How one researcher is using common-cold viruses as vaccine delivery platforms for infectious diseases such as SARS-CoV-2 coronavirus
Dr. Lynda Coughlan is a researcher and Assistant Professor at the Icahn School of Medicine at Mount Sinai in New York City. Interested in virology since childhood, Dr. Coughlan’s academic career has taken her from her native Ireland to Scotland, England, and the USA. She earned her PhD at Barts Cancer Institute in London, where her research involved manipulating adenoviral vectors to achieve targeted gene delivery to tumor cells.
We recently interviewed Dr. Coughlan to learn more about her research in developing adenovirus vectors for use as a possible coronavirus vaccine delivery system, as well as her thoughts on the challenges faced by women in academia, the sudden rise of Internet virology “experts,” and the trials of working through a pandemic.
Can you tell us a bit about your research?
My research is focused on developing adenoviral (Ad) vectors, which are common-cold viruses as vaccine delivery platforms for infectious diseases such as influenza virus or the recently emerged SARS-CoV-2 coronavirus.
The adenovirus vaccine cannot replicate but can be stuffed with fragments of DNA coding for proteins from influenza (flu) or SARS-CoV-2. We select proteins from these viruses which are involved in viral entry. Our goal is to stimulate an immune response that blocks that interaction, allowing the virus to be neutralized and preventing it from causing infection. Once we immunize with the modified Ad vector, it churns out copies of the flu or CoV-2 protein, which the immune system then recognizes and responds to by mounting an immune response.
The benefit is that no parts of flu or CoV-2 which are involved in replication are included, so the virus cannot infect the person being immunized. Essentially, it is a safer way to trick the immune system into thinking there is an infection while, in fact, only a harmless protein is being produced.
We use animal models to evaluate the immune response to our vectors. We evaluate both T-cell responses and antibody responses which are specific to the insert in our Ad vaccines. Once we have identified lead vaccines, we then test those in challenge models of disease.
Is there any difference between developing vectors for SARS-CoV-2 vs. influenza?
The approach to making an adenoviral vectored vaccine for SARS-CoV-2 is identical to that used for influenza. This is why I love working with this delivery platform. It is very easy to adapt to newly emerging viruses. Several lead vaccines based on adenoviruses are now being tested in clinical trials to protect against SARS-CoV-2, including an Ad5, Ad26 and chimpanzee adenovirus, ChAdOx-1. Because there are already so many advanced Ad platforms for SARS-CoV-2, we are focusing on using our Ad vaccines as a tool to better understand the type of immune response needed to protect against SARS-CoV-2.
What are some of the different ways your work is advancing knowledge about SARS-CoV-2 and viral infections generally?
Our research may support the development of new and improved vaccines against viral infections that affect humans. Additionally, these vaccines can be used as tools to improve our understanding about the immune response to influenza or CoV-2. For example, by testing our vaccines in animal models, we can learn more about how protective immune responses work. Our research can answer questions like:
– Are there weak points in the virus that we should try target to make a better vaccine?
– Which components of the immune system are most important in providing protection or limiting the severity of disease?
Both figuratively and literally, Mount Sinai has been at the center of the fight against coronavirus. How has the pandemic affected your work life?
Since the beginning of the pandemic, staff in the Department of Microbiology at Icahn School of Medicine at Mount Sinai have been working around the clock. It has been the busiest period of our lives. We have all tried to refocus our skills to address the pandemic. Our research ranges from developing animal models to new vaccines and therapeutics to generating reagents and assays to measure antibody responses to the virus.
Although it has been an exciting time scientifically, it was also particularly stressful during the period when our location–New York City–was the epicenter of the pandemic. After months of remote work, changed work schedules, and long hours, many of us are exhausted.
When you have witnessed firsthand how hard all the healthcare workers, scientists and other essential staff are working at trying to protect us, it is especially frustrating to read so many conspiracy theories and lies about the virus, as well as witness a lack of leadership by the government.
Has the pandemic caused any bottlenecks with your current research?
The peak of the pandemic in New York was a difficult time. Both of my technical staff were working remotely so I had to perform all of the wet lab work that is normally done by a team of three. At the same time, we had to write grants and papers, revise animal protocols, review papers, etc. We managed well in dividing our work, but I am glad to have both staff members back in the lab again. The biggest challenge now is trying to make up for lost time and also trying to advance our non-CoV-2 projects. These were stalled for several months as our institute only permitted ongoing work for SARS-CoV-2 and deemed other research as non-essential.
How does DNASTAR software fit into your research?
I have been using DNASTAR Lasergene for about eight years now.
My team largely uses SeqBuilder Pro and SeqMan Pro. We find the software easy to use and annotate. I particularly like the plasmid auto-annotation feature in SeqBuilder Pro, which helps quickly identify common regions when we receive plasmid construct maps from other labs.
We also love the ability to align multiple sequence reads while viewing the nucleotide and amino acid sequence, annotated regions on the backbone template and the chromatogram display at the same time. As we are sequencing large plasmids (approximately 40kbp), this helps us quickly identify any problem regions in the viral genome.
In addition, when the COVID-19 pandemic hit New York city hard in March/April 2020, the DNASTAR team was fantastic in setting up portable licenses for my staff to work remotely.
How do you think the changes we’ve seen during the pandemic will impact the research community long-term?
