Synthetic DNA vaccine strategies against persistent viral infections

Abstract

The human body has developed an elaborate defense system against microbial pathogens and foreign antigens. However, particular microbes have evolved sophisticated mechanisms to evade immune surveillance, allowing persistence within the human host. In an effort to combat such infections, intensive research has focused on the development of effective prophylactic and therapeutic countermeasures to suppress or clear persistent viral infections. To date, popular therapeutic strategies have included the use of live-attenuated microbes, viral vectors and dendritic-cell vaccines aiming to help suppress or clear infection. In recent years, improved DNA vaccines have now re-emerged as a promising candidate for therapeutic intervention due to the development of advanced optimization and delivery technologies. For instance, genetic optimization of synthetic plasmid constructs and their encoded antigens, in vivo electroporation-mediated vaccine delivery, as well as codelivery with molecular adjuvants have collectively enhanced both transgene expression and the elicitation of vaccine-induced immunity. In addition, the development of potent heterologous prime-boost regimens has also provided significant contributions to DNA vaccine immunogenicity. Herein, the authors will focus on these recent improvements to this synthetic platform in relation to their application in combating persistent virus infection.

Figure 1. Kinetics of viral load during viral infection and after different therapies

(A) The prevention of viral production and infection when a prophylactic vaccine is administered and establishes effective memory immune responses. (B) The course of an acute infection. Virus-specific T-cell effectors become activated and control the virus infection. After viral clearance, effector cells contract to become memory cells, which are pivotal in preventing reinfection with the same virus. (C) The cycle of a latent persistent viral infection that stays with the host indefinitely. After viral acquisition, virus production ceases; however, because the virus genome is not completely eradicated, the virus can reactivate. Upon the required stimulus for reactivation, the virus can begin producing viral progeny (lytic form of viral cycle), allowing disease to resurface. (D) The natural course of a chronic infection in which incessant viral production exhausts immune responses and disease can no longer be controlled or prevented. Continuous exposure of T cells to viral-specific antigens eventually causes effector cells to become exhausted, leading to deletion of these dysfunctional cells. (E) New therapeutic approaches for chronic viral infections might reconstitute virus-specific immune responses and lead to virus clearance and disease prevention.