It seems as if everyone is holding their breath for the release of a COVID-19 vaccine. The most recent development (at the time of writing) is the announcement of results from the Phase Three testing of the Moderna vaccine. Moderna announced that preliminary results suggest that the vaccine is over 90% effective in preventing contraction of COVID-19, much greater than the 60-70% margin required to create herd immunity in the population (Gates, 2020 Apr). This is great news for the fight against the coronavirus. Some are even predicting that a vaccine will be mass-produced and given to the public by the start of 2021.
However, other predictions, including some by the United States government and World Health Organization, suggest we might have to keep holding our breath for a while longer. We must remember, companies are blitzing out development of these vaccines. Before SARS-CoV-2, the fastest development of a vaccine took four years (Cagle, 2020 May). Considering that the genome of this virus was only made available in January of 2020, we must remember to be patient for the vaccine to become available.
And even after a vaccine is approved for public administration, what happens then? First off, many have voiced concerns about the safety of such a vaccine that might have accumulated errors by rushing its production. But we would need most of the population to receive a vaccine to receive its full effects. How can we ensure the vaccine will be safe, and assure people that it is? There are also potential issues that can arise with production and distribution: how are billions of vaccines going to be created in a short time frame? This article will answer these important questions and more, including how the vaccine might work, the very latest vaccine developments, and the approximate time frame for production.
To understand how these vaccines will protect us from the coronavirus, it is first helpful to remember how the immune system fights infections. After the immune system detects foreign pathogens in the body, it produces proteins called antibodies to fight the infection. It knows which antibodies to produce by identifying the pathogens through substances on the surface of the microbes called antigens. The antibodies that the immune system produces correspond specifically to these antigens on that specific invader; for a different invader, they would not be effective. After the infection has been vanquished, the immune system “remembers” the antigens on the pathogens they just fought. If it ever detects these antigens again, it can quickly mass-produce the right antibodies to kill the microbes. This is how immunity is created within the body. (Gates, 2020 Apr)
Vaccines take advantage of this system of “remembering” antigens to artificially create immunity in the human body (Jeyanathan, 2020 Sept). By introducing dead or weakened viruses to cells, or even just bits of viral protein or genetic information, the body can go through the cycle of identifying antigens, and “destroying” the infection that was never really a threat in the first place. Since the viruses are dead or extremely impotent, there is a very low chance of infection, and still results in immunity in the body.
An important caveat to this principle is that viruses can mutate over time (and as a result, may have different receptors on their surface). So, if a new viral strain enters the body that is just different enough from an old infection, the immunity built up by the body may not be enough to swiftly control the infection before it takes hold. This is why we have to receive a flu vaccine every year: the influenza virus mutates extremely rapidly, making it resistant to the immunity built up in the body. In contrast, diseases such as measles or polio can typically be prevented with only one or two vaccines throughout one’s entire lifetime. (NIAD, 2020 Nov)
The flu vaccine uses “inactivated” vaccines (containing dead viruses) or “live” vaccines (containing extremely weakened viruses). These are the traditional methods of bringing the viral antigens in contact to the immune system, and thus inducing immunity through vaccines. However, these traditional vaccines are very time-consuming to research and create. That’s why the leading vaccines for COVID-19 utilize a nontraditional approach. Most of these vaccines are RNA vaccines (Frederiksen et al., 2020 July). Rather than injecting the pathogens themselves into the body, RNA vaccines introduce viral genetic information (called RNA) into cells. The cells then use this genetic information to produce viral proteins, just as if the RNA was a part of its own genome. When the correct RNA strand is introduced to the human cells, they produce and display the virus’s unique antigens on the surface of their cells. This invites the immune system to attack the cells and remember the antigens, leaving the vaccine receiver immune to future infections (Brisse et al., 2020 Sept).
