This post was reviewed by Dr. Zachary Benet, one of our subject matter experts.
The paper we’re demystifying today can be found here, if you’d like to follow along.
TL;DR
BNT162b1 is an RNA-based vaccine against SARS-CoV-2. This Phase 1/2 clinical data is promising, because it shows that vaccination causes a strong antibody response, including neutralizing antibodies. Although this vaccine caused side effects, none were life threatening and all the side effects resolved (went away) on their own in a short period of time. It’s important for us to remember that although this vaccine seems to be inducing an antibody response, we don’t know yet whether it works. Later phases of the study will look into whether this vaccine is actually protective against COVID19 infection.
Introduction
Today’s research comes from researchers at NYU Langone Vaccine Center, NYU Grossman School of Medicine, University of Maryland School of Medicine, Pfizer Inc, University of Texas, BioNTech, University of Rochester and Cincinnati Children’s Hospital. This paper was published in Nature on August 12, 2020 and it describes the Phase 1/2 trial data for yet another SARS-CoV-2 vaccine candidate: BNT162b1. Our Canadian readers may recognize the name- this is the vaccine that Pfizer Canada has agreed to provide to the Canadian Government, pending Health Canada approval.
First, let’s meet our lucky contestant. BNT162b1 is an RNA vaccine. This vaccine consists of a vector (remember those?) that has a small snippet of SARS-CoV-2 RNA in it. When someone is given this vaccine, their cells make copies of that snippet of SARS-CoV-2 RNA. But, because it’s only a snippet of RNA and not the whole thing, the cells don’t make full, infectious virus particles. Instead what happens is the cells only produce the portion of the virus that that bit of RNA has the instructions for. In the case of BNT162b1, that portion is the SARS-CoV-2 virus spike protein. We talked more about vaccines and vectors in this article about Oxford’s vaccine candidate. For more about how RNA carries instructions, check out our Central Dogma sidebar. RNA vaccine candidates are attractive because they can be designed very quickly. RNA is considered safe and is easily metabolized and removed from the body. Also, there have been many clinical trials based around RNA therapeutics that have shown this technology to be relatively safe and well-tolerated.
What’s With Phases?
Before we get into the study itself, let’s talk a bit about the phases of clinical studies. What does Phase 1/2 mean? Why’s Phase 3 such a big deal? The answer there is that each phase asks a different question, and each question has a different set of experiments that have to be done to get an answer. Here’s a summary of the phases, specifically for a vaccine trial:
Phase 1: Is the vaccine safe?
In Phase 1 trials, the new vaccine is given to a small group of healthy volunteers. The goal of Phase 1 trial is to see how safe the vaccine candidate is, and what sort of side effects it produces. Phase 1 trials might also collect some data on what sort of immune response the vaccine candidate can induce. Phase 1 trials typically have a relatively small sample size, anywhere from 10 to just under 100 people.
Phase 2: Dosage and Safety
Phase 2 trials are aimed at finding the proper dosage and schedule for the vaccine candidate. In other words, how much of the vaccine candidate should be given per injection? Do we need a booster? How long should we wait to give a booster? Phase 2 trials also continue the safety assessment from Phase 1, especially over a longer period of time. Phase 2 trials typically have more participants than Phase 1, around 50-500.
Phase 3: How well does it work?
In Phase 3 trials, the researchers give the vaccine candidate to thousands of people and wait to see how well it protects against the disease. Participants are split into a trial group and a placebo group and then observed for a period of time. If the researchers see that the trial group (people who received the vaccine) seems to be getting the disease less often, that’s an indication that the vaccine works! Phase 3 trials may also help us spot the really rare side effects that didn’t show up in earlier trials
For more about the phases of a vaccine clinical study, and to track the vaccine candidates currently in trials, check out this article.
Now that we understand the clinical phases, let’s move on to the study.
Study design
After screening participants, 45 were selected for the trial. These 45 participants were all healthy adults. Pregnant individuals were not included in the trial. All the participants were between 19 to 54 years old and the majority were white.
The 45 people were randomized and assigned to different groups:
- 12 participants received two 10 µg doses of the vaccine on days 1 and 21
- 12 participants received two 30 µg doses of the vaccine on days 1 and 21
- 12 participants received a single 100 µg dose of the vaccine on day 1
- 9 participants received a placebo (saline)
This was an observer-blinded study, which means that the patients receiving the vaccine and the people analyzing the data didn’t know which vaccine a particular participant got.
Side Effects
The most common side effects in the seven days following a vaccine dose was pain at the injection site. This pain was seen after dose 1 and dose 2 in participants at all dosage levels. This pain was reported to be mild/moderate for the most part, with the exception of one case of severe pain after a 100 µg dose of the vaccine.
The most common body-wide responses in the 7 days after vaccination were fatigue and headache. These were reported in the vaccine groups but not in the placebo group. Participants who received the vaccine also reported chills, muscle and joint pain. The severity of these side effects increased with the dose level and more participants reported these side effects after the second dose than after the first.
