Current Vaccine ProgressLast updated October 2nd 2020, 4:39:37pm
Read about the different methods of development and how a COVID-19 vaccine elicits an immune response in our Vaccine explainer.
Before any vaccine is used on a human, scientists first need to show evidence that it will be both safe and effective. This relies on laboratory testing, frequently using animals such as mice and monkeys. In the United States, the FDA oversees approval for clinical trials. In normal times, the preclinical phase of development takes years.
If a vaccine successfully protects animals in these “preclinical” experiments, scientists move on to clinical trials with humans. These trials usually proceed in three phases:
- Phase I tests safety and optimal vaccine dosage. A small number of healthy volunteers receive the vaccine at a variety of doses. Participants are monitored for the development of side effects. Traditionally, this phase lasts between 6 months to a year. Vaccine efficacy is not evaluated at this stage. If it is deemed safe, the vaccine will be approved to go to Phase II trials.
- Phase II begins to test efficacy using the same dose in a larger group of people (on the scale of tens to hundreds), including those who are ultimately intended to receive it. In the case of COVID-19, this may include people who are elderly or who have comorbidities that put them at higher risk of severe disease. Most trials apply the optimal doses determined from Phase I. Like Phase I, this phase typically takes six months to a year to complete. Phase II trials investigate if the vaccine produces an immune response but do not investigate if it protects participants from becoming infected.
- Phase III, the largest and longest phase, tests efficacy in a very large group of individuals, often hundreds to thousands of people across multiple locations. The selected individuals are often “high-risk individuals” — for example with COVID-19, think nurses and doctors or the elderly. Scientists administer the vaccine candidate or a placebo, wait to see how many people become infected, and then compare the infection rates between the vaccinated and placebo groups. The FDA has said that in order to be considered effective, a COVID-19 vaccine must protect at least 50% of vaccinated people.
Typically, very few vaccine candidates successfully complete this pipeline. However, if one does, it is ready for general clinical use.
Obviously, these timelines are slow. In the case of COVID-19, these trials have been dramatically accelerated. The FDA is determining which vaccines can go on to clinical trials (without preclinical animal testing) oftentimes based on previous safety and efficacy data of the type of vaccine that is being proposed. Many companies have combined trial phases into Phase I/II and II/III. Additionally, multiple initiatives, including ones from the Bill & Melinda Gates Foundation and the NIH as well as Operation Warp Speed have been launched to further speed up development and access to vaccines.
Current Vaccine Development
As of September 26th, there are over 174 vaccines in development, with 51 of them in human trial phases. For a continuously updated tracker of vaccine candidates, check out BioRender and the NIH website. There are many different groups developing vaccines and it can be difficult to predict which candidates will succeed, as it is common for many vaccines to fail during one of the phases (due to problems with safety, efficacy, or other things). Here, we’ll highlight a few candidates that are at the forefront of the clinical trial phases and are worth watching.
Most Advanced and Promising Vaccine Candidates (as of this writing, 9/26):
A group at the Jenner Institute of Oxford University in the UK has partnered with pharmaceutical company AstraZeneca and is employing a chimpanzee adenovirus to make a COVID-19 vaccine (this is an example of a viral vector approach). On July 20th, they reported promising results of their PhaseI/II trial. The results indicate that their vaccine produces an increased antibody and immunological response, and that this response can be maximized with a second “booster” dose. The vaccine produced no severe side effects in all 1077 subjects (although mild side effects included fever and headache were widespread, researchers believe these can be managed with Tylenol). The results of these Phase I and Phase II trials confirm that the vaccine effectively induces a protective response and is safe, but they do not yet confirm whether the vaccine can prevent people from becoming infected with COVID-19. The vaccine has now entered Phase III trials in Brazil, South Africa, and the US. AstraZeneca plans to enroll 50,000 volunteers globally, including 30,000 volunteers from the US — the largest enrollment for a COVID vaccine trial yet.
AstraZeneca’s trials were briefly paused when a patient fell ill but have since been resumed. Depending on the results of the Phase III trials, they believe that they might be able to deliver emergency vaccines in October. They have produced millions of doses for trials and say that if their candidate is approved, the supply capacity will be nearly three billion doses.
