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. 2025 May 31:57:127219.
doi: 10.1016/j.vaccine.2025.127219. Epub 2025 May 7.

A novel immunogen comprising a bc loop and mutant fusion loop epitopes generates potent neutralization and protective abilities against flaviviruses without risk of disease enhancement

Shiu-Bii Lien  1 , Qiao-Wen Yang  2 , Hong-Wei Huang  2 , Kuo-Chou Chiu  3 , Sui-Lung Su  4 , Ching-Len Liao  5 , Li-Chen Yen  6
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Free article

A novel immunogen comprising a bc loop and mutant fusion loop epitopes generates potent neutralization and protective abilities against flaviviruses without risk of disease enhancement

Shiu-Bii Lien et al. Vaccine. .
Free article

Abstract

Flaviviruses, including Dengue virus (DENV), Zika virus (ZIKV) and Japanese encephalitis virus (JEV), remain major global health threats, and currently, there are no widely available vaccines for humans. The fusion loop region of the flavivirus envelope protein plays a crucial role in eliciting neutralizing antibodies and providing protection against secondary DENV infections. However, these antibodies often exhibit dual functionalities, with both neutralizing and enhancing activities, posing a challenge for vaccine development. In this study, we focused on optimizing the fusion loop epitope as the primary immunogen and incorporated the adjacent bc loop which we had reported previously as a complementary element, aiming to enhance the immunogen capable of robust neutralization and protection without inducing the risk of antibody-dependent enhancement (ADE). This newly designed immunogen was named as muBCFL which comprises sequences spanning from amino acid 69 to 116 primarily on DENV-2 envelope protein, along with four specific mutations (T76A, W101A, G106Q, and L107D). The synthesized muBCFL peptide elicited neutralizing antibodies against all four DENV serotypes, ZIKV, and JEV, with particularly strong neutralization activity against DENV-2, ZIKV, and JEV. Besides, compared to pre-immune sera, muBCFL-immune sera significantly reduced viremia levels in DENV- or ZIKV-infected AG129 mice and increased the survival rates of JEV-challenged ICR mice. Furthermore, in vitro and in vivo ADE assays validated that muBCFL-immune sera did not induce ADE compared with the control 4G2 monoclonal antibody. These findings indicated that the muBCFL sequence holds great potential as a safe and effective immunogen for developing a flavivirus vaccine in the future.

Keywords: Antibody-dependent enhancement; Dengue virus; Flavivirus; Neutralizing epitope; Vaccine.

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Conflict of interest statement

Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Li-Chen Yen reports financial support was provided by National Science and Technology Council, Taiwan. Kuo-Chou Chiu reports financial support was provided by Taichung Armed Forces General Hospital. If there are other authors, they declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

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