So how far along are current COVID vaccines? By November 16th, 2020, there are a total of 141 vaccines in development worldwide: 54 in human clinical trials, and 87 in animal preclinical trials. Since vaccine development only started in March, it is very impressive that 12 of these 141 vaccines have reached the final states of testing. (Corum et al., 2020 Nov)
Vaccine development has four main stages of testing: Preclinical Testing, Phase 1 Safety Trials, Phase 2 Expanded Trials, and Phase 3 Efficacy Trials. Prior to even preclinical testing, scientists must produce a vaccine using inactivated, live, RNA, or even other methods. Each of the four stages of testing can then take months, and if a vaccine fails even one of these tests, development can come to a halt or even restart altogether. Furthermore, all of these trials must be double-blinded, to ensure accurate results. That means both the health professionals administering the vaccine and the participants receiving the vaccine do not know if their dose of the vaccine is real, or a placebo. These are some reasons why it is taking so long to produce a safe, efficacious vaccine. (Gates, 2020 Apr)
After the plans for a vaccine seem promising, it moves to Preclinical Testing, or tests on cell cultures and animals. Scientists do this to determine whether the vaccine truly causes an immune response to be developed in cells.
After being approved to pass Preclinical trials, the vaccine moves to Phase 1 Safety Trials. The purpose of these trials is predominantly to ensure the vaccine is safe for use on humans. These trials only apply to a small number of people, and healthy adults in the population, to reduce the possible risk as much as possible.
When the vaccine is deemed safe enough, Phase 2 Expanded Trials are the next step. Researchers administer the vaccine to hundreds of people to determine mostly the vaccine’s safety, and to a lesser extent its stimulation of the immune system. These trials also include groups such as the elderly and children.
The previous two stages will have largely determined the safety of the vaccine. Phase 3 Efficacy Trials test whether the vaccine legitimately prevents coronavirus infection. Of course, researchers cannot simply bring participants into contact with the SARS-CoV-2 virus and see if they develop an infection; that would be horribly unethical. So, they give the vaccine (and a placebo) to thousands of participants. Then, they simply must wait for a portion of these individuals to become infected. (Side note: a few “human challenge trials” are planned to intentionally infect young, healthy volunteers with COVID-19 to test vaccine efficacy, but these trials are few and have relatively small sample sizes (Kirby, 2020 Oct).
After months, scientists can determine whether the vaccine was successful or not by comparing the number of infected who received the true vaccine and the number who received the placebo. The U.S. Food and Drug Administration advised that to move to the mass-production stage, any vaccines must be at least 50% effective at stopping infection (FDA, 2020 June). For comparison, the flu vaccine is typically about 45% effective at stopping infection (Gates, 2020 Apr). Phase 3 trials also reveal any rarer side effects that had not been previously identified.
Some countries, such as Russia and China, rush vaccines into “Early or Limited Approval” status directly after Phase 2 testing has been completed (Corum et al., 2020 Nov). However, experts say these protocols are very risky for the health and safety of the public, and for the long-term results of using the vaccine. However, in most countries, vaccines must pass Phase 3 trials before reaching “Approval” status. At this point, the vaccine has been deemed safe and efficacious enough to administer to the public. Of course, scientists will continue to very closely monitor the vaccines’ effects as it is given to more people. As of November 16th, no vaccine has reached this Approval status, although a few have received “Early Approval” from foreign countries, and are currently being used in select populations, such as the Chinese military.
