Impact of pre-existing cross-reactive antibodies on cyclic dengue outbreaks in the hyperendemic region of Bali, Indonesia

The four serotypes of the dengue virus (DENV) cause a range of diseases ranging from mild fever to severe conditions. Understanding the immunological interactions among the four serotypes is crucial in comprehending the dynamics of serotype shifting during outbreaks in areas where all four serotypes co-circulate. Hence, we evaluated the neutralizing antibody and antibody-dependent enhancement responses against the four DENV serotypes using acute-phase plasma samples collected from 48 laboratory-confirmed dengue patients during a dengue outbreak in Bali, Indonesia in 2022. Employing single-round infectious particles to exclusively investigate immunogenicity to the structural surface proteins of DENV, which are the targets of antibodies, we found that individuals with a probable prior history of DENV-1 infection exhibited increased susceptibility to secondary DENV-3 infection, attributed to cross-reactive antibodies with limited neutralizing activity against DENV-3 (geometric mean 50 % neutralization titer (GMNT₅₀) = 47.6 $\pm$ 11.5). This susceptibility was evident in vitro, with a mean fold enhancement of 28.4 $\pm$ 33.9. Neutralization titers against DENV-3 were significantly lower compared to other serotypes (DENV-1 GMNT₅₀ = 678.1 $\pm$ 9.0; DENV-2 GMNT₅₀ = 210.5 $\pm$ 8.7; DENV-4 GMNT₅₀ = 95.14 $\pm$ 7.0). We demonstrate that prior immunity to one serotype provides limited cross-protection against the other serotypes, influencing the dominant serotype in subsequent outbreaks. These findings underscore the complexity of dengue immunity and its implications for vaccine design and transmission dynamics in hyperendemic regions.