Our worst COVID-19 fears have been realized. We’re currently seeing well over 200,000 cases diagnosed per day in the U.S., with out-of-control spread in almost every state. Hospitals and ICUs in particular are overwhelmed, as we warned was possible in the spring. Deaths have topped 3,000 per day. And with Christmas around the corner, cases aren’t likely to recede any time soon.
But finally, there is hope on the horizon. Following a massive effort, two vaccine companies have submitted applications with the Food and Drug Administration (FDA) to receive an Emergency Use Authorization (EUA), which would allow people to start getting these vaccines outside of clinical trials. Pfizer’s EUA application was approved on December 11, and Moderna’s was approved on December 18. Pfizer began shipping their vaccine out, with the first inoculations scheduled on December 14. Moderna will reportedly begin administering its vaccine as quickly as possible now that it’s been authorized. Health care workers and individuals in long-term care facilities are the top priorities for early vaccination. Both vaccines were at least 94% to 95% effective at preventing symptomatic coronavirus infections in Phase III trials, with side effects generally including symptoms such as sore arms and fatigue, along with fever, body aches, and other classic signs of the intended protective immune response.
Not surprisingly, with two vaccines being rolled out by the end of 2020, some questions remain about the science of the vaccines and the logistics of their authorization, approval, and distribution. I spoke with four experts to find out their thoughts on the vaccine itself, the logistics of approval, and what it will mean for all of us in the coming months. Kevin Ault, M.D., FACOG, is a physician and scientist at the University of Kansas Medical Center in Kansas City; Heather Lander, Ph.D., is a virologist currently serving as a senior research development specialist at the University of Texas Medical Branch; Rebecca Dutch, Ph.D., is a virologist at the University of Kentucky, and Dorit Reiss, Ph.D., is a legal scholar with expertise in vaccination at the University of California Hastings College of the Law.
Crucially, both the Pfizer and Moderna vaccines are mRNA vaccines—a type that has not previously gained approval for use in humans. Most of the vaccines we currently use either contain live viruses that have been weakened (such as measles and mumps), organisms that have been killed (like the influenza vaccine), or pieces and parts of a pathogen (such as the vaccines for Streptococcus pneumoniae, hepatitis B, and many others). So, how do these mRNA vaccines work, and why have they been a leading candidate during the pandemic? Keep reading to learn those answers and more.
1. What is an mRNA vaccine, and why are the first U.S. vaccines both this type specifically?
To begin, let’s be clear about the core purpose behind these vaccines, says Lander: “As with all vaccines, those vaccinated with an mRNA vaccine are protected from developing COVID-19 without risking the very real consequences of natural SARS-CoV-2 infection.” For now, as I mentioned above, these two mRNA vaccines seem to be quite effective at preventing symptomatic coronavirus infections. We don’t yet know about the other protections these viruses may confer—I’ll delve into that more in a bit.
Here’s how these vaccines work: mRNA carries the information for how to make a protein, Dutch explains. Specifically, the mRNA in these vaccines carries the instructions for how to make the SARS-CoV-2 spike protein, or a portion of it, depending on the vaccine. With the actual virus, this spike protein is what enables SARS-CoV-2 to enter a person’s cells and replicate, causing infection. But when our own cells already have the information about how to make this protein, they can generate an immune response to it so they know how to protect us from the virus if we actually encounter SARS-CoV-2 naturally at some point. In order for this protection to happen, though, the vaccine needs to get into our cells in the first place. To make this possible, manufacturers “place the mRNA inside a small particle, termed a nanoparticle, that is made up of [components such as lipid, or fats], and these help ferry the mRNA into cells,” says Dutch. Once inside the cells, the cells make the spike protein, which elicits an immune response.
This is a fairly rapid process because the mRNA is fragile. “This mRNA is eventually degraded by the cell, so this new expression of [the spike protein] is not a permanent change,” says Dutch. It’s unclear how long this degradation takes. With regular mRNA, it’s within hours. The special coating involved with mRNA coronavirus vaccines may make this take a bit longer, but how much longer is uncertain.
It’s that fragility that has made mRNA vaccines tough to create in the past. Previously, it’s been difficult to get the mRNA to be stable enough to initiate an immune response. Lander quips about mRNA, “You play the wrong music and it disintegrates. Use the wrong color tube and it laughs as it disappears into the ether.” (As someone who’s worked with mRNA in the past, I concur.) But the mRNA vaccines are encased in a matrix of fats, sugars, and salts that increase their stability. Lander notes, “The scientists who created these SARS-CoV-2 vaccines have solved that problem and are to be celebrated. It’s really brilliant vaccine technology that will transform how we make vaccines moving forward. As someone who doubted they could do it this quickly, I am thrilled I was wrong.”
