Greater Breadth of Vaccine-Induced Immunity in Females than Males Is Mediated by Increased Antibody Diversity in Germinal Center B Cells
Rebecca L. Ursin, Santosh Dhakal, Hsuan Liu, Sahana Jayaraman, Han-Sol Park, Harrison Powell, Morgan L. Sherer, Kirsten Littlefield, Ashley L. Fink, Zexu Ma, Alice L. Mueller, Allison Chen, Kumba Seddu, Yishak A. Woldetsadik, Patricia J. Gearhart, H. Benjamin Larman, Robert W. Maul, Andrew Pekosz, Sabra L. Klein
Abstract
Adult females develop greater antibody responses to influenza vaccines than males. We hypothesized that female-biased immunity and protection would be dependent on the extent of virus diversity as well as molecular mechanisms in B cells which constrain the breadth of epitope recognition. We developed a panel of mouse-adapted (ma) A/Cal/09 viruses that had mutations in the immunodominant hemagglutinin. Following vaccination against maA/Cal/09, females were better able to neutralize maA/Cal/09 than males, but neutralization of mutant maA/Cal/09 viruses was equally poor in both sexes, despite vaccinated females being better protected against these viruses. Vaccinated females benefited from the greater production of class-switched, somatically hypermutated antibodies generated in germinal center B cells, which increased recognition of more diverse maA/Cal/09 hemagglutinin antigen epitopes. Female-biased protection against influenza infection and disease after vaccination is driven by differential mechanisms in males versus females and should be considered in the design of novel vaccine platforms.