Can the human body be tricked into defending itself from viral infections? We interviewed Dr. Rajan George, Adjunct Faculty of the University of Alberta’s Pharmacy and Pharmaceutical Sciences Department. Dr. George is also Vice President of Research and Development for the Division of Infection Diseases of ViRexx Medical Co. As part of the team of University of Alberta scientists, a therapeutic vaccine is now being developed which may inoculate against Hepatitis, Anthrax and Avian Flu H5N1.
Interviewer: Can you describe ViRexx Medical’s Chimigen™ therapeutic vaccine?
Dr. Rajan George: Chimigen therapeutic vaccine is used to produce immune responses in a host against infections which are difficult to produce immune responses, by targeting the vaccine to dendritic cells. The Chimigen platform can be extended to develop therapies for difficult-to-treat chronic infectious diseases.
Interviewer: Does that mean the Chimigen platform can be used to treat any infectious disease?
Dr. Rajan George: Yes, except in cases where the immune system is non-functional, as in the case of HIV.The Chimigen platform can be used to produce either a therapeutic vaccine or a prophylactic vaccine. This depends on the disease target and the antigen plugged into the platform. Some antigens have a use in treating infection, while others have a use in preventing an infection. Either one would be targeted to the dendritic cells. The therapeutic vaccine generates a cytotoxic T cell response. A prophylactic vaccine would generate a B cell response and antibody production.
Interviewer: From the way you’ve described the Chimigen™ vaccine, it appears potentially useful for many applications beyond Hepatitis B and C. How broad are the applications?
Dr. Rajan George: We should be able to use this platform for cancer therapy, depending upon the cancer antigen we use. We can plug in a specific cancer antigen into this platform, and the vaccine targeted to dendritic cells. The dendritic cells would process and present the right antigen, then generating immune responses (T &B cell) against the cancer. We are also evaluating some bioterrorist viruses, the biological weapons terrorists would use. We just started a project to look at one of those viruses to see if we can come up with the prophylactic vaccines to prevent diseases that would be caused by organism that could be used in bioterrorism.
Interviewer: Would the Chimigen™ vaccine be effective as a prophylactic against avian flu, H5N1?
Dr. Rajan George: It could work for bird flu if we just plugged in the bird flu antigen into the platform. Then we can use it as a prophylactic. It generates antibody to generate B-Cell response. You can produce a prophylactic vaccine using this platform. The Chimigen™ platform is quite adaptable.
Interviewer: How high is your confidence level in producing a prophylactic vaccine for the avian flu virus?
Dr. Rajan George: My thinking is that it is quite high. I think very highly of having a vaccine like that. But, the ultimate proof has to come from humans. Our HepaVaxx B clinical trial will give us a lot of information on how the technology really works. Until then, our optimism is based on laboratory results.
Interviewer: Can you describe what comprises the Chimigen platform?
Dr. Rajan George: The platform has two components. The first one is from the infectious agent. The second component is from a murine monoclonal antibody. Part one is fused with a fragment of part two by recombinant technology to produce a new entity, the Chimigen™ vaccine. We are recombining one thing with another. We have a virus which has certain antigens. We take one of those, and we produce a recombinant molecule with the fragment we have taken from a murine monoclonal antibody. Chimigen is the term we came up with to include the meaning of the full phrase, chimeric antigen. Chimeric means it comes from two different sources. We put them together and create a new molecule. One is from the virus. The other one is from the mouse, the monoclonal antibody. Now we have by recombinant methods produced a protein which is a chimeric protein. That’s the Chimigen™ vaccine.
Interviewer: How do you produce such a flexible vaccine, one that appears capable of treating nearly any infection?
Dr. Rajan George: To produce a Chimigen™ vaccine to treat nearly any infection, we start with an antigen (protein) from the infectious agent. We fuse it with a fragment called Fc of a mouse monoclonal antibody. This is done using recombinant methods. We end up with a new protein. This protein is made in a cell culture of commercially available insect cells. The protein is produced by the insect cells. From the culture, we purify this particular protein that we made. The insect cell system is just a tool. By virtue of its production in insect cells, the protein attains special properties which are useful in generating better immune responses. Producing this protein in insect cells gives it some very peculiar properties, which are different from our own mammalian proteins. Once we have it coming out of the cell, we purify it and make it really pure. Now we have a protein with the virus antigen murine monoclonal antibody with modified properties. This is a totally new entity.
Interviewer: What do you mean when you say, “useful in generating better immune responses”?
