Talking with Daniela Verthelyi, Chief, Laboratory of Immunology, Office of Biotechnology Products, Office of Pharmaceutical Quality, CDER
In order to effectively regulate products that diagnose, treat or prevent infectious diseases, scientists and reviewers in the Center for Drug Evaluation and Research must understand the bacteria, viruses, and parasites that cause diseases. Scientists in CDER conduct many programs to advance regulatory science and research on pathogens -- agents that cause infection or disease. There are many pathogens being studied at CDER’s Office of Biotechnology Products – from food and blood-borne bacteria, to infections caused by parasites, and viruses such as the Zika virus. CDER is charged with advancing public health through the review, regulation, and research of potential treatments. How does the study of bacteria and viruses help drug development and review? Let‘s explore.
We’ll start with the basics. What are pathogens?
Pathogens include viruses, bacteria, fungi, and parasites that invade the body and can cause health issues. Anthrax, HIV, Epstein-Barr virus, and the Zika virus, among many others are examples of pathogens that cause serious diseases.
Why is the research of pathogens important?
A key component of our mission is to ensure that decisions involving drug approvals are based on the best available science. In order to do this, we benefit from having expert knowledge and first-hand experience with emerging diseases and the latest technologies for diagnosis and treatment. CDER regulates many products used to treat patients with infectious diseases caused by pathogens, so it is important that we understand how infections become diseases and how pathogens interact within the human body.
How does your research aid drug development and approval?
The research helps us understand some of the issues that may be encountered when potential drug products are developed for specific infectious diseases. We have to make sure that we ask the right questions when reviewing potential treatments. The better we understand pathogens and the products used to treat the infectious diseases they cause, the better we will be at regulating the products to treat them. We can use our knowledge to understand what questions need to be asked to address potential safety issues. For example, we can use animal models to understand the changes that correlate with protection and use those as biomarkers. In short, the knowledge we gain from our research often translates into more targeted reviews and faster approvals of treatments for infections.
Give me some examples of important discoveries from CDER’s research
Dr. David Frucht (Acting Director, DBRR II) developed mouse models with the anthrax infection in their blood. This enabled us to investigate interactions between the host and the pathogen, and to study the effectiveness of potential treatments.
Another success occurred during the Ebola outbreak last year. The laboratory directed by Dr. Kathleen Clouse (Director, DBRR I) developed better investigative procedures to study the Ebola virus by using non-infectious components of the virus to study how it enters and infects human cells. We are now able to test potential treatments that block Ebola entry or replication without exposure to use infectious virus. Her lab is developing a similar system for the Zika virus.
My lab developed a new model of infection with Zika virus in immunologically competent mice. It is a mouse model that will allow us to study the immune response to the virus. By understanding what immune cells are important in the response to Zika infection and which contribute to the disease, we can perform better risk assessments for proposed therapeutics.
How about a brief overview of pathogens currently being studied
The laboratories in OBP look at a wide variety of pathogens. We are studying Bacillus anthracis, which causes anthrax infection, a potentially lethal infectious disease. Dr. Frucht’s lab works with a weakened version of the bacteria that is incapable of causing anthrax in people, but is still very useful to study.
Another is the Epstein-Barr virus, which is one of the most widely distributed viruses in humans, causing infectious mononucleosis.
Of course, there’s the human immunodeficiency virus – HIV, studied also by Dr. Clouse’s laboratory. As you know, this virus is spread through certain body fluids and attacks the body’s immune system, specifically a subset of T lymphocytes, often called T cells. Over time, HIV can destroy so many of these cells that the body cannot fight off infections that are easily resolved in those without HIV.
Now, sometimes my lab works on microbes that serve as models for other more pathogenic microbes. For example, the studies my laboratory performs on Sindbis and Tacaribe viruses serve as models to study other viruses that are highly pathogenic to humans, such as Ebola, Junin, and Machupo viruses, which cause hemorrhagic fever. With these models, we are specifically assessing the effect of the infection and of possible therapeutics on the central nervous system, particularly in newborns.
Some viruses are simply used as tools in the lab. For example, vesicular stomatitis virus (VSV) is used in the lab as a tool to study the role of proteins from other viruses. VSV helps scientists assess the effect of those proteins without using the whole virus, making study of the pathogen safe.
And my laboratory is also looking at the Zika virus that we’ve heard so much about. While Zika usually causes a mild flu-like disease, it has been linked to problems in the development of the nervous system and to Guillain-Barre syndrome, an autoimmune disease that involves the nervous system. These findings have underscored the urgent need for new diagnostics, treatments, and vaccines. Our lab used the knowledge obtained working with Tacaribe virus to develop a new infection model that is more representative of the human disease than the existing animal models. Using that model, we are exploring whether the immune response to the virus plays a detrimental role in some cases of Zika infections leading to neurological disease. Learning about the types of immune responses that may be connected with adverse effects helps focus the reviewers on possible safety issues with candidate treatments.
Why is there so much attention focused on immune responses?
In our lab we study the immune response because the symptoms in many infectious diseases are partly caused by the pathogen, and are partly a side effect of the battle the immune system is fighting to eliminate the pathogen. For example, I mentioned before the Tacaribe virus. In that infection a strong immune response to the virus results in damage to the cerebellum, the part of the brain that deals with equilibrium. We put together what we learn about the pathogens and what we know about the mechanism of action of the product to help us foresee the possible risks and to help us to ask the right questions to the sponsors.
Are all of the pathogens being studied found in the United States?
Not necessarily. For example, the leishmania parasite, which we are studying with a demonstration grant from the World Health Organization, isn’t found in this country but is a neglected disease that affects millions around the world. Of note, it did become a public health issue when American soldiers went to the Middle East. Many came home affected by leishmaniasis.
What are the symptoms of this infection?
Leishmaniasis is spread by the bite of sand flies. Some infected people don’t show any symptoms or signs of disease. But those that develop evidence of infection have sores on their skin that can sometimes take up to a year to heal.
How does your lab prioritize research?
It’s based on public health importance and on what will be needed to regulate anti-microbial and anti-viral therapies. Early in 2016, the World Health Organization declared the Zika virus a public health emergency of international concern. CDER began research on the virus because we knew we would soon need to regulate small molecule drugs and biologic therapeutics. Establishing models to study the Zika virus and its effects on the central nervous system is important for the development and regulation of Zika therapeutics and vaccines. However, we also keep an eye on what may be coming in the future, both in terms of the pathogens that may become problematic, as well as new therapeutics and approaches are being developed to control them.
How safe is it working with potentially infectious pathogens?
The personnel who work in the lab are thoroughly trained on how to work with pathogens very safely. The labs have strict rules and regulations that are aimed at keeping the investigators and supporting staff safe. In some cases, the virus or bacterial strains we use in research are not pathogenic to humans, including the anthrax strain used in one of the labs. However, even then, our research is performed using all the required procedures and containment controls. For example, physical containment is provided by working in biosafety hoods and the use of “negative air pressure” laboratories. This type of system allows air to flow into an isolated room, but not escape from the room in which the work is being done. Nothing can leak out to the main lab and hallways, so there is no threat to people on campus.
In addition, our people use personal protective equipment (PPE) that shields them from infection. They also follow careful procedures to remove the PPE before leaving the lab to further contain any pathogens. Lastly, each Center has a team of scientists devoted to ensure lab safety.