A Prototype-Pathogen Approach for the Development of Flavivirus Countermeasures

Abstract

Flaviviruses are a genus within the Flaviviridae family of positive-strand RNA viruses and are transmitted principally through mosquito and tick vectors. These viruses are responsible for hundreds of millions of human infections worldwide per year that result in a range of illnesses from self-limiting febrile syndromes to severe neurotropic and viscerotropic diseases and, in some cases, death. A vaccine against the prototype flavivirus, yellow fever virus, has been deployed for 85 years and is highly effective. While vaccines against some medically important flaviviruses are available, others have proven challenging to develop. The emergence and spread of flaviviruses, including dengue virus and Zika virus, demonstrate their pandemic potential. This review highlights the gaps in knowledge that need to be addressed to allow for the rapid development of vaccines against emerging flaviviruses in the future.

Keywords: antibody neutralization; antibody-dependent enhancement; arbovirus; dynamics; flavivirus; interferon; vaccine; virus-host interaction.

Figure 1.

Transmission cycle of 3 prototype flavivirus pathogens. Dengue virus (DENV) and West Nile virus (WNV) are transmitted via mosquito vectors. For WNV, birds serve as a reservoir for virus and can transmit virus during a mosquito blood meal. Mosquitoes replicate virus and transmit to other vertebrate species, with humans (and horses, not shown) serving as an incidental dead-end host. In contrast, DENV in its urban cycle can be transmitted from a human, because of its high viremia, to a mosquito, and following an intrinsic incubation period in the female mosquito can be transmitted to a naive human host. Rodents serve as a primary reservoir for tick-borne encephalitis virus (TBEV) and, as its name implies, it is transmitted via ticks. Humans are incidental hosts for this virus.

Figure 2.

Flavivirus genome organization, polyprotein translation, and virus particle morphologies. A, The polyprotein genome organization and topology with proteolytic cleavages shown by black arrows (signal peptidase), red arrowhead (furin), and green arrowheads (viral 2B/3C protease). B, A side view of the prM-E trimer colored by domains: E domain I, red; domain II, yellow; domain III, blue; transmembrane domain, cyan; and prM, pink. On the right is a surface-shaded view of the immature virion. C, The E dimer found in the mature virion colored as in (B). The surface shaded view of the mature virion is shown to the right. D, Surface shaded view of subviral particles. E, Surface shaded images of flavivirus particles that have been observed or inferred from cryoelectron microscopy studies. Abbreviations: C, cytoplasmic capsid protein; E, envelope protein; NS, nonstructural protein; prM, precursor membrane protein.

Figure 3.

Antibodies produced following native flavivirus infection or vaccination. Epitopes elicited by flaviviruses differ based on the immunogen presented. In native infections, mature, immature, and mixed virions (partially mature) present complex epitopes that are conformationally dependent on the arrangement of not only E protein dimers, but E protein rafts and the presence of prM, resulting in a diversity of antibody specificities. A gap in knowledge is which types of antibodies provide the best protection and which vaccine strategy can elicit optimal responses. Abbreviations: E, envelope protein; LAV, live-attenuated vaccine; prM, precursor membrane protein.