On the subject of speed, some people have concerns about the speed of coronavirus vaccine development. It certainly has happened more quickly than any other vaccine scientists have developed by far. Lander notes that experts were able to complete this mRNA technology so quickly in part because “mRNA is much easier to make than virus particles or proteins. It’s cheaper, easier, and faster,” which has allowed us to get from identification of the virus in January to authorized vaccines in December. The fact that scientists have been researching how this mRNA vaccine technology might work for years has also helped expedite the process.
The development of these coronavirus vaccines is critical in light of continuing calls, including from some scientists and politicians, for “herd immunity” from natural SARS-CoV-2 infection. That could theoretically happen if enough people in a community got COVID-19 and produced antibodies that would protect them against the virus in the future, even if not permanently. As I wrote previously for SELF, herd immunity from natural COVID-19 infection could lead to even more deaths as well as increase how many people have to cope with lingering consequences from the coronavirus.
2. Overall, how do we know these vaccines are safe and effective?
As SELF outlined previously, each vaccine that is being tested has to undergo a number of phases in clinical trials, first to show safety and then to show both safety and effectiveness. All vaccines that are authorized for use in the United States have been approved only after these trials have been completed or have generated enough data to meet the FDA’s safety and effectiveness requirements. Dutch says, “All of the data to date indicate that these mRNA vaccines are very effective, with high-level protection from illness in about 95% of vaccinated individuals. There have not been significant safety issues reported.” Pfizer reported that their vaccine “showed similar efficacy point estimates across age groups, genders, racial, and ethnic groups,” while at one point the Moderna vaccine did appear to be slightly less effective in older age groups (95.6% effective in those 18–65 years of age versus 86.4% in those 65 and older). And while there may be concern that people in these trials have been studied for only a short time (on the order of months, not years), Dutch explains, “in general, issues with vaccines show up relatively soon after vaccination, so the fact that there have not been serious complications in the thousands of vaccinated people supports the idea that this is safe.”
As more individuals receive the vaccine, including those who may not have been able to participate in the initial trials because of health conditions, we may see some additional reactions. Lander describes one such issue: “We recently learned of two incidents of allergic reactions in people in the first wave of U.K. Pfizer vaccinations. The individuals have recovered and the incidents are being investigated. We need to wait and see whether they were caused by the vaccine or not.” The Centers for Disease Control and Prevention’s policy, after review of the data, will allow people with severe allergies to be vaccinated with the Pfizer vaccine but also cautions anyone in this position to discuss the risks with their physician and stay after vaccination for 30 minutes of monitoring.
As noted previously in SELF, the clinical trials will also continue even after vaccine authorization. “The clinical trials include assessing for problems that might occur down the road by following participants for at least two years. In addition, safety data from the first series of health care workers and long-term care facility residents and workers vaccinated will also be documented. We are not skimping on safety data regarding any COVID-19 mRNA vaccines,” Lander says.
Finally, I’ve seen some people express concern about the vaccines somehow “changing our DNA.” In response, Dutch clarifies: “The molecule being introduced—mRNA—cannot itself integrate into DNA or change DNA. Our cells do not have the protein needed to make DNA from RNA, so there is not a way for the introduced mRNA to be made into DNA.”
3. Do we know yet if the vaccines prevent asymptomatic transmission?
This is a key unanswered question. Dr. Ault notes this is a common issue in vaccine trials: “The initial trials are based on clinical disease, and that is the usual starting point. Later research will address this point.” Dutch says it is likely that, when examined, “we will see reductions or elimination of transmission, based on the fact that vaccinated people have protection that may prevent the virus from growing to high levels in their respiratory system, but more work is needed to be sure.” Analysis of Moderna’s vaccine data suggested a reduction in asymptomatic transmission, but we need additional data to confirm this. This means that vaccinated people need to continue to wear masks around others outside of their households, as they have a chance of being infected but asymptomatic.
4. Do mRNA vaccines provide immunity? How long will immunity last?
We will be examining the nuances of immunity for years, as participants in the original trials are monitored for both their levels of antibodies as well as any COVID-19 diagnoses. Dutch says of the Moderna mRNA vaccine trial, “A study looking at them [participants] 119 days after vaccination found that they all maintained high levels of protective antibodies at that point. They will need to continue to monitor to see if protection reduces over longer periods, but these initial results are very promising.”
Long-term immunity is complicated because even for infection with the actual virus, immunity seems to wane. Lander notes, “We know from other coronaviruses that natural immunity is discussed in terms of year(s), not decades.” It’s likely that we will need boosters at some point, but how long after the original vaccination is uncertain right now. “It’s entirely possible we end up needing a yearly vaccine for COVID-19. It’s also possible we will only need a booster every few years or not at all. Unfortunately, we have to wait and see,” says Lander.
Dutch notes that this isn’t quite like vaccination for influenza, which SARS-CoV-2 is often compared to as a respiratory virus. The possible need for booster shots is because immunity to SARS-CoV-2 may wane, not because of significant changes expected in the virus itself. “The influenza vaccine has to be given each year because the strains of the virus that are circulating in the human population change. There have been only minor changes in SARS-CoV-2, so re-vaccination will likely not be needed because of strain changes.” (If you’re wondering how the new strain of coronavirus that is causing travel restrictions in London may impact all of this, you can read more about that here.)
