Epitope Based Vaccines for Flaviviruses

Flaviviridae are a family of positive, single-stranded enveloped RNA viruses that are typically transmitted to humans via mosquitoes and ticks. Yellow Fever virus, West Nile virus and Dengue virus are examples of human Flavivirus pathogens. Dengue virus has 4 serotypes, and getting infected by one serotype, does not protect against the other three. Moreover, pre-infection by one serotype can actually lead to more severe disease upon second infection by a different serotype, a phenomenon referred to Antibody Dependent Enhancement (ADE). Here we propose a novel vaccine modality designed to prevent ADE. A select neutralizing epitope of the Dengue virus envelop protein has been reconstituted to provide a unique epitope-based immunogen. Using such a focused, targeted vaccine should elicit protective antibodies without producing non-neutralizing antibodies that mediate ADE. In view of the fact that the envelop structure of numerous pathogenic Flaviviruses is highly conserved, we propose that the method used to produce the Dengue epitope-based vaccine can be applied to a variety of other Flavivirus human pathogens.

Vaccines against Flaviviruses vary in their efficacy. The Yellow Fever Vaccine is highly protective. Unfortunately, attempts to produce an effective cross-protective Dengue Vaccine have been unsuccessful leading to a recall of a Sanofi Pasteur product that led to ADE in some vaccinees that were breakthrough infected post vaccination. Hence, the proposed epitope-based vaccine has been designed to obviate ADE.

The underlying mechanism of ADE is thought to be due to the production of non-neutralizing antibodies along with neutralizing antibodies in response to vaccination or the clearance of clinical disease. The non-neutralizing antibodies can then cross react with other serotypes of Dengue. Obviously, these antibody/virus complexes are not neutralized, and continue to be infectious. Moreover, due to the bound antibodies, the viruses can bind to Fc-receptors of macrophages and infect them, thus leading to enhanced infection and disease. Our technology focuses the immune response exclusively to the neutralizing epitope of the virus and does not elicit any non-neutralizing antibodies.

The immediate application is to produce an effective epitope targeted vaccine for Dengue. One approach would be to reconstitute an epitope-based immunogen that elicit cross protection. The alternative would be to reconstitute a separate immunogen corresponding to each of the 4 serotypes. Furthermore, we can also explore the reconstitution of neutralizing epitopes for closely related Flaviviruses such as Zika virus.

Thus far we have reconstituted a neutralizing epitope of Dengue virus serotype 1. Preliminary data have been produced illustrating that this epitope can elicit antibodies in mice that can bind VLPs of Dengue.

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