Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve

Jurre Y Siegers; Judith M van den Brand; Lonneke M Leijten; Marco Wg van de Bildt; Peter R van Run; Geert van Amerongen; Koert J Stittelaar; Marion P G Koopmans; Albert D M E Osterhaus; Thijs Kuiken; Debby van Riel

doi:10.1093/infdis/jiw123

Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve

Jurre Y Siegers, Judith M van den Brand, Lonneke M Leijten, Marco Wg van de Bildt, Peter R van Run, Geert van Amerongen, Koert J Stittelaar, Marion P G Koopmans, Albert D M E Osterhaus, Thijs Kuiken, Debby van Riel

Department of Viroscience, Erasmus Medical Center, 3015 CN Rotterdam, The Netherlands; [email protected] [email protected].
Viroclinics Biosciences, 3029 AK Rotterdam, The Netherlands. [email protected].
Viroclinics Biosciences BV, Rotterdam Artemis One Health, Utrecht, The Netherlands Research Center for Emerging Infections and Zoonoses, University of Veterinary Medicine, Hannover, Germany.

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

BACKGROUND: Influenza A viruses can replicate in the olfactory mucosa and subsequently use the olfactory nerve to enter the central nervous system (CNS). It is currently unknown whether intervention strategies are able to reduce or prevent influenza virus replication within the olfactory mucosa and subsequent spread to the CNS. Therefore, we tested the efficacy of homologous vaccination and prophylactic oseltamivir to prevent H5N1 virus CNS invasion via the olfactory nerve in our ferret model.

METHODS: Ferrets were vaccinated intramuscularly or received oseltamivir (5 mg/kg twice daily) prophylactically before intranasal inoculation of highly pathogenic H5N1 virus (A/Indonesia/05/2005) and were examined using virology and pathology.

RESULTS: Homologous vaccination reduced H5N1 virus replication in the olfactory mucosa and prevented subsequent virus spread to the CNS. However, prophylactic oseltamivir did not prevent H5N1 virus replication in the olfactory mucosa sufficiently, resulting in CNS invasion via the olfactory nerve causing a severe meningoencephalitis.

CONCLUSIONS: Within our ferret model, vaccination is more effective than prophylactic oseltamivir in preventing CNS invasion by H5N1 virus via the olfactory nerve. This study highlights the importance of including the olfactory mucosa, olfactory nerve, and CNS tissues in future vaccine and antiviral studies, especially for viruses with a known neurotropic potential.

Original language	English
Pages (from-to)	516-24
Number of pages	9
Journal	Journal of Infectious Diseases
Volume	214
Issue number	4
DOIs	https://doi.org/10.1093/infdis/jiw123
Publication status	Published - 15 Aug 2016
Externally published	Yes

Keywords

Animals
Antiviral Agents
Chemoprevention
Disease Models, Animal
Female
Ferrets
Influenza A Virus, H5N1 Subtype
Influenza Vaccines
Injections, Intramuscular
Meningoencephalitis
Olfactory Nerve
Orthomyxoviridae Infections
Oseltamivir
Treatment Outcome
Journal Article

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10.1093/infdis/jiw123

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Siegers, J. Y., van den Brand, J. M., Leijten, L. M., van de Bildt, M. W., van Run, P. R., Amerongen, G. V., Stittelaar, K. J., Koopmans, M. P. G., Osterhaus, A. D. M. E., Kuiken, T., & van Riel, D. (2016). Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve. Journal of Infectious Diseases, 214(4), 516-24. https://doi.org/10.1093/infdis/jiw123

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title = "Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve",

abstract = "BACKGROUND: Influenza A viruses can replicate in the olfactory mucosa and subsequently use the olfactory nerve to enter the central nervous system (CNS). It is currently unknown whether intervention strategies are able to reduce or prevent influenza virus replication within the olfactory mucosa and subsequent spread to the CNS. Therefore, we tested the efficacy of homologous vaccination and prophylactic oseltamivir to prevent H5N1 virus CNS invasion via the olfactory nerve in our ferret model.METHODS: Ferrets were vaccinated intramuscularly or received oseltamivir (5 mg/kg twice daily) prophylactically before intranasal inoculation of highly pathogenic H5N1 virus (A/Indonesia/05/2005) and were examined using virology and pathology.RESULTS: Homologous vaccination reduced H5N1 virus replication in the olfactory mucosa and prevented subsequent virus spread to the CNS. However, prophylactic oseltamivir did not prevent H5N1 virus replication in the olfactory mucosa sufficiently, resulting in CNS invasion via the olfactory nerve causing a severe meningoencephalitis.CONCLUSIONS: Within our ferret model, vaccination is more effective than prophylactic oseltamivir in preventing CNS invasion by H5N1 virus via the olfactory nerve. This study highlights the importance of including the olfactory mucosa, olfactory nerve, and CNS tissues in future vaccine and antiviral studies, especially for viruses with a known neurotropic potential.",

keywords = "Animals, Antiviral Agents, Chemoprevention, Disease Models, Animal, Female, Ferrets, Influenza A Virus, H5N1 Subtype, Influenza Vaccines, Injections, Intramuscular, Meningoencephalitis, Olfactory Nerve, Orthomyxoviridae Infections, Oseltamivir, Treatment Outcome, Journal Article",

