COVID-19 Update #4: Vaccine: A Challenging Marathon

For the past several months, COVID-19 has made havoc around the world. As of now (May 18th), more than 4.9 million people have been infected, and more than 320 thousand died from the virus. Governments have adopted different strategies to combat the virus but find it challenging to balance between suppressing the virus and opening up the economy.

Vaccination is widely regarded as the panacea to the virus’ spreading, humans hold high expectations for this measure. How far along the way are we in COVID-19 vaccination development? What are the bottlenecks? How reliable and safe can it be? Bridge Point Capital Analyst composes this article based on the most up-to-date information, providing you with the prospects of vaccine development and future application.

The Race for Coronavirus Vaccines: A Graphical Guide

Vaccine Marathon: Who Is Leading the Way?

Since the disclosure of COVID-19 genetic sequence in January, many global institutions and enterprises have started competing for producing an effective vaccine. Generally speaking, the vaccine development process, which consists of research, clinical, approval and commercialization, can take as long as more than ten years.

A Draft landscape of COVID-19 candidate vaccines published by WHO in May shows that according to incomplete statistics, there are 8 vaccines currently in the clinical phase, with other 110 candidates in the pre-clinical phase.

It is not hard to see that the COVID-19 vaccine is being developed at record speed. However, this is just the first step of a hard battle - usually it takes up to a year and a half to finish all clinical trials. Then, production, cost control, efficiency testing and commercialization become great challenges facing researchers, pharmaceuticals, governments and the public.

So far, several institutions and companies from China, U.S., U.K. and Germany have become the leaders in vaccine development: Among the ones that have already entered clinical trials, China claims four of them, including a viral vector vaccine co-developed by Academician Chen Wei’s team and CanSino Biologics, and three other inactivated vaccines. U.S. claims two, which are Moderna’s mRNA vaccine and Inovio’s DNA vaccine. Britain’s Oxford University is developing a viral vector vaccine; another mRNA vaccine co-developed by Pfizer and Germany’s BioNTech has also gained approval at the end of April.

Among these leaders, a viral vector vaccine developed by Academician Chen Wei’s group in CanSino Biologics became the first to enter phase II clinical in the world on April 12. In a live stream with People’s Daily (the largest newspaper group in China) on April 25, Wei indicated that 508 phase II volunteers for the viral vector vaccine have completed inoculation, and they are currently under observation. If everything goes well, unblinding will take place in May.

Although we cannot precisely predict the time when the first batch of public-use vaccine becomes available, September seems to be the most optimistic estimate according to researchers.

Oxford University’s viral vector vaccine has seen a phase I trial of more than a thousand people, and the imminent phase II and III trials will involve around 5,000 people. Professor Sarah Gilbert, who is part of the development effort, said that if the regulatory authority could grant emergency approval and the vaccine is tested to be effective, then a couple millions of vaccines could be produced by September.

Coincidentally, Pfizer and BioNTech also announced recently that if clinical trial started on May 4th went well, they estimated that their mRNA vaccine could be put into use as early as September in the U.S..

Types of Vaccines: Difference?

Inactivated Vaccine:

The coronavirus will be inactivated, making it no longer contagious. However, the virus would still activate responses from human immune system, giving the recipient corresponding immunity. As the traditional vaccine development method, an inactivated vaccine needs a large reservoir of virus culture and faces risks of failure to deactivate virus.

Adenovirus Vector Vaccine:

This type of vaccine, by genetically engineering the harmless adenovirus, makes adenovirus express S protein (spike protein) of coronavirus, which then triggers immune responses. During infection, S protein will bind to its predominant cellular receptor ACE2 and initiates the viral entry, so when coronavirus infects human bodies, since humans already have immunity against S protein, coronavirus is no longer able to infect.

However, research shows that this type of vaccine cannot fully guarantee its effectiveness, since human immune system sometimes responds to the adenovirus itself, resulting in no production of coronavirus antibodies. Nonetheless, the advantage is obvious - the technology is mature, and it can be swiftly put into use after completion of clinical trials.

