Abstract
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.
Highlights
The live-attenuated yellow fever (YF) vaccine based on the 17D virus strain is considered to be one of the most successful vaccines ever produced [1,2]
Structural details of flaviviruses have been elucidated for dengue, tick-borne encephalitis (TBE), West Nile (WN), and Japanese encephalitis viruses using X-ray crystallography and cryo-electron microscopy [7,8], but no such data are yet available for YF virus
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
Summary
The live-attenuated yellow fever (YF) vaccine based on the 17D virus strain is considered to be one of the most successful vaccines ever produced [1,2]. Despite the broad immunological stimulation, there is strong evidence that humoral immunity mediated by virus-neutralizing antibodies is the primary effector mechanism of protection [1]. Such antibodies may persist for more than 45 years and apparently protect against all naturally occurring genotypes of YF virus [1]. Immature virions (Figure 1A, left panel) are assembled in the ER and contain three structural proteins, designated as C (capsid), prM (precursor of membrane) and E (envelope) These particles contain 60 trimeric spikes of prM-E heterodimers and are secreted through the exocytotic pathway of the cell [9].
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