Understanding DNA Vaccines
Potential for breakthrough vaccines against cancers and infectious diseases
Immunotherapies represent a promising approach for treating an array of significant diseases with significant unmet treatment needs. In particular, active immunotherapies focused on up-regulating the immune system — and capable of generating a strong T-cell response — are considered to provide the greatest potential to better address cancers and chronic infectious diseases such as HIV and hepatitis C virus. While conventional vaccines were a tremendous breakthrough for providing preventive protection against multiple devastating infectious diseases, a new generation of vaccine technology is required to provide more capable prophylactic (prevent against future disease) and therapeutic (treat existing disease) agents. DNA-based immunotherapies and DNA vaccines represent a promising technological path to achieve these goals, with the potential to address diseases with significant unmet treatments needs.
The advantages of DNA vaccines: prevention AND therapy
DNA vaccines use a fragment of DNA to enable the body itself to produce a specific protein, or antigen, uniquely associated with a cancer or an infectious disease such as a bacteria or a virus. This foreign protein is intended to induce a rapid, strong immune response and also build memory of this antigen. If this antigen and therefore the cancer or infectious disease associated with it already exists in the body, or if it is encountered in the future, the immune system will attack it.
This mechanism compares to conventional vaccines, the type of preventive vaccines most of us have received to protect us against diseases like mumps and measles. Such vaccines are simply a live or weakened version of a particular virus or bacteria, which normally present unique proteins on their surface. The body's immune system identifies these antigenic proteins as "foreign," elicits near term antibody production in response to these antigens, and builds memory to protect against future infection.
Conventional vaccines are also active immunotherapies, but one of their key limitations is that they primarily generate antibodies and not T-cells, which are now considered vital to tackling cancers and chronic infectious diseases. In the case of DNA-based immunotherapies and DNA vaccines, because the antigens they code for are expressed by cells of the body, they initiate a sequence of events in the immune system that is able to generate not only antibodies but also a strong T-cell response. DNA-based immunotherapies and DNA vaccines possess other notable advantages over conventional vaccines, as highlighted in the following table:
Inovio and its partners are focused on developing multiple DNA-based immunotherapies and DNA vaccines against cancers and chronic infectious diseases such as HIV and hepatitis C virus.
Read about the challenges of DNA delivery.
More about DNA vaccines...
Why is the immune system often unable to cope with certain diseases?
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 or on the surface of an infected cell. When an infectious disease first enters the body, the immune system may generate an antibody response against the virus or bacteria. If the virus or bacteria is not cleared by this initial immune response, some diseases will progress further by entering and infecting cells. Once a virus or bacteria enter a cell, it is then immune to an antibody response because antibodies don't enter cells. Clearing infected cells is then dependent upon the body generating a T-cell response. If the body's immune system actually attacks cancerous cells, this is also undertaken by T-cells.
But the immune system is often unable or is too slow to recognize a foreign antigen and mount an immune response against it:
- The immune 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 influenza virus infection.
- A virus or bacteria may evolve or mutate quickly under the selective pressure of the immune system; by the time the 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 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.
The magic and the missing elements of conventional vaccines
When it was discovered that creating a prior sensitivity and memory of the immune system against a specific invader would help the body to mount a faster and more powerful attack against this invader if it was again encountered, the idea of preventive vaccination was born. A live or weakened version of a virus is used to make a vaccine, which introduces into the body an antigenic protein (a protein the body recognizes as "foreign") uniquely associated with a particular virus or bacteria. 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 virus or bacteria and is able to generate a more rapid and robust antibody response. This approach led to numerous successful "conventional" vaccines.
Unfortunately, conventional vaccine technology faces a number of challenges and inherent weaknesses:
- Conventional vaccines are effective at triggering an antibody response. But they are only able to address infectious diseases that do not evolve/mutate too rapidly and only prior to the disease infecting cells. Therefore antibody responses and conventional vaccines are not effective against chronic diseases like HIV and hepatitis C virus.
- Conventional vaccines are not adept at generating a T-cell response, which is required to address cells that are already infected or transformed by mutation. Conventional vaccines therefore have a limited ability to treat cancers.
- Conventional vaccines use a live or weakened version of a virus, which is not desirable with diseases such as HIV due to a small risk of infection and disease caused by the vaccine.
- Conventional vaccines can be complicated and expensive to manufacture.
Is there a better approach to stimulate the immune system?
Scientists have been seeking to develop a new generation of immunotherapies to overcome these limitations. The solution they are vigorously pursuing is DNA vaccines, which have the following characteristics:
- Instead of using a live or weakened virus as a vaccine, scientists identify a DNA sequence capable of producing a protein associated with the infectious disease or cancer that they want the immune system to recognize. This DNA sequence is delivered into a cell. The cell's own machinery will transiently "express" the protein encoded by the DNA sequence, potentially producing sufficient quantities of this antigenic protein to trigger the body's immune system.
- DNA vaccines are effective in stimulating antibody responses to attack infectious diseases before they can infect cells, therefore acting as a preventive vaccine.
- Notably, DNA vaccines are efficient at generating T-cell responses because they produce antigen from within cells (antigens produced in this way are readily processed by antigen-presenting cells). T-cells are required to kill cells that are cancerous or already infected by a virus or bacteria. DNA vaccines are therefore not only preventive, but can treat patients with the targeted disease (i.e. they can be used as a therapy).
- 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 such vaccines as the chickenpox vaccine.
- They can be readily and cost effectively manufactured using off-the-shelf fermentation technology.
- In most cases, they do not require cold storage and distribution.
Development progress and successes of DNA-based therapeutics
A broad spectrum of pharmaceutical and biotechnology companies as well as government and non-government research organizations are making a substantial commitment to researching and developing immunotherapy products in general. Two blockbuster immunotherapy products are represented by the following examples:
- Rituxan is a monoclonal antibody (a passive immunotherapy) 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.
In addition, big pharmaceutical companies have announced deals to in-license or acquire DNA-based vaccines and related technology. Examples of these types of transactions are:
- Sanofi-Aventis signed a license agreement in March 2007 for Oxford Biomedica's cancer immunotherapy, based on Phase II results from a renal cancer study. The deal included $39M upfront, $651M in milestone payments, and escalating royalties. The agent, TroVax®, has potential application in a wide range of solid tumors, including renal, colorectal, lung, breast and prostate cancer.
- Roche concluded a license agreement in April 2007 with Transgene for their human papilloma virus (HPV) DNA vaccine, based on Phase II data. The deal included $18M upfront, $270M in milestone payments, and double-digit escalating royalties.
- Pfizer acquired DNA vaccine delivery company PowderMed, developer of the gene gun, in October 2006 for a reported $400M.
What are the development prospects for DNA vaccines?
These approvals and deals provide technical and anecdotal evidence that immunotherapy approaches including DNA vaccines hold significant potential to be successfully developed, provide clinical benefit, and deliver value to the companies pursuing these developments.
Despite the successes, one persistent challenge to the advancement of DNA vaccines has been delivery. The DNA vaccine must enter cells in selected tissue — and in sufficient quantities — in order for the cellular machinery to begin production of the protein for which the vaccine was encoded. Achieving this step requires a safe and efficient method — and ideally cost effective — to enable cellular uptake of a DNA vaccine and significantly enhance its potency. This has been elusive — but Inovio is achieving promising results with its novel, proprietary DNA delivery technology called electroporation.