RNA Vaccine:

By injecting messenger RNA that codes the coronavirus S protein into human bodies, the S protein is expressed. At the same time, the immune system will identify and remember this new type of protein, generating immunity and protecting the human body from being infected by coronavirus.

This technology is convenient and fast - as long as the researchers know the genetic sequence of the virus, they can quickly create antigens. For example, the mRNA-1237 vaccine by Moderna took only three months to enter phase I clinical trial since the genetic sequence of the virus is released to the public. On May 18, Moderna reported that mRNA-1273 could successfully trigger the immune responses in vivo and stop viral replication. Though there are much more studies need to be done, Moderna’s current results indicates it’s promising to prevent people from being infected by COVID-19 with the help of mRNA vaccine.

DNA Vaccine:

After this vaccine writing the genetic sequence that codes the coronavirus’ S protein into DNA plasmids and injecting the plasmids into human bodies, they can be ingested by human cells, the protein of which are then used to synthesize the virus protein. The virus protein is then identified by the immune system, which in turn gives immunity to the human body. As of now, DNA vaccines are applied in veterinary field, but it has not yet past clinical trials on human. This is similar to RNA vaccine in that it does not follow the traditional approach and instead uses the most cutting-edge gene editing and engineering technology to develop the vaccine. This type of vaccine requires less research time, but its safety deserves more attention.

What Are the Bottlenecks? Do We Have Solutions?

It is extremely sophisticated to successfully develop a COVID-19 vaccine. According to the state of development of vaccines for SARS and MERS, members of the coronavirus family, the COVID-19 vaccine development situation is not so clear – and here is why:

Safety is always the most important aspect of vaccine development. Based on the failure cases of SARS vaccine development, most vaccines have advanced survival rate of animals but cannot prevent the virus from infecting; some vaccines also result in complications, such as lung tissue damage. That is why all phase I clinical trials have the purpose of testing its safety. It is only meaningful to resume research after verifying that vaccine will not induce any harm to the human body.

Having a long-acting anti-virus mechanism seems to be another issue. Since COVID-19 has displayed characteristics of drifting (small range gene mutation), which will greatly trouble vaccine evolution. As soon as the virus mutates, any previous vaccines would become invalid; and that is why we need to have so-called “rolling vaccines” to assure their efficacy over the long run.

Last but not least, researchers have to consider vaccines’ effects among various groups of people. The Coalition for Epidemic Preparedness Innovations (CEPI) indicates that there currently exists no vaccine that can guarantee the effect after inoculation. This is because the vaccine efficacy depends on many factors, ranging from race, age, environment and individual differences, which result in different reactions to the same vaccine. And it is a laborious and challenging process to collect and analyze these data and make updates to the vaccine accordingly.

In response to these bottlenecks, vaccine has evolved into two types.

One is the “once for all” kind: this type of vaccine, by stimulating human immune system and conservative protein (proteins that are less susceptible to mutation) that identify the virus, evades the issue of vaccine failure resulted from mutation.

Another kind is of shorter duration, a good example of which is influenza vaccine. This type produces a vaccine targeting the dominant mutated virus strain of that year. Based on the genetic drifting characteristics COVID-19 has shown, it is more likely that we adopt the latter kind.

One World, One Fight

The renowned Chinese epidemiologist, Nanshan Zhong, recently said that COVID-19 vaccine development is urgent yet uneasy; the optimistic estimation for the time needed is a year and a half. Additionally, considering there could be antibody dependent enhancement (ADE) effects associated with COVID-19 and other factors, it could take even longer to produce effective vaccines. And then, it might take several more years to verify if the vaccine is effective. Therefore, in order for the COVID-19 vaccine to be put into use, there is a long way ahead.

Now, we would like to use Zhong’s words as the conclusion of this article: “No matter what, vaccine development is the most urgent matter, and this requires each country to learn from each other and to conduct good international cooperation, so that we can create a better vaccine for the entire human race. Every country’s researcher should focus on which kind of vaccine is safe and effective not on who develops the vaccine first. After all, we dwell in the same world and are fighting the same battle.”