Three separate covid vaccine trials have now had their results published in peer-reviewed journals (Astra-Zeneca, Pfizer, and Moderna), and the vaccines have already been approved for use in multiple countries. In light of that, I think it’s time to look in to how effective and safe the vaccines are, especially considering that many of us are about to be given the option to take them (and some of us already have).
First out of the gate was the Astra Zeneca vaccine, for which trial data was published in The Lancet on the 8th of December. All vaccines have the same underlying principle – to activate a person’s immune system so that it develops immune memory to a specific disease, without actually causing the person to have the disease you want to protect against. But there are multiple ways in which that goal can be achieved. The Astra Zeneca vaccine is a so called “adenoviral vector” vaccine.
In order to understand how this vaccine works, you first need to understand how a virus works. In general, a virus consists of two main parts, a shell made of protein, and inside the shell, a string of nucleotides that make up the viral genome (which can be DNA or RNA depending on the type of virus). The shell latches on to a target cell that it’s going to infect, and then it injects the genome in to the cell. The target cell has a hard time telling the difference between the virus’s genome and its own DNA or RNA, so it treats the viral genome like its own, and starts using it as a blueprint to produce new viruses.
Luckily our ancestors have been dealing with viruses for hundreds of millions of years, so our bodies have some tricks up their sleeves to deal with them. One of those tricks is to take proteins that are being produced inside the cell, and present them on the surface of the cell. This allows the immune system to detect unusual proteins that aren’t normally produced by the body, and to mount an immune response.
The adenovirus vector vaccine uses this as the basis for creating immunity to covid. Adenoviruses are common, and frequently cause disease in humans. In an adenovirus vector vaccine however, one of the viral genes has been deleted, which means that the virus can infect a cell, but it can’t get the cell to start producing new copies of itself. Thus, it can’t generate a real infection. While removing a gene, another gene is also added – a gene that is normally produced by the virus that you want to create immunity against. In the case of the Astra-Zeneca vaccine, the gene that has been added codes for the SARS-CoV-2 spike protein, which is the part of the virus that attaches to the target cell.
What happens when you inject the vaccine in to a person is that the adenovirus infects cells, and injects its genome in to them. Those cells then start producing the proteins that the viral genome codes for, including the specific protein that you want the immune system to react to. These proteins then get expressed on the surface of the infected cells, and this results in activation of the immune system, and hopefully long term immunity.
Ok, now we know how the Astra-Zeneca vaccine is supposed to work (this is also how the Russian Sputnik vaccine is supposed to work, but I’m not discussing that vaccine in this article because no phase three trial data have yet been published in a peer-reviewed journal). Let’s get in to the details of the trial.
This was a randomized controlled trial, split in to three separate arms, a British arm, a Brazilian arm, and a South African arm. The work was financed by Astra-Zeneca, the Bill and Melinda Gates foundation, the British government, and a couple of other private and public organizations.
The three arms varied somewhat in terms of the methodology used. The British and Brazilian arms were single-blind, while the South African arm was double-blind. In other words, in both the British and the Brazilian arm, the researchers knew who was in the vaccine group and who was in the control group. This is strange, and really quite unforgivable, because it makes it much easier for the researchers to manipulate the results in lots of little ways when they know who is in which group. There is no reason why a big, well-financed study like this shouldn’t use a double-blind methodology across all trial arms.
A second oddity about the study is that the control group in both the British and Brazilian arm wasn’t getting a placebo. It was getting another vaccine, for meningococcus. The South African arm however did get a proper placebo consisting of saline (salt water). The researchers motivate the use of another vaccine in the control group by saying that it decreases the risk of the participants being “unblinded”, in other words that they will realize whether they are in the vaccine group or in the control group. This is true to an extent. If you develop a fever shortly after getting the vaccine, you’ll probably deduce that you’ve been given a real vaccine, not a placebo. But many people don’t develop a fever after getting a vaccine, so not getting a fever isn’t going to tell you that you’re in the placebo group. Therefore I really don’t see why the researchers were so concerned about unblinding of participants, especially considering that they didn’t bother to blind themselves to the group allocation.
The main problem with not giving the control group a placebo is that it makes it harder to determine the extent to which the vaccine causes side effects, and it will tend to make the vaccine look more harmless than it is. Overall, the South African arm is therefore the one with the soundest methodology, since it is the only arm that is double-blind, and also the only arm that has given the control group a placebo rather than an active drug. Unfortunately, the South African arm had barely accrued any cases when the researchers decided to push ahead with getting their results published, so the published data actually only includes results from the UK and Brazilian arms.
