The bright and the dark side of human antibody responses to flaviviruses: lessons for vaccine design

Abstract

Zika and dengue viruses belong to the Flavivirus genus, a close group of antigenically related viruses that cause significant arthropod‐transmitted diseases throughout the globe. Although infection by a given flavivirus is thought to confer lifelong protection, some of the patient's antibodies cross‐react with other flaviviruses without cross‐neutralizing. The original antigenic sin phenomenon may amplify such antibodies upon subsequent heterologous flavivirus infection, potentially aggravating disease by antibody‐dependent enhancement (ADE). The most striking example is provided by the four different dengue viruses, where infection by one serotype appears to predispose to more severe disease upon infection by a second one. A similar effect was postulated for sequential infections with Zika and dengue viruses. In this review, we analyze the molecular determinants of the dual antibody response to flavivirus infection or vaccination in humans. We highlight the role of conserved partially cryptic epitopes giving rise to cross‐reacting and poorly neutralizing, ADE‐prone antibodies. We end by proposing a strategy for developing an epitope‐focused vaccine approach to avoid eliciting undesirable antibodies while focusing the immune system on producing protective antibodies only.

Zika Virus Dependence on Host Hsp70 Provides a Protective Strategy against Infection and Disease

“…Given its burden on global health, antiviral treatments or effective vaccines for ZIKV are urgently needed. Some anti-ZIKV vaccines have shown promise (reviewed in Fernandez and Diamond, 2017), but establishing their safety and efficacy can take a significant amount of time and faces significant challenges (Rey et al, 2018). Small-mole-cule therapeutics against ZIKV should provide an important countermeasure alternative (Barrows et al, 2016; Xu et al, 2016), particularly if they are also effective against related mos-quito-borne flaviviruses, such as dengue virus (DENV), which also causes devastating illness.…”

Common Features of Enveloped Viruses and Implications for Immunogen Design for Next-Generation Vaccines

“…The resulting opsonized particles are efficiently internalized via Fcg receptors into macrophages and other cells of the immune system, where the virus particle, which is not neutralized by the bound antibody, fuses with the endosomal membranes and infects the cell in an antibody-dependent enhancement (ADE) of the infection. As reviewed recently (Rey et al, 2018), the mechanism behind ADE appears to be related to particle heterogeneity introduced by partial maturation of the UGP as well as conformational dynamics of the fusion protein on the mature virions (illustrated in Figure 3B).…”

Les vaccins de demain

“…De nombreuses technologies se mettent en place pour améliorer les vaccins existants ou en découvrir de nouveaux champs de recherche sont en cours pour mieux comprendre les mécanismes susceptibles d'influencer la réponse vaccinale, par exemple le microbiome [40] mais également leurs possibles effets secondaires qu'ils soient non spécifiques ou liés à la spécificité de la réponse immunitaire induite, comme c'est le cas pour les flavivirus [41]. Il reste également à intensifier les recherches sur l'immunité de groupe afin d'estimer son impact sur les calendriers vaccinaux afin de voir s'il convient de cibler les classes d'âge chez lesquelles la réponse immunitaire est la plus optimale [42].…”