Dr. Osvaldo Aguilera Batista, MD. First-Degree Specialist in Family Medicine and Immunology. Professor. Vladimir I. Lenin University General Hospital, Holguín, Cuba.
The emergence and re-emergence of multiple arboviral diseases represent an increasingly important global public health challenge. Changes in climate, urbanization, human mobility, vector distribution, and population susceptibility have contributed to the geographic expansion and increasing incidence of several arboviral infections. Recognizing this growing threat, the World Health Organization (WHO) launched the Global Arbovirus Initiative in 2022, with the objective of strengthening global preparedness, surveillance, prevention, and control of epidemic-prone arboviruses (1).
Conventional vaccine platforms can contribute substantially to reducing the incidence and burden of arboviral diseases. However, innovative vaccine technologies may offer additional advantages, including improved safety, rapid development and manufacturing, enhanced immunogenicity, and the potential for broader protection against emerging or antigenically diverse viruses (1).
One particularly innovative approach involves insect-specific viruses (ISVs). These viruses naturally infect and replicate in insects but are unable to productively replicate in vertebrate cells. Examples include Eilat virus, Yada virus, Binjari virus, Aripo virus, YN15-283-02 virus, and Chaoyang virus (1). This intrinsic host restriction makes ISVs attractive candidates for the development of novel and potentially safer vaccine platforms.
Through genetic engineering, structural genes from ISVs can be replaced with the corresponding structural genes of pathogenic alphaviruses or orthoflaviviruses (1). The resulting chimeric viruses express structural proteins derived from the target pathogenic arbovirus while retaining the replication machinery and vertebrate host restriction of the ISV. Consequently, these chimeric viruses can replicate efficiently in mosquito-derived cells used for vaccine production but are unable to productively replicate in vertebrate cells (1). This approach combines the strong antigenic presentation associated with viral particles with an important biological safety mechanism.
Eilat virus represents an important example of this strategy. Eilat virus-based chimeric vaccine candidates have been developed against several medically important alphaviruses, including Mayaro virus, Venezuelan equine encephalitis virus, eastern equine encephalitis virus, and chikungunya virus. In experimental models, some of these non-adjuvanted vaccine candidates have provided protection after a single dose, including in mouse and non-human primate studies. Their immunogenicity may be partly related to activation of innate immune pathways, including type I interferon responses mediated through pattern-recognition receptors such as Toll-like receptors and RIG-I-like receptors (1).
Similarly, Tanelus and collaborators demonstrated that vaccination with the chimeric ARPV/ZIKV platform induced strong antibody responses together with cellular immune responses, further supporting the potential of ISV-based chimeric vaccines as a strategy against emerging arboviruses (2).
Another highly promising vaccine technology is messenger RNA (mRNA). The remarkable development and large-scale use of mRNA vaccines during the COVID-19 pandemic demonstrated the feasibility of rapidly designing, manufacturing, and deploying vaccines based on this platform. Rather than delivering the antigen itself, mRNA vaccines provide genetic instructions encoding selected viral antigens, allowing host cells to transiently produce the antigenic proteins and subsequently stimulate both humoral and cellular immune responses (3).
mRNA vaccines offer several potential advantages over conventional vaccine technologies. Antigens do not need to be produced and purified through traditional manufacturing processes, and vaccine production does not require the propagation of large quantities of pathogenic virus. Moreover, mRNA platforms can induce both CD4+ and CD8+ T-cell responses, in addition to antibody responses. Because they do not contain replication-competent infectious agents, they may also offer important safety advantages for populations in whom live-attenuated vaccines may be contraindicated (3).
Several types of RNA-based vaccine technologies are currently being investigated, including non-replicating mRNA (nrRNA), virus-derived self-amplifying RNA (saRNA), trans-amplifying RNA (taRNA), and circular RNA (circRNA) platforms (3). These technologies differ in their mechanisms of antigen expression, duration of protein production, required RNA dose, and potential applications.
