New life from dead cells: necrotic cell vaccines and immunotherapy

New life from dead cells: necrotic cell vaccines and immunotherapy

New life from dead cells: necrotic cell vaccines and immunotherapy (#31)

Eric J Gowans ¹

Virology Laboratory, Department of Surgery, University of Adelaide, Basil Hetzel Institute for Translational Medicine, Adelaide, SA, Australia

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.

Authors contributing to this presentation.

Gowans, E.J

Eric Gowans completed his early training in Edinburgh in diagnostic Bacteriology and Virology through Napier College (now Napier University). He then spent some time as a full time electron microscopist with emphasis on Virology and was recruited to work with Professor Barrie Marmion and Dr (now Professor) Christopher Burrell to investigate the cause of an outbreak of hepatitis in the renal dialysis unit. He was recruited to the IMVS, Adelaide in 1979 and subsequently completed a PhD on aspects of the replication strategy of HBV. He was awarded a Senior Research Fellowship from the National Health and Medical Research Council (NHMRC) in 1993, He was appointed as Director, Sir Albert Sakzewski Virus Research Centre, Brisbane in 1995 and Honorary Professor in the University of Queensland. As a result of a contract from the Federal Government, he showed that hepatitis G virus was not pathogenic and as a result of this work, the Federal Government decided against the introduction of HGV testing in the Blood Banks, at an annual saving of $30M (1998). He then took up the position of Senior Principle Research Fellow in the Burnet Institute, Melbourne and continued his work on HCV. He was awarded a grant from the National Institutes of Health in the USA to examine the efficacy of dendritic cell immunotherapy in HCV infection. This work culminated in a clinical trial in HCV patients that was completed in 2008, immediately before he moved back to Adelaide. He was appointed as Honorary Professor in the Discipline of Surgery, University of Adelaide and established his laboratory at the Basil Hetzel Institute, the research wing of The Queen Elizabeth Hospital. He has continued his work to design novel vaccines for HCV, and because many of the problems and issues related to a vaccine for human immunodeficiency virus (HIV) are similar, he and his laboratory staff also study HIV vaccine design. Throughout his career, Eric Gowans has supervised 17 PhD graduates and 2 Masters graduates, and is currently the principal supervisor for 4 PhD students. His laboratory is currently funded by grants from the National Health and Medical Research Council, from the Australian Centre for HIV and Hepatitis Virology and from the Australia-India Biotechnology Fund.

New life from dead cells: necrotic cell vaccines and immunotherapy (#31)

Add notes

Gowans, E.J

Login