Limitations of vaccines for protection against COVID-19
One of the key countermeasures under development to protect people from SARS-Cov-2 (the virus that causes COVID-19 infection) is vaccination. Vaccines have the benefit of being widely distributable as a means of protection populations from disease. However, they have some key limitations for COVID-19 prevention. One of the main issues, is that they are dependent on the recipient’s immune system to develop a protective response against the coronavirus. Not everyone’s immune system has the same ability to mount a protective response after vaccination. This is particularly true of the elderly, who are one of the high-risk groups for COVID-19. Other groups that have trouble mounting a good immune response are infants, people who are immunosuppressed (like organ transplant patients) and people with certain diseases, like people with heart or lung disease. A second issue with using vaccines to create immune protection, is that establishing immunity takes time. It can be weeks before the level of immune response is adequate in some diseases. It is unknown how long it will take for people to mount protective immunity against SARS-CoV-2; successful vaccination may ultimately require multiple injections over time, like vaccines against hepatitis or human papillomavirus. Another limitation of infectious disease vaccines is that they are typically intended for protecting healthy people and do not have much effect if someone is already infected.
A key part of the immune response in humans is for specific white cells in the body (called B cells) to produce a protein that can attach (bind) to the virus and disable it. These proteins are called antibodies. After overcoming an illness like COVID-19, people have circulating levels of antibodies that can disable or neutralize the virus to protect them from repeat infections. The body can retain the ability to produce these antibodies for years or decades in some cases. An alternative way to protect someone is therefore to give them an infusion of antibodies that are targeted against the virus. When your body makes antibodies against a virus there are usually many different kinds that bind different parts of the virus, this is called a polyclonal antibody response. If one of these single types of antibodies—an antibody that is particularly good at binding to and neutralizing the virus—is cloned out so that many antibodies can be made that are all the same, these are called monoclonal antibodies. Protein drugs made from a single clone of antibody or monoclonal antibody (“mAb”) have become a mainstay of medical therapy since the approval of the first therapeutic mAb in 1986. More recently there has been a focus on using mAbs to fight infectious diseases with the idea that mAbs can bind to and neutralize a range of pathogens. There have been many studies also looking at using mAbs as a preventative treatment against infectious diseases including cytomegalovirus, Ebola, influenza, HIV, rabies and respiratory synctitial virus (RSV). One mAb, Palivizumab (Synagis, MedImmune), is already approved by the FDA to protect infants from RSV.
One key advantage of mAbs for infectious diseases is that they can be given regardless of the patient’s infection status. Even if intended to prevent disease, they can help neutralize virus in an active infection. While they may not be curative in all people, they can offer more help to the infected person’s immune system than a vaccine.
Artistic rendering of monoclonal antibodies (in red) binding to a virus. Source: Science Clarified
Monoclonal antibodies are typically used to treat disease. But here we are interested in preventing disease. The number of sick people to be treated for a disease may be limited, but the number of people that need to be treated to prevent a disease is much, much larger. For the current coronavirus infection, the number of people that will need to be vaccinated or treated will be in the millions. In the face of this required scale, mAbs have two important limitations. The first is cost. Therapeutic antibodies can be priced at tens and hundreds of thousands of dollars. This is obviously not a practical approach to protecting millions of people from infection. Part of the challenge in the use of antibodies is their relatively high cost of production. Facilities to produce mAbs for treating large populations can cost $300-$500 million to build and require thousands of people to staff. They are also expensive to produce, with costs of commercial mAbs at about greater than $100 per dose. The other limitation of antibodies is that many of them require intravenous administration, which again is not feasible when millions of people need to be treated or protected.
Image of a new facility used to produce monoclonal antibodies. Source: Baker Hicks
SmartPharm Approach: Gene MAbs™ for Coronavirus
SmartPharm is applying our non-viral gene therapy platform to develop an effective preventive treatment for SARS-CoV-2. We are using DNA designed to produce in the muscle of the person who receives the gene a monoclonal antibody (“Gene Mab™”) that could be protective against the SARS-CoV-2 virus. To do this, we are utilizing a novel DNA vector with low immunogenicity, durable expression potential and cost-effective manufacturing up to millions of doses. We are coupling this type of DNA vector with a delivery system that significantly enhances DNA expression in the muscle and is also capable of high-volume, economic production. Coupled together, these represent a way to generate protective mAbs in many people to provide “pop-up immunity” in this population against COVID-19 regardless of their immune status or their infection status.
The first step in developing a Gene MAb™ against SARS-CoV-2 is to determine a mAb sequence that possesses both a high binding affinity to the coronavirus (so it stays attached to the virus for a long time) and the ability to neutralize the virus (block it from invading cells or attract immune response against the virus). We have implemented strategic partnerships with a number of organizations to do this, including Sorrento Therapeutics. Sorrento has initiated an accelerated program to identify potent neutralizing antibodies against SARS-CoV-2 that can be used for either treatment or prophylaxis. Based on this collaboration as well as internal work, SmartPharm will define a DNA that can express these antibodies in human skeletal muscle and use a delivery technology designed to allow the DNA to be delivered directly into the muscle. The SmartPharm delivery system is designed to be used with a standard hypodermic needle, the way most vaccines are delivered.
1. Antibodies with significant neutralizing efficacy against SARS-CoV-2 are identified in recovered COVID-19 patients. 2. The antibody is sequenced and incorporated into a DNA plasmid. 3. Plasmids are combined with a delivery system for a final formulation of the Gene MAb™ drug. 4. The Gene MAb™ is given to people using a standard hypodermic injection.
After delivery in the muscle, the DNA is designed to produce antibodies in the muscles within a matter of hours. Within a day or two—a much faster time than a typical vaccine—protective levels of antibody could be produced, resulting in what we refer to as “pop up-immunity”: a rapidly-established window of immune protection against the virus.
Antibody production lasts a number of weeks or even months and is effective regardless of what the recipient’s immune system is like or whether they are infected or not. Creating pop-up immunity with Gene MAbs™, which are both cost-effective and scalable for large population protection, introduces a way to quickly mount a protective immune barrier in treated people and reduce the infectivity of the virus in larger populations.