The US company Moderna is developing a vaccine that delivers mRNA instructions for the SARS-CoV-2 spike protein to our cells. In May, they were the first company to report results showing that people who were given the vaccine produced antibodies against the virus. The results were widely interpreted as positive and sent stock prices surging. The full data was released on July 17th and showed that volunteers produced a promising immune response after a second injection spaced four weeks after the first. Moderna has entered Phase III trials and is working towards their goal of enrolling 30,000 participants in the US. They plan to wait until a significant number of volunteers become sick with COVID-19, and then see how many of these volunteers received that vaccine compared to placebo. Moderna has agreed to supply the US with 100 million doses if the vaccine is approved.
Like AstraZeneca’s candidate, Moderna’s vaccine candidate requires a booster shot several weeks after the first injection. Moderna’s vaccine must be stored at minus 20 degrees celsius until it is injected, a temperature that poses a challenge to distribution and requires lab-grade freezers and a lot of dry ice.
US company Pfizer and German company BioNTech are collaborating on an mRNA vaccine that has produced promising Phase II trial results. They plan to enroll 44,000 Phase II/III trial participants in the US and are currently three-quarters of the way to this goal. They hope to have Phase III trial data ready by the end of October and state that if approval is obtained, they have secured manufacturing capacity for 100 million doses by the end of 2020 and 1.3 billion doses by the end of 2021.
Like the AstraZeneca and Moderna vaccine candidates, Pfizer’s candidate requires a booster dose several weeks after the first injection. It also requires storage at minus 80 degrees celsius, which poses a challenge to large-scale distribution efforts. Maintaining this temperature will require a complex, expensive “vaccine cold chain” — a supply chain that keeps the vaccine vials at minus 80 degrees from the moment it is manufactured until it is administered. Companies are attempting to tackle this challenge by scaling up manufacturing of dry ice and outfitting planes, trucks, and warehouses with lab-grade freezers.
Other Vaccines in Pipeline:
Johnson & Johnson has developed a vaccine candidate employing adenoviruses, a different type of virus, as the delivery vehicle to deliver DNA that encodes SARS-CoV-2 spike protein. Early trials showed that the virus produced an immune response in both monkeys and humans and does not cause any severe side effects. They began Phase III trials on September 22nd. Although they are a few months behind Moderna and Pfizer, they plan to enroll 60,000 participants in their Phase III, which will be the largest Phase III trial yet. Additionally, their candidate has several advantages over Moderna and Pfizer’s vaccines: it doesn’t need to be stored at subzero temperatures, and it may only require one dose to be effective.
Another American company, Novavax, has developed a candidate that includes the administration of a proprietary adjuvant, already shown to be safe, to encourage the activation of immune cells that help mediate memory cell formation. The company has now entered Phase III trials in the UK and plans to begin Phase III trials in the US next month. Like Johnson & Johnson, they are several months behind the leading vaccine candidates. However, some experts claim that early trials showed “markedly higher” antibody levels than other published vaccine results. Phase III trials will demonstrate if these antibody levels have an impact on vaccine efficacy. Novavax’s candidate requires two different shots spaced 21 days apart but doesn’t need to be stored at subzero temperatures. If trials are successful, Novavax hopes to deliver 100 million doses in the US by early 2021.
China and Russia have both approved vaccines for emergency use without waiting for Phase III trial results, a move that experts say has “serious risks.” One such vaccine, developed by the Wuhan Institute of Biological Products and the Beijing Institute of Biological Products, employs a killed/weakened virus (read more about how this type of vaccine works here). While this inactivated virus method often provides the most robust immune response (since the virus vaccine better represents the actual SARS-CoV-2), extra care is required to ensure its safety. Phase III trials are in progress in the United Arab Emirates, Peru, and Morocco. On September 14th, the UAE granted emergency approval for this vaccine to be used on health care workers.
