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

BACKGROUND: The 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 its longstanding success, few studies have characterized the capacity of 17D-immune sera to neutralize wild-type (WT) yellow fever viruses (YFVs). METHODS: We use 17D and a panel of 13 WT YFVs that represent the known YFV genotypes and a unique cohort of 36 non-endemic vaccinees with diverse Orthoflavivirus infection histories to conduct focus neutralization tests to characterized the potency and breadth of 17D-elicited serum neutralizing antibodies against these WT YFV. 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 (SA-I) isolates. Vaccinee sera with serologic evidence of heterologous Orthoflavivirus infection had significantly greater potency against SA-I strains compared to 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.