DNA Vaccines Background
To appreciate how DNA vaccines are extending the boundaries of the boundaries of immunotherapy research, the following sections summarize the capabilities and limitations of the immune system and conventional vaccine technology and then introduce DNA vaccines and their advantages.
Immune system limitations
The body's immune system is capable of addressing many potentially harmful diseases. It does this by recognizing "foreign" proteins, or antigens, on the surface of a virus or bacteria. When an infectious disease first enters the body, if the immune system recognizes the pathogen as being foreign, it will generate an antibody response against the virus or bacteria. If the virus or bacteria is not cleared by this initial immune response, some pathogens will enter and infect cells.
Once a virus or bacteria enters a cell, it is then relatively protected from an antibody response because antibodies don't enter cells. Clearing infected cells is then dependent upon the body generating a T-cell response to destroy those cells. In the case of cancers, IF the body's immune system is able to identify a cancerous cell as harmful and mount an immune response, it is again T-cells that must be generated to efficiently kill those cells.
Unfortunately, the immune system is often unable or is too slow to recognize an antigen associated with a pathogen or infected/cancerous cell and mount an immune response for a number of possible reasons:
- The immune system's antibody response is often too slow against diseases that grow rapidly once they enter the body. The disease may simply overwhelm the immune system. An example of this is an influenza virus infection in a naïve host.
- A virus or bacteria may evolve or mutate quickly under the selective pressure of the immune system. By the time a robust immune response is mounted by the body, the infectious agent may have changed into different forms that the immune system is not specifically seeking. An example of this is HIV.
- If the potentially antigenic proteins are produced by cells in the body, i.e. cancerous cells or cells already infected by a virus, the body may perceive them to be "self," not foreign, and will not attack them.
These inherent immune system weaknesses have allowed centuries of numerous infectious diseases to have devastating effects on populations – smallpox alone was responsible for an estimated 300-500 million deaths in the 20th century – and served as a catalyst to the discovery of and continuing research on vaccination.
Conventional vaccine limitations
When it was discovered that creating a prior sensitivity and immune system memory against a specific invader would help the body mount a faster and more powerful attack against this invader if it was again encountered, the idea of preventive vaccination was born. A dead or weakened pathogen (virus or bacteria) is used to make a vaccine, which when introduced into the body presents an antigenic ("foreign") protein uniquely associated with that particular pathogen. The immune system responds to this "attacker" and then develops long-term memory of this protein. If the real virus or bacteria enters the body, the immune system recognizes the unique protein associated with the pathogen and generates a more rapid and robust antibody response. This approach led to the development of numerous successful conventional vaccines.
Unfortunately, conventional vaccine technology has key weaknesses when tested against more chronic infectious diseases and cancer. Conventional vaccines:
- Are designed to attack specific pathogen strains and may provide little or no protection against, for example, new strains of influenza that evolve over time, or against a virus such as HIV, which can evolve once it enters the body.
- Are not adept at generating T-cell responses to kill cells infected by a pathogen that was able to avoid the first-responder antibodies or to kill mutated cells.
- May use a weakened version of a virus, which is not desirable for diseases such as HIV due to a possible risk of infection caused by the vaccine.
- Are complicated and expensive to design.
- Are often difficult and time consuming to manufacture. Because of the need to grow vaccines in chicken eggs, significant manufacturing bottlenecks do not facilitate rapid production increases to address rapidly spreading diseases such as pandemic influenza.
The next generation: DNA vaccine advantages
Scientists have been seeking to develop a new generation of immunotherapies to overcome these weaknesses of conventional vaccine technology. One important approach Inovio is vigorously pursuing is DNA-based vaccines, which have the following characteristics:
- Instead of using a killed or attenuated virus as a vaccine, scientists identify a unique antigenic protein(s) associated with the pathogen and the DNA sequence that produce the protein(s). This DNA sequence, itself innocuous, is delivered into cells of the body. The cells' own machinery may then produce the protein encoded by the DNA sequence.
The intent is to produce sufficient quantities of this foreign (antigenic) protein to trigger the body's immune system to attack the targeted disease. - DNA vaccines are effective in stimulating antibody responses to attack infectious diseases as they enter the body, before they can infect cells, therefore acting as a preventive vaccine.
