Globally, a process of immunization has started. The first Covid-19 vaccines have been approved by national and regional medicinal drug supervisors such as the UK MHRA, US FDA, and the EU EMA (The Economist, 2020). The Netherlands does not have a big biotech/pharma company (anymore) and is therefore not a leading contender in vaccine production.
Traditionally, vaccines put (a part of) a weakened or inactivated virus/bacterium into our bodies in order to trigger an immune response. The method of creating traditional vaccines can take years. This year has seen the further development and production of a new type of vaccine, vaccines based on messenger RNA medical technology
The Development of an mRNA Vaccine
DNA and RNA are two types of nucleic acids, the “building blocks of life.” Together, RNA and DNA team up to create proteins. DNA stores genetic information and codes for your traits like height, blood type, and eye color. DNA’s information gets transcribed into RNA molecule, and RNA’s information gets translated into protein. mRNA’s job is to carry a message based off of the DNA into protein. Ribosomes “read” the message of the mRNA sequence in order to determine which amino acids should join a growing protein molecule. In this way, mRNA can “instruct” our cells how to make a protein (or a piece of a protein). mRNA vaccines aim to utilize this process in order to create protein which can trigger an immune response inside of your body (YouTube).
The theoretical concept of creating protein to trigger immune responses inside your body seems simple.Namely, it is relatively easy to fit the necessary codes for protein onto an mRNA strand. However, it took decades for science to figure out how to repress a violent immune response, encourage cells in the immune system to accept the mRNA, encourage cells to make a large enough dose of the necessary protein, and learn how to enclose the mRNA inside microscopically small capsules (The Scientist, 2020). If mRNA is not protected properly, it is quickly destroyed by enzymes in our cells. Furthermore, the mRNA molecule is a very fragile molecule that degrades within minutes in an exposed environment. This explains why transportation in ultra-cold environments (-80 °C) is necessary.
Unable to tackle these challenges, many large biotech firms abandoned this approach to vaccine development and shifted back to traditional models. BioNTech and Moderna, two long-time mRNA “believers”, were the first to successfully develop a vaccine against Covid-19. The published potential efficacy rates of 90-95% are wild, especially when compared to earlier, more futile attempts.
Both Moderna and BioNTech have made big bets to ensure the successful development of mRNA technology. Some have attributed the success of Moderna’s efforts as it had already long been working on collaborating with researchers from the National Institutes of Health on a vaccine for another coronavirus, Middle Eastern Respiratory Syndrome (MERS). However, it should be kept in mind that MERS binds to different receptors and MERS has a different pattern of disease than Covid-19. Success can also be attributed to funding; Moderna was the recipient of $483 million of the US BARDA, the highest amount ever diverted by the division of the US HHS Department (CNN, 2020).
However, since its founding in 2010, Moderna has never brought a product to market, or gotten any of its nine or so vaccine candidates approved for use by the FDA. It has also never brought a product to the third and final phase of a clinical trial. Similarly, in the eight years since its inception, BioNTech has published 150 scientific papers. Save for the vaccine, BioNTech has 13 compounds in clinical trials for a variety of illnesses but as of yet, nothing has been approved (Boston Globe, 2020). Prior to the Covid-19 vaccine, both BioNTech and Moderna had not produced a single drug that had passed Phase 3 Clinical Trial (CNN, 2020).
Prior to the Covid-19 mRNA vaccine, no mRNA vaccine was ever successfully developed and passed through clinical trials. The two young biotech firms who managed to do so have tried – but failed – to pass other products through clinical trials. So, it remains a guess which of the many factors ultimately contributed to the success of the Covid-19 vaccines from both Moderna and BioNTech. Another oddity is that these vaccines have shown such high potential efficacy rates, when former attempts to develop mRNA proven so futile.
An mRNA Medical Revolution?
The successful (albeit emergency) authorization of the mRNA vaccines, is very exciting – why? It had been so hard to develop mRNA vaccines due to the vulnerability of the mRNA molecule, the low levels of protein it naturally produces and the insecurity of the type of immune response it might eventually trigger. Two key technological jumps helped to contribute to the success of the Covid-19 mRNA vaccine; the discovery that the nucleosides of the RNA had to be altered and the encasing of mRNA in small bubbles of fat (lipid nanoparticles) to enhance delivery (Harvard Health, 2020).
