Increasing the flavivirus envelope glycoprotein dimer stability to elicit potent and broadly neutralizing antibody responses

Dengue, a mosquito borne virus is estimated to infect 390 million people annually, leading to 25,000 deaths. Although recent approaches to vector control appear promising, it is generally agreed that the only way to achieve a step change is an efficacious vaccine. Recent Phase IIB&III trials of a tetravalent live-attenuated-vaccine gave suboptimal efficacy and in particular appeared poor at protecting those not previously exposed to dengue or infection by serotype-2 viruses. This vaccine has been licensed for older children who have previously been infected with dengue, a less than ideal vaccine strategy versus targeting the younger dengue naïve age group. We have recently reported an analysis of the human antibody response to dengue infections and described a major new epitope, the E-dimer epitope, recognized by a class of human antibodies, which are amongst the most potent described to dengue. They efficiently neutralize virus produced in insect as well as primary human cells (the latter being the most difficult to neutralize), most importantly, many of these antibodies potently cross-neutralize the four viruses representing the dengue serocomplex and very recently we have also discovered that they also neutralize Zika virus. These results raise the possibility of using stabilized E-dimers as an immunogen.