Several participants reported a fever- 1 each in the 10 µg and 30 µg groups and 6/12 in the 100 µg group. After the second dose, 1/12 participants in the 10 µg group and 9/12 participants in the 30 µg group reported a fever. Based on this increase in reported fevers, the researchers decided not to give a second dose to the patients in the 100 µg group. All the reported fevers were mild to moderate and only lasted about 1 day. Most of the local and body-wide side effects were gone by seven days after vaccination. Two patients reported a severe fever 2 days after vaccination (30 µg) and one patient in the 100 µg group reported sleep disturbance. These side effects were not unexpected and are pretty common as far as vaccines go. For example, side effects for the flu vaccine include soreness, headache, fever, nausea, muscle aches and fainting. The important part is that no patients that received BNT162b1 showed any life threatening side effects, and all the observed side effects only lasted for a little while. The researchers also took lab tests of their patients to check lymphocyte and neutrophil levels after vaccination. Lab tests in some patients showed a decrease in lymphocyte count and others showed a decrease in white blood cell count. In all cases, these decreases were short-lived and blood cell counts returned to normal without medical intervention or causing any symptoms in the patients.
Immune response
Antibodies against the receptor binding domain (RBD) of the SARS-COV-2 spike protein were detected at 21 days after the first dose of the vaccine. In the 10µg and 30µg test groups, the antibody levels increased significantly after a second dose. As a reminder, the 100 µg test group did not receive a second dose.
When comparing antibody levels of the vaccinated patients to serum antibody levels in perople who had been naturally exposed to SARS-Cov-2, the researchers noticed the following:
- Antibody levels in patients after receiving one 10 µg dose of the vaccine were similar to antibody levels in SARS-CoV-2 exposed patients
- Antibody levels in patients after one 30 µg dose of the vaccine were higher than the levels in SARS-CoV-2 exposed patients
- After a second dose with 10 µg or 30 µg of the vaccine, the antibody levels were 8 to 50x higher than the levels in naturally exposed patients.
As we’ve said before, neutralizing antibodies are very valuable when it comes to virus immunity. They can also be a better measure of a vaccine’s ability to protect against the virus. When researchers looked at neutralizing antibody levels in their vaccinated patients, they saw very high neutralizing antibody levels by day 28. It’s important to note that we don’t know what antibody levels are needed to protect against the virus- that means that even though we saw neutralizing antibodies, that doesn’t prove that this vaccine is effective. The researchers plan to figure out how effective the vaccine is during a critical phase 3 trial.
Dosage wise, there were no major differences in the immune response between the 10 µg group and the 30 µg group. The researchers suspect that the optimal dose for future trials is in the 10 µg -30 µg range.
Limitations
This study has several limitations. The number of people taking part in the trial is relatively small, although that is to be expected from a Phase 1/2 trial. The researchers will have to test their candidate in many more people ( thousands!) during phase 3 before this vaccine will be ready to roll out to the public. Additionally, this study didn’t look into T cell responses, so we don’t know if this vaccine is capable of training T cell memory. For a recap of what T cells are and why they’re important, check out Deanna’s sidebar here. As a quick explanation: In addition to immediately inducing an antibody response, vaccines train your immunological memory, which can involve memory B cells and/or memory T cells. When your body faces the same virus again, this immunological memory kicks into gear and quickly clears out the infection before you get sick. There are studies suggesting that the T cell response plays a key role in the body’s response to COVID19. In the case of BNT162b1, the researchers will have to do more research to tell whether a T cell response is being induced by this vaccine candidate. Another limitation of this study is that, as we said higher up, we don’t know what antibody levels are needed to protect against infection, so its hard to draw conclusions on whether or not the vaccine works with the data we currently have Beyond that, the available data did not follow patients for more than 2 weeks after receiving the vaccine- a longer follow-up time is needed to determine vaccine safety and how long the vaccine provides protection for (durability). This study is still ongoing so we will be seeing the data from the follow-up once it is available. This study is also limited by the age group of the participants- this study was done on healthy adults between 19 and 55 years of age, but the age group at most risk from COVID19 is 65+. The researchers say that they have enrolled adults over 65 years of age and are currently gathering data. These later phases of the study will also focus on recruiting participants from more diverse ethnic backgrounds.
Conclusions
BNT162b1 is an RNA-based vaccine against SARS-CoV-2. This Phase 1/2 clinical data is promising, because it shows that vaccination causes a strong antibody response, including neutralizing antibodies. Although this vaccine caused side effects, none were life threatening and all the side effects resolved (went away) on their own in a short period of time. It’s important for us to remember that although this vaccine seems to be inducing an antibody response, we don’t know yet whether it works. Later phases of the study will look into whether this vaccine is actually protective against COVID19 infection.
This vaccine is moving into further studies, which will look at additional immune responses (including cell immune responses). These studies will also give us safety data following a longer observation period and will investigate the vaccine’s efficacy in a more diverse group of individuals.
