- Chimera vaccine platform to provide coverage against all four DENV serotypes.
- Feasibility of approach demonstrated in non-human primate studies, where serotype-specific neutralizing antibodies were generated.
- Genetic engineering approaches to improve the efficacy of DENV vaccine constructs and to reduce unwanted effects from antibody dependent enhancement.
Mosquito-borne Dengue Virus (DENV) is a major global public health concern with ~400 million new cases of DENV infections annually. There are four serotypes of DENV and exposure to one serotype does not guarantee immunity from infection by the other three serotypes. This is a significant problem as previous DENV infection puts individuals at an increased risk of developing hemorrhagic fever when re-infected by a different DENV serotype. As a result, an effective vaccine must elicit immunity to all DENV serotypes. The only FDA approved vaccine for Dengue does not elicit a balanced cross-neutralizing response against all DENV serotypes. Consequently, there is an urgent need for a DENV vaccine that can provide protection against all four serotypes.
Researchers in the Departments of Epidemiology and Microbiology and Immunology, led by Drs. Ralph Baric and Aravinda Desilva, have developed a novel chimeric DENV vaccine platform to provide protection across all four DENV serotypes. Binding sites of DENV-neutralizing antibodies have been identified, which form the basis of the vaccine candidates. Based on these epitopes, recombinant chimeric DENVs have been developed, in which the EDI, EDII, or EDIII domain of the E protein of one DENV serotype are individually transplanted into the backbone of another DENV serotype. For example, serotype 3 is the backbone and E domain II residues from serotype 1 are transplanted to create a 3/1 chimera. Combinations of all four serotypes have been developed, 3/1, 2/4, 1/3, and 4/2. To provide coverage across all four serotypes, an example prime-boost strategy would be to prime with the 3/1 and 2/4 chimeras, followed by a boost with the 1/3 and 4/2 chimeras. Studies in non-human primates have demonstrated the feasibility of the approach, as DENV 2 and DENV 4 serotype-specific neutralizing antibodies have been identified in non-human primates receiving a 2/4 DENV chimera vaccine.
To improve the efficacy of DENV vaccine constructs and reduce antibody dependent enhancement (ADE), the researchers have also developed genetically mature DENV particles through engineering of the prM protein and the fusion loop. The dengue virus prM glycoprotein goes through a maturation process in which the protein is cleaved by furin. During a normal human infection, the prM protein is consistently presented in its mature state. However, it has been found that in cell culture and in manufactured virus that there is an inconsistent mix of mature and immature protein that affect the virus’ ability to generate neutralizing antibodies. Genetic engineering of the prM protein also enhances stability of the vaccine constructs. While genetic engineering of the fusion loop results in a vaccine construct that would elicit neutralizing antibodies, but not ADE antibodies, and result in a safter vaccine candidate This genetic engineering approach can be used to enhance the safety and efficacy of exiting flavivirus vaccine constructs or could be combined with the chimeric DENV vaccine constructs also under development. UNC Refs. 22-0095, 22-0036, 21-0099, 19-0125, 17-0116
Name: Matthew Howe