A Perspective on Current Flavivirus Vaccine Development: A Brief Review

Abstract

The flavivirus genus contains several clinically important pathogens that account for tremendous global suffering. Primarily transmitted by mosquitos or ticks, these viruses can cause severe and potentially fatal diseases ranging from hemorrhagic fevers to encephalitis. The extensive global burden is predominantly caused by six flaviviruses: dengue, Zika, West Nile, yellow fever, Japanese encephalitis and tick-borne encephalitis. Several vaccines have been developed, and many more are currently being tested in clinical trials. However, flavivirus vaccine development is still confronted with many shortcomings and challenges. With the use of the existing literature, we have studied these hurdles as well as the signs of progress made in flavivirus vaccinology in the context of future development strategies. Moreover, all current licensed and phase-trial flavivirus vaccines have been gathered and discussed based on their vaccine type. Furthermore, potentially relevant vaccine types without any candidates in clinical testing are explored in this review as well. Over the past decades, several modern vaccine types have expanded the field of vaccinology, potentially providing alternative solutions for flavivirus vaccines. These vaccine types offer different development strategies as opposed to traditional vaccines. The included vaccine types were live-attenuated, inactivated, subunit, VLPs, viral vector-based, epitope-based, DNA and mRNA vaccines. Each vaccine type offers different advantages, some more suitable for flaviviruses than others. Additional studies are needed to overcome the barriers currently faced by flavivirus vaccine development, but many potential solutions are currently being explored.

Keywords: Japanese encephalitis and tick-borne encephalitis; West Nile; Zika; clinical trials; dengue; flavivirus; vaccines; yellow fever.

Figure 1

Bayesian evolutionary analysis sampling tree cladogram of the mosquito- (blue) and tick- (green) borne flavivirus-infecting vertebrates. The tree was constructed using the Bayesian Markov chain Monte Carlo method available in MrBayes v.3.2.3 [3]. The six medically relevant viruses, DENV (serotype 1–4), ZIKV, WNV, YFV, JEV and TBEV, have been highlighted in red.

Figure 2

Countries at risk for DENV infections. Countries labeled Frequent/Continuous are currently experiencing DENV outbreaks or ongoing DENV transmission, while Sporadic/Uncertain suggests a varying and unpredictable risk and the unavailability of country-wide data [11]. Map created using QGIS software (small countries not included).

Figure 3

The global distribution and countries at risk for flavivirus infections. ZIKV is found throughout the sub-tropical and tropical regions of the Americas, Africa and Asia [9]. The risk for WNV infection is localized in Europe, parts of Africa and the Americas [12,13], whereas the risk for YFV is only found in South America and Africa [14]. Ongoing transmission of JEV occurs in Asia and Oceania [15,16], and TBEV is distributed throughout Europe and northeast Asia [17,18]. Map created using QGIS software (small countries not included).

Figure 4

Flavivirus vaccine strategies.