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As the first doses of the Pfizer/BioNTech vaccine were administered yesterday, most of the US public began a potentially long waiting game, as the vaccine will be in short supply for many months and is being administered to healthcare workers and the elderly first. For most of the US, that means waiting until manufacturing can catch up with our needs.
One thing that could significantly speed vaccinations is the approval of additional vaccines, and here the news is also good: today, the Food and Drug Administration released detailed data on Moderna’s RNA-based vaccine, finding it well over 90 percent effective. These numbers make it highly likely that the FDA will issue an Emergency Use Authorization when it considers the issue on Thursday.
Looking good
The previous data on the vaccine’s efficacy had been delivered by press release in mid-November. The FDA’s documentation is, as you’d expect, far more detailed. We’ll provide a summary of it here.
Like the Pfizer/BioNTech vaccine, Moderna’s mRNA-1273 vaccine uses a specially packaged RNA molecule to induce human cells to produce a coronavirus protein, which the immune system will identify as foreign and attack. While many of the techniques involved have been heavily tested in other contexts, this is the first time they’ve been used in human vaccines, making safety and efficacy trials unusually important. Moderna had enrolled over 30,000 participants in its placebo-controlled trial. The initial analysis uses data from November 7, by which point nearly 28,000 of the participants had gone a median of seven weeks after their second vaccine dose.
At that date, there were five cases of SARS-CoV-2 infections in the vaccine group, compared to 90 in the placebo group, leading to a vaccine efficacy of 94.5 percent. There were no significant differences in efficacy when the data was broken down based on age, gender, or ethnicity. By November 21, with more cases, the efficacy remained at 94.1 percent, a statistically indistinguishable difference. That comes from 11 infections in the vaccine group compared to 185 among those who received a placebo. While the raw numbers suggest mRNA-1273 is slightly more effective in younger people (95.6 percent for those under 65 vs. 86.4 percent for those over), the confidence intervals for these numbers overlapped, meaning that the difference may not be statistically significant.
The trial also had a pre-defined “severe” category of COVID-19. By November 7, there were 19 cases in the placebo group and none in those who received the vaccine. As of November 21, it had gone to 30 cases among the placebo group, but the mRNA-1273 group remained without any cases. It’s unclear whether this was because the vaccine also limits the severity of infection or because there were so few cases in the vaccinated group that the odds of having a severe case were low.
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One good, two better
There’s some indication that just one dose of the vaccine is helpful. At the time of the second injection, participants were tested for SARS-CoV-2; 38 in the placebo group had picked up an infection, compared to 14 in the mRNA-1273 group. The difference between placebo and vaccine groups also became significant by 14 days after the first vaccinationtwo weeks before the booster is normally administered.
Side effects were typical for vaccines: the immune response tended to produce some flu-like symptoms, like fatigue, headache, and muscle and joint pain. Problems were more common after the second dose. There were also reports of pain at the injection site and swelling and tenderness of that arm. Severe health events like heart or kidney problems occurred in both groups at roughly equal levels. The one exception was Bell’s palsy, a temporary paralysis of facial muscles, which occurred in three people in the vaccine group, but only one in the placebo group.
Overall, these results look extremely promising, and similar efficacy was enough to gain an Emergency Use Authorization for the Pfizer/BioNTech vaccine. Having a second vaccine, and the added manufacturing capacity that comes with it, could greatly increase the speed at which public health authorities are able to move through their priority list.
Update, 5:30pm EST
As mentioned above, the data here is released as part of an evaluation of the vaccine for an Emergency Use Authorization. That requires that there are no approved treatments, that there’s reason to think that the vaccine will be effective, and that the vaccine’s benefits outweigh its risks. One of the key items here is that the FDA has concluded that it now has enough information to make that determination. The document itself goes on to detail all the different ways the data was broken down in order to make the evaluation easier, as well as the criteria for various items tracked during the trial.
These include the standard for determining whether a participant has had COVID-19. The criteria include any two of the following: fever, chills, myalgia, headache, sore throat, and an olfactory disorder. Alternately, people could have a positive RT-PCR test accompanied by cough, shortness of breath or difficulty breathing, or clinical or radiographical evidence of pneumonia.
These criteria risk missing some asymptomatic cases. But it’s difficult to handle in any other way. RT-PCR testing remains limited enough in the United States that the entire study population can’t be expected to be regularly screened that way, and these tests do generate some false positives. (The vaccine causes people to generate antibodies to the virus, so antibody tests aren’t helpful.) There will undoubtedly be data from participants who were regularly tested post-vaccination, and that will be valuable for a more detailed analysis. But for the purposes of this decision, asymptomatic cases won’t be counted.
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Similarly, “severe COVID-19” was defined as at least one of a set of respiratory issues, systematic shock, kidney, liver, or neurological problems, intensive care admission, or death.
There were also details provided on the side effects. Again, most of these side effects were flu-like symptoms that are caused by the immune system’s reaction to the vaccine and thus more common in people who didn’t receive the placebo. For example, about two-thirds of those receiving the vaccine reported fatigue, while only one-third of the placebo group did. Fever was reported by 15 percent of the vaccine recipients and almost nobody who got the placebo. Thirteen deaths took place during the trial: six in the vaccine group and the rest in the placebo.
Still, while all this was common, none of it was severe enough to cause many people to drop out; out of the 30,000 participants, only about 40 dropped out, and they were roughly equally split between vaccine and placebo groups. And the benefits were dramatic, as a graph from the document makes clear.
Enlarge/ Blue shows the cases among the placebo group, while red shows the (far lower) number of cases among those who received the vaccine.
Next steps
Given the extremely promising results, it will likely be determined that ethics demand the placebo group be given access to the vaccine. The FDA evaluation suggests that any Emergency Use Authorization include stipulations about how the clinical trial will maintain participation once vaccines become widely available, given that we’ll need ongoing monitoring of long-term safety and efficacy. Moderna has indicated that it will try to enroll participants in the placebo group in long-term monitoring as they get vaccinated.
The document also lists a lot of areas where we’d like to have more information. These include the duration of protection, how well the vaccine works in those under 17 and in high-risk populations, and whether giving the vaccine to those who’ve had a SARS-CoV-2 infection helps block reinfection. The document also highlights data that will be difficult to get given the current study design, such as the vaccine’s impact on asymptomatic infections and long-term COVID-19, as well as how it influences transmission among those who are vaccinated yet pick up an infection.
While we could normally figure out some of these by looking at the population level, that’s going to be difficult here, given that several distinct vaccines are likely to be in use at the same time. Instead, we’ll probably need to rely on contact tracing once infections are rare to determine some of this.