- DNA vaccines are efficient at generating T-cell responses that may kill targeted cancerous cells or cells infected by the targeted virus or bacteria. DNA vaccines may therefore also be used as a therapeutic to treat existing disease. This capability provides the potential to treat chronic infectious diseases such as HIV and hepatitis C virus, as well as the possibility to develop therapeutic cancer vaccines.
- DNA vaccine technology provides the opportunity to design sophisticated, multi-antigen vaccines and/or vaccines based on conserved genes and antigens that are common to evolved strains of a pathogen, e.g. the potential exists to develop a universal influenza vaccine to protect against both seasonal influenza strains as well as new influenza strains that cannot be known in advance and which present pandemic risk, such as new strains of avian influenza or the Mexican H1N1 influenza.
- DNA sequences from multiple strains of a virus like influenza can also be designed in a "consensus" form where one antigen is able to confer protection against any one of the original viral strains.
- DNA vaccines can potentially be developed from concept to FDA approval in eight to 10 years, rather than as much as 20 years that it took to develop, for example, the chickenpox vaccine.
- They can be readily and cost effectively manufactured using off-the-shelf, well-proven fermentation technology.
- In most cases, they do not require cold storage and distribution.
The following table compares conventional and DNA vaccines:
Inovio Biomedical is focused on advancing its DNA vaccine discovery, development and delivery capabilities to create a broad platform with which to create compelling new vaccines. The company is specifically developing vaccines against HIV, HCV, HPV, and influenza. Partners and collaborators are also using Inovio's delivery technology for vaccine research and development focused on cancers and infectious diseases.
What are the development prospects for DNA vaccines?
A broad spectrum of pharmaceutical and biotechnology companies as well as government and non-government research organizations have made a substantial commitment to researching and developing products under the broad scientific umbrella of immunotherapies.
A number of notable technical and commercial accomplishments over the last decades have marked the advancement of the immunotherapy field and provided growing evidence and encouragement that DNA vaccines can be successfully developed, provide clinical benefit, and deliver value to the companies pursuing these developments.
Examples of blockbuster immunotherapy products are:
- Rituxan: This monoclonal antibody (a passive immunotherapy) was approved by the FDA in November, 1997, for use in the treatment of mild cases of B-cell non-Hodgkin Lymphoma (NHL), a type of cancer. This immunotherapy, made by Genentech, Inc., had already achieved $1.8 billion in annual sales labeled as only a cancer treatment before receiving approval in 2006 to also treat rheumatoid arthritis.
- In 1998, the U.S. Food and Drug Administration granted approval to trastuzumab (Herceptin®, made by Genentech, Inc.), a passive immunotherapy used as part of a treatment regimen for the treatment of women with HER2-overexpressing breast cancer.
All of the big vaccine companies have DNA vaccine development programs. As an example of their interest, in April, 2007, Roche concluded a license agreement with Transgene for their human papilloma virus (HPV) DNA vaccine, based on Phase II data. The deal included €23m in upfront payments, €195m in potential milestone payments plus double-digit escalating royalties.
As another potential indicator of DNA vaccine development success in humans, there have been multiple recent product approvals for DNA-based products for animals:
- In 2005, the US Department of Agriculture approved a DNA vaccine for use in horses against West Nile virus.
- In 2005, a DNA vaccine was approved to protect farmed salmon from infectious hematopoietic necrosis, which was killing large numbers of the fish.
- In 2007, the US Department of Agriculture provided conditional approval of a DNA vaccine against melanoma for dogs.
- In 2008, the Australian Pesticides and Veterinary Medicines Authority approved a DNA-based growth hormone-releasing hormone, delivered using electroporation, for use in swine. The product was developed by VGX Pharmaceuticals, which merged with Inovio, to decrease perinatal mortality and morbidity and increase sow productivity.
The success of these DNA-based agents in larger animals provides additional encouragement regarding the potential success of DNA-based therapies in humans.
As a leader in DNA vaccine design optimization and development as well as DNA delivery, Inovio Biomedical is well-positioned to potentially achieve important breakthroughs in this promising field.