic mechanisms will be of potential public health benefit.

 

7. DHCCP DNA Methylation in Transcriptional Silencing of Human Papillomavirus (HPV) Associated Cervical Carcinogenesis  

M.S. Rajeevan

HPV life cycle is tightly linked to epithelial differentiation, and HPV infection may result in a lack of coordination between differentiation and proliferation resulting cervical dysplasia. Results from our recent epidemiologic and in vitro studies hypothesize a role for DNA methylation in the extensive transcriptional silencing of the viral genes (1) and cellular genes in HPV associated cervical dysplasia (2). This project entails methylation profiling of the viral and host genomes, and correlation of methylation profiles with viral gene expression, viral load, HPV physical status (episomal/integrated), and cervical disease status. Samples will be used from in vitro models of dysplasis (raft cultures) and women participating in the NCI’s Early Detection Research Network. Major goals of this research are (a) to define the role of DNA methylation in regulating the viral persistence and viral induced block in terminal differentiation leading to dysplasis, (b) to identify DNA based biomarkers to reduce the burden of cervical cancer and cervical precursor lesions, and (c) to gain fundamental insights into the mechanism of viral clearance and persistence in general using HPV as a model system.

References

Rajeevan M.S., Swan D.C., Nisenbaum R.A., Lee D.R., Vernon S.D., Ruffin M.T., Horowitz I.R., Flowers L.C., Kmak D., Tadros T., Birdsong G., Husain M., Srivastava S., Unger E.R. 2005. Epidemiologic and viral factors associated with cervical neoplasia in HPV-16 positive women, Int. J. Cancer (in press)

 

8. DHCPP Molecular Virulence Determinants of RNA Viruses Associated with Hemorrhagic Fevers

C.G. Albariño, E. Bergeron, B.H. Bird, S.T. Nichol

With the emergence of hantavirus pulmonary syndrome in the United States and the ongoing activity of Ebola, Rift Valley fever, and Lassa viruses in Africa, a tremendous amount of interest and research activity has been focused on these and related RNA viruses. The Viral Special Pathogens Branch has an active program using reverse genetics systems for Ebola, Rift Valley fever, Junin, and other arenaviruses to investigate the molecular mechanisms of transcription, replication, protein processing, virus particle maturation and interactions with host cellular factors that may influence the high virulence of these pathogens. These studies will have significant impact on our basic understanding of the molecular determinants of attenuation and should provide a basis for the rational design of novel vaccine candidates.  In house technologies include Roche 454 sequencing platform, ABI 7500 qPCR, and others for high throughput cloning and other molecular analyses. Excellent opportunities exist for collaborative studies with other scientists within CDC and also with other U.S. and international collaborators.

References

Nichol, S. T., C. F. Spiropoulou, S. Morzunov, P. E. Rollin, T.G. Ksiazek, H. Feldmann, A. Sanchez, S. Zaki, J. Childs, and C. J. Peters. 1993. Genetic identification of a hantavirus associated with an outbreak of acute respiratory illness. Science 262:914-917.


Bergeron, E., M. J. Vincent, and S. T. Nichol. 2007. Crimean-Congo hemorrhagic fever virus glycoprotein processing by the endoprotease SKI-1/S1P is critical for virus infectivity. J Virol 81:13271-6. 


Albarino, C. G., E. Bergeron, B. R. Erickson, M. L. Khristova, P. E. Rollin, and S. T. Nichol. 2009. Efficient reverse genetics generation of infectious Junin viruses differing in glycoprotein processing. J Virol 83:5606-14. 



