Assessing the effect of flaviviral pre-immunity on the humoral response following Yellow Fever vaccination
Ruklanthi de Alwis1,2, Kuan Rong Chan1, Eugenia Ziying Ong1,2, Esther Shuyi Gan1,2, Xin Mei Ong1, Jenny G. H. Low1,2,3, Raphael Zellweger1,2, Eng Eong Ooi1,2
1Emerging Infectious Disease, Duke-NUS Medical School; 2ViREMiCS, SingHealth Duke-NUS Academic Medical Centre, 3Singapore General Hospital, Singapore
Yellow Fever virus (YFV) belongs to the flavivirus family of arboviruses, which have a long-standing history of causing human disease. There are several licensed efficacious live-attenuated YF vaccines for human use. However, recent repeated YF outbreaks across Brazil and parts of Africa have depleted the global YF vaccine stock piles. This leaves the world unprepared to handle future YF epidemics, especially in naïve populations, for example in Asia. Hence, a better understanding of the protective mechanisms is important to develop ways to improve the immunogenicity of YF vaccination to mitigate vaccine shortage.
Interestingly, vaccine efficacy is markedly improved in the presence of cross-reactive flavivirus pre-immunity, as observed during dengue virus vaccinations in pre-immune individuals. Pre-existing cross-reactive antibodies have the potential to shape both antigen-recognition and effector functions of vaccination-induced humoral response through Fc-receptor (FcR) mediated signaling. Therefore, to characterize the role of pre-existing cross-reactive antibodies in modulating flaviviral vaccine-induced immune responses, our group recently completed a randomized clinical trial in an adult Singaporean population. This study capitalized on the cross-reactive response of JEV vaccination with YFV and compared immune responses of YF 17D vaccination in flavivirus-naïve individuals to those of JEV pre-vaccinated individuals. As expected, JEV pre-vaccination produced cross-reactive antibodies to YF. We then conducted a series of serological assays with serum taken 1 month after YF vaccination. The presence of these cross-reactive antibodies significantly affected both antigen-recognition properties (such as antigen binding, neutralization and affinity) as well as effector properties (such as IgG subclasses, FcR binding). Our current work may provide further insight into understanding of protective mechanisms following flaviviral vaccination and hopefully improve current flaviviral vaccine regiments.