New Insights Into an Old Vaccine: Potency and Breadth of Neutralizing Antibodies Elicited by Yellow Fever Vaccine 17D Are Boosted by Heterologous Orthoflavivirus Infection

BACKGROUND: Yellow fever vaccine 17D has controlled yellow fever for almost 90 years and is considered highly successful. However, with recent outbreaks in South America and Africa, yellow fever continues to represent a significant threat to public and global health. Despite the long-standing success, few studies have characterized the capacity of 17D-immune sera to neutralize wild type (WT) yellow fever viruses (YFVs). METHODS: Using 17D and 13 WT YFVs, we conducted focus neutralization tests against sera from a unique cohort of 36 nonendemic vaccinees with diverse Orthoflavivirus histories. By using WT YFVs that represent the known YFV genotypes, we characterized the potency and breadth of 17D-elicited serum neutralizing antibodies against these WT YFVs in the context of heterologous Orthoflavivirus infection. RESULTS: We found significant variability in neutralization test titers and rates of seropositivity of 17D-immune sera across all viruses and specifically against South America genotype I isolates. Vaccinee sera with serologic evidence of heterologous Orthoflavivirus infection had significantly greater potency against South America genotype I strains as compared with sera without evidence of Orthoflavivirus infection, suggesting a boosting effect from heterologous Orthoflavivirus immunity. CONCLUSIONS: These results add significantly to what is known regarding the WT YFV antigenic immune landscape, including novel insights into the role of heterologous Orthoflavivirus infection in 17D immunity that have the potential to improve future vaccine design and deployment strategies.