COVID-19 Vaccine Production & Distribution Explained
How Do the Current Vaccine Candidates for COVID-19 Work?
The mRNA seems to be the most promising vaccine type in Western countries, and includes the Moderna and Pfizer-BioNTech vaccines. How do they work? It's important to fully understand the disease mechanism of SARS-COV-2. Basically, the distinctive trait of SARS-COV-2 is that it works by using a spike protein on the outer surface to facilitate its entry into the cells of our bodies. This entry is camouflaged so that our cells can't detect it. The way this vaccine type works is because it contains the mRNA (the genetic information) to produce the spike protein once it enters the cells. This genetic information is first covered in a lipidic fat to prevent its degradation until it reaches the cells. The mRNA basically contains the "instructions" on how to produce a part of this S protein once it reaches the cells. Once this protein is made, the mRNA is degraded and it is revealed on our own cells' outer surface. It then activates our B cells (which will produce antibodies) and T Cells (which are basically "memory cells") against the virus. Therefore, if and when we actually get exposed to the virus, our immune system has already built a response (or a "memory"), so the effects of the disease are much more attenuated.
Other types of vaccines being developed include:
• Protein subunits: These include proteins or parts of the SARS-COV-2 to focus the immune system on a single target (for example, the Novavax vaccine). It may lead to an insufficient immune response and require multiple doses or adding other chemicals to boost a long-term immunity.
• Viral vectors: These take another harmless virus, and modify it to present the part of the SARS-COV-2 that will induce immunity in our bodies (for example, the Oxford-AstraZeneca, Johnson & Johnson, Sputnik V, CanSino Biologicals vaccines). A disadvantage is that an immune response to the virus may reduce the effectiveness.
• Inactivated pathogens: These include the whole virus, but it has been “killed” by different mechanisms (for example, the vaccines from the Chinese companies Sinovac and Sinopharm).
• Live attenuated: These include a weakened version of the virus (for example, the Codagenix and Indian Immunologicals vaccines). It may not be safe for individuals with a compromised immune system.
Overview of Vaccine Development and Approval Stages in the West
To begin, there are small-scale studies performed by the pharma companies to ensure a vaccine’s quality. Then, there's the non-clinical phase when in vitro and in vivo studies are performed. In the European Union, a vaccine then needs to be evaluated by the European Medicines Agency (EMA) and European Commission until it is approved. All vaccines must also be evaluated and approved by the relevant national regulatory authority of each member state. In the United States, the Food and Drug Administration (FDA) is the agency that evaluates and approves vaccines. Upon approval, the vaccines are distributed at scales determined by the developer along with its public and private partners.
Vaccine development has 4 phases:
Phase I - A small group of healthy individuals receive the vaccine (20-100 people). The goal of this step is to test major safety issues, clarify that it can reach the targeted area, deliver clear benefits, and gain evidence of its therapeutic and/or preventive value.
Phase II - The group that received the trial vaccine has similar characteristics to the demographic that the vaccine is intended for (we can compare a group that is receiving the vaccine to one that is either using a placebo or another treatment). It's important to minimize bias at this phase, for example, using double-blind controls (or when the participants and the investigators don't know who is receiving the active substance or the placebo/other treatment).
Phase III - The vaccine is given to larger groups (in the thousands), so we can test the safety and effectiveness, confirm ideal doses, and identify potential side effects. There's, to date, 14 candidates at this phase.
Phase IV - This final phase constitutes studies being conducted after the vaccine is approved and licensed. To date, one has been approved: the Pfizer-BioNTech. After being launched, the Global Safety Board takes over the monitoring, with the goal being to ensure that a given vaccine’s benefits always outweigh its risks.
There's many companies involved in the manufacturing of vaccines. The most prominent include AstraZeneca, Janssen, Moderna, Novavax, and Pfizer-BioNTech, which are all in stage III. There's also newer ones, such as Germany’s CureVac (which can be stored at 5°C, as of phase I, a major distributional advantage that will be discussed further later). At the present moment, there's 58 vaccine candidates: 14 at phase III, and 1 at phase IV.