All three arms gave two doses of the vaccine, although the amount of vaccine in the doses varied somewhat, and the time that was allowed to pass between the first and second dose also varied somewhat (it is common with vaccines to give one dose first, and then give a second “booster” dose a few weeks or months later, since this has been shown to increase the probability of developing long lasting immunity).
The published data include results from 12,000 participants (half from the UK, and half from Brazil), and the total amount of follow-up after receiving two doses is 29,000 months, so an average of 2,4 months of follow-up per participant (if you instead go by when participants received their first dose, the average follow-up period is 6,4 months). Of the 12,000 participants, 87% were aged 18-55. None were aged below 18. 8% were between 56 and 70, and only 4% were over 70. This is a problem. Even though we know that people under 70 years of age are at very low risk of severe disease, and the only real reason to even bother making a vaccine is that there is some risk to people over 70, this group made up only a tiny portion of the total population being studied.
This is in my opinion the biggest weakness of the study, bigger than not blinding the researchers, and bigger than using another vaccine for the control group instead of a placebo. It is well known that older people are less likely to respond favorably to vaccines than younger people, because they have less well functioning immune systems. In other words, the probability that an 80 year old is going to develop immunity after a vaccine is often much lower than the probability that a 40 year old is going to develop immunity. And yet this study was done almost entirely in young people below the age of 55.
This study is not even close to being powered to answer the question of whether people over 70 will develop effective immunity after taking the vaccine. As you probably noticed, children were also excluded from the study, so the study doesn’t tell us anything about what effect the vaccine might have on children either, or whether it’s safe for them.
Additionally, the average BMI (Body Mass Index) of the participants was pretty ideal, around 25, which is pretty much the healthiest BMI you can have. Again, this is a problem, because the people most at risk from covid are the seriously obese, and this study tells us nothing about whether the vaccine works for them. Just as with older people, people who are obese have less well functioning immune systems, and are probably less likely to develop immunity after receiving a vaccine.
Participants in the study were in general pretty healthy in other ways too. Only 11% had underlying cardiovascular disease. Only 12% had underlying respiratory disease. And only 2% had diabetes. So, even before we get to the results, we know one thing – this study cannot tell us anything about the ability of the vaccine to protect the people who are most at risk of severe disease. And it cannot tell us whether the vaccine is safe for these people either.
As mentioned earlier, follow-up was on average only 2,4 months per participant. This should be enough to catch most side-effects, since vaccine side-effects tend to develop within the first days and weeks after injection, but it is still very much on the short side. It means for example that a side-effect that develops three months after getting the shot won’t detected in the study. Apart from that, the results that were published on December 8th only included 12,000 people, which is quite small for a vaccine trial. It means that the study is likely to detect common side and even quite uncommon side effects, but rare side effects that only affect say 1 in 10,000 people, won’t be detected.
Rare side-effects don’t matter so much for normal drugs that are used to relieve symptoms of existing diseases. But they do matter with vaccines, because you’re essentially giving a healthy person something that they don’t need, in order to slightly lessen their risk of catching a disease at some point in the future. Because the benefit from a vaccine to an individual is generally much smaller than for drugs that are used for treatment of existing conditions, the side effects that are considered acceptable also have to be much less common.
The primary endpoint for the trial was PCR confirmed symptomatic covid-19. If participants developed symptoms that could be suggestive of covid, they were supposed to get in touch with the organizers of the trial, and they would then be tested for covid with a PCR test.
I think this endpoint is problematic, because to me the important thing isn’t whether the vaccine prevents young people getting a cold, it’s whether it prevents frail elderly people dying. And the design chosen makes that question impossible to answer. If it had been up to me, the trial would only have included people over 70 years of age with underlying co-morbidities, and the primary end point would have been death, a nice hard end point with little scope for manipulation. Unfortunately Astra-Zeneca never asked me for my opinions on the subject, so now this very flawed and limited study is what we have. Anyway, let’s get to the results.
Among the participants who got the vaccine, 0,5% developed symptomatic covid over the course of follow-up. Among the control group, 1,7% developed symptomatic covid. This is a 70% relative risk reduction in favor of the vaccine, and it is statistically significant. This is actually a pretty good result, for what it is. If you’re a young, otherwise relatively healthy adult, then the vaccine reduces the probability that you will develop symptomatic covid by around two thirds.
