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Coronavirus mRNA Vaccine Safety and Efficacy

Educational Objective
To identify the key insights or developments described in this video
0.25 Credit CME

Millions of people are now being immunized with mRNA vaccines from Pfizer-BioNTech and Moderna. Both vaccines have very high efficacy and look safe in the short-term. This video reviews experience with the vaccines since they were authorized for use in December 2020. (Produced February 2021).

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Transcript

In December 2020 the FDA authorized two coronavirus vaccines, both with unexpectedly high efficacy.

Let’s look at what we know about these vaccines and what we have yet to find out.

The first vaccine to be authorized was developed by Pfizer and BioNTech, and the Moderna vaccine was authorized a week later. Both are messenger RNA, or mRNA vaccines. They work by inducing an immune response to viral spike proteins. These are the proteins that stud the surface of the SARS-CoV-2 virus and make it look crown-like, which incidentally is where the coronavirus gets its name. You can think of the vaccines as target practice for your immune system: the target being the spike.

But instead of the actual spike proteins, these vaccines contain the genetic information, in the form of mRNA, that codes for the spike. When the vaccine mRNA enters the cells in your body, it gets taken up by the machinery of those cells, which then make the spike proteins.

Del Rio: So we're basically just using the machinery of the cells to produce spike protein and put it on the surface of the cells so the immune system can then come and see the spike protein and then generate an immune response.

This immune response to the spike would help you fight a future infection with the SARS-CoV-2 virus.

Importantly, the vaccine mRNA does not enter the cell nucleus, which contains the cell's DNA. So the vaccine has no effect on DNA or body genetics.

The vaccine mRNA also does not replicate and it does not stick around permanently.

The mRNA disappears, it goes away so it doesn't even stay in the cytoplasm of the cells. This is what the cells normally do. mRNA in the cells disappears after it forms proteins.

Data suggest the highest levels of spike protein are produced 48 hours after vaccination, and are cleared by 72 hours. The mRNA is actually gone even sooner--by 24 hours.

Now let's look at the data on efficacy.

The overall efficacy for these vaccines was determined by comparing the number of participants who developed symptomatic COVID-19 in the vaccine and placebo groups in large phase III trials. Here are the numbers for Pfizer and for Moderna.

So how do you calculate efficacy? Let's look at Pfizer. First you divide the cumulative incidence of disease in the vaccinated group by the cumulative incidence in the placebo group; this gets you the risk ratio. Then you subtract the risk ratio from 1, and the number you come up with is the efficacy. So the efficacy for Pfizer is .95 or 95%.

Here again are the numbers for Moderna. Using the same calculation gets you an efficacy of 94%.

These numbers are encouraging. But it’s important to keep in mind that participants in both the Pfizer and Moderna trials were tested only if they developed symptoms of COVID-19. So while these data tell us if the vaccines prevent clinically recognizable disease, they do not tell us if the vaccines also prevent infection and transmission of the virus. Which means a few possible scenarios could be at work for those who are vaccinated:

So a typical scenario could be (a) that someone is protected against infection, and certainly if against infection, against clinically recognizable disease. But there's also a likely scenario where someone was protected against clinically recognizable disease, but they still have replication-competent virus in their nasopharynx. Hence, by definition, they are infected.

And if that second scenario is at play with these vaccines--that is that people who are vaccinated don't develop symptoms but still get infected--a follow-up question is whether the vaccines might still prevent or at least decrease transmission. According to Dr Fauci it is conceivable that the immune response that protects someone from symptomatic disease would also lower the amount of virus in the nasopharynx.

So you could be infected, but not have enough virus in your nasopharynx to transmit it.

Studies are already underway to figure out if these vaccines prevent infection and transmission as well as symptomatic disease. Some very preliminary data indicate that they do, and more data are expected soon. But given the uncertainty, public health authorities are recommending continued preventive measures like mask wearing and physical distancing, even for people who have been vaccinated.

And there are other unknowns when it comes to efficacy that are still being researched, like the duration of immunity, whether evolving virus strains could make the vaccines less effective, or how efficacy varies for different demographic groups.

Now let's look at safety.

The FDA would normally want to see at least 2 years of safety follow-up data for a vaccine. But given the urgency of making an effective vaccine available for pandemic control, when the vaccines were authorized for emergency use the available follow-up data was only about 6 months for the earliest participants and 2 months for the phase III trial participants.

According to that data, the most common reactions were pain at the injection site, fatigue, and headache, most often after the second dose. Most adverse events were mild to moderate, and resolved within a few days. Such reactions are to be expected with all vaccines, and are most often just a sign of the immune system working.

Importantly, even though these vaccines have already been authorized, safety monitoring is ongoing.

Safety considerations go well beyond the clinical trial. There's observation of potential adverse events, you know, well into the implementation of the vaccine distribution. So, if you look at the numbers of people in the clinical trial, there were 44 000 in the Pfizer trial. Once you push the button and start distributing vaccines, you are going to be giving it to millions of people.

And you're only going to find out a rare serious adverse event post-approval. That's definitely true. That's always true. But the good news is there's systems in place like the Vaccine Safety Datalink or VAERS or the CISA system to pick that up.

These are government systems designed to detect post-approval safety signals. And the US has ramped up its safety surveillance capabilities for COVID-19 vaccines.

An example of these systems at work is the recent publication by the CDC of data on severe allergic reactions, also called anaphylactic reactions. The US got a heads up about anaphylactic reactions after two cases were reported in the UK on December 9. A CDC analysis published in JAMA reports on more than 9 million administered doses of the Pfizer vaccine and more than 7 million doses of the Moderna vaccine. The rate of anaphylactic reactions was 4.7 cases per million doses for the Pfizer vaccine, and 2.5 cases per million doses for the Moderna vaccine. This is slightly higher than the rate of anaphylactic reactions following flu vaccination for example, but still extremely rare.

Two months into the vaccine rollout, both the Pfizer and Moderna vaccines still appear to be safe.

It's amazing, I mean, here you have a virus--this elusive, difficult to characterize virus that's had a number of clinical surprises and pathological surprises--which you are meeting with a technology, messenger RNA vaccines, with which we have no commercial experience. I mean, I was--I think anybody who was paying attention to this was worried that there might have been something unpleasant that we were going to find out eventually that we wish we knew now, but for right now, no. I mean, Maurice Hilleman, who I consider the father of modern vaccines, said it best, quote, "I never breathe a sigh of relief until the first 3 million doses are out there." Well, the first 3 million doses are out there. The first 40 million doses are out there in the US, and hundreds of millions of doses are out there in the world.

FDA and CDC scientists and others are continuing to watch safety and efficacy signals vigilantly as more and more people get their doses. Continuing research should help us answer key remaining questions. And some of the uncertainty is the byproduct of getting two remarkably effective vaccines to the public within just 11 months of the virus being sequenced.

I think it's reasonable to be vaccine-hesitant. I think, you know, it's a frightening virus. A lot of the language that surrounded the development was a little scary, you know? "Operation Warp Speed," "Race for a Vaccine," "Who's going to be the first to cross the finish line?" That's a little scary. And it's a novel technology. I mean, I think you reasonably could say, "Wait, let me just see how this plays out initially." Well, it has played out. I mean, once 40 million people have been vaccinated, I think you now have a large platform on which to stand. That you can say the effectiveness is remarkable, and the safety, as far as we know, appears to be, you know, reassuring. I think we're all vaccine skeptics. I think everybody who sits around the FDA Vaccine Advisory Committee table is a vaccine skeptic. You want to see the data. Well, now you have the data.

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