9. DHCPP Immunological Interactions contributing to the pathogenesis of Viral Hemorrhagic Fevers


C.F. Spiropoulou, B.H. Bird,S.T. Nichol

Over the past 30 years there has been a dramatic increase in our understanding and recognition of the public health impacts of RNA viruses causing viral hemorrhagic fevers (VHFs). The ongoing activity of Ebola, Rift Valley fever, Lassa and other viruses in Africa and the potential for bioterrorism, has stimulated a large amount of interest and research focused on these pathogens. The Viral Special Pathogens Branch has an active program in basic viral pathogenesis and in the development and validation of immmunotherapeutics and antivirals for these significant health threats.  Potential opportunities exist to explore 1) the interactions of the VHF viruses with host cell in order to discover new targets for antiviral and immunotherapeutic therapies, 2) the innate immune responses to VHF infections and the different strategies that VHF viruses have evolved to invade immunity, 3) the development of animal models for preclinical testing of new therapies and 4) the contribution of the innate and adaptive immunity to the mechanisms of protection in animal model systems. Excellent opportunities exist for collaborative studies with other scientists within CDC and also with other U.S. and international collaborators.  In house technologies include Luminex 200, Agilent microarray, ABI 7500 qPCR, FACS and others for high throughput analyses.

References 

Radoshitzky SR, Abraham J, Spiropoulou CF, Kuhn JH, Nguyen D, Li W, Nagel J, Schmidt PJ, Nunberg JH, Andrews NC, Farzan M, Choe H. 2007. Transferrin receptor 1 is a cellular receptor for New World haemorrhagic fever arenaviruses. Nature. 446:92-6.  


Spiropoulou CF, Albariño CG, Ksiazek TG, Rollin PE. 2007. Andes and Prospect Hill hantaviruses differ in early induction of interferon although both can downregulate interferon signaling. J Virol. 81:2769-76. 


Bird, B. H., C. G. Albarino, A. L. Hartman, B. R. Erickson, T. G. Ksiazek, and S. T. Nichol. 2008. Rift valley fever virus lacking the NSs and NSm genes is highly attenuated, confers protective immunity from virulent virus challenge, and allows for differential identification of infected and vaccinated animals. J Virol 82:2681-91. 

 
Spiropoulou, C. F., P. Ranjan, M. B. Pearce, T. K. Sealy, C. G. Albarino, S. Gangappa, T. Fujita, P. E. Rollin, S. T. Nichol, T. G. Ksiazek, and S. Sambhara. 2009. RIG-I activation inhibits ebolavirus replication. Virology 392:11-5.
  


Shrivastava-Ranjan P, Rollin PE, Spiropoulou CF. 2010. Andes virus disrupts the endothelial cell barrier by induction of VEGF and down-regulation of VE-cadherin. J. Virol. 84:1045-10.

 

10. DHCPP Development of Countermeasures for Variola

V. Olson, K. Karem, D. Carroll, I. Damon

Interest remains high in the development of next generation vaccines and therapeutics for variola (the causative agent of smallpox).  Since the eradication of smallpox over 30 years ago, concerns of the use of this agent as a bioterrorist weapon remain.  Studies to expand our understanding of the available countermeasures and generation and testing of new countermeasures require high containment laboratory research for the testing of reagents against variola.  Studies may include vaccine efficacy testing, animal model development, and anti-viral testing in vitro and in vivo.  Surrogate models of smallpox infection may include testing with monkeypox virus or vaccinia.  Analysis of outcomes may include viral neutralization, animal protection studies or measures of immune markers, and viral clearance.
 

11. DHCPP Poxvirus Bioinformatics

Y. Li, D. Carroll, Kevin L. Karem, I. Damon  

 

Advances in DNA sequencing technology have permitted a significant database expansion of poxvirus genome sequences.  The Poxvirus Team has an extensive collection of viruses (including variola, monkeypox, cowpox, vaccinia, parapoxviruses) available for genomic study. Comparative bioinformatics or other specific analysis of poxvirus genome sequences can provide additional information to depict and understand the pathogenesis and the evolution of poxviruses. Potential projects include the comparative analysis of orthopoxviruses genome sequences, the origin and evolution of orthopoxviruses, and the pathogenetic differences between low and high GC content genome poxviruses.