One aspect of the pandemic which has been both a blessing and a curse has been the rise of pre-prints. Being able to quickly find well written, well-designed studies reporting early findings, sequences, and vaccine constructs during this pandemic has helped the research community to advance vaccine and therapeutic platforms. Sadly, it has also been the source of some very poor or sensationalistic data which has “gone viral” on social media before scientists had the time to criticize it.
We have also witnessed the rise of many “experts” who have huge numbers of followers on Twitter. They present themselves as authorities on SARS-CoV-2 but do not have relevant expertise or training and frequent misinterpret or misreport new publications or research findings. This has resulted in a need for scientists to spend time on social media trying to counteract bad science.
The good news is that there will likely be a lot more interest in vaccine research! Perhaps I’m biased, but I like to think that this pandemic will inspire a diverse new generation of young people to consider the fields of virology, immunology, and vaccinology as an exciting future career choice.
Speaking of young people, we mentioned you’ve been interested in virology since childhood. How and when did you decide to become a scientist?
I was a very curious child and was always drawn to biology. When I was child, my mother was studying Art and had a lot of art books around the house. I remember being fascinated by a book with anatomical drawings by Leonardo da Vinci, and perhaps that stimulated an interest in the human body. As a young child, I was also very fortunate to have great teachers who were interested in nature, plants, and animals.
I grew up in the 1980s, when the HIV epidemic was prominent news. During that time, I became interested in viruses and microbiology. This interest stayed with me right into high school where I selected biology, chemistry, and physics as my main non-core subjects. It was always clear to me that I wanted to be a scientist, and I knew that someday I wanted to have my own research group. It’s rare to be sure of what you want to do from a very young age, so I am thankful that I have managed to successfully achieve my childhood dreams.
What are your thoughts on scientific collaboration? Have you noticed any increase in collaboration during the pandemic?
A good collaboration should be a two-way, mutually beneficial relationship. I have found that the best collaborations are when there is limited competing interest (overlap) and investigators are fair, honest, and upfront about contributions and plans for formal acknowledgement.
In the past, I have encountered unsupportive mentors or co-workers who sought to exclude, undermine, or disregard my expertise or contribution to collaborative projects. That was actually a good lesson to learn in terms of resilience and choosing collaborators wisely. If you believe in your research ideas then you should listen to and appreciate those colleagues who take the time to offer constructive advice and new perspectives. At the same time, you must learn to ignore those who dismiss you or your hypotheses without offering any constructive criticism.
During the pandemic, I have witnessed increased collaboration but also an undesirable undercurrent of competitiveness and a desire to “be the first”, rather than working for the greater good. I suppose this is the nature of academia, but it has just become more prominent during the pandemic.
I know that a lot of female scientists or scientists with parental or caring duties have been negatively impacted by school closures and the need to work remotely. Although institutes are trying to support them, it is not enough. The long-term damage to their careers may sadly drive a lot of talent out of research.
In the USA, women make up only about a quarter of STEM faculty. What challenges have you faced being a female researcher in academia?
Many women and other under-represented minorities working in academia find it frustrating that their perceived value and their opportunities for networking or career advancement are diminished in comparison to that of male colleagues. There is often a lack of transparency and culture of silence around this topic in academia.
I have personally experienced pay disparities between my salary and that of equally or less-qualified male peers. I have also experienced covert “exclusionary sexism”: not getting a seat at the table when important meetings or discussions are happening, despite having relevant or key expertise.
How do you deal with setbacks in your research?
In terms of research, I have always found that challenges and setbacks that might seem upsetting at the time often lead to new breakthroughs or force you to approach a problem from a new angle. This is part of the struggle in academia that I enjoy…to an extent!
Let’s end with a non-science question. What are your interests outside work?
I love travel and the outdoors, including hiking and camping. I have had the opportunity to travel to some amazing locations in recent years, including Borneo, Vietnam, Cambodia, Laos, Singapore, Mexico, Peru, Argentina, Namibia, and Kenya. I also had the chance to do some hiking in Utah and Arizona, which was incredible.
Luckily, as a scientist working on infectious disease, there are many opportunities to travel to conferences in exotic locations! I love trying new cuisines and adding new cooking and baking recipes to my skill set. I also like running, as it not only keeps me fit, but is also beneficial for my mental health and helps me offload stress or anxiety.
Thank you, Dr. Coughlan, for taking the time to share your experiences and research on our blog!
If you’re a Twitter user, you can follow Dr. Coughlan @virusnerdette. For a list of selected publications, please see the bottom of this post.
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Some of Dr. Coughlan’s recent publications
– Freyn AW, Ramos da Silva J, Rosado VC, Coughlan L, et al. A Multi-Targeting, Nucleoside-Modified mRNA Influenza Virus Vaccine Provides Broad Protection in Mice. Mol Ther. 2020;28(7):1569-1584. doi:10.1016/j.ymthe.2020.04.018.
– Coughlan L. Factors Which Contribute to the Immunogenicity of Non-replicating Adenoviral Vectored Vaccines. Front Immunol. 2020;11:909. Published 2020 May 19. doi:10.3389/fimmu.2020.00909.
– Bliss CM, Parsons AJ, Nachbagauer R, Coughlan L, et al. Targeting Antigen to the Surface of EVs Improves the In VivoImmunogenicity of Human and Non-human Adenoviral Vaccines in Mice. Mol Ther Methods Clin Dev. 2019;16:108-125. Published 2019 Dec 24. doi:10.1016/j.omtm.2019.12.003.