Having said that, we don’t really care about preventing colds (at least I don’t). What matters is preventing severe disease requiring hospitalization, and death. This study was too small to have any chance of seeing a significant effect on deaths in such an otherwise healthy group of participants, but not too small to see an effect on hospitalizations.
It generally takes a few weeks after receiving the vaccine until robust immune memory has developed, so it makes sense to start looking for an effect on hospitalizations a few weeks after immunization. From three weeks after receiving the first dose of vaccine, there were 10 hospitalizations for covid in the control group and zero in the vaccine group.
That is impressive. To me, it’s far more impressive than the 70% reduction in symptomatic covid, because it’s the reduction in severe disease that really matters.
Of course, it’s not just the effectiveness of the vaccine that matters. We also want to know that it is likely to be safe. So let’s look at the safety data. Overall, 0,7% of individuals in the vaccine arm had a serious adverse event after at least one dose of vaccine, compared with 0,8% in the control arm. Of course, the control arm wasn’t receiving a placebo, it was getting a meningococcal vaccine, so it’s actually impossible to say what the risks of the vaccine are in relation to placebo. All we can say is that the covid vaccine overall doesn’t appear to cause more adverse events than the meningococcal vaccine.
In total, there were 79 serious adverse events in the group getting the vaccine, and those adverse events are evenly spread out among lots of different types of event, the vast majority of which could not possibly have anything to do with the vaccine.
The only really worrying thing is that two people in the covid vaccine group developed transverse myelitis a few weeks after getting the vaccine, an extremely rare and serious neurological condition that normally affects about one in 200,000 people per year. One of those people had an underlying undiagnosed multiple sclerosis, a condition which strongly predisposes to development of transverse myelitis, but that doesn’t mean that it wasn’t the vaccine that triggered the myelitis.
So, it is possible that the covid vaccine causes transverse myelitis in a small proportion of those vaccinated. At present it seems like the the risk of developing transverse myelitis after getting the vaccine is about one in 3,000, but it could be much higher or much lower. We won’t know until many more people have received the vaccine.
Would I take this vaccine personally? No, because I’m young and healthy and I therefore estimate that the risk of me getting severe covid is infinitesimal, and I’m not convinced that the benefits outweigh the potential harms, considering the possible risk of transverse myelitis. If there wasn’t that possible signal of harm, then I’d probably be willing to take the Astra-Zeneca covid vaccine.
On balance, the benefits probably outweigh the harms for older adults, who are at greater risk of severe disease. I say that even though they were not really included in this study to any great extent. Even if the vaccine is less effective in older adults than in younger adults, which it probably is, this group is also at much higher risk of severe disease, so the risk/benefit ratio probably favors getting the vaccine.
Would I let my children have it? No way. Not until there are studies showing that it’s safe and effective in children. It’s only little over a decade since an influenza vaccine (pandemrix) was rushed through and given to children based on limited evidence, causing hundreds in Europe to develop narcolepsy, a debilitating lifelong disease.
There is one final thing about the Lancet article that is odd, and that is that the exclusion criteria are not listed anywhere in the text. Normally inclusion and exclusion criteria are listed clearly in the method section, but as far as I can tell, they’re not there. This is very strange. It’s possible that they’re buried somewhere in the book length appendix, but I wasn’t personally able to find them there either. We know that children were excluded from the data, but we don’t know if there were any other groups that were intentionally excluded. Were people with previous allergic drug reactions excluded? Were people with autoimmune diseases excluded? What about pregnant women? Until this is clarified, people who belong to these groups should think twice about taking the vaccine.
Let’s move on, and look at the next vaccine. Two days after the Astra Zeneca vaccine data was published in The Lancet, the Pfizer vaccine data was published in the New England Journal of Medicine. The Pfizer vaccine is an mRNA vaccine (as is the Moderna vaccine, which we’re going to discuss after we’ve finished going through the data on the Pfizer vaccine). This is a new vaccine technology, that hasn’t been used previously. Fundamentally though, the technology isn’t that different in practice from the previously described adenoviral vector vaccine. The mRNA vaccine consists of two parts – a sequence of RNA nucleotides that code for a specific protein, and an outer “shell” that is in this case made of lipids, known as a lipid nanoparticle.