Dr. Rajan George: When a person has a chronic virus infection, his or her body ignores the virus and associated proteins. The body treats the virus as part of itself. The body does not recognize this virus as something foreign to it. Therefore the immune system does not attack the virus. But, by combining the virus antigen with a foreign protein such as the murine antibody fragment, the whole chimeric protein now is recognized by the body’s immune system as “foreign,” different from something of its own. In essence, this is a re-education of the immune system to switch its recognition of the virus from “self” to “foreign”.
Interviewer: From where did the scientific model come, and does it have similarities to another ViRexx Medical product, OvaRex MAb®?
Dr. Rajan George: This scientific model arose from discussions among the three lead scientists of the company, Dr. Tony Noujaim, Dr. Lorne Tyrrell, both founders of the company and myself. I am a biochemist by training and the collective thoughts of all of us went into the design of the Chimigen™ platform. One major similarity between Chimigen and OvaRex is that both involve a murine monoclonal antibody. Another similarity is that both target dendritic cells. The Chimigen model came from thoughts about targeting dendritic cells, but without the use of antibodies. OvaRex is a murine monoclonal antibody against the cancer antigen CA-125. The Chimigen™ vaccine has a fragment of a murine monoclonal antibody. OvaRex needs the CA-125 antigen in a cancer patient to bind to. The bound complex goes to the dendritic cells. The Chimigen™ vaccine does not need to look for the antigen in a patient because it already has the relevant antigen built in it.
Interviewer: It sounds as though the Chimigen™ vaccine acts in a similar way to OvaRex® in dealing with a hostile threat to the body’s health. How do they differ?
Dr. Rajan George: There are similarities and there are differences. OvaRex binds to the antigen CA-125. Then, the CA-125/Ovarex complex binds to the dendritic cells. The complex is internalized and processed. The peptides generated from the antigen are presented to the T cells, and the chain of events in the immune system gets stimulated. The activated cytotoxic T cells eliminate the cancer cells which contain the CA125 antigen. In the case of the Chimigen™ vaccine, the vaccine itself contains the antigen. It goes through the dendritic cell pathway and triggers the CTL response to clear the virus-infected cells. The system also produces antibodies to viral antigens, which bind virus and viral antigens and accelerate their removal. Because of the presence of the murine monoclonal antibody fragment, which is foreign to humans, along with the antigen from the virus, the body’s immune system treats this as a new threat and takes action. That is the immune response.
Interviewer: How would this work in treating Hepatitis B?
Dr. Rajan George: Developing a treatment for Hepatitis B chronic infection, for someone who already has the infection, would involve re-educating the immune system to react differently than it previously has. The infected person already has this virus and the derived antigens. If you put some more of the same antigens into the person, the person’s immune system is not going to know the difference His body is going to say, “Well, what’s the difference? I already have it. I am not going to do anything with it.” The body will ignore it. That’s what is called tolerance. With the Chimigen™ therapeutic vaccine, we have changed the body’s immune response to the virus.
Interviewer: How then have you changed the body’s response to the infection?
Dr. Rajan George: In a Hepatitis B chronic infection, let’s say I have the infection. My system is tolerating the virus. It’s ignoring the presence of the virus. While that is happening, the virus may be causing disease in with my liver. With time, it’s going to get my liver into trouble and my immune system has not responded adequately to remove the threat. We inject the protein – the one we just produced, which we call the Chimigen™ Therapeutic Vaccine – into the HBV chronic carrier, a person who has a chronic hepatitis B virus infection. What happens is when our protein is administered, the dendritic cells are going to look for anything new which enters the body. Those cells are the immune system’s first-line surveillance. The dendritic cells are going to see this new foreign protein, and they are going to think that this is different from what was previously inside. Their recognition of the molecule has changed from what it was before. Before the virus protein was recognized as a “self” protein. Now it is being recognized as a “foreign” protein. In chronic hepatitis B virus infection, the dendritic cells saw the virus as part of the “self” of the host, the vaccine changes the recognition of the virus protein as “foreign” to the host. Because the viral antigen is linked to the fragment of the mouse monoclonal antibody the direct the chimigen to dendritic cells it will enter the dendritic cell and be processed and stimulate an immune response.
Interviewer: And after the vaccine injection, what does the body see?
Dr. Rajan George: The body’s immune system see a new foreign antigen composed of a portion of the mouse monoclonal antibody linked to the viral antigen. It’s a foreign antigen.” The new “chimigen” stimulates an immune response to the antigen as well as the viral antigen. This is very important because the virus antigen was previously being ignored. Now, it’s being recognized as foreign through linked recognition of the mouse antigen as being foreign.
