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Protection Against Influenza A(H5N1) by Primary Infection with Influenza A(H3N2) and MVA-Based Vaccination

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Protection Against Influenza A(H5N1) by Primary Infection with Influenza A(H3N2) and MVA-Based Vaccination Protection Against Influenza A(H5N1) by Primary Infection with Influenza A(H3N2) and MVA-based Vaccination Bescherming Tegen Influenza A(H5N1) door Primaire Infectie met Influenza A(H3N2) en op MVA gebaseerde Vaccinatie Proefschrift ter verkrijging van de graad van doctor aan de Erasmus Universiteit Rotterdam op gezag van de rector magnificus Prof.dr. H.G. Schmidt en volgens besluit van het College voor Promoties. De openbare verdediging zal plaatsvinden op donderdag 3 september 2009 om 13:30 uur door Johannes Henricus Cornelus Maria Kreijtz geboren te Vorstenbosch Protection Against Influenza A(H5N1) by Primary Infection with Influenza A(H3N2) and MVA-based Vaccination Thesis, Erasmus University, Rotterdam, the Netherlands. With summary in Dutch ISBN: 978-94-9032-001-0 ©J.H.C.M. Kreijtz, 2009 All rights reserved. Save exceptions stated by law, no part of this publication may be produced or transmitted in any form or by any means, electronic or mechanical, without prior written permission of the author, or where appropriate, of the publisher of the articles Voor ons pap en mam Promotie commissie Promotor: Prof.dr. A.D.M.E. Osterhaus Co-promotor: Dr. G.F. Rimmelzwaan Overige leden: Prof.dr. T. Kuiken Prof.dr. G. Sutter Prof.dr. B.N. Lambrecht The research described in this thesis was financially supported byZonMW Grant 91402008 (Netherlands Influenza Vaccine Research Consortium (NIVAREC)) Financial support by the following companies and foundations is gratefully acknowledged: Viroclinics Solvay Biologicals Nobilon International BV Roche Nederland BV Clean Air Techniek BV Cover illustration: Lung john silver by JK Table of Contents Chapter 1 Introduction and outline of the thesis page 9 partially based on: Human vaccines, 2009 Chapter 2 Primary influenza A virus infection induces cross-protective page 39 immunity against a lethal infection with a heterosubtypic virus strain in mice Vaccine, 2007 Chapter 3 Infection of mice with a human influenza A/H3N2 virus page 55 induces protective immunity against lethal infection with influenza A/H5N1 virus Vaccine, 2009 Chapter 4 Vaccination against human influenza A/H3N2 virus prevents page 73 the induction of heterosubtypic immunity against lethal infection with avian influenza A/H5N1 virus PLoS ONE, 2009 Chapter 5 Cross-recognition of avian H5N1 influenza virus by human page 91 cytotoxic T lymphocyte populations directed to human influenza A virus Journal of Virology,2008 Chapter 6 Recombinant modified vaccinia virus Ankara (MVA)-based page 105 vaccine induces protective immunity in mice against infection with influenza virus H5N1 Journal of Infectious Diseases, 2007 Chapter 7 Recombinant modified vaccinia virus Ankara expressing HA page 121 confers protection against homologous and heterologous H5N1 influenza virus infections in macaques Journal of Infectious Diseases, 2009 Chapter 8 MVA-based H5N1 vaccine affords cross-clade protection page 139 against influenza A/H5N1 viruses at low doses and after single immunization Submitted for publication Chapter 9 Summarizing Discussion page 155 References page 165 Chapter 10 Nederlandse Samenvatting page 181 Chapter 11 About the author page 191 Curriculum Vitae page 193 List of publications page 194 PhD portfolio page 196 Chapter 12 Dankwoord page 201 Appendix Chapter 1: introduction Partially based on: Vaccination strategies and vaccine formulations for epidemic and pandemic influenza control J.H.C.M. Kreijtz, A.D.M.E. Osterhaus, G.F. Rimmelzwaan: Department of Virology, Erasmus Medical Centre, Rotterdam, the Netherlands Human Vaccines 2009; 5:3, 126-35 introduction Influenza viruses Influenza A viruses belong to the family of the orthomyxoviridae that consists of five genera: Thogoto virus, Isavirus and Influenza virus A, B and C. The generae CHAPTER 1 of influenza viruses are distinguished based on their membrane channel protein, genome size and surface glycoprotein(s).[1] Influenza A viruses are classified based on their surface glycoproteins: hemagglutinin (HA) and neuraminidase (NA). So far 16 HA subtypes and 9 NA subtypes have been identified based on genetic and antigenic analysis.[2] The nomenclature of influenza viruses is based on: subtype, host of origin (except humans), isolation site (geographical), strain number, year of isolation and followed by the description of the antigenic subtype, e.g. A/Chicken/ Netherlands/1/03 (H7N7). HA NA M2 NS M NA NP HA PA PB1 PB2 Figure 1 Impression of Influenza A virus particle and gene segments. The PB1 segment encodes also the PB1-F2 protein (present only in infected cells). The M segment encodes the M1 and M2 protein and the NS segment encodes the NS1 (present only in infected cells) and NS2 protein. Structure of influenza A virus Influenza A virus particles are enveloped and have a diameter of 80-120nm. Their single stranded negative sense RNA genome is divided over eight gene segments that encode 11 different proteins (Figure 1).