Anti-DENV-ED3 antibody cross-talks generate immune interference among the four DENVs

Abstract

Objective: To evaluate the effects of primary anti-dengue virus envelop protein domain 3 (DENV-ED3) antibodies on secondary heterotypic anti-DENV ED3 antibody responses and the status of anti-DENV antibody responses against multivalent DENV ED3s in mice.

Methods: Four different DENV-ED3s were purified and their biophysical characteristics were confirmed. Swiss albino mice aged 3-4 weeks were immunized with four different DENV-ED3s and the anti-ED3 IgG responses were determined by ELISA.

Results: Firstly, the primary 1ED3-2ED3-3ED3 cross-reactive anti-DENV1 ED3 response boosted the secondary anti-2ED3 and anti-3ED3 antibody responses. In contrast, primary anti-2ED3 and anti-3ED3 antibodies neither had cross-recognition of 1ED3, nor had any effect on secondary anti-1ED3 response. Besides, the strict serospecificity of the anti-4ED3 sera did not affect other secondary anti-DENV ED3 responses. Secondly, 1ED3, 2ED3, and 3ED3 were co-dominantly immunogenic in trivalent ED3 formulations. However, the poorly immunogenic 4ED3 became almost non-immunogenic when injected after or together with 2ED3 and 3ED3, but showed slightly increased immunogenicity when injected with 1ED3, suggesting an adjuvanticity of 1ED3 on 4ED3’s immunogenicity.

Conclusions: Although DENV1~4 ED3s share similar sequence homologies and structures, their immune induction potentials differ significantly in terms of immune magnitude, sero-specificity, and sero-cross-reactivity. Such intrinsic features of DENV1~4 ED3s may lead to ‘antigen interference’, limiting both the understanding of dengue etiology and the success of dengue vaccine development, which needs to neutralize all four DENV serotypes equivalently.

Keywords

Dengue viruses (DENVs) / DENV sero-specificity / DENV serotype-cross-talks / Primary DENV infections / Secondary DENV infections / Multivalent DENV-ED3s

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