Current status and future prospects of yellow fever vaccines

Abstract

Yellow fever 17D vaccine is one of the oldest live-attenuated vaccines in current use that is recognized historically for its immunogenic and safe properties. These unique properties of 17D are presently exploited in rationally designed recombinant vaccines targeting not only flaviviral antigens but also other pathogens of public health concern. Several candidate vaccines based on 17D have advanced to human trials, and a chimeric recombinant Japanese encephalitis vaccine utilizing the 17D backbone has been licensed. The mechanism(s) of attenuation for 17D are poorly understood; however, recent insights from large in silico studies have indicated particular host genetic determinants contributing to the immune response to the vaccine, which presumably influences the considerable durability of protection, now in many cases considered to be lifelong. The very rare occurrence of severe adverse events for 17D is discussed, including a recent fatal case of vaccine-associated viscerotropic disease.

Keywords: empiric; empiric vaccine; flavivirus; live-attenuated; primary seed; rational vaccine; recombinant vaccine; secondary seed; vaccine; viral diversity; yellow fever virus.

Figure 1

Canonical genome organization of YFV and members of the genus Flavivirus. The virus particle carries a single-stranded, positive sense strand of RNA, which is immediately translated. Structural proteins (red) are placed upstream and occur sequentially, and similarly for the downstream nonstructural proteins. 17D vaccine genomes are identically organized.

Figure 2

Lineage of 17D and derivative substrains, considering only present production of 17D vaccines. Substrains 17DD, 17D-204, and 17D-213 are shown in blue, green, and tan respectively. S1: Primary seed. S2: Secondary seed. V: Final vaccine lot. Adapted from [30] [6].