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

Financial & competing interests disclosure

The authors were supported by grants from the National Institutes of Health (R21 AI 113407) and the Gillson-Longenbaugh Foundation. AS Beck was supported in part by National Institutes of Health grant T32 AI 060549. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Key issues

• YFV vaccines are historically significant as they were developed by empiric methods, and were among the first vaccines of this class.

• The 17D strain is still manufactured by legacy technologies involving embryonated chicken eggs that have changed little since the 1940s; manufacture in alternative cell culture systems has been investigated but has not been implemented by any producer.

• The World Health Organization and the Global Alliance for Vaccines and Immunizations vaccine alliance have undertaken to immunize all people in sub-Saharan Africa who are at risk for yellow fever disease, a target population in excess of 250 million people.

• All RNA viruses consist of a quasispecies structure consisting of a ‘cloud’ of RNA species with ‘high diversity’. The low diversity of 17D vaccine virus is thought to contribute to the high level of attenuation and great safety record of the vaccine.

• 17D is considered to be highly safe and protective; however, the increasing use of 17D nonstructural genomic components in rationally designed vaccine products demands closer scrutiny into the discrete mechanisms of attenuation for the vaccine strain.

• International recommendations for 17D booster schedules have been reduced for healthy adults; the 10-year booster International Health Regulations requirement has been modified to reflect an expectation that protection conferred by the vaccine is lifelong.

• Systems biology approaches have been used successively to interrogate the molecular basis of immunogenicity of 17D vaccine.

• YFV vaccines represent a lengthy history of deployment, and as such represent a large historical dataset for interrogation of flaviviral pathogenesis mechanisms, including those of interferon antagonism, cellular immunity and viral quasispecies theory.

Notes