12. DHCPP Molecular Virulence Determinants of RNA Viruses Associated with Hemorrhagic Fevers

C.G. Albarino, E. Bergeron, B.H. Bird, S.T. Nichol, C.F. Spiropoulou

 

With the emergence of hantavirus pulmonary syndrome in the United States and the ongoing activity of Ebola, Rift Valley fever, and Lassa viruses in Africa, a tremendous amount of interest and research activity has been focused on these and related RNA viruses. The Viral Special Pathogens Branch has an active program using reverse genetics systems for Ebola virus, Crimean-Congo hemorrhagic fever virus, Rift Valley fever virus, Junin virus, and Lujo virus to investigate the molecular mechanisms of transcription, replication, protein processing, virus particle maturation and interactions with host cellular factors that may influence the high virulence of these pathogens. These studies will have significant impact on our basic understanding of the molecular determinants of attenuation and should provide a basis for the rational design of novel vaccine candidates. In house technologies include Roche 454 sequencing platform, ABI 7500 qPCR, and others for high throughput cloning and other molecular analyses. Excellent opportunities exist for collaborative studies with other scientists within CDC and also with other U.S. and international collaborators.

 

References

 

Bergeron E, et al., Reverse genetics recovery of lujo virus and role of virus RNA secondary structures in efficient virus growth; J Virol. 2012 Oct;86(19):10759-65. Epub 2012 Jul 25.

 

Albariño CG, Bird BH, Chakrabarti AK, Dodd KA, Erickson BR, Nichol ST., Efficient rescue of recombinant Lassa virus reveals the influence of S segment noncoding regions on virus replication and virulence., J Virol. 2011 Apr;85(8):4020-4. Epub 2011 Feb 9.

 

Albarino, C. G., E. Bergeron, B. R. Erickson, M. L. Khristova, P. E. Rollin, and S. T. Nichol. 2009. Efficient reverse genetics generation of infectious Junin viruses differing in glycoprotein processing. J Virol 83:5606-14.

 

Bergeron, E., M. J. Vincent, and S. T. Nichol. 2007. Crimean-Congo hemorrhagic fever virus glycoprotein processing by the endoprotease SKI-1/S1P is critical for virus infectivity. J Virol 81:13271-6.

 

13. DHCPP  Immunopathogenesis, therapeutics, and vaccine development for Viral Hemorrhagic Fevers

B.H. Bird, M. Flint, S.T. Nichol, C.F. Spiropoulou


Over the past 30 years there has been a dramatic increase in our understanding and recognition of the public health impacts of RNA viruses causing viral hemorrhagic fevers (VHFs). The ongoing activity of Ebola, Rift Valley fever, Lassa and other viruses in Africa and Hantaviruses in Americas, has stimulated a large amount of interest and research focused on these pathogens. The Viral Special Pathogens Branch has an active program in basic viral pathogenesis, animal modelling, and the development and validation of immmunotherapeutics and vaccines for these significant health threats.  Potential opportunities exist to explore 1) the interactions of the VHF viruses with host cells in order to discover new targets for antiviral and immunotherapeutic therapies, 2) the innate immune responses to VHF infections and the different strategies that VHF viruses have evolved to invade immunity, 3) the development of animal models for preclinical testing of new therapies and 4) the contribution of the innate and adaptive immunity to the mechanisms of protection in animal model systems. Excellent opportunities exist for collaborative studies with other scientists within CDC and also with other U.S. and international collaborators.  In house technologies include Luminex 200, Agilent microarray, ABI 7500 qPCR, FACS and others for high throughput analyses.

 

References

 

Bird BH, Dodd KA, Erickson BR, Albariño CG, Chakrabarti AK, McMullan LK, Bergeron E, Ströeher U, Cannon D, Martin B, Coleman-McCray JD, Nichol ST, Spiropoulou CF. Severe Hemorrhagic Fever in Strain 13/n Guinea pigs infected with Lujo virus., PLoS Negl Trop Dis. 2012 Aug;6(8):e1801. Epub 2012 Aug 28.