Following decades of research and trial and errors, scientists were able to develop and clinically test an mRNA vaccine to battle the current SARS-CoV2 virus, the first of its kind! While celebrating the success of the vaccine and keeping the caveats in mind, the development of the mRNA vaccine does signal exciting times for vaccines. One of the biggest advantages of the mRNA technology is its flexibility (The Scientist, 2020). Knowing we can use mRNA to develop vaccines against Covid-19, scientists can continue research in order to apply mRNA to an entire range of infectious diseases and cancer immunotherapy.
Yet, previous attempts to harness mRNA to fight off pathogens haven’t been successful. There have been unsuccessful attempts to produce drugs for infections such as Ebola or Zika. Moreover, scientists are attempting to produce anti-melanoma protein or protein for people who suffer from diseases like cystic fibrosis (Harvard Health, 2020). The acknowledgement of the success of the Covid-19 mRNA vaccine will beckon in a new era to continue to try to apply the technology to other infectious diseases as well (Nature, 2018). Norbert Pardi of the University of Pennsylvania is already researching whether one single vaccine can encode multiple viruses (The Scientist, 2020). While attempts remain in vain, we can (prematurely) already start to imagine a future in which a child can receive one or two vaccines and be set for life against dysentery, polio, tetanus, hepatitis, measles, mumps, Covid-19, the list goes on…
The promise of mRNA technology is two-fold; in the future, science can try to develop it as an all-in-one vaccine against different infections, and secondly, as a form of immunotherapy to kill cancerous cells (The Scientist, 2020; Moderna). In this logic, mRNA technology can be utilized to harness the immune system to fight current and future illnesses via immunotherapy or vaccines. Recent breakthroughs are promising, but still far from practical application.
The mRNA medical revolution has other consequences, too. Not only is this a disruptive change for biotech and biopharma companies as the makers of vaccines, but it can also have consequences for countries too. Without a doubt, Covid-19 is not the last pandemic humanity will have to deal with. On 11 January 2020, the virus’ genetic code was identified, and merely 63 days later, Moderna’s clinical trial started with its first human injection (MIT Sloan, 2020). Provided scientists continue to work on the mRNA technology to be able to develop reliable and efficient vaccines, the possibilities are great if/when a future pandemic happens. Furthermore, by developing mRNA technology, governments and public health officials will have new tools to rapidly treat current and future infectious diseases. For example, what will be the effect of a country quickly developing mRNA technology to vaccinate against Covid-19 or one vaccine against multiple infections? Will a country’s public health authority be required to share these mega vaccines with other countries and the WHO? What happens if they do not? What happens if these vaccines are not shared equitably across the world? Will this create an imbalance of inoculation power?
China’s Vaccine Program
Which vaccines is China currently developing, and where? At the start of the global pandemic and before the first wave in the Netherlands, a Dutch consortium under the lead of UMC Utrecht actually applied to clinically test an unspecified Chinese vaccine. However, Covid-19 cases were not (yet) running rampant, and the Netherlands was subsequently passed over, an employee at UMC Utrecht recalls. Nevertheless, there are currently at least eight Chinese vaccine candidates which have entered clinical trials, of which three have already been approved by health authorities of various countries. These three are inactivated vaccines, which use inactivated or ‘killed’ versions of the virus that trigger immune responses but cannot replicate in human cells. On the 23rd of December, Sinovac met the efficacy threshold set by the Brazilian health regulator Anvisa of above 50%. CoronaVac began its phase three trials in Brazil in July and has since expanded to other overseas trial sites including Turkey and Indonesia. On December 30th, China Daily clamed Sinopharm’s vaccine shows an efficacy rate of 79.34% (SCMP, 2020). While rates of 50% and just under 80% sound quite low after the immensely high numbers from BioNTech and Moderna, an efficacy rate of at least 50% is actually pretty standard for a vaccine.
