A Dengue/Zika Vaccine That Avoids Antibody-Dependent Enhancement

The present project provides a solution to the principal problem of dengue vaccine development, wherein the use of licensed (and soon to be licensed) vaccines based on existing vaccine strategies runs the risk (in a finite number of cases) of giving rise to 'antibody dependent ehnancement' of dengue infection, making it worse rather than preventing it. Enhancement is a feature of natural infection (where antibodies sent to neutralize the virus are subverted to gain access to human bodily cells), usually upon encounter with a second 'serotype' of virus, resulting in more severe symptoms. Vaccination, while for the most part conferring protection, is liable also to give rise to cases of the severe 'dengue haemmhoragic fever' (DHF), upon first exposure to a wild dengue virus: i.e. 'iatrogenic' cases of DHF, which would not have occurred but for the vaccine. Furthermore, existing vaccine approaches also have the potential to create a population of vaccinated individuals who develop iatrogenic-DHF, at some interval after the vaccine (or vaccine course) has been administered (eg. several years). This is because, as immunity to dengue wanes, protective antibodies reach a concentration where they 'enhance' rather than prevent infection. Also, the rate of decay of 'immunological memory' (where the immune system recalls encounter with a wild virus or vaccine shot) is not synchronous for the four serotypes of the vaccine, such that immunity to each serotype of dengue is lost at different times, successively increasing the risk of severe disease. This gradual failure of immune memory likewise creates a new population of individuals who are now predisposed to DHF (when bitten by an infected mosquito), instead of protected, as a result of previous vaccination. The solution is to make a vaccine that has zero or minimal propensity to give rise to 'antibody dependent enhancement', while preserving efficacy, in a manner amenable to incorporation into several of the various vaccine formats now in existence (live vector, DNA vaccine, oral vaccine, subunit vaccine etc.). For the purposes of this project zika is accorded the status (metaphorically speaking) of a 'fifth dengue serotype'. This is because dengue infection (and current dengue vaccines) have the potential to facilitate the spread of zika by generating infection-enhancing antibodies which also react with zika virus. The object of this project is to generate a safer dengue vaccine with zika built in - in order to avoid the risk of vaccine-mediated facilitation of pandemic spread of zika infection by dengue vaccination. Given the immense societal need and interest on the part of governments and pharma/vaccine companies in vaccinating against dengue and related virus infections, the intellectual property going into this project and generated by it, will become a valuable commodity for new vaccine developers seeking competitive advantage in the marketplace based on safety. 'Safety' will become a criterion of increasing value given the complexities of new epidemics of related viruses (such as the present zika pandemic) and how they interact with national vaccination programmes. The role of natural dengue infection in paving the way for pandemic zika infection has been elaborated recently by Philip K Russell of the Sabin Vaccine Institute (PLoS Negl Trop Dis. 2016 Mar 18;10(3)). Current vaccines may meanwhile be of substantial 'net' benefit to public health, but the safer option promised by the present proposal has the potential to win out.