A bispecific mRNA vaccine against zika and dengue viruses to overcome antibody-dependent enhancement and provide protection in preclinical models

Zika virus (ZIKV) and dengue virus (DENV) are two widespread flaviviruses that pose a significant threat to public health. Owing to their extensive co-circulation and antigenic cross-reactivity, both viruses carry the risk of antibody-dependent enhancement (ADE), a phenomenon that renders existing vaccines unable to simultaneously protect against both pathogens. To overcome this limitation, we developed a bispecific mRNA vaccine against ZIKV and DENV (bis-mZDV) by integrating orthogonal B-cell and T-cell modules. The B-cell module was constructed by fusing ZIKV EDIII to the self-adjuvanting complement component C3d to enhance neutralizing antibody titers. The T-cell module incorporated conserved epitopes from ZIKV and DENV, thereby inducing cross-reactive CD8⁺ T cells without eliciting ADE-prone B-cell responses. Notably, the new bis-mZDV achieved up to an 8-fold enhancement in neutralizing antibody titers compared to the unadjuvanted EDIII mRNA vaccine. More importantly, in immunodeficient mice, it conferred protection against both ZIKV and DENV challenges and elicited robust humoral and cellular immune responses. The bis-mZDV represents a promising strategy that may be applicable to co-circulating pathogens and other viruses associated with ADE.