Open Access

Oksana Vratskikh, Karin Stiasny, Jürgen Zlatkovic, Georgios Tsouchnikas, Johanna Jarmer, Urs Karrer, Michael Roggendorf, Hedwig Roggendorf, Regina Allwinn, Franz X. Heinz

• The live attenuated yellow fever (YF) vaccine has an excellent record of efficacy and one dose provides long-lasting immunity, which in many cases may last a lifetime. Vaccination stimulates strong innate and adaptive immune responses, and neutralizing antibodies are considered to be the major effectors that correlate with protection from disease. Similar to other flaviviruses, such antibodies are primarily induced by the viral envelope protein E, which consists of three distinct domains (DI, II, and III) and is presented at the surface of mature flavivirions in an icosahedral arrangement. In general, the dominance and individual variation of antibodies to different domains of viral surface proteins and their impact on neutralizing activity are aspects of humoral immunity that are not well understood. To gain insight into these phenomena, we established a platform of immunoassays using recombinant proteins and protein domains that allowed us to dissect and quantify fine specificities of the polyclonal antibody response after YF vaccination in a panel of 51 vaccinees as well as determine their contribution to virus neutralization by serum depletion analyses. Our data revealed a high degree of individual variation in antibody specificities present in post-vaccination sera and differences in the contribution of different antibody subsets to virus neutralization. Irrespective of individual variation, a substantial proportion of neutralizing activity appeared to be due to antibodies directed to complex quaternary epitopes displayed on the virion surface only but not on monomeric E. On the other hand, DIII-specific antibodies (presumed to have the highest neutralizing activity) as well as broadly flavivirus cross-reactive antibodies were absent or present at very low titers. These data provide new information on the fine specificity as well as variability of antibody responses after YF vaccination that are consistent with a strong influence of individual-specific factors on immunodominance in humoral immune responses. Author Summary: The live-attenuated yellow fever vaccine has been administered to more than 600 million people worldwide and is considered to be one of the most successful viral vaccines ever produced. Following injection, the apathogenic vaccine virus replicates in the vaccinee and induces antibodies that mediate virus neutralization and subsequent protection from disease. In principle, many different antibodies are induced by viral antigens, but it is becoming increasingly clear that only a subset of them is capable of inactivating the virus, and some antibody populations appear to dominate the immune response. However, to date there has been very little information on individual-specific variations of immunodominance and how such variations can affect the functionality of antibody responses. In our study, we addressed these issues and analyzed the fine specificities of antibodies induced by YF vaccination as well as the contribution of different antibody subsets to virus neutralization in 51 vaccinees. We demonstrate an extensive degree of individual variation with respect to immunodominance of antibody populations and their contribution to virus neutralization. Such variations can have an impact on vaccine-mediated protection, and thus insight into this phenomenon can provide leads for novel strategies in modern vaccine design.