In February 2018, ‘Disease X’ was added to the WHO (World Health Organization) list of priority diseases that needed research and development in preparation for a global health crisis. The enigmatic “X” stands for the unknown, as in middle school mathematics, thus ‘disease X’ refers to a pathogen yet unknown to us but one that may potentially cause an outbreak of an international epidemic in the future. Listed along with familiar diseases such as MERS (Middle East Respiratory Syndrome), Ebola, and Zika that threatened the human race in the past, ‘disease X’ emerged in front of us under the name of Covid-19 (Coronavirus Disease 2019). So exactly how can WHO detect and prepare for an unknown disease?
CEPI (The Coalition for Epidemic Preparedness Innovations) was founded in 2017 with a mission to develop a vaccine for the future epidemic. The organization was funded by the governments of Norway, Japan, India, and Germany as well as the Bill & Melinda Gates Foundation, with the couple’s known interest in the development of new vaccines. As an international alliance encompassing the private and the public sector under a common purpose, CEPI works as an engine for the development of new vaccines, coordinating and financing appropriate research organizations or corporates. CEPI is leading the vaccine development for Covid-19.
One of CEPI’s missions is to complete the development of a vaccine for disease X ‘just-in-time’. Many attempts to complete a vaccine during an outbreak have failed. Vaccines for new diseases usually take a decade to complete, and the epidemic is over by that time. As the outbreaks of SARS (Severe Acute Respiratory Syndrome) in 2002 and MERS in 2012 show, if the epidemic stops during the vaccine development period, it is difficult to complete the vaccine. One of the crucial steps of development is the third clinical trial, which requires thousands of subjects with the virus, and this number is almost impossible to achieve once the virus is gone. Corporates are no longer interested in investing in a field that lacks marketability. In essence, the existing approaches to vaccine development may not be a solution for unexpected outbreaks such as Covid-19.
The new strategy for CEPI is to utilize ‘platform technologies’. Traditional vaccines deal with the virus directly. Platform technologies, on the other hand, takes a modular approach. Once the genetic material (DNA or RNA) of a novel virus is extracted, it is ready to be put onto the pre-defined platform base. Simply put, a platform is proven to be stable as a carrier of genetic materials from the virus. Inject Zika genetic material into the platform, a vaccine for the Zika virus is made, inject Covid-19 genetic material, a vaccine for Covid-19 is made.
The biggest benefit is, of course, speed.
“Remarkable speed in vaccine development for Covid-19”
On January 23, CEPI announced funding for developing a vaccine against Covid-19 using platform technologies. Two companies, ‘Inovio’, a pharmaceutical company developing vaccines through a DNA platform, and ‘Moderna’, using an RNA/mRNA platform, were selected for funding. The development speed of both companies is eye-opening. On February 24, Moderna announced that the company had sent a candidate for an RNA vaccine to NIH (National Institute of Health). It had been no longer than 42 days since the genome sequence of the virus was revealed.
Nam Jae-Hwan, virus researcher and professor of biotechnology at the Catholic University of Korea, commented that the vaccine development is happening at “record-breaking speed”. The traditional vaccine manufacturing goes through growing candidate material that induces neutralizing antibodies (immune substance), followed by a preclinical test on animals, three clinical trials on humans, approval from health authorities, and finally, commercialization (Page 34, see diagram). The first clinical trial of the mRNA vaccine candidate by Moderna is expected to happen in April. Since the 4th of March 45 volunteers have been recruited in the Seattle area (USA) to participate in the test. Inovio announced a similar schedule for a DNA vaccine. The US health authorities approving an exemption from the toxicity tests has enabled such a prompt schedule for human clinical trials.
Song Man-Ki, head of the clinical research laboratory at the International Vaccine Institute, explains the reasoning behind the decision. “Platforms used for RNA or DNA vaccines are considered empirically tested for stability because other vaccines using the same platform have gone through the clinical trials multiple times. Hence, under emergencies like this, the authorities agreed not to waste time on toxicity tests on animals and proceed with human subjects.”
However, although the development has proceeded unprecedentedly smoothly so far, from the first clinical test to the completion there is a long journey ahead. Normally, it takes 2 to 4 years for the first and the second trial completion, and the third clinical trial alone takes 3 to 5 years. A shortening the testing stage for the vaccine for Covid-19 is currently under discussion. While stability standards for side effects are not to be compromised, the monitoring period can be briefer. Vaccines with only a few months of effectiveness can be valuable during an urgent crisis.
On February 11, WHO Director-General Tedros Adhanom Ghebreyesus announced at a media briefing in Geneva that the first vaccine for Covid-19 could be ready in 18 months. 18-months is the best-case scenario possible we have, which is why we should be cautious about the media fuss over the vaccine as if it could be ready in a few weeks.
CEPI’s goal regarding Covid-19 is to conclude the first and second clinical trial during the pandemic and initiate the third trial in a region where the virus continues to prevail. This strategy is called a ring vaccination. It is a method to vaccinate the high-risk group so that the effectiveness of the vaccine can be screened. Last year, the FDA-approved Ebola vaccine ‘Ervebo’ completed its third clinical trial with this approach.