However, there are about a dozen vaccines truly in the Phase 3 stage of testing. This article will cover a few that have the most promising results and that we have the most information on:
Firstly, the American company Pfizer and German company BioNTech have partnered to create an as-of-yet unnamed vaccine in Phase 3 development. On November 9th, these companies released data suggesting their vaccine is 90% effective at preventing coronavirus infection. If these results hold for the remainder of the Phase 3 study, this would be an extraordinary triumph for medicine. This is double the average efficaciousness of the flu vaccine and would leave a wide margin of error to ensure herd immunity in the population (assuming it is distributed properly). The Pfizer-BioNTech vaccine consists of two RNA-based designs. Phase 1 and 2 testing results indicated that both designs were effective at inducing immunity through both antibody and T Cell (a type of immune cell) production. One design, eloquently named BNT162b2, possessed significantly less side effects, which is the one that has been pushed for Phase 3 testing with over 40,000 test subjects and will most likely be approved by the United States government in the coming months. Pfizer is expected to apply for Emergency Use Authorization in the end of November, which (if passed) would allow for the use of the vaccine in the general population. Many national governments have already made deals with Pfizer and BioNTech for large orders of vaccines, contingent upon the design’s approval. The U.S. has paid for 150 million doses, Japan for 120 million doses, and the European Union for 200 million doses. Pfizer expects that it will be able to roll out over 1.3 billion doses worldwide by the end of 2021. All of this paints a bright future for the vaccine and its distribution. However, the main drawback with the Pfizer-BioNTech vaccine is its storage. Because of its RNA-based design, the vaccine must be stored at -80°C or -112°F until just before it is injected into the body. While Pfizer is specially designing freeze-boxes to keep vials cooled, this will be a major problem for distribution across the world, especially to locations with less infrastructure (which in some cases, have been hit the hardest by the pandemic). (Gandel, 2020 Nov)
Another RNA-based design has been created by Moderna, an American biotech company based in Massachusetts. As a part of Operation Warp Speed, the federal government has provided nearly $1 billion in support of their vaccine development. This company was the very first to put its vaccine into human clinical trials. On November 16th, Moderna made public preliminary results from its Phase 3 testing, which indicated that the vaccine was 94.5% effective (Jackson et al., 2020 July). Like the Pfizer-BioNTech vaccine, this rate is fantastic. The smallpox vaccine was 95% effective, and smallpox has now been eradicated (Belongia & Naleway, 2003). In August, the United States agreed to give Moderna $1.5 billion in exchange for 100 million doses of the vaccine, when it becomes available; other countries such as Canada, Japan, and Qatar, have struck similar deals with the company. The most encouraging thing about the Moderna vaccine is that it can be stored at standard refrigeration temperatures of 2°C to 8°C (or 36°F to 46°F) for 30 days, and -20°C or -4°F for six months. This is great compared to Pfizer’s temperature requirements that are far below freezing. (Corum et al., 2020 Nov)
One leading vaccine outside of the western world is produced by the Chinese company CanSino Biologics. Their vaccine uses an adenovirus-based blueprint, rather than the more common RNA-based design. It works by implanting the relevant COVID-19 gene into an adenovirus, a type of virus that is very efficient at infecting human cells. After injection, the adenoviruses infect human cells and introduce the COVID-19 gene, again leading to production of the SARS-CoV-2 antigen and thus immunity. Of course, the adenoviruses are heavily weakened so that they will not cause a significant infection themselves. After the vaccine exhibited promising Phase 2 study results, China surprised the world by approving the vaccine for use in special circumstances, before a Phase 3 study was conducted. CanSino has continued Phase 3 testing as it is being used in the Chinese military. The extent of its use, however, is not public information. (Chung et al., 2020 Oct)
Lastly, the Gamaleya Research institute within Russia’s Ministry of Health is developing their vaccine named “Sputnik V” This is another adenovirus-based vaccine that has shown promising results. On November 11th, Russia announced that Sputnik V was 92% effective in preliminary data from Phase 3 trials. However, this only applied to 20 coronavirus cases that had been documented in test subjects. Much more time and cases will be needed to confirm whether this 92% figure is the true rate of immunity. (Corum et al., 2020 Nov)
There are many other promising vaccine candidates in the works, such as those developed by Johnson & Johnson, AstraZeneca, Novavax, Bharat Biotech, and The Murdoch Children’s Research Institute in Australia. In light of these developments, Director of the National Institute of Allergy and Infectious Diseases Anthony Fauci has stated that “We project by the end of December that there will be doses of vaccines available for individuals in the higher risk category” (Georgiou, 2020 Nov).