After being injected in to the body, the lipid nanoparticles are taken up by cells through a process known as endocytosis (a standard method through which cells take things up from the outside environment). The RNA sequence is then released inside the cell. Just as with the viral vector vaccine, the cell is unable to tell the difference between this imported RNA and its own RNA, so it uses it as a blueprint and produces proteins based on it. These proteins are then presented on the cell surface, and this results in activation of the immune system, which recognizes them as foreign. As with the Astra-Zeneca vaccine, the Pfizer vaccine and the Moderna vaccine cause the body’s cells to start producing the SARS-CoV-2 spike protein.
Ok, now we understand how the mRNA vaccine works. Let’s get in to the details of the Pfizer study. This was a randomized controlled trial with a total of 44,000 participants, in which 22,000 people received two doses of the Pfizer covid vaccine and 22,000 people received an inert placebo. Just from this, two things are obvious. First, the results from Pfizer involve many more people than those discussed above from Astra-Zeneca. And second, Pfizer have actually given the control group a placebo (consisting of saline) instead of another vaccine. Just those two things make me like this study a lot more before knowing anything else about it.
In order to be included in the study you had to be at least 16 years old and you had to be fundamentally healthy. Chronic health conditions were ok if they were deemed to “stable”. You were excluded from the study if you were receiving immunosuppressive therapy or if you had an immune compromised state for any other reason, if you had ever had a severe allergic reaction to a vaccine, if you were pregnant or breastfeeding, or if you had an auto-immune disease.
So this study says nothing about whether the vaccine is safe and effective for children. It doesn’t say anything about whether the vaccine is effective or safe for pregnant women and breastfeeding women. It doesn’t say anything about whether the vaccine is safe and effective for people with weakened immune systems.
The study doesn’t say anything about whether the vaccine is safe and effective for people with auto-immune diseases. This is a problem, as we’ve already seen with the Astra Zeneca vaccine and the participant with undiagnosed MS who developed transverse myelitis less than two weeks after receiving the vaccine. People with known auto-immune diseases are more likely to develop auto-immune complications after taking a vaccine.
And the study doesn’t say anything about whether the vaccine is safe and effective for people who tend to have strong allergic reactions. In fact we now know it isn’t safe for this group, since a couple of people in the UK did develop anaphylaxis after getting the Pfizer vaccine. If this group had been included in the study, the problem would have been discovered before the vaccine started being rolled out to large numbers of people outside of studies.
So, there’s a pretty extensive group of people we know, even before getting in to the results, that this study cannot provide useful information for. In fact, the list of people excluded is so extensive that I wouldn’t be surprised if more than half of all the people on the planet would be excluded for one reason or another. If you belong to one of these groups, then this study cannot tell you whether the vaccine is safe and effective for you.
Apart from the long list of exclusion criteria, it is of course a problem that people needed to be fundamentally healthy to be included in the study. As we’ve already discussed, the people who get really sick and risk dying of covid are not fundamentally healthy. The average person who dies of covid has three known underlying conditions. And those are the people we need the vaccine to be safe and effective for. Unfortunately, the design of this trial, just like with the Astra-Zeneca vaccine trial, makes is very hard to answer that question.
The primary end point of the study was, similarly to the Astra-Zeneca trial, reduction in symptomatic covid-19, defined as a positive PCR test and at least one symptom suggestive of the disease. As mentioned before, 22,000 people were recruited in to each group, so there were 44,000 people in total. That’s a pretty good number, and should be enough to detect all but the most uncommon side effects. The participants were recruited at a number of different sites around the world (USA, Argentina, Brazil, South Africa, Germany, Turkey).
The median follow-up period after the second shot was only two months, which is short, but should be enough to catch the vast majority of side effects. The two cases of transverse myelitis that occurred with the Astra-Zeneca vaccine both happened within two weeks of vaccination, and as far as I am aware pretty much every single case of narcolepsy occurring after the Pandemrix vaccine disaster also happened within a few weeks.
35% of participants were obese, which is excellent, since this is a group that is at risk of severe disease, and we want to know if the vaccine protects them. Less good is that the study had a very small proportion of elderly people. As with the Astra-Zeneca study, less than 5% of participants were 75 years or older.
Ok, let’s get to the results. Among those getting the placebo, 0,9% developed symptomatic covid. Among those getting the vaccine, 0,05% developed symptomatic covid. That is a 95% relative risk reduction and it is highly statistically significant. That is an impressive result, much better than I ever would have thought would be possible in such a short space of time.