Despite the lower efficacy, the Sinovac vaccine can be stored at a normal refrigerator temperature which makes it much more attractive to countries lacking the means to ensure transportation by extreme cold-chain logistics as required by the mRNA vaccines from BioNTech and Moderna. A handful of countries have made purchase agreements already with Sinovac, such as Hong Kong, Brazil, Turkey, Indonesia, Singapore and Chile. Alongside China, the UAE and Bahrain have approved the Sinopharm vaccine for use (NOS, 2021; The Economist, 2021). Curiously, both Sinovac and Sinopharm have been hesitant to be fully transparent and release the results, data and sample size of their respective Phase 3 trials.
China’s mRNA Development
Within the span of a few weeks after hearing about the success of the mRNA vaccine technology, China similarly began to work on a facility to manufacture its first Covid-19 mRNA vaccine (Reuters, 2020). This is not China’s first attempt to develop an mRNA vaccine. In the beginning of the pandemic, BGI group managed to sequence the Covid-19 virus and develop an mRNA vaccine. However, a BGI employee recalls, funding and other resources were not able to launch a full-scale clinical trial. Another vaccine based on mRNA was considered at the end of January 2020. However, Lei Chaozi, director of Science and technology Department of the Chinese Ministry of Education doubted the technology as no product had ever been put on the market (Xinhua News, 2020).
At the end of June, Walvax ran a Phase 1 clinical trial to evaluate the safety of an mRNA vaccine against Covid-19. There were 168 participants, aged 18 to 59 and above 60. The clinical trial was sponsored by the Academy of Military Medicine, Academy of Military Science and Suzhou Abogen Biosciences The online Chinese Clinical Trial Registry does not report any conclusions from this study (ChCTR, 2020). Four months later, in mid-October, Walvax ran a second Phase 1 clinical trial to again evaluate the safety of an mRNA vaccine against Covid-19. For this trial, there were only 120 participants, aged 18 to 59 (ChCTR, 2020).
It is unknown why previous trials were never published. Nevertheless, at the end of 2020, People’s Daily, a Chinese state media, reported that the Academy of Military Science (AMS), Walvax Biotechnology and Suzhou Abogen Biosciences would jointly develop an mRNA vaccine plant. It would be operational within eight months and have the capacity for 120 million doses (Reuters, 2020). This news came mere weeks after the announcements on the effectiveness and emergency authorizations of the BioNTech and Moderna mRNA vaccines. Following this announcement, we can wonder whether the Chinese government now felt pressure to similarly produce an mRNA vaccine. However, Chinese Center for Disease Control and Prevention head George Gao has publicly called into question the efficacy of US-produced vaccines which are based on mRNA technology (NYT, 2021; AP News, 2021). The double attitude of the Chinese government towards mRNA technology is somewhat confusing. Whatever their intentions, it will be interesting to track the development of a Chinese vaccine plant set to produce a vast number of mRNA vaccine doses that have yet to make it pass a Phase 1 clinical trial.
After many barriers, i.e., the fragility and complicated nature of the structure of the mRNA molecule, science has been able to develop an mRNA vaccine against Covid-19. Not only is this exciting in terms of fighting the current global pandemic, but we can also look further into the future and question mRNA’s possibilities to vaccinate us against multiple different infections (at once). The potential of mRNA is uncertain, yet promising. In the future, mRNA might be used to develop vaccines, drug therapeutics or even all-in-one vaccines.
China has recognized mRNA’s future potential. So much so, that China has invested, scaled up production and intends to produce 120 million doses in eight months’ time without the backing of completed clinical trials. While the Chinese effort to join the mRNA technology revolution is appreciated, Chinese state media has peddled conspiracy theories questioning the efficacy of US-developed vaccines, specifically those based on mRNA technology (Washington Post, 2021).
So – where does that leave the rest of us, and what are the implications for the Netherlands? As a country without big biotech industry players, the Netherlands cannot produce its own vaccine and it is left to follow the EMA guidelines. To a large extent, the Netherlands has become vulnerable; the Netherlands is increasingly forced to rely on other countries’ efforts for vaccines. Furthermore, in a world where countries can be tempted to save (vaccinate) themselves first, this creates vulnerabilities, especially during pandemics.
Written by: Claire Selbeck