title: Obesity Outweighs Protection Conferred by Adjuvanted Influenza Vaccination.
abstract: Obesity is a risk factor for developing severe influenza virus infection, making vaccination of utmost importance for this high-risk population. However, vaccinated obese animals and adults have decreased neutralizing antibody responses. In these studies, we tested the hypothesis that the addition of either alum or a squalene-based adjuvant (AS03) to an influenza vaccine would improve neutralizing antibody responses and protect obese mice from challenge. Our studies demonstrate that adjuvanted vaccine does increase both neutralizing and nonneutralizing antibody levels compared to vaccine alone. Although obese mice mount significantly decreased virus-specific antibody responses, both the breadth and the magnitude of the responses against hemagglutinin (HA) and neuraminidase (NA) are decreased compared to the responses in lean mice. Importantly, even with a greater than fourfold increase in neutralizing antibody levels, obese mice are not protected against influenza virus challenge and viral loads remain elevated in the respiratory tract. Increasing the antigen dose affords no added protection, and a decreasing viral dose did not fully mitigate the increased mortality seen in obese mice. Overall, these studies highlight that, while the use of an adjuvant does improve seroconversion, vaccination does not fully protect obese mice from influenza virus challenge, possibly due to the increased sensitivity of obese animals to infection. Given the continued increase in the global obesity epidemic, our findings have important implications for public health.
  
  
  
  Vaccination is the most effective strategy for preventing influenza virus infection and is a key component for pandemic preparedness. However, vaccines may fail to provide optimal protection in high-risk groups, including overweight and obese individuals. Given the worldwide obesity epidemic, it is imperative that we understand and improve vaccine efficacy. No work to date has investigated whether adjuvants increase the protective capacity of influenza vaccines in the obese host. In these studies, we show that adjuvants increased the neutralizing and nonneutralizing antibody responses during vaccination of lean and obese mice to levels considered "protective," and yet, obese mice still succumbed to infection. This vulnerability is likely due to a combination of factors, including the increased susceptibility of obese animals to develop severe and even lethal disease when infected with very low viral titers. Our studies highlight the critical public health need to translate these findings and better understand vaccination in this increasing population.
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Erik A
authors.initials: EA
authors.lastname: Karlsson
authors.affiliation: The Shraga Segal Department of Microbiology, Immunology and Genetics, Ben-Gurion University of the Negev, Be'er-Sheva, Israel National Institute of Biotechnology in the Negev, Be'er-Sheva, Israel Vaccine and Infectious Disease Division, Fred Hutchinson Cancer Research Center, Seattle, Washington, USA.
authors.forename: Tomer
authors.initials: T
authors.lastname: Hertz
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA.
authors.forename: Cydney
authors.initials: C
authors.lastname: Johnson
authors.affiliation: Department of Medical Microbiology and Immunology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
authors.forename: Andrew
authors.initials: A
authors.lastname: Mehle
authors.affiliation: Department of Microbiology, Icahn School of Medicine at Mount Sinai, New York, USA.
authors.forename: Florian
authors.initials: F
authors.lastname: Krammer
authors.affiliation: Department of Infectious Diseases, St. Jude Children's Research Hospital, Memphis, Tennessee, USA stacey.schultz-cherry@stjude.org.
authors.forename: Stacey
authors.initials: S
authors.lastname: Schultz-Cherry
mesh_terms: D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000534:Alum Compounds / Q000008:administration & dosage; D000818:Animals; D057134:Antibodies, Neutralizing / Q000097:blood*; D000914:Antibodies, Viral / Q000097:blood*; D004195:Disease Models, Animal; D004338:Drug Combinations; D019267:Hemagglutinin Glycoproteins, Influenza Virus / Q000276:immunology; D006801:Humans; D064766:Influenza A Virus, H7N9 Subtype / Q000302:isolation & purification; D007252:Influenza Vaccines / Q000008:administration & dosage* / Q000276:immunology*; D007251:Influenza, Human / Q000517:prevention & control*; D008810:Mice, Inbred C57BL; D008820:Mice, Obese; D009439:Neuraminidase / Q000276:immunology; D009765:Obesity / Q000276:immunology*; D011136:Polysorbates / Q000008:administration & dosage; D012137:Respiratory System / Q000821:virology; D013185:Squalene / Q000008:administration & dosage; D016019:Survival Analysis; D016896:Treatment Outcome; D019562:Viral Load; D014764:Viral Proteins / Q000276:immunology; D024502:alpha-Tocopherol / Q000008:administration & dosage
chemical_list: D000276:Adjuvants, Immunologic; D000534:Alum Compounds; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D004338:Drug Combinations; D019267:Hemagglutinin Glycoproteins, Influenza Virus; D007252:Influenza Vaccines; D011136:Polysorbates; D014764:Viral Proteins; C041524:aluminum sulfate; D013185:Squalene; C550253:AS03 adjuvant; C487630:NA protein, influenza A virus; D009439:Neuraminidase; D024502:alpha-Tocopherol