 

Dodd KA, Bird BH, Metcalfe MG, Nichol ST, Albariño CG., Single-dose immunization with virus replicon particles confers rapid robust protection against Rift Valley fever virus challenge. J Virol. 2012 Apr;86(8):4204-12. Epub 2012 Feb 15.

 

Albariño CG, Bird BH, Chakrabarti AK, Dodd KA, Flint M, Bergeron E, White DM, Nichol ST., The major determinant of attenuation in mice of the Candid1 vaccine for Argentine hemorrhagic fever is located in the G2 glycoprotein transmembrane domain., J Virol. 2011 Oct;85(19):10404-8. Epub 2011 Jul 27.

 

Bird, B., L. Maartens, S. Campbell, B. Erasmus, B. Erickson, K. Dodd, C.F. Spiropoulou, D. Cannon, C. Drew, B. Knust, A. McElroy, M. Khristova, C.Albarino, and S.T. Nichol. Rift Valley fever virus vaccine lacking the NSs and NSm genes is safe, nonteratogenic, and confers protection from viremia, pyrexia, and abortion following challenge in adult and pregnant sheep. J Virol. 2011 Dec;85(24):12901-9. Epub 2011 Oct 5.

 

Shrivastava-Ranjan P, Rollin PE, and C.F. Spiropoulou. 2010. Andes virus disrupts the endothelial cell barrier by induction of vascular endothelial growth factor and downregulation of VE-cadherin. J. Virol. 84:11227-34.

 

14. DHCPP  Molecular and Immunological Investigations of Hemorrhagic Fever Viruses in Their Natural Reservoir Hosts

 

J.S. Towner, B.R. Amman, S.T. Nichol

 

With the continuing emergence and re-emergence of RNA viruses causing deadly diseases such as Ebola and Marburg hemorrhagic fevers, Rift Valley fever (RVF), Crimean Congo hemorrhagic fever (CCHF) and hantavirus pulmonary syndrome, Viral Special Pathogens Branch has an active program to study these viruses in their natural vertebrate and invertebrate reservoir hosts and determine the mechanisms by which these viruses are maintained in nature. Recently we identified the Egyptian fruit bat, Rousettus aegyptiacus, as a major natural reservoir for Marburg virus, opening the door for multiple lines of investigation to 1) characterize the Marburg virus life cycle in a natural reservoir through ecological investigations of existing African bat colonies with known Marburg virus circulation, 2) establish R. aegyptiacus as a model system for studying filovirus maintenance in a natural reservoir host through experimental infection of captive bats, and 3) use established reverse genetic approaches to examine filovirus virulence determinants and their role in modulating reservoir host immune responses. These investigations provide excellent opportunities for collaboration with U.S. and international investigators.

 

References

 

Amman BR, Carroll SA, Reed ZD, Sealy TK, Balinandi S, et al. (2012) Seasonal Pulses of Marburg Virus Circulation in Juvenile Rousettus aegyptiacus Bats Coincide with Periods of Increased Risk of Human Infection. PLoS Pathog 8(10): e1002877.

 

Towner, J.S., Amman, B.R., Sealy, T.K., et al., (2009) Isolation of genetically diverse Marburg viruses from Egyptian fruit bats. PLoS Pathogens, 5(7): e1000536.

 

Towner, J.S., Sealy, T.K., Khristova, et al., (2008) Newly discovered Ebola virus associated with a hemorrhagic fever outbreak in Uganda. PLoS Pathogens, 4(11): e1000212.

 

Bird, B.H., Githinji, J.W.K., Macharia, J.M., et al., (2008) Multiple virus lineages sharing recent common ancestry were associated with a large Rift Valley fever outbreak among livestock in Kenya during 2006-2007. J. Virology, 82 (22):11152-66.

