title: Correlation between Virus Replication and Antibody Responses in Macaques following Infection with Pandemic Influenza A Virus.
abstract: Influenza virus infection of nonhuman primates is a well-established animal model for studying pathogenesis and for evaluating prophylactic and therapeutic intervention strategies. However, usually a standard dose is used for the infection, and there is no information on the relation between challenge dose and virus replication or the induction of immune responses. Such information is also very scarce for humans and largely confined to evaluation of attenuated virus strains. Here, we have compared the effect of a commonly used dose (4 × 10(6) 50% tissue culture infective doses) versus a 100-fold-higher dose, administered by intrabronchial installation, to two groups of 6 cynomolgus macaques. Animals infected with the high virus dose showed more fever and had higher peak levels of gamma interferon in the blood. However, virus replication in the trachea was not significantly different between the groups, although in 2 out of 6 animals from the high-dose group it was present at higher levels and for a longer duration. The virus-specific antibody response was not significantly different between the groups. However, antibody enzyme-linked immunosorbent assay, virus neutralization, and hemagglutination inhibition antibody titers correlated with cumulative virus production in the trachea. In conclusion, using influenza virus infection in cynomolgus macaques as a model, we demonstrated a relationship between the level of virus production upon infection and induction of functional antibody responses against the virus.
  
  
  OBJECTIVE
  There is only very limited information on the effect of virus inoculation dose on the level of virus production and the induction of adaptive immune responses in humans or nonhuman primates. We found only a marginal and variable effect of virus dose on virus production in the trachea but a significant effect on body temperature. The induction of functional antibody responses, including virus neutralization titer, hemagglutination inhibition titer, and antibody-dependent cell-mediated cytotoxicity, correlated with the level of virus replication measured in the trachea. The study reveals a relationship between virus production and functional antibody formation, which could be relevant in defining appropriate criteria for new influenza virus vaccine candidates.
authors.affiliation: Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Gerrit
authors.initials: G
authors.lastname: Koopman
authors.affiliation: Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands mooij@bprc.nl.
authors.forename: Petra
authors.initials: P
authors.lastname: Mooij
authors.affiliation: Crucell Holland B.V., Janssen Pharmaceutical Companies of Johnson & Johnson, Leiden, The Netherlands.
authors.forename: Liesbeth
authors.initials: L
authors.lastname: Dekking
authors.affiliation: Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Daniëlla
authors.initials: D
authors.lastname: Mortier
authors.affiliation: Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Ivonne G
authors.initials: IG
authors.lastname: Nieuwenhuis
authors.affiliation: Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Melanie
authors.initials: M
authors.lastname: van Heteren
authors.affiliation: Crucell Holland B.V., Janssen Pharmaceutical Companies of Johnson & Johnson, Leiden, The Netherlands.
authors.forename: Harmjan
authors.initials: H
authors.lastname: Kuipers
authors.affiliation: Department of Parasitology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Edmond J
authors.initials: EJ
authors.lastname: Remarque
authors.affiliation: Crucell Holland B.V., Janssen Pharmaceutical Companies of Johnson & Johnson, Leiden, The Netherlands.
authors.forename: Katarina
authors.initials: K
authors.lastname: Radošević
authors.affiliation: Department of Virology, Biomedical Primate Research Centre, Rijswijk, The Netherlands.
authors.forename: Willy M J M
authors.initials: WM
authors.lastname: Bogers
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood; D000914:Antibodies, Viral / Q000097:blood*; D000917:Antibody Formation; D004306:Dose-Response Relationship, Immunologic; D004797:Enzyme-Linked Immunosorbent Assay; D006385:Hemagglutination Inhibition Tests; D053118:Influenza A Virus, H1N1 Subtype / Q000276:immunology* / Q000502:physiology*; D008252:Macaca fascicularis; D008297:Male; D009500:Neutralization Tests; D014132:Trachea / Q000821:virology; D019562:Viral Load; D014779:Virus Replication
chemical_list: D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral