Dr. Anh Tran completed her postdoctoral fellowship in Prof. Tania Watts’ laboratory, where she investigated the role of microRNAs in T cell survival. Currently, she holds the title of Research Officer at the National Research Council (NRC) Canada located in Ottawa, Ontario. Anh shares with us her transition from academia to the NRC and her involvement in viral vaccine development with the government.
Viruses are a component of our ecosystems. They can be transmitted to humans through direct and indirect interactions with our environment, such as via waterborne or airborne routes. Viral vaccines are created to mitigate viral spread to prevent the initiation and progression of endemics, epidemics, and pandemics from occurring. The main criteria of an appropriate viral vaccine include being immunogenic, long-lasting, stable, and safe for human consumption. Scientists such as Anh are vital to the development of viral vaccines.
Anh’s Post-Doctoral Training
Coming from a molecular virology background, Anh realized that to better understand viral mechanisms, investigating the immune response generated in the host is vital. One research area that the Watts lab focused on is studying the host immune response in mice by utilizing virus models such as influenza and chronic lymphocytic choriomeningitis (LCMV). As a virologist transitioning into the Watts lab, Anh considered what knowledge she could gain, and what contributions she could make to existing projects and the potential projects she could initiate.
When Anh first joined the Watts lab, they had just conducted an RNA sequencing (RNAseq) analysis on T cell co-stimulating molecules. They had identified the molecules GITR (glucocorticoid-induced TNFR family related protein) and 4-1BB to play an important role in viral immunity against influenza infection. Anh found that the microRNA (miRNA) called miR-17~92 was one of the resulting hits from the RNAseq analysis, and that GITR signalling may regulate miR-17~92 activities. Their preliminary results showed that GITR activation leads to the upregulation of miR-17~92, and that a potential downstream target of this miRNA is the co-stimulatory molecule called death receptor 6 (DR6). As such, one of the main hypotheses Anh investigated during her postdoctoral fellowship was that GITR is potentially promoting the survival of T cells by upregulating miR-17~92, which in turn downregulates DR6. This has possible implications in explaining how GITR plays a role in sustaining the T cell mediated response against influenza infection.
Transitioning from Academia to the NRC
Anh talked about how she always had an interest for viral infections and infectious diseases and that she had the intention of continuing her career in that field. Anh described the transition to the NRC to not be far from the normal routine she experienced in academia with one exception. In addition to her own research, she also uses her scientific expertise to assist Canadian biotechnology and biopharmaceutical companies. Anh’s role at the NRC is a balance between laboratory and administrative duties (e.g. meetings and emails). Her role primarily is to conduct molecular virology research, specifically investigating vaccines and therapeutics development. Currently, she coordinates her own lab and develops research projects pertaining to viruses on which the NRC focuses. This includes the ongoing coronavirus project regarding the viral respiratory illness Middle East Respiratory Syndrome (MERS). She has now expanded her work to include the new coronavirus, SARS-CoV-2, which causes COVID-19 in the current outbreak.
Anh works on several internal research projects in addition to completing projects for business clients with whom the NRC works. Anh explains that normally client projects take priority as there are hard deadlines that need to be met. Anh stated, “priority is usually given based on the importance of the research outcome or by mandates issued by the government.” For example, vaccine and therapeutic research pertaining to the COVID-19 pandemic is currently a high priority.
In order to fund her projects, she relies heavily on internal competitions. Due to her role as a federal government scientist, she is unable to apply as a primary applicant to tri-council granting agencies such as the Canadian Institutes of Health Research (CIHR) and Natural Sciences and Engineering Research Council (NSERC). However, she can apply as a collaborator or co-applicant. For example, she is currently a co-applicant on a submission for a CIHR grant regarding COVID-19 research.
Anh expressed that a motivation supporting her involvement with the NRC is the translational aspect of her research for the public. She said “looking for actual therapeutics at the end of your research is not just simply publishing a paper, but you also have an end product that you can put into clinical [settings], and you can actually see it helping people with treatments, such as vaccines and therapeutics”.
Process of Vaccine Research and Development
In order to develop an effective viral vaccine, Anh explained that the vaccine design would need to include the most antigenic part of the virus of interest in order to produce a protective immune response. Antigens are components of the virus that can induce an immune response resulting in virus-specific neutralizing antibodies. An additional factor to consider includes the vaccine platform such as a virus vector, DNA-, or RNA-based delivery platforms. Other factors in vaccine development also include the storage and transportation of the vaccine and ensuring its stability. This is particularly important during viral outbreaks that occur in remote areas, for example in Ebola cases.
Anh explained a good vaccine candidate would first demonstrate an efficacious immune response in small animal models, such as in mice. Subsequently, the potential efficacy and toxicity of the vaccine candidate would then need to be tested in non-human primates. Following these steps, the vaccine candidate would enter into a phase I clinical trial, which would assess its immunogenicity and potential side effects in healthy human participants. But of course, there is a long road ahead before a potential vaccine gets approved. Once a candidate is deemed relatively safe in phase I, it then progresses to phase II with a slightly larger number of participants in order to show efficacy and further elucidate potential side effects. Finally, a large-scale, often multicentre and double-blinded phase III trial is required to expand on efficacy and safety data, before being considered for approval.
A major challenge associated with developing efficacious viral vaccines are mutations that occur in regions targeted by neutralizing antibodies. This can result in escape mutants, which are viral strains that are resistant to the neutralizing antibodies that were mounted against the initial strain. For example, a reason why a new vaccine for the seasonal flu needs to be developed yearly is due to the dynamic changes the virus undergoes with each subsequent infection. Therefore, “one of the main challenges and one of the main goals is to try to find a conserved target such that you don’t have to develop a new vaccine every year”.
Future Directions of Viral Vaccine Development
Anh explained that the main goals of vaccines and therapeutics development is improving vaccine efficacy and generating innovative vaccine platforms. This would promote a quicker transition of getting efficacious vaccine candidates to clinical trials, and therefore making them more readily available to the public. Implementing quicker applications of vaccines would increase viral preparedness in anticipation of an outbreak occurring, such as from new viruses that emerge due to crossover from animals to humans. Anh explained a way to combat potential outbreaks would be to “design vaccines that may be more broadly applicable such that we can be more prepared for Disease X, that may come out in the near or far future.”
At the end of our conversation, Anh reiterated how viruses, despite being just small packages of proteins and nucleic acids, have such a tremendous impact on our health and public health, as evidenced by the current COVID-19 outbreak. To prevent viral spread on a local and global scale, scientists at the NRC coordinate with other government departments, the Public Health Agency of Canada (PHAC) and Health Canada, to translate novel vaccines and therapeutics to the public.