Kurt Kamrud from Harrisvaccines: Alphavirus Platform Interview

Dr. Kurt Kamrud, Vice President of Research and Chief Scientific Officer for Harrisvaccines, is an expert in the field of infectious diseases. After completing his doctorate in microbiology, focusing on the use of alphavirus vectors to examine insect/virus interactions, he conducted research at the United States Army Medical Research Institute for Infectious Diseases (USAMRID) developing alphavirus replicon-based vaccines. Prior to joining Harrisvaccines in 2010, Dr. Kamrud served as the Director of Discovery at AlphaVax, Inc., the commercial developer of the alphavirus replicon vaccine system used at Harrisvaccines. Dr. Kamrud has been granted four international patents pertaining to the alphavirus replicon system. Here he explains more in depth the alphavirus platform used to produce vaccines at Harrisvaccines.

Question: Could you give an overview of the alphavirus platform used at Harrisvaccines?

Answer: Alphaviruses are positive-sense, single-stranded RNA viruses found in the Togaviridae family of viruses.  They have a broad host range and therefore are capable of replicating in many vertebrate and invertebrate cells. Expression vectors have been engineered from Alphaviruses in which the structural protein gene region has been replaced by heterologous genes and have been shown to express high levels of the heterologous protein in cultured cells. These RNA vectors, known as replicons, are capable of replicating on their own but are not packaged into virus-like particles unless the structural proteins are provided in trans. Thus, replicons are single cycle vectors incapable of spreading from infected to non-infected cells.

Question: Why was this platform an area of focus?

Answer: Because of the features I just described, Alphavirus replicon vectors are being developed as a platform vaccine technology for numerous viral, bacterial, protozoan and tumour antigens where they have been shown to be efficient inducers of both humoral and T cell responses. In addition, as the Alphavirus structural proteins are not expressed in vaccine recipients, anti-vector immune responses are generally minimal, allowing for multiple effective immunizations of the same individual.

Question: What are the benefits verses traditional vaccines?

Answer: Advances in the fields of molecular biology, virology and recombinant DNA technologies have led to development of replicon-based vaccines that extend the scope of vaccination to noninfectious diseases and therapeutic vaccination; areas that traditional live attenuated or recombinant subunit approaches have struggled to excel in.

Question: How did this platform come to light and what had been done previously to address the challenge?

Answer: Development of Alphavirus expression vectors began with the study of defective interfering (DI) particles.  DI particles were used to identify the cis-acting sequences essential for replication and packaging of Alphavirus RNAs.  Key discoveries started in the late 1980’s and continued through the late 1990’s.

Question: Who was involved in this discovery?

Answer: The original discoveries came out of academic laboratories both in the United States and in Europe.  The U.S. Army also played an important role in extending the use of alphavirus replicon systems; a human vaccine company named AlphaVax refined manufacturing processes and conducted the first-ever human clinical evaluations with the system.  Subsequently, Harrisvaccines has advanced the replicon system toward USDA regulatory approval and commercial veterinary use.

Question: What was the “aha” moment?

Answer: Because Alphaviruses have a positive-sense RNA genome, full-length cDNA clones of them could be used to generate RNA transcripts that, when introduced into cells, would initiate a complete virus replication cycle and generate infectious virus.  The full-length cDNA clones then served as a DNA-based tool to study an RNA virus genome; study of DI genomes isolated from preparations of live virus then lead to the development of replicon systems in use today.

Question: What challenges have you run into during the process of taking the vaccine closer to USDA licensure?

Answer: Initial characterization of Alphaviruses and the exploitation of their genomes to develop replicon vector systems has occurred over nearly a 30 year time span.  The development of the first licensed replicon-based vaccine for use in veterinary applications will occur very soon; a process that has taken 6 years.