Zika virus (ZIKV) is a major public health concern of international proportions. While the incidence of ZIKV infections has declined substantially in recent years, the potential for the reemergence or reintroduction remains high.

The severe consequences of the Zika virus (ZIKV) infections resulting in congenital Zika syndrome in infants and the autoimmune Guillain–Barre syndrome in adults warrant the development of safe and efficacious vaccines and therapeutics. Currently, there are no approved treatment options for ZIKV infection. Herein, we describe the development of a bacterial ferritin-based nanoparticle vaccine candidate for ZIKV. The viral envelope (E) protein domain III (DIII) was fused in-frame at the amino-terminus of ferritin. The resulting nanoparticle displaying the DIII was examined for its ability to induce immune responses and protect vaccinated animals upon lethal virus challenge. Our results show that immunization of mice with a single dose of the nanoparticle vaccine candidate (zDIII-F) resulted in the robust induction of neutralizing antibody responses that protected the animals from the lethal ZIKV challenge. The antibodies neutralized infectivity of other ZIKV lineages indicating that the zDIII-F can confer heterologous protection. The vaccine candidate also induced a significantly higher frequency of interferon (IFN)-γ positive CD4 T cells and CD8 T cells suggesting that both humoral and cell-mediated immune responses were induced by the vaccine candidate. Although our studies showed that a soluble DIII vaccine candidate could also induce humoral and cell-mediated immunity and protect from lethal ZIKV challenge, the immune responses and protection conferred by the nanoparticle vaccine candidate were superior. Further, passive transfer of neutralizing antibodies from the vaccinated animals to naïve animals protected against lethal ZIKV challenge. Since previous studies have shown that antibodies directed at the DIII region of the E protein do not to induce antibody-dependent enhancement (ADE) of ZIKV or other related flavivirus infections, our studies support the use of the zDIII-F nanoparticle vaccine candidate for safe and enhanced immunological responses against ZIKV.

Vaccines are one of the most effective medical interventions, playing a pivotal role in treating infectious diseases. Although traditional vaccines comprise killed, inactivated, or live-attenuated pathogens that have resulted in protective immune responses, the negative consequences of their administration have been well appreciated. Modern vaccines have evolved to contain purified antigenic subunits, epitopes, or antigen-encoding mRNAs, rendering them relatively safe. However, reduced humoral and cellular responses pose major challenges to these subunit vaccines. Protein nanoparticle (PNP)-based vaccines have garnered substantial interest in recent years for their ability to present a repetitive array of antigens for improving immunogenicity and enhancing protective responses. Discovery and characterisation of naturally occurring PNPs from various living organisms such as bacteria, archaea, viruses, insects, and eukaryotes, as well as computationally designed structures and approaches to link antigens to the PNPs, have paved the way for unprecedented advances in the field of vaccine technology. In this review, we focus on some of the widely used naturally occurring and optimally designed PNPs for their suitability as promising vaccine platforms for displaying native-like antigens from human viral pathogens for protective immune responses. Such platforms hold great promise in combating emerging and re-emerging infectious viral diseases and enhancing vaccine efficacy and safety.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in regulating cellular defense against oxidative stress and maintaining redox homeostasis. In the context of viral infections, Nrf2 signaling emerges as a double-edged sword. On one hand, it activates a broad spectrum of antioxidant and cytoprotective genes, contributing to host defense and antiviral immunity. On the other hand, certain viruses exploit the Nrf2 pathway to create a favorable environment for replication, persistence, or immune evasion. This review summarizes the current understanding of Nrf2’s antiviral and proviral roles in both RNA and DNA virus infections, delineates the underlying mechanisms, and discusses the therapeutic implications of targeting Nrf2. We emphasize the need for context-dependent modulation of Nrf2 activity and highlight future directions in precision antiviral strategies.

The transcription factor nuclear factor erythroid 2-related factor 2 (Nrf2) plays a critical role in regulating cellular defense against oxidative stress and maintaining redox homeostasis. In the context of viral infections, Nrf2 signaling emerges as a double-edged sword. On one hand, it activates a broad spectrum of antioxidant and cytoprotective genes, contributing to host defense and antiviral immunity. On the other hand, certain viruses exploit the Nrf2 pathway to create a favorable environment for replication, persistence, or immune evasion. This review summarizes the current understanding of Nrf2’s antiviral and proviral roles in both RNA and DNA virus infections, delineates the underlying mechanisms, and discusses the therapeutic implications of targeting Nrf2. We emphasize the need for context-dependent modulation of Nrf2 activity and highlight future directions in precision antiviral strategies.

Vesicular stomatitis virus (VSV) is a promising oncolytic virus whose replication efficiency and tumor selectivity are strongly influenced by host cell metabolism. Cancer cells, including glioblastoma, exhibit profound rewiring of central carbon metabolism to sustain proliferation, redox balance, and biosynthetic demand, yet how these metabolic states regulate VSV replication remains incompletely defined. Here, we investigated the dependency of VSV replication on glycolysis, the pentose phosphate pathway (PPP), and glutamine metabolism in A172 human glioblastoma cells. Pharmacologic inhibition of glycolysis using 2-DG strongly suppressed VSV replication in a dose-dependent manner, highlighting a robust requirement for glycolytic flux and downstream intermediates. While inhibiting the PPP with 6-AN, a nicotinamide adenine dinucleotide (NAD) analog, markedly impaired viral replication, D-ribose was unable to rescue the inhibition, indicating that nucleotide precursor limitation alone was insufficient to explain this effect. Interestingly, depletion of glucose 6-phosphate dehydrogenase (G6PD), a key enzyme in the PPP, resulted in significant enhancement of VSV replication. Restoration of viral replication by NAD⁺ precursors in the presence of 6-AN or suppression of replication by the NAMPT inhibitor FK866 suggested NAD⁺ availability as a critical determinant of VSV replication. Additionally, blockade of glutaminase activity with BPTES reduced viral replication, underscoring the importance of anaplerotic pathways in glioblastoma cells. Collectively, these findings demonstrate that VSV replication is tightly coupled to metabolic programs, particularly those governing energy production and NAD(P)H balance. This work provides a metabolic framework for optimizing oncolytic VSV therapies and suggests that metabolic interventions in cancer treatment may influence oncolytic virus efficacy.