By Arielle Yeo (21S07B) and Matthew Ethan Ramli (21S03F)
Cover image by Neo Xin Yuan (21A01D)
In the global fight against the COVID-19 pandemic, the vaccine is the elixir to life as we know it. Joining Singapore’s efforts to develop it are RJC alums, Dr. Jenny Low (‘92) and Dr. Shirin Kalimuddin (‘99). As clinician-scientists at the Singapore General Hospital (SGH), they are responsible for conducting the clinical trials for the COVID-19 vaccine. Co-developed by Duke-NUS and US-based company, Arcturus Therapeutics, the vaccine has to be tested in an adaptive phase 1/2 clinical trial to ensure both its safety and efficacy.
Although trained medical professionals specialised in infectious diseases, both doctors have chosen to commit 70% of their full-time career to clinical research. And when it’s currently all hands on deck during the pandemic, their research focus has shifted to finding a cure and a preventative vaccine.
Having envisioned a future solely in clinical practice, their transition into the world of research was unexpected. Now, they work with funding from the National Medical Research Council to find ways around the infectious diseases that they then treat as clinicians. Dr. Low has worked on the Zika response in 2016 and in the international effort to combat yellow fever during the 2017-18 epidemic, alongside constant research efforts on the Dengue virus endemic in Singapore. On the other hand, Dr Kalimuddin set out with an interest in bacterial infections. She has worked on diseases such as the 2015 outbreak of raw fish related group B streptococcal (GBS) infections in Singapore. On top of their consultancy roles at the Department of Infectious Diseases at SGH, they are also professors at Duke-NUS Medical School’s Programme in Emerging Infectious Diseases.
As illustrated in the comic above, vaccines act like training exercises for the body: by using weakened or dead viruses, they provoke an immune response, prompting the body to send out ‘soldiers’ to combat the foreign pathogens. Should the patient be infected by the same virus again, the body would be able to quickly recognise the pathogens and send out the fighter cells within hours, successfully defeating the virus in a much shorter span of time. These pathogens are therefore prevented from destroying cells that serve critical body functions, which otherwise may result in catastrophic consequences such as major organ failure.
Vaccines in development from Oxford, Moderna and Duke NUS/Arcturus use a part of the SARS-CoV-2 virus’s genetic material called mRNA (messenger ribonucleic acid). These fragments are used by the cells template in producing a portion of the viral components to be put into the body’s immune memory. Unlike traditional vaccines, which need to be grown in a biological medium such as a chicken embryo, mRNA vaccines can be produced on a large scale. Although none have been approved for human use yet, given the urgency of the situation, the ability to mass produce efficiently and cheaply is integral to stopping community spread worldwide. Should traditional vaccines with longer gestation periods be used, it might take years before enough doses are manufactured to attain a sufficient level of immunity in the community.
Vaccines have to undergo stringent regulation before they can be distributed in order to ensure the people’s safety. In the 1950s, the Cutter polio vaccine, wrongly thought to be sufficiently attenuated, infected 40,000 children with polio and caused other side effects. Later in 1976, a vaccine against swine flu was found to increase the risk of individuals contracting Guillain-Barre syndrome, a neurological disorder. These disastrous incidents in the early history of vaccine development necessitated the setting-up of regulatory bodies to mandate rigorous practices that safeguard against unknown side effects.
Now, vaccines must undergo three phases of human trials, each with increasing sample sizes and number of patient types. Working closely with the primary researchers at Duke-NUS, Dr. Low and Dr. Kalimuddin administer the vaccines to healthy volunteers. They also collect and analyse their blood samples to observe for any potential side effects and monitor the development of protective antibodies.
The trials are often double-blinded to maintain objectivity, a common practice in any type of clinical trial. Neither researchers nor subjects are aware of who has been injected with the vaccine, and who has been injected with a dummy such as normal saline. Placebos are given to demonstrate that the detection of an immune response is indeed caused by the vaccine instead of an induced hormonal or neurological response from the belief that one has received the vaccine. Meanwhile, blinding on the researcher’s side seeks to eliminate confirmation bias.
When asked about possible ethical problems involved in testing an unknown vaccine on humans, Dr. Kalimuddin conveyed that the doctors have to act on their own conscience, quoting the first principle in the Hippocratic Oath: “first, do no harm”. All clinical trials also have to be approved by an ethics committee made up of both doctors and laypeople before they can be allowed to proceed.
In Singapore, the Health and Science Authority (HSA), an agency under the Ministry of Health, is the official regulator for all drugs and vaccines. They act as a third-party overseer to ensure that the vaccine is safe to be released into the general population. The third clinical phase often requires hundreds of thousands of individuals and at least several months of monitoring before the vaccine can be licensed. Every country has its own regulatory body, with companies aiming to be approved by as many countries as possible in order/so as to/to maximise their profits. At the time of writing, The Duke-NUS/Arcturus vaccine has just started its first phase of trials and recruitment of volunteers is ongoing. Phase 1 of the trial is anticipated to be complete by October 2020. However, refinements like testing for the best dose and frequency of doses to be administered will have to be tested in another larger trial, which is expected to start before the end of 2020.
The urgency to find a vaccine, or even a cure for COVID-19, has fueled global efforts on an incredibly large scale, with the search for a HIV treatment in the ‘80s being the closest precedent. As they own the proprietary rights to the vaccine, pharmaceutical companies are not obliged to produce or sell the vaccine in any particular country. Drs Low and Kalimuddin note that while vaccine development is usually only taken on by pharmaceutical companies, there has been an unparalleled rise in partnership between the private sector and academia. In the case of the Duke-NUS/Arcturus vaccine partnership, funding is provided by both Arcturus Therapeutics and the Singapore government while vaccine development is primarily conducted at the university. Such partnership greatly enhances the speed of vaccine development, and should the vaccine prove to be safe and effective against COVID-19, gives Singapore early access to the vaccine.
For Rafflesians thinking of joining the medical profession, “Keep an open mind” is the pair’s advice, suggesting that students should not be too fixated on a single specialisation and career course when entering medical school, noting the numerous twists and turns in the journey. Stamina is equally important: Dr Low remembers that while her friends pursuing law and economics were climbing the ranks early on, she spent long arduous years in medical training. But in the end everything is worth it, as Dr. Kalimuddin enthuses, as you get to do something new every day. Although more than two decades have passed since their days at RJC, they still carry fond memories of the school and attend yearly reunions with their batch. Dr. Kalimuddin explains how her Outdoor Adventure and Activities Club (ODAC) get-togethers have grown significantly in size to even include spouses and children. Meanwhile, Dr. Low still remembers her days competing nationally with her netball team. Although having attended RJC 6 years apart, both are now colleagues in vaccine research.
Before an effective COVID-19 vaccine becomes widely available, the COVID-19 ‘new normal’ will remain a part of our life for some time. With the gradual easing of measures to keep the economy afloat, Dr. Low and Dr. Kalimuddin predict small peaks of infection that are still manageable in our healthcare system’s capacity. Masks should still be worn in the foreseeable future and crowds avoided. While the health care professionals strive to develop a vaccine, we too should play our part in keeping others around us safe."A Researcher’s Guide: the COVID-19 Vaccine",