5. Should people who have already gotten COVID-19 get vaccinated?
This is an active area of investigation. Dutch says, “There is some evidence that the vaccines facilitate a more potent immune response than natural illness, which would suggest that even those who have had COVID should be vaccinated. However, this will need to be further studied, to be sure.” Lander adds, “I agree with Dr. Fauci on this and do think those who have had SARS-CoV-2 infection, with or without acute disease, should be vaccinated.” This is for several reasons: We don’t know how long natural immunity will last, and we also don’t know if a second infection would be more mild than a first.
Some people—perhaps as much as 10%—in the trials for Pfizer and Moderna reportedly had a prior COVID-19 infection, so continued monitoring will help to evaluate how effective vaccination is for those individuals as well.
6. What about people for whom the vaccines haven’t yet been tested, such as those who are pregnant or breastfeeding, or children?
The current opinion of the American College of Obstetricians and Gynecologists is that those who are pregnant and nursing should have the choice to receive these vaccines. “While I understand the FDA can’t approve the vaccines for those groups without clinical trial data, knowing the molecular and cellular actions of the vaccine, and how short-lived the mRNAs will be, I don’t see how pregnant women could be more adversely affected by an mRNA vaccine than non-pregnant women,” explains Lander. “In addition, injected mRNA will not reach a fetus. We know it’s just too short-lived and fragile for that.”
Similarly, for people who are breastfeeding, Lander notes: “I would expect vaccination with an mRNA vaccine to be safe and that maternal immunity would be protective for the infant.” (This is similar to why the CDC recommends that those who are pregnant or breastfeeding get the flu vaccine to pass those protective antibodies to their babies.) As always, people who are pregnant or breastfeeding will need to discuss the potential risks should they develop COVID-19 versus possible risks from the vaccine with their physicians or other medical personnel to make an informed choice.
Both of the companies making the mRNA vaccines authorized for use in the U.S., Moderna and Pfizer, are working on trials with children. Pfizer began to include children in U.S. trials in September, and Moderna recently started one for children ages 12–17. Pfizer’s vaccine has been granted authorization for individuals age 16 and older, and Moderna’s for people 18 and up. For now, children younger than 16 cannot receive either vaccine.
7. How do the various authorizations and approvals work?
“An emergency use authorization is a procedure under which a product—not just a vaccine—is approved for use before full data has been collected because there’s an emergency situation that creates high risk,” says Reiss. This process allows for rapid review of a product’s data: “An EUA can be approved in weeks, based on limited—but promising—data,” she explains. This is in contrast to a biologics license application (BLA), which is the usual process of approval. A BLA is “very involved, including a lot of data both about the product and data about the manufacturing facilities and process. They are very lengthy and review takes a long time,” says Reiss.
For the vaccines under review, many additional committees review the data presented by the manufacturing companies: in the FDA, the Vaccines and Related Biological Products Advisory Committee (VRBPAC), and at the CDC, the Advisory Committee on Immunization Practices (ACIP). These committees also weigh in on the data presented and present advice to others within their organizations.
8. What are the next steps after an EUA is approved? What does it take for full approval to happen?
Reiss explains that the next step for the company is to apply for a BLA, which is a very involved process, typically taking 10–12 months, though it may be expedited when it comes to coronavirus vaccines. Dr. Ault notes that the companies will continue their large Phase III trials during this time, and the additional data collected will eventually be used for full approval.
During this time as well (after the EUA but before the BLA), there are multiple surveillance systems in place that will catch and allow researchers to examine issues that may relate to the vaccines. Dr. Ault notes these can be divided into “real time” and reported events. “‘Real time’ involves looking for issues starting with the initial doses of the vaccine, and one exciting new tool will involve reporting on your cell phone,” he says. “Reported events would involve you or your health care provider reporting a concern to a central system.”
9. Will vaccine mandates become commonplace?
We’ve already seen some possible uses of vaccine mandates, such as for taking an international flight. The Equal Employment Opportunity Commission has also said workplace mandates may be possible. Reiss notes that this is a messy area. There is legal uncertainty on whether vaccines can be mandated when they’re under an EUA, because the language of EUAs is unclear in this regard. “The language suggests that there are limits on mandates, but also [implies] things like workplace mandates—job loss can be a consequence—are possible,” notes Reiss. Such mandates may come down the line. Education mandates, at least for younger children, are not possible at this time as the vaccines have not yet been tested in children, but school mandates may happen once there are vaccines approved for kids.
But mandates aren’t Reiss’s immediate concern. “At first, there will not be enough vaccine for everyone, and the first challenge will be scarcity: not enough vaccines for people who want them.”