Following administration, lipid nanoparticle-formulated mRNA is taken up by cells, including antigen-presenting cells such as dendritic cells and macrophages, primarily through endocytic pathways. After endosomal escape, the mRNA reaches the cytoplasm, where host ribosomes translate it into the encoded antigen. The antigen can subsequently be processed into peptides and presented through MHC class I molecules to CD8+ T cells. Antigen uptake and processing through MHC class II pathways also promotes CD4+ T-cell activation, supporting antibody production and the development of coordinated cellular immunity (3).
The potential application of mRNA technology to arboviral vaccines is particularly promising. Experimental mRNA-LNP vaccines against dengue virus (DENV) encoding antigens such as envelope domain III and NS1 have demonstrated broad neutralizing antibody responses in animal models, including activity against all four DENV serotypes (3). Such approaches are particularly relevant for dengue, where vaccine development is complicated by the existence of four antigenically distinct serotypes and the potential consequences of unbalanced immunity.
Similarly, Richner and collaborators demonstrated that mRNA vaccination against Zika virus (ZIKV) can induce robust antigen-specific antibody responses, including IgG subclasses, together with cellular immune responses. These findings contributed important proof-of-concept evidence supporting mRNA technology as a platform for vaccines against emerging arboviruses.
Finally, self-assembling protein nanoparticles represent another innovative approach to vaccine antigen delivery (4). Among these, ferritin has attracted particular interest because of its ability to spontaneously assemble into highly organized nanoparticles capable of displaying multiple copies of an antigen. Ferritin is naturally present in both bacterial and mammalian systems, and bacterial ferritins can exhibit substantial resistance to thermal and chemical degradation. Ferritin nanoparticles were initially explored as vaccine platforms for influenza, where multivalent antigen presentation generated strong neutralizing antibody responses.
In the context of arboviral diseases, ferritin-based nanoparticle vaccines could similarly provide an efficient mechanism for presenting selected viral antigens to the immune system. For ZIKV, Pattnaik and collaborators developed a bacterial ferritin-based vaccine candidate displaying domain III of the ZIKV envelope protein (E-DIII). This approach generated neutralizing antibody responses without evidence of antibody-dependent enhancement (ADE), an especially important consideration in the development of vaccines against antigenically related flaviviruses (4).
Collectively, ISV-based chimeric vaccines, mRNA technologies, and self-assembling nanoparticle platforms such as ferritin illustrate how modern vaccine technology may expand the tools available to confront emerging and re-emerging arboviral diseases. These approaches offer opportunities to combine improved safety with potent humoral and cellular immunity, rapid adaptability, and potentially broader protection. As arboviruses continue to expand geographically and epidemiologically, developing and evaluating such innovative vaccine platforms should remain an important component of global preparedness and prevention strategies.
Conclusion
The continued emergence and re-emergence of arboviral diseases demand vaccine strategies that are safe, adaptable, rapidly scalable, and capable of inducing broad and durable immunity. Innovative platforms, including ISV-based chimeric vaccines, mRNA technologies, and self-assembling ferritin nanoparticles, provide promising alternatives to conventional approaches. Although further clinical evaluation is required, these technologies could play an important role in strengthening global preparedness against both currently circulating and future emerging arboviruses.
References:
- Hall RA, Nguyen W, Khromykh AA, Suhrbier A. Insect-specific virus platforms for arbovirus vaccine development. Front Immunol. 2025; 16:1521104. doi:10.3389/fimmu.2025.1521104.
- Tanelus M, López K, Smith S, Muller JA, Porier DL, Auguste DI, et al. Exploring the immunogenicity of an insect-specific virus vectored Zika vaccine candidate. Sci Rep. 2023;13(1):19948. doi:10.1038/s41598-023-47086-9.
- Sun N, Su Z, Zheng X. Research progress of mosquito-borne virus mRNA vaccines. Mol Ther Methods Clin Dev. 2025;33(1):101398. doi: 10.1016/j.omtm.2024.101398.
- Pattnaik A, Sahoo BR, Struble LR, Borgstahl GEO, Zhou Y, Franco R, et al. A ferritin nanoparticle-based Zika virus vaccine candidate induces robust humoral and cellular immune responses and protects mice from lethal virus challenge. Vaccines (Basel). 2023;11(4):821. doi:10.3390/vaccines11040821.
