Abstract
The human virome-comprising viruses that can persist in a host, those that benefit the host, and those that remain latent-has gained increasing acceptance as a modulator of immune response toward vaccination. The factors known to influence vaccine efficacy include host genetics, age, and bacterial microbiota, while the virome is a much less considered fourth dimension. This article reviews how components of the virome such as Torque Teno Virus (TTV), cytomegalovirus (CMV), Epstein-Barr virus (EBV), and bacteriophages impact both innate and adaptive immune responses, including mechanisms of immune pre-activation, trained immunity, and molecular mimicry from both beneficial and detrimental perspectives for vaccine-induced immunization. Emphasis is given to immunocompromised populations such as transplant recipients and those with HIV, where virome composition has been shown to correlate with vaccine responsiveness. Experimental models support clinical observations on how chronic viral exposures can either enhance or inhibit vaccine efficacy. Finally, we discuss virome-aware precision vaccinology and call for the integration of the virome in the development of immunization strategies, thus improving outcomes through customization.