title: Alum boosts TH2-type antibody responses to whole-inactivated virus influenza vaccine in mice but does not confer superior protection.
abstract: Clinical trials with pandemic influenza vaccine candidates have focused on aluminium hydroxide as an adjuvant to boost humoral immune responses. In this study we investigated the effect of aluminium hydroxide on the magnitude and type of immune response induced by whole-inactivated virus (WIV) vaccine. Balb/c mice were immunized once with a range of antigen doses (0.04-5 microg) of WIV produced from A/PR/8 virus, either alone or in combination with aluminium hydroxide. The hemagglutination inhibition (HI) titers of mice receiving WIV+aluminium hydroxide were 4-16-fold higher than HI titers in mice receiving the same dose of WIV alone, indicating the boosting effect of aluminium hydroxide. WIV induced a TH1 skewed humoral and cellular immune response, characterized by strong influenza-specific IgG2a responses and a high number of IFNgamma-secreting T cells. In contrast, immunization with WIV adsorbed to aluminium hydroxide resulted in skewing of this response to a TH2 phenotype (high IgG1 levels and a low number of IFNgamma-producing T cells). To assess the effect of the observed immune response skewing on viral clearance from the lungs mice immunized once with 1 microg WIV without or with aluminium hydroxide were challenged with A/PR/8 virus 4 weeks later. The immunized mice showed a significant decrease in viral lung titers compared to control mice receiving buffer. However, despite higher antibody titers, mice immunized with WIV adsorbed to aluminium hydroxide suffered from more severe weight loss and had significantly higher virus loads in their lung tissue than mice receiving WIV alone. Major difference between these groups of mice was the type of immune response induced, TH2 instead of TH1, indicating that a TH1 response plays a major role in viral clearance.
authors.affiliation: Department of Medical Microbiology, Molecular Virology Section, University Medical Center Groningen and University of Groningen, Postbus 30.001, 9700 RB Groningen, The Netherlands.
authors.forename: Laura
authors.initials: L
authors.lastname: Bungener
authors.forename: Felix
authors.initials: F
authors.lastname: Geeraedts
authors.forename: Wouter
authors.initials: W
authors.lastname: Ter Veer
authors.forename: Jeroen
authors.initials: J
authors.lastname: Medema
authors.forename: Jan
authors.initials: J
authors.lastname: Wilschut
authors.forename: Anke
authors.initials: A
authors.lastname: Huckriede
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage / Q000494:pharmacology*; D000536:Aluminum Hydroxide / Q000008:administration & dosage / Q000494:pharmacology*; D000818:Animals; D000914:Antibodies, Viral / Q000097:blood*; D001835:Body Weight; D005260:Female; D006385:Hemagglutination Inhibition Tests; D007117:Immunization, Secondary; D007074:Immunoglobulin G / Q000097:blood; D007252:Influenza Vaccines / Q000008:administration & dosage / Q000276:immunology*; D007371:Interferon-gamma / Q000096:biosynthesis; D008168:Lung / Q000821:virology; D051379:Mice; D008807:Mice, Inbred BALB C; D009976:Orthomyxoviridae Infections / Q000517:prevention & control; D013601:T-Lymphocytes / Q000276:immunology; D015164:Vaccines, Inactivated / Q000008:administration & dosage / Q000276:immunology
chemical_list: D000276:Adjuvants, Immunologic; D000914:Antibodies, Viral; D007074:Immunoglobulin G; D007252:Influenza Vaccines; D015164:Vaccines, Inactivated; D000536:Aluminum Hydroxide; D007371:Interferon-gamma