Live attenuated viruses represent the most successful viral vaccines currently licensed for use. Although these viruses are attenuated, they are still cytolytic and consequently result in necrosis of cells which are infected after vaccination. This results in the extracellular appearance of a number of damage associated molecular patterns (DAMPs) which act as natural adjuvants that are recognised by pattern recognition receptors (PRRs), which include TLRs, NLRs and RIG-I like receptors, and necrotic cells are known to be highly immunogenic .
In order to mimic the ability of live attenuated virus vaccines which elicit humoral and cellular immunity very effectively, we evaluated the effect of encoding a cytolytic protein in a DNA vaccine along with the immunogenic protein. The strategy is designed to ensure that the natural adjuvants (DAMPs) stimulate dendritic cells (DC) and other antigen presenting cells, and to ensure that viral antigens which are expressed from the DNA vaccine are phagocytosed and cross presented. A DNA vaccine designed to induce cell necrosis enhanced DC activation and cross presentation of the HIV gag protein in vaccinated mice. This induced a broad, multifunctional T cell response and increased protection, relative to the canonical DNA vaccine, against challenge with a chimeric virus, EcoHIV.
Using a similar hypothesis, we performed a clinical trial using necrotic, HCV antigen-positive autologous dendritic cells to stimulate HCV-specific immunity in HCV-infected individuals who have previously failed conventional interferon-based therapy. This Phase I dose escalation trial resulted in de novo immune responses and a significant reduction in the viral load in several patients.
The enhanced immunity depends on the mechanism and timing of cell death, but we showed that the induction of necrosis in cells which express an immunogenic protein can significantly improve the immunogenicity of different vaccine formulations.