The Pfizer-bioNTech and Moderna vaccines are both mRNA types, and seem to be more than 90% (~95%) effective. Meanwhile, Oxford-AstraZeneca, a viral vector vaccine, only seems to be 62-90% effective. All vaccine candidates, except the one being developed by Johnson & Johnson, require 2 shots for it to build enough protection.
The EMA received an application for conditional marketing authorization for BNT162b2, the mRNA vaccine developed by BioNTech and Pfizer. This basically means that the EMA could authorize medicines that are not fully studied, in case the benefits of its immediate availability outweighs the risks. To date, an official answer has not been disclosed, and no vaccine has been approved by either the EMA or the FDA.
The United Kingdom's Medicines and Healthcare Products Regulatory Agency recently approved the Pfizer-BioNTech vaccine, and distribution to the British public is already underway. Canada's national regulator, Health Canada, has just approved this same vaccine.
In China, an inactivated vaccine produced by the Sinopharm company has already been given to more than a million people, even though the approval status from the National Medical Products Administration (China's drug regulator) remains unclear. This vaccine is also being tested in Brazil, Indonesia, and Turkey.
There's obviously tremendous pressure from world leaders across the political spectrum to launch a vaccine. A vaccine represents the single best measure to protect people on a meaningful scale from COVID-19 and our best chance to get the global economy back on track.
Traditionally, vaccine development takes years (or even decades). At the moment, there are still several challenges to overcome:
1. Understanding a vaccine's role in people infected with COVID-19, and its possible preventive value in healthy individuals, along with the fact that its disease mechanism is still unclear.
2. Disagreement on the most common antigens (the molecule of the virus that can be found by an antibody) of the virus between scientists.
3. Lacks of studies on animals. There's also no specific studies on vulnerable populations, such as children and pregnant women.
4. The duration of protection given by our immune system in people infected with COVID-19.
Focusing exclusively on the mRNA vaccines, it is important to note that, until now, none of them have gone past small clinical trials when being tested previously for other diseases (for example rabies, zika virus, flu, cytomegalovirus). No vaccine that uses this technology has ever been approved or distributed before. So it is not clear why it seems to work so effectively in COVID-19. This lack of understanding could present some potential health risks, and should not be overlooked. Another big concern when it comes to this vaccine class is that traditionally they may generate inflammation and autoimmune conditions in the human body. So it's not yet clear if that is the case here.
Another potential issue is the fact that tests in animal models do not produce a similar clinical course as in humans, so the need for human volunteers is crucial. The potential complications and safety issues that may arise are much more worrying because of the lack of available treatment options for COVID-19 at the present.
Another concern is that the safety, tolerability, and efficacy should be evaluated in people from all parts of the world. This could pose some concerns since vulnerable populations from less-developed countries should have the same access to treatment and proper care in case deleterious events arise.
It is also important to add that countries (especially lower to middle-income ones) may end up relying on deals for vaccine distribution, whereby they are compelled to conduct large-scale trials in their populations in exchange for vaccine access. This could pose some ethical issues, since these countries are rushing to get a vaccine distributed to attenuate the devastating economic consequences of the pandemic.
As an example, the United Arab Emirates and Bahrain already have had the Sinopharm vaccine available since the beginning of this month. Countries like Chile, Indonesia, and Turkey have already signed up for millions of doses of the Coronavac from Sinovac, in exchange for testing it on thousands of people in their respective countries. These vaccines need to have their safety tested in more "transparent" clinical trials, since previous inactivated vaccines showed that they could actually make the disease worse. For instance, concerns have arisen due to the lack of reported serious or severe effects from these companies’ large-scale trials in China. According to various experts, including Kinch and William Haseltine, it is “extremely unlikely” that not one reported serious or severe effect (even if it happened by chance and was not related to the vaccine) occurred in the more than 100,000 people that were reportedly tested. The lack of transparency of these vaccine results, and the companies’ refusal to comment on it publicly, could pose future risks to any countries that opt to use these vaccines.
As mentioned previously, there's currently 14 candidates at phase III of the trials, awaiting approval. Nonetheless, most Western countries have already signed contracts with major companies (including Pfizer-BioNTech, Moderna, and Oxford-AstraZeneca), and generally secured “enough” vaccines for its population in need.
