The emergence of significant arboviruses and their spillover transmission to humans represent a major threat to global public health. No approved drugs are available for the treatment of significant arboviruses in circulation today. The repurposing of clinically approved drugs is one of the most rapid and promising strategies in the identification of effective treatments for diseases caused by arboviruses. Here, we screened small-molecule compounds with anti-tick-borne encephalitis virus, West Nile virus, yellow fever virus and chikungunya virus activity from 2580 FDA-approved drugs. In total, 60 compounds showed antiviral efficacy against all four of the arboviruses in Huh7 cells. Among these compounds, ixazomib and ixazomib citrate (inhibitors of 20S proteasome β5) exerted antiviral effects at a low-micromolar concentration. The time-of-drug-addition assay suggested that ixazomib and ixazomib citrate disturbed multiple processes in viruses’ life cycles. Furthermore, ixazomib and ixazomib citrate potently inhibited chikungunya virus replication and relieved virus-induced footpad swelling in a mouse model. These results offer critical information which supports the role of ixazomib as a broad-spectrum agent against arboviruses.

Coronaviruses (CoVs) are emerging pathogens with a significant potential to cause life-threatening harm to human health. Since the beginning of the 21st century, three highly pathogenic and transmissible human CoVs have emerged, triggering epidemics and posing major threats to global public health. CoVs are enveloped viruses encased in a lipid bilayer. As fundamental components of cells, lipids can play an integral role in many physiological processes, which have been reported to play important roles in the life cycle of CoVs, including viral entry, uncoating, replication, assembly, and release. Therefore, research on the role of lipids in the CoV life cycle can provide a basis for a better understanding of the infection mechanism of CoVs and provide lipid targets for the development of new antiviral strategies. In this review, research advances on the role of lipids in different stages of viral infection and the possible targets of lipids that interfere with the viral life cycle are discussed.

Although recombinant vaccines with various adjuvant systems are widely deployed in global coronavirus disease 2019 immunization, their distinct immune profiles have not been fully elucidated. In this study, we evaluated immune responses induced by four clinically validated adjuvants—aluminum hydroxide (Al), two water-in-oil emulsions (Montanide ISA720 and ISA51), and an oil-in-water emulsion (Sepivac SWE)—formulated with the prefusion-stabilized ancestral severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike trimer (S-2P) in mouse models. Both S-2P:ISA720 and S-2P:ISA51 elicited potent humoral immunity, including cross-neutralizing antibodies against Omicron variants, along with robust interferon gamma-producing T-cell responses in the spleen and lung. Immunization with S-2P:ISA720 conferred complete protection against lethal challenge with the ancestral virus as well as Omicron subvariants BA.5 and BF.7. In contrast, S-2P:Al and S-2P:SWE elicited substantially weaker antibody responses, undetectable T-cell immunity, and markedly reduced protective efficacy. Prime-boost immunization with S-2P:ISA720 induced sustained peak antibody titers against both homologous SARS-CoV-2 and the Omicron BA.2 subvariant, affording complete protection for up to 17 weeks post-vaccination. While a third dose of S-2P:Al following a prime-boost regimen triggered a robust increase in antibody levels, titers declined rapidly thereafter, recapitulating the decay kinetics observed after the second dose. Both ISA720 and Al formulations exhibited age-dependent declines in antibody responses and protective efficacy. Notably, aged mice displayed markedly attenuated neuroinflammatory responses following SARS-CoV-2 challenge and significantly compromised protection after adoptive transfer of immune serum. These results underscore adjuvant-specific determinants of broad and durable immunity and reveal novel age-related constraints in vaccine-induced protection against SARS-CoV-2. IMPORTANCE: Persistent viral evolution, rapid waning of vaccine-induced immunity, and the heightened vulnerability of elderly populations remain major challenges for COVID-19 vaccination strategies. In this study, we systematically assessed immune responses elicited by the ancestral spike protein formulated with four distinct adjuvants in mouse models. We demonstrate that an optimized adjuvant formulation markedly enhances the magnitude and breadth of antibody responses, potentiates T-cell immunity, and rapidly induces sustained peak antibody titers against both homologous virus and Omicron variants. Vaccine-induced antibody responses were significantly attenuated in aged mice, and furthermore, both the protective efficacy of antibodies and inflammatory cytokine responses upon viral challenge were impaired in aged animals. These results provide compelling evidence that rational adjuvant selection is critical for enabling recombinant vaccines to achieve rapid-onset, broad, and durable immune protection. Furthermore, our study offers new mechanistic insights into the reduced vaccine efficacy observed in the elderly.

• Scientific question: The continual evolution of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), compounded by immune imprinting, poses an ongoing challenge to the development of broadly protective coronavirus disease 2019 (COVID-19) vaccines. How exactly pre-existing immunity, particularly its magnitude and affinity, shapes the strength and breadth of the recall antibody response remains poorly understood. • Evidence Before This Study: Previous studies have shown that booster vaccinations and breakthrough infections can broaden immunity against SARS-CoV-2 variants. It is also established that extending the interval between antigen exposures or increasing antigenic distance between variants can attenuate original antigenic sin. • New Findings: We demonstrate that adjuvants substantially affect both the potency and epitope diversity of antibodies elicited by recombinant vaccines. Furthermore, pre-existing high-affinity antibodies mediate epitope masking of immunodominant sites, thereby shifting the immune response toward conserved, subdominant epitopes with cross-neutralizing potential. • Significance of the Study: The quantity and quality of pre-existing antibodies critically guide the recall antibody response toward broad neutralization and affinity maturation upon re-exposure. This insight offers a rational framework for developing next-generation vaccines against SARS-CoV-2 and other antigenically variable pathogens.