Hartman, A.L., Bird, B.H., Towner, J.S., Antoniadou Z.A., Zaki, S.R., and Nichol, S.T. (2008) Inhibition of IRF-3 activation by VP35 is critical for the high level of virulence of ebola virus. J. Virology 82: 2699-704

15. DHCPP Molecular Genetics of Pathogenic Aerobic Actinomycetes

B. A. Lasker

Aerobic actinomycetes consist primarily of gram-positive, filamentous or branched bacteria that may cause severe infections in humans and animals. Research opportunities exist in the following areas: (i) to characterize molecular mechanisms contributing to antimicrobial resistance; (ii) to develop rapid and accurate molecular methods for identification of aerobic actinomycetes using the analysis of multiple gene sequences and or MALDI-TOF mass spectrometry; (iii) to determine the phylogenetic relationships among aerobic actinomycetes using de novo assembly and analysis of whole-genome sequences; and (iv) to develop and evaluate new PCR- and whole genome sequence-based typing methods.

References

Apostolou, A., S.J. Bolcen, V. Dave, N. Jani, B.A. Lasker, C.G. Tan, B. Montana, J.M. Brown and C.A. Genese. 2012. Nocardia cyriacigeorgica infections attributable to unlicensed cosmetic procedures – an emerging health problem? Clin. Infect. Dis. 55: 251-253.


Lasker, B. A., B. Moser, and June M. Brown. “Gordonia” Molecular Detection of Human Pathogens, Taylor and Francis CRC Press. 2011. (D. Liu, ed).

 

Niwa, H. and B.A. Lasker. 2010. Mutant selection window and characterization of allelic diversity for ciprofloxacin-resistant mutants of Rhodococcus equi. Antimicrob.Agents Chemother. 54:3520-3523.

 

16. DHCPP Emerging Lyssavirus Infections: Epizootiology, Pathobiology, Prevention and Control 

J.D. Blanton, R. Franka, I. Damon 

Activities involve the epizootiology, diagnosis, pathobiology, prevention, treatment, and control of lyssaviruses. Projects include antigenic and molecular analysis of lyssaviruses affecting global reservoirs, especially bats and mammalian carnivores; improvement of ante- and postmortem diagnostics in the rabid patient; pathogenesis of rabies in relevant hosts, such as domestic animals and wildlife, to determine appropriate public health guidelines for management of the biting animal; evaluation of monoclonal antibodies as a replacement for rabies immune globulin in postexposure prophylaxis; field activities on the ecology of emerging infectious diseases at the human-domestic animal–wildlife interface in a ‘one-health’ context; and development of safe and efficacious rabies vaccines, especially oral immunogens for free-ranging carnivores, particularly raccoons, coyotes, skunks, foxes, dogs, and mongoose. 

References

Blanton JD, Palmer D, Rupprecht CE. Rabies surveillance in the United States during 2009. J Am Vet Med Assoc. 2010; 237:646-57.

Streicker DG, Turmelle AS, Vonhof MJ, Kuzmin IV, McCracken GF, Rupprecht CE. Host phylogeny constrains cross-species emergence and establishment of rabies virus in bats. Science. 2010;329:676-9.

Turmelle AS, Jackson FR, Green D, McCracken GF, Rupprecht CE. Host immunity to repeated rabies virus infection in big brown bats. J Gen Virol. 2010;91:2360-6.

Rupprecht CE. Bats, emerging diseases, and the human interface. PLoS Negl Trop Dis. 2009 28;3:e451.


Rupprecht CE, Briggs D, Brown CM, Franka R, Katz SL, Kerr HD, Lett S, Levis R, Meltzer MI, Schaffner W, Cieslak PR. Evidence for a 4-dose vaccine schedule for human rabies post-exposure prophylaxis in previously non-vaccinated individuals. Vaccine. 2009;27:7141-8.

Rupprecht CE, Barrett J, Briggs D, Cliquet F, Fooks AR, Lumlertdacha B, Meslin FX, Müler T, Nel LH, Schneider C, Tordo N, Wandeler AI. Can rabies be eradicated? Dev Biol (Basel). 2008;131:95-121.

 

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