Problem is the Mutation
Undoubtedly, the case of Ebola is different from Covid-19. Ebola appeared in 1976 in Congo and has threatened many African nations, but never escalated into a more global scale. However, the outbreak in 2013 was capable of spreading across the continent, infecting European and American countries on its way. But because of its notorious past, the vaccine candidate for the Ebola virus had already completed the second clinical trial before the recurrence in 2013 and the third clinical trial was swiftly done in 2014. The Ebola vaccine shifted the paradigm of vaccine development.
Song Man-Ki from the International Vaccine Institute said, “After the first and the second clinical trial, the vaccine candidate prepares for the next outbreak. And what comes next is to vaccinate the whole region, because the vaccine’s safety has already been demonstrated in the previous tests. So now you have the advantage of being able to control the situation in the affected area and also to prove the vaccine’s effectiveness.” This is CEPI’s strategy for the recurrence of any virus that is currently dormant, such as MERS.
One of the factors that challenges the vaccine development for the coronavirus is mutation. The virus is known for its fast mutation, enabled by its crown-shaped spike proteins. Once the spike proteins mutate and change their shapes, the vaccine becomes useless (See the article in the right box). Influenza viruses that cause common flu are another case with fast mutation, which is why you are advised to get vaccinated every year. GISRS (Global Influenza Surveillance and Response System) of WHO makes an annual announcement on the estimated mutations of the influenza virus, and pharmaceutical companies release vaccines in correspondence. This system was developed because the virus has not disappeared with time; rather, it has evolved to settle down in the human world.
Some say that vaccine development may be useless under current circumstances, pointing out that it will take years to complete the vaccine and the pandemic will be over by then. On the controversies over the necessity, Song Man-Ki says “No one can predict how the situation will grow. The coronavirus could disappear in months, or stay with us, like the influenza virus. But if we do nothing on the virus, hoping for early closure and if it keeps coming back, there’s no undoing of that. So the best prevention method is to be prepared for every scenario imaginable.”
As of now, no vaccine manufactured using platform technologies has arrived at the final commercialization stage. If a Covid-19 DNA vaccine or RNA vaccine is completed, it would be the first to be called a platform vaccine. ‘Disease X’ Covid-19 is truly challenging the human race on all fronts.
The Science of Vaccines to Combat Epidemics
Vaccines are our most powerful weapon against epidemics. Treatments (antiviral agents in the case of the coronavirus) may cure patients who are already infected, but vaccines can prevent contagion at the start and block the human infection sources. While a vaccine does not directly fight a pathogen, it rather trains our immune system to fight back against a specific pathogen. Smallpox was eradicated in 1980 with the smallpox vaccine introduced by Edward Jenner in the 18th century. Just like that, the mighty virus that devastated the New World disappeared into the backstage of history.
The key condition for the vaccines to be approved is whether the vaccine creates a ‘neutralizing antibody’. For a virus to survive inside a human body, it has to make contact with human cells. The novel coronavirus uses little bumps that are shaped like a crown to bind to the receptors on the surface of the host cell to enter into the cell. These bumps are called ‘spike proteins’ (See figure도표/picture그림?). The job of the neutralizing antibodies is to stick to these spike proteins to prevent the receptor from making contact with cells which would enable the virus invasion.
Dead virus vaccines are the most typical type of traditional vaccines. They use killed (inactivated) viruses that are no longer harmful but appear similar to an active virus. The simplified mechanism of how inactivated virus vaccines work goes like this. Once immune cells recognize the invasion, they mass produce neutralizing antibodies adjusted to the shape of the virus. Some of the immune cells turn into memory cells (memory B cells). What happens when we get a flu shot is that later, when the influenza virus enters into the body, these trained memory cells immediately produce a large amount of antibodies against the virus.
The most important element in vaccine development is the connecting part where a virus binds to a receptor of a cell. In the case of the coronavirus, ‘spike proteins’ are that part. If a spike protein is injected into a human body, without the whole virus, as in the case of inactivated virus vaccines, immune cells of our body will automatically start to produce neutralizing antibodies of the same shape.
Platform technologies focus on the spike proteins. Once the spike protein is extracted from the genetic sequence of the Covid-19 virus, it is put onto a pre-defined platform base. When it is injected into human beings, the genetic materials of the vaccine will manifest as spike proteins, as the gene works like a plan designing the proteins. Platform technologies offer a faster and efficient option for the development of vaccine candidates. While traditional vaccines such as inactivated virus vaccines must go through the incubation period in a mass facility, RNA vaccines can be assembled in a laboratory.
Professor Nam Jae-Hwan says “While vaccines may not play the biggest role in the current crisis, they will be of invaluable help for the next pandemic to come.” Undoubtedly, Covid-19 vaccines are owing a great deal to previous vaccine research on SARS and MERS. It is true that the testing cycle for those vaccines remains incomplete, but the research shed a light on revealing some characteristics of coronaviruses, such as the information about spike proteins being a vaccine candidate. Based on these previous efforts, vaccine development for Covid-19 is expected to be faster than ever.
translated by Wonjeong Song
translation supervised by Franz Maier, Sumi Paik-Maier