It is looking more and more likely that a vaccine will be available soon. That is why we must ask ourselves: “What happens after approval?” First of all, the manufacture of literally billions of vaccines will prove a great challenge. According to the Center for American Progress, achieving herd immunity in just the United States alone would require 462 million doses (Spiro & Emanuel, 2020 July). This would be a tall order in a normal year, but the pandemic has exacerbated the problem by disrupting supply chains throughout the nation and the world. Add to this the special conditions in which these vaccines must be stored, such as temperatures well below freezing, and it is clear that there will be a vaccine shortage even after production is well under way. According to the Center for Disease Control (CDC), it is very possible that “not everyone will be able to be vaccinated right away” (2020 Nov)
So who gets the vaccine first? The CDC states that the vaccines will be distributed “based on national recommendations,” but it is unclear exactly what these recommendations are (2020 Nov). However, they may be following those of The National Academies of Sciences, Engineering, and Medicine (NASEM), who created a plan for the order in which vaccines should be distributed at the request of the CDC and the National Institute of Health (NASEM, 2020 Sept). During the first wave of distributions (15% availability), NASEM proposes that high-risk healthcare workers, first responders, those with underlying medical conditions that can increase the risk of contracting COVID-19 (such as heart failure or a BMI greater than 40), and the elderly should be the first groups vaccinated. During the second wave (35% availability), vaccines would be distributed to any remaining elderly and people with underlying conditions, those living in homeless shelters or jails, and essential workers such as teachers. In the third phase (85% availability), children, young adults, and workers “essential to the functioning of society” would be included. Phase four finally (100% availability) finally opens the doors to all Americans to get the vaccine.
These are fairly thought-out plans for the order of distribution of vaccines within the United States. However, what about other countries? Some countries, such as those in the European Union, Australia, Russia, China, etc. are centralized enough to control their own vaccination efforts. But what about those in third-world countries? Many African governments will be unable to distribute the vaccine quickly to their people, and certainly not equitably. Will an international organization step in? This question is so complicated and has the potential to inflame so much international conflict, that it probably won’t be decided until many months after the vaccine becomes first available.
Then, there is the issue of paying for the vaccines themselves. According to NPR, pharmaceutical companies are expected to charge between $4 and $20 per dose to Americans, since they have already been paid by the federal government for most of the costs of production (Lupkin, 2020 Aug). With insurance, most of the United States will be vaccinated with zero out-of-pocket costs (Radcliffe, 2020 Aug). This is remarkable, and a great accomplishment. But again, there is the issue of less developed countries. They most likely do not have the funds to pay for the vaccines that more developed countries do. The issue of who will pay for their vaccines may come down to long international negotiations, while people are still dying in these countries.
Some believe that the vaccine should be released into the public domain, so that any companies would be able to manufacture it, without any patent laws hindering them (e.g. Yunus et al., 2020 October). This would drive the price of the vaccine down significantly, making it more affordable for everyone. However, this of course greatly reduces the incentives for companies to create the vaccine in the first place. Furthermore, because world governments have already made deals with companies such as Moderna and Pfizer, this solution is unlikely to occur.
Lastly, there is the issue of convincing enough people to willingly receive the vaccine. According to an October poll conducted by CNN, only 51% of Americans would try to get vaccinated when the treatment becomes available, and 45% would not try to get vaccinated (CNN, 2020 October). Furthermore, these results show a downward trend from those who would try to get vaccinated in other survey results taken in May and August. Another poll by STAT-Harris corroborated these results, with 58% of Americans willing to be vaccinated (Silverman, 2020 Oct). These results are not encouraging, because they suggest that, even when a vaccine becomes available, too little Americans would voluntarily become vaccinated to create herd immunity, possibly leaving the pandemic to continue killing. The U.S. government needs to decide how to convince more Americans to receive the vaccine, without infringing on their rights.
All in all, the development of the COVID-19 vaccine has gone remarkably smoothly. Multiple candidates show preliminary results of 90% efficiency or more, and a final product will most likely be available to first responders and vulnerable individuals by the start of 2021. However, there are still many issues to be considered, including the distribution of billions of vaccines around the world in the safest, fastest, and most equitable ways possible. While we are beginning to see the light at the end of the COVID tunnel, we must always strive to remain patient and informed on the latest vaccine developments.
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Written by Alex Borengasser
Edited by Devanandh Murugesan
Graphics by Tiya Shah
Group advised by Lakshmi Sriram