Zika virus (ZIKV) is an arbovirus linked to severe complications and for which there is no approved vaccine yet. ZIKV is an enveloped virus, the virion is composed by three structural proteins: capsid (C), precursor-membrane (prM) and envelope (E), which is the glycoprotein responsible for mediating cell entry and, consequently, a major target of the antibody response. A relevant complication in the design of a ZIKV vaccine is its proximity to dengue virus and the risk to stimulate cross-reactive and poorly neutralizing antibodies, responsible for antibody-dependent enhancement of infection (ADE).

The often-incomplete maturation process of the E protein together with the metastability of its dimers are responsible for the dynamic behaviour of the virus, the so-called “viral breathing”, which is an essential feature for the virus biology, but it has also important consequences on its antigenicity.

We compared two ZIKV isolates belonging to the Asian lineage: the Brazilian PE243 and the Puerto Rican PRVABC59. Despite sharing high sequence similarity and identical in vitro growth kinetics, PE243 exhibited lower pathogenicity in mouse and poor dissemination capacity, both in mouse and in mosquito. Interestingly, PE243 was more susceptible to antibody-mediated neutralization when treated with polyclonal sera, whilst no differences were observed with monoclonal antibodies, suggesting a higher exposure of cryptic epitopes. Structural stability and dynamic properties of the two viruses were evaluated by molecular dynamics, taking into consideration several key structural descriptors. The comparative analysis indicated that PE243 exhibits a more destabilized and flexible profile.

These findings suggest that the mutations in PE243 may exert an influence on viral structure and dynamics, particularly affecting regions involved in membrane fusion. Tailoring down to the single mutations responsible for it may allow the design of more stable vaccines, able to elicit antibodies with stronger neutralization capacity and lower potential of stimulating Dengue ADE Dengue.