Santos-Peral et al.
Prior flavivirus immunity skews the yellow fever vaccine response to cross-reactive antibodies with potential to enhance dengue virus infection. Nat Commun. 2024;15(1):1696. doi:10.1038/s41467-024-45806-x
Flaviviruses share a common similar structure and the glycoprotein E covering the surface. This glycoprotein consists of three defined domains DI, DII and DIII among which DII contains the highly conserved fusion loop FL. A significant portion of antibody response to flaviviruses is directed to epitopes of FL (FLE), and these antibodies are cross-reactive, but mostly not neutralizing. Such antibodies can impact the immune response and clinical course of secondary infections, e.g. by facilitating virus entry by Fcγ-receptor-mediated phagocytosis in a process termed antibody-dependent enhancement (ADE) of infection and which has been described for dengue virus infections.
In a recent study, it was investigated if pre-existing TBE antibodies (after vaccination) may have an influence on the immune response of yellow fever vaccination (YF17D).
TBE-pre-immunity did not impair the neutralizing antibody response to YF17D. However, TBE-pre-vaccinated individuals developed a high amount of cross-reacting antibodies with poor neutralizing capacity, while TBE-naïve individuals elicited a non-cross-reacting YF17D-IgG response with neutralizing capacity. TBE vaccinees had cross-reactive IgG antibodies to YF17D and showed cross-reactivity with all flaviviruses tested at similar magnitude. This pan-flavivirus cross-reactive IgG signature was boosted upon vaccination with YF17D vaccine, while in non-TBE-vaccinated individuals YF17D vaccine induced only a non-cross reacting specific IgG response to YFV.
In in-vitro experiments, an enhanced YF17D infection of FcγR-expressing cell lines could be observed in the presence of serum from TBE-pre-vaccinated individuals, and this ADE was IgG-dependent (not IgM-dependent). This effect was blocked in the presence of FcγR-blocking antibodies. YF17D infection enhancement was observed only with sera from TBE virus experienced individuals.
The immunogenicity of both TBE virus and YF17D vaccines was excellent. The TBE vaccination followed by YF17D did not hamper the immunogenicity and neutralization response induced by these vaccines. In-vitro experiments showed that sequential TBE and YF17D elevated cross-reactive antibodies that could enhance Dengue and Zika virus infections in-vitro via ADE, but these data must be interpreted with caution and the clinical impact remains unknown.