Strategies to enhance DNA vaccine efficacy against emerging arboviruses: lessons from ZIKA and Chikungunya viruses.

The mosquito-borne arboviruses Zika and Chikungunya pose serious health threats worldwide, often co-circulating and causing co-infections in Aedes endemic regions. While no licensed vaccine is currently available for Zika virus (ZIKV), recent progress has led to the approval of vaccines for Chikungunya virus (CHIKV) in few countries, highlighting the need for improved vaccine strategies. Zika virus (ZIKV) presents unique challenges, including its neurotropism, association with congenital abnormalities, and potential for sexual and vertical transmission, whereas Chikungunya virus (CHIKV) is characterized by viral persistence in joint-associated tissues, leading to chronic inflammatory manifestations such as long-term arthralgia, along with comparatively limited clinical trial data for vaccine candidates. DNA vaccines offer a promising platform since they are safe and easy to produce; but their immunogenicity in humans is limited. The rational use of adjuvants and optimized delivery systems is important for enhancing DNA vaccine efficacy. This review discusses current adjuvant classes, including Toll-like receptor (TLR) agonists, molecular adjuvants, and classical adjuvants, focusing on their mechanisms to enhance immune cell activation and adaptive immunity. We summarize preclinical and clinical findings on DNA vaccines for ZIKV and CHIKV, highlighting the synergy of adjuvants with different delivery technologies and discuss the rationale for multivalent DNA vaccine strategies to address co-circulating arboviral infections. Finally, we have identified research gaps and suggested a translational roadmap to accelerate the development of effective DNA vaccines against these emerging arboviruses.