[3] The surface glycoproteins hemagglutinin (HA) and neuraminidase (NA) are located on the viral envelope. The M2 protein, which functions as an ion channel is also incorporated in the viral envelope. The other proteins are located inside the virion: the Matrix protein (M1), the nucleoprotein (NP), polymerases PB1, PB1-F2, PB2 and PA, and the non-structural protein NS2.[3, 4] The M1 proteins form a layer that underlies the lipid bilayer of the viral envelope 10 introduction that was derived from the infected cell. The M1 protein, in combination with NP CHAPTER 1 and polymerase proteins, is also associated with the ribonucleoproteins (RNPs) that contains the vRNA. The NP is abundant in the nucleocapsid of the RNP whereas the PB1, PB2 and PA proteins are located on one end. The PB1-F2 and non-structural protein NS1 are only found in infected cells and are not incorporated in the virion and the PB1-F2 is not expressed by every influenza A virus. NS2 is a structural component, present at a low copy number and associated with the M1 protein. Influenza virus replication cycle The influenza virus attaches to the cell by binding of the HA to galactose-linked sialic acids on the glycoprotein receptors of the host cell membrane (Figure 2).[5] Depending on the HA subtype the virus can either bind to alpha2-3 or alpha2-6 galactose-linked sialic acids. Human influenza viruses prefer the alpha2-6 sialic acid, abundantly present in the upper respiratory tract but not in the lungs, whereas the alpha2-3 linked sialic acid, preferred by avian influenza viruses, is also present in the lower respiratory tract.[6, 7] Binding of the virus to and infection of cells in the upper respiratory tract, in combination with additional mutations that facilitate efficient replication at this site (e.g. PB2-E627K) are required for efficient human- to-human transmission.[3] Human influenza A viruses are able to spread easily among humans whereas the avian influenza A/H5N1 viruses do not replicate in the upper respiratory tract and are not transmitted efficiently from human to human. Mutations that result in amino acid substitutions in the receptor binding pocket of the HA molecule could change its receptor specificity and result in a virus capable of human-to-human transmission. After binding, the influenza virion enters the cell through receptor-mediated endocytosis and subsequently fuses with the mild acidic primary endosome. [5] The low pH in the endosome triggers the membrane fusion activity of HA by conformational changes in the protein. This results in fusion of the viral and endosomal membranes releasing the RNPs into the cytoplasm. Prior to this event the M2 ion channels, activated by the low pH, allow H+ ions to enter the virion upon which they detach the M1 protein from the RNPs to prepare it for transport to the nucleus, chaperoned by the NP.[8] In the nucleus the three types of influenza virus RNA are formed. The template RNA, which consists of full length positive sense copies of vRNA from which new vRNA is transcribed that will constitute the genome of the newly formed 11 introduction virus particles, and mRNA from which the viral proteins are translated after nuclear export, regulated by NS1. Once the viral RNA is produced, new RNPs are assembled in the nucleus, transported to the cytoplasm and then transported towards the CHAPTER 1 apical membrane, chaperoned by M1. The membrane associated proteins HA, NA and M2 are produced by ribosomes bound to the membrane of the endoplasmatic reticulum (ER). Subsequently they enter the ER for post-translational modification and are transported to the Golgi apparatus where additional modifications take place. From there the HA and NA proteins, that use lipid rafts for transport, and the M2 proteins, are directed to the apical plasma membrane where virus assembly will take place.[9]To allow the newly formed virus particles to be separated from the cell, a process called budding, the cell membrane will bulge outward, most likely mediated by accumulation of M1 under the lipid bilayer. The virus then bulges out of the cell until the cell membrane fuses at the bottom of the virion, hereby closing it. The actual release of the virions from the cell is mediated by the enzymatic activity of NA that catalyses the cleavage of the sialic acids thus preventing binding of newly formed particles to the cell.[10] Fusion & Uncoating Attachment Low pH ER Endocytosis Translation Packaging & Budding Posttranslational mRNA processing vRNA Nucleus Figure 2 Impression of Influenza virus replication cycle. (ER= Endoplasmatic Reticulum)(vRNA= viral RNA)(mRNA= messenger
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