On September 2nd, the CDC outlined preparation measures for states to distribute “Vaccine A and Vaccine B” in late October or early November for high risk individuals. Although the vaccines are unnamed, the details match vaccines developed by Moderna and Pfizer. Dr. Fauci and Dr. Hahn have both said that a vaccine may be available for certain groups of people before clinical trials are completed, depending on the data. This has led to speculation that vaccines produced by Pfizer and Moderna might be available to certain groups in the US in November. However, this speculation is countered by pushback from scientific experts who caution that a vaccine will not be readily available to Americans until the middle of 2021.
On September 17th, both Moderna and Pfizer released their protocol for determining if their vaccine candidates are safe and effective, as well as details about how participants are monitored and the conditions under which the trial could be stopped early. Pfizer has said that they hope to have results as early as November, while Moderna’s timetable estimates they will need until the end of 2020 or early 2021 to receive adequate data. However, Moderna’s CEO has said that their vaccine will not be available for widespread use until the spring of 2021.
These timelines may be altered as the FDA plans to release stricter guidelines for emergency vaccine authorization. These guidelines are the most detailed outline yet by the federal government about how vaccines will be vetted. The guidelines state that Phase III trial participants should be tracked for a median of two months after receiving the final vaccination dose (which would be the second dose for Moderna and Pfizer’s candidates), a guideline that hopes to allow developers to more accurately determine long-term immunity and responses. The guidelines also require a minimum of five cases of severe infection in the placebo group, which will assess whether the vaccine lowers the risk for severe cases of COVID-19. These guidelines may be formally released by October.
Caveats and Concerns
The speed of vaccine development in COVID-19 is unprecedented. Because of the desire to go fast, most of the vaccine development has focused on newer technologies, not the traditional weakened virus approach. These newer technologies have to pick a particular protein to focus on, and all of the candidates in development target the same protein in SARS-CoV-2: the spike protein, or S-protein. The differences across technology are largely in how they deliver instructions to your cells for how to make it.
The biomedical community is developing S-protein based vaccines because research in SARS and MERS suggests that an antibody response to S-protein could be protective, and we know that the S protein plays a key part in the induction of antibodies. However, we don’t know for sure that it’s going to provide immunity from SARS-Cov-2 infection.
At least some scientists are worried that we have all of our eggs in one S-protein basket, so to speak. We are relying on an assumption that the immune response to the S-protein works — and while this is an assumption based on promising data, it could still be wrong. If raising a vaccine mediated immune response to S-protein doesn't provide protection (regardless of the different delivery technologies) we could be months to years behind.
It is worth keeping in mind that a successful vaccine will not function as an off-switch to the pandemic. Producing and distributing a vaccine will depend on and strain our distribution networks, supply chain, global cooperation, and public trust. The FDA has agreed to approve a vaccine so long as it is at least 50% effective, meaning not all vaccinated patients will have guaranteed immunity. Trials so far suggest that people will need two doses of a vaccine spaced several weeks apart before effectively gaining immunity. We still don’t know how long immunity will last, and it’s likely that people will need to be revaccinated (see our Immunity Explainer for more on this).
Additionally, no single vaccine manufacturer can produce enough doses to vaccinate the planet at the timescale that we need. In order to vaccinate a large proportion of the global population, we will need to see several vaccine candidates succeed. That said, many vaccine companies have already partnered with manufacturing companies to ensure optimum production capabilities are where they need to be if their vaccine is successful — meaning distribution to millions of people as quickly as possible.
Progress is being made on vaccine development at an unprecedented rate. Many different companies are racing towards the same goal through different approaches, which provides some (but not perfect) hedging against failure of a single candidate. A process that usually takes years is being condensed into months. Vaccine companies have partnered with manufacturing companies before they’ve seen positive results to ensure high production capabilities. As different vaccine candidates are being accelerated through the pipeline, companies and government agencies must still ensure safety in addition to efficacy.
While some vaccines enter or near approval in and outside of the US, experts caution that the vaccine landscape is still uncertain and evolving. Trials that test effectiveness and safety can take years to yield reliable results, and there are risks to approving a vaccine before completion of all safety trials. As the pandemic continues to take lives across the globe, experts agree that we must continue to weigh safety and urgency as we prepare for a complex and vast vaccination effort.