author = "Siegers, {Jurre Y} and {van den Brand}, {Judith M} and Leijten, {Lonneke M} and {van de Bildt}, {Marco Wg} and {van Run}, {Peter R} and Amerongen, {Geert van} and Stittelaar, {Koert J} and Koopmans, {Marion P G} and Osterhaus, {Albert D M E} and Thijs Kuiken and {van Riel}, Debby",

year = "2016",

month = aug,

day = "15",

doi = "10.1093/infdis/jiw123",

language = "English",

volume = "214",

pages = "516--24",

journal = "Journal of Infectious Diseases",

issn = "0022-1899",

publisher = "Oxford University Press",

number = "4",

}

Siegers, JY, van den Brand, JM, Leijten, LM, van de Bildt, MW, van Run, PR, Amerongen, GV, Stittelaar, KJ, Koopmans, MPG, Osterhaus, ADME, Kuiken, T & van Riel, D 2016, 'Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve', Journal of Infectious Diseases, vol. 214, no. 4, pp. 516-24. https://doi.org/10.1093/infdis/jiw123

TY - JOUR

T1 - Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve

AU - Siegers, Jurre Y

AU - van den Brand, Judith M

AU - Leijten, Lonneke M

AU - van de Bildt, Marco Wg

AU - van Run, Peter R

AU - Amerongen, Geert van

AU - Stittelaar, Koert J

AU - Koopmans, Marion P G

AU - Osterhaus, Albert D M E

AU - Kuiken, Thijs

AU - van Riel, Debby

PY - 2016/8/15

Y1 - 2016/8/15

N2 - BACKGROUND: Influenza A viruses can replicate in the olfactory mucosa and subsequently use the olfactory nerve to enter the central nervous system (CNS). It is currently unknown whether intervention strategies are able to reduce or prevent influenza virus replication within the olfactory mucosa and subsequent spread to the CNS. Therefore, we tested the efficacy of homologous vaccination and prophylactic oseltamivir to prevent H5N1 virus CNS invasion via the olfactory nerve in our ferret model.METHODS: Ferrets were vaccinated intramuscularly or received oseltamivir (5 mg/kg twice daily) prophylactically before intranasal inoculation of highly pathogenic H5N1 virus (A/Indonesia/05/2005) and were examined using virology and pathology.RESULTS: Homologous vaccination reduced H5N1 virus replication in the olfactory mucosa and prevented subsequent virus spread to the CNS. However, prophylactic oseltamivir did not prevent H5N1 virus replication in the olfactory mucosa sufficiently, resulting in CNS invasion via the olfactory nerve causing a severe meningoencephalitis.CONCLUSIONS: Within our ferret model, vaccination is more effective than prophylactic oseltamivir in preventing CNS invasion by H5N1 virus via the olfactory nerve. This study highlights the importance of including the olfactory mucosa, olfactory nerve, and CNS tissues in future vaccine and antiviral studies, especially for viruses with a known neurotropic potential.

AB - BACKGROUND: Influenza A viruses can replicate in the olfactory mucosa and subsequently use the olfactory nerve to enter the central nervous system (CNS). It is currently unknown whether intervention strategies are able to reduce or prevent influenza virus replication within the olfactory mucosa and subsequent spread to the CNS. Therefore, we tested the efficacy of homologous vaccination and prophylactic oseltamivir to prevent H5N1 virus CNS invasion via the olfactory nerve in our ferret model.METHODS: Ferrets were vaccinated intramuscularly or received oseltamivir (5 mg/kg twice daily) prophylactically before intranasal inoculation of highly pathogenic H5N1 virus (A/Indonesia/05/2005) and were examined using virology and pathology.RESULTS: Homologous vaccination reduced H5N1 virus replication in the olfactory mucosa and prevented subsequent virus spread to the CNS. However, prophylactic oseltamivir did not prevent H5N1 virus replication in the olfactory mucosa sufficiently, resulting in CNS invasion via the olfactory nerve causing a severe meningoencephalitis.CONCLUSIONS: Within our ferret model, vaccination is more effective than prophylactic oseltamivir in preventing CNS invasion by H5N1 virus via the olfactory nerve. This study highlights the importance of including the olfactory mucosa, olfactory nerve, and CNS tissues in future vaccine and antiviral studies, especially for viruses with a known neurotropic potential.

KW - Animals

KW - Antiviral Agents

KW - Chemoprevention

KW - Disease Models, Animal

KW - Female

KW - Ferrets

KW - Influenza A Virus, H5N1 Subtype

KW - Influenza Vaccines

KW - Injections, Intramuscular

KW - Meningoencephalitis

KW - Olfactory Nerve

KW - Orthomyxoviridae Infections

KW - Oseltamivir

KW - Treatment Outcome

KW - Journal Article

U2 - 10.1093/infdis/jiw123

DO - 10.1093/infdis/jiw123

M3 - Article

C2 - 27448390

SN - 0022-1899

VL - 214

SP - 516

EP - 524

JO - Journal of Infectious Diseases

JF - Journal of Infectious Diseases

IS - 4

ER -

Vaccination Is More Effective Than Prophylactic Oseltamivir in Preventing CNS Invasion by H5N1 Virus via the Olfactory Nerve

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Keywords

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