Pfizer and Moderna have factories located throughout the United States and Europe. So it's safe to say that the capacity of production and distribution of COVID-19 vaccines is much higher in these areas. In fact, it's estimated that the United States could produce 4,686 million doses from now through the end of next year.
What about less-developed countries that can not afford to make direct deals with big pharma companies, or don't have the manufacturing infrastructure to accommodate such factories?
The Pfizer-BioNTech vaccines require freezing storage temperatures (under -70°C), which would necessitate special refrigerators that are not widely available in Africa, Asia, and South America at the moment.
Even the vaccines that don't require such cold temperatures (for example the Moderna one, which claims that it can be maintained safely at -20°C) still poses some distribution challenges for less-developed countries, since a significant number of ships, trains, trucks, and planes with adequate refrigeration would be needed to ensure sufficient vaccine coverage.
Some possible solutions are in the works, though:
An international program to help raise funds for countries in need: COVAX, which is a program led by the World Health Organization (WHO), Gavi, and the Coalition for Epidemic Preparedness Innovations (CEPI), is raising funds to ensure equitable distribution to every country in the world, with a special focus on lower-income ones. This program, which includes 187 countries so far, is putting a great deal of effort into ensuring that every country gets a fair shot at acquiring the best vaccines. It is estimated that only 3% of the global population will receive vaccines through this program at the beginning of next year, but their intent is to try to cover 20% of the most vulnerable populations in countries in need over the next year. To do so, these countries will pay a small commission of up to 4 US dollars per two vaccine doses (even though it initially was intended to be free).
The creation of new production sites, with an emphasis on easier-to-store vaccines. For example, Oxford-AstraZeneca aims to expand its manufacturing to India. This could help solve distribution discrepancies massively if proven safe and effective, since this adenoviral vector vaccine could be stored between 2-7 °C (which is the temperature of a typical home refrigerator), and its shelf life is 6 months. This represents a huge advantage over the Pfizer-BioNTech and Moderna vaccines, which both need to be stored at much colder temperatures, and their shelf lives are only 5 and 30 days, respectively. Another benefit of the Oxford-AstraZeneca vaccine is that the price per dose is only 3-4 US dollars, as opposed to 19.50 US dollars for the Pfizer-BioNTech one and 32-37 US dollars for the Moderna vaccine. Two doses are required by these 3 candidates to build enough strong immunity. Given the lower production costs of the Oxford-AstraZeneca vaccine, along with the favorable storage temperature, it could help cover a larger extent of the global population. For instance, the Mexican and Argentine governments are set to distribute millions of doses of this vaccine next year. However, the Oxford-AstraZeneca vaccine has been shown to be less effective than the other two (62-90%, as opposed to ~95%).
Lastly, we can't forget about the costs of the healthcare staff responsible for administering the vaccines and related materials, which could add up to 15-20% of the total bill.
With the intent of surpassing these difficulties, a few solutions have come up. Pfizer-BioNTech is intending to use its own refrigerators and ensure the distribution themselves. The company is also considering the development of a powered vaccine. UNICEF is also getting involved, and plans on building 65,000 solar-powered fridges for lower-income countries next year.
It is also important to be aware of potential corruption and inequality in less transparent countries (which, for example, could jeopardize at-risk or minority groups), and understand the challenges of equitable distribution in countries without a public healthcare system.
It is in everyone's best interest that an effective and safe vaccine for COVID-19 is developed, approved, and distributed worldwide as soon as possible. Nonetheless, vaccine development is a complex process that usually takes years to decades to be proven efficacious and risk-free. While vaccines are, undoubtedly, the most important tool to help fight this terrible pandemic, it is important to maintain the measures we've been using (such as physical distancing, mask usage, and washing our hands) in the meantime until widely-available vaccines become a reality.
Dr. Filipa Madalena Teixeira, M.D. is finishing a general residency at the Hospital of Faro in Portugal. In January 2021, she will be beginning a Family Medicine specialty in Madeira, Portugal. She is a graduate of the NOVA Medical School in Lisbon, Portugal. Her research interests include Psychiatry and Public Health.
The views expressed above are those of the author and do not reflect the official position of the M74 Group, which remains neutral on all matters. Publishers assume no liability for content.