Interviewer: How do the dendritic cells react after they recognize this foreign threat?
Dr. Rajan George: The dendritic cells are the sentries of the immune system. They guard what comes in. When they recognize a “foreign situation,” what does the immune system do? It treats the whole molecule, the whole protein including the virus antigen, as foreign. The dendritic cells chop up this protein into small pieces called peptides. These peptides also are called “epitopes.” There are T cell epitopes which are smaller, and B cell epitopes which are longer. These small peptides bind to MHC I and activate Cytotoxic T lymphocytes (CTLs). The dendritic cells have a system where they put the T-cell epitope on another protein, MHC Class I, and bring it to the surface of the dendritic cell. They are presented as a complex on the surface of the dendritic cell to attract the T-cells. The T-cells come and see this, then get activated. Now, the activation is also specific to the virus protein. There are different varieties of T-cells, but the cytotoxic T-Cells are the most important in eliminating infections that already exist. The activated cytotoxic T-cells are the ones who do the attacking. They are the ones who start killing the virus infected cells.
Interviewer: And what about the B Cells?
Dr. Rajan George: That is the other side to this story. The dendritic cells can present another kind of peptide epitope. There is a second class of peptides, which are also produced when the protein is chopped up. The dendritic cells stimulate the B-Cells, B-Lymphocytes. And B-lymphocytes produce antibodies. The longer peptides bind to MHC II and activate B lymphocytes (B cells). B cells produce antibodies against the peptides. The antibodies are specific to the antigens we put in the Chimigen™ Therapeutic Vaccine. Antibodies bind to viral proteins that are on the surface of and block the ability of the virus to bind to a target cell to cause an infection and prevent the infection. This is the basis of a prophylactic vaccine. The antigen can bind to the invading virus and form a complex that the body eliminates. The B-Cells produce antibodies against the virus antigen, which we have put in the Chimigen™ vaccine. What do these antibodies do? The antibodies are specific to the antigen and bind to the viruses because they have the antigen. The system removes the virus by binding with the antibody. Also, the system removes infected cells using cytotoxic T-lymphocytes. Both of these actions are achieved by the Chimigen™ vaccine.
Interviewer: Aren’t there a lot of antibodies being investigated as therapeutics?
Dr. Rajan George: There are a lot of antibodies being investigated as therapeutics. OvaRex is the prime example. Avastin and Herceptin are two others, both of which are doing very well in the market. Another is Remicade, which is used to treat diseases such as rheumatoid arthritis. There are antibodies that are in various stages of clinical development, many are humanized antibodies where you want to avoid an immune response to the antibody. Our chimigen technology is new as we are trying to increase the immune response on a virus or a cancer through linked recognition. It is not found anywhere outside of our laboratories. This approach has not been tried before for chronic HBV or HCV infections.
Interviewer: Why would your vaccine work where others have tried and failed?
Dr. Rajan George: The reason is because of the novelty of the technology. We are re-educating the body’s own immune system to do the work by using the Chimigen™ technology. When you inject a xenotypic antibody , that is a non-human antibody that is linked to a specific antigen. The body recognizes the whole molecule as foreign and produces immune responses with both T- and B-Cell immunity. We believe that this enhanced immune response will be helpful in controlling the viral infection in the case of viral chimigens.
Interviewer: Much of the research has been within the laboratory. How much of this is hypothetical?
Dr. Rajan George: Our experiences so far have been mostly with isolated systems, meaning experimental systems outside of the body. For example, ViRexx’s Chimigen™ vaccine for treating chronic hepatitis B infection is what we call HepaVaxx B. This is waiting to go into Phase I clinical trials. We have done a lot of ex vivo experiments in the lab to evaluate the immune responses it can produce. We showed what we had predicted in theory has been true. We have also done some animal experiments, where the vaccine showed similar effects, again, as predicted. For HepaVaxx B, the animal results are also showing great progress and promise. We believe the Phase I studies will show safety and maybe some immunological data. The advanced clinical trials, Phase II and III, will tell us exactly what happens in humans (efficacy) with a chronic infection of Hepatitis B. I believe the Chimigen™ vaccine platform can make a difference in the area of immunotherapy of infectious diseases and cancer. For HCV, there is neither a therapeutic vaccine nor a prophylactic vaccine available in the market right now. Current available therapies are not very efficient, are expensive and have severe side effects. We do need more effective vaccines, both prophylactic and therapeutic, to prevent new hepatitis C virus infections and to eliminate existing infections. It is not an easy challenge but hepatitis C is an important target.
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Content: PLR, Image: Pixabay