The result appears at first sight to hold up even for the people aged 75 years and older, with 5 cases among those getting placebo and zero cases among those getting the vaccine. Unfortunately, due to the small size of that group, the result is not statistically significant, so we can’t actually say based on this study that the vaccine protects people aged 75 and older.
With that said, the vaccine does seem to protect most people against infection. However, just as with the Astra-Zeneca vaccine, we don’t care about whether the vaccine decreases the number of people experiencing a cold, we want to know whether the vaccine protects against severe disease. After having gotten at lest one dose of the vaccine, one person in the vaccine group developed severe covid, while nine people in the placebo group developed severe covid. The reduction in relative risk after getting at least one dose of vaccine is 89%, which is again very impressive. So the Pfizer vaccine does seem to protect against severe covid, just like the Astra-Zeneca vaccine does.
But is it safe?
Overall there were 240 events in the vaccine group that were classified as severe, compared with 139 in the placebo group. That is concerning. Severe adverse events were 73% more common in the vaccine group than in the placebo group. The vaccine should ideally decrease severe adverse events (by decreasing the number of people experiencing severe covid). It certainly shouldn’t increase them. Unfortunately Pfizer aren’t kind enough to provide a breakdown of what the adverse events were, so it’s impossible for us to figure out whether the drastic increase in severe adverse events after vaccination is something we need to be concerned about, and whether it should cause us to avoid the vaccine.
Note that, when it comes to adverse events, severe and serious are not the same thing. A severe adverse event is something that causes a lot of symptoms, but not necessarily something that is serious in terms of its consequences for the patient. A serious adverse event is, on the other hand, well, serious.
If we instead look at serious adverse events, the difference is much smaller. 0,6% developed a serious adverse event in the vaccine group, compared with 0,5% in the placebo group. However, it’s not great that there were more serious adverse events in the vaccine group. If anything, that number should be lower in the vaccinated group, not higher. And again, Pfizer are not telling us what those adverse events were.
Would I personally be willing to take the Pfizer vaccine? No, not until Pfizer publishes a detailed breakdown of what the adverse events were, so I can tell if there’s something in there that I should be worried about or not. If Astra-Zeneca hadn’t provided a breakdown of adverse events, it would have been impossible to see that there is a signal that their vaccine might cause a seriously increased risk of transverse myelitis.
Having said that, the proportion of people experiencing a severe or life threatening adverse event in the vaccine group was only 1,2%, so 98,8% didn’t experience one. If you are over 70 years old or otherwise belong to a risk group, it’s likely worth taking the vaccine even without having the adverse event information, just due to the fact that the vaccine is clearly highly effective against covid, and so the benefit/risk calculation becomes quite different than it is for someone who is young and healthy.
Let’s move on to the final trial, of the Moderna vaccine. I’m going to run through this one a little bit more quickly, because in many respects it is similar to the previous two trials. The results were published in The New England Journal of Medicine at the end of December. The technology used for this vaccine is identical to the technology used for the Pfizer vaccine, so it’s reasonable to expect that the results would be similar. This was a randomized controlled trial involving 30,000 participants, who were recruited from a large number of sites across the United States. The study was primarily funded by the US government and by Moderna. Half the participants received two doses of the Moderna covid vaccine one month apart, and half received two doses of a placebo injection (consisting of saline). The median length of follow-up after receiving the second dose was two months.
As with the previous two trials, the primary objective of the study was to see if there was a reduction in cases of covid-19, which in this study was defined as at least two symptoms suggestive of covid-19 plus a positive covid PCR test.
The study included adults over the age of 18. As with the previous studies, participants had to be healthy or “stable” in terms of any underlying chronic conditions. The study excluded pregnant and breastfeeding women, people with allergies, and people who were immunosuppressed. The average BMI was 29. Only 5% of participants were over the age of 75, so as with the other two studies the proportion of participants in the oldest category was low. 5% had chronic lung disease. 5% had significant cardiac disease. 7% were obese. And 10% had diabetes.
Ok, so what were the results?
Among those who had received the placebo injections, 1,3% developed covid. Among those who had received the vaccine, 0,07% developed covid. That represents a 94% reduction in cases, and it is highly statistically significant. If we look at those over 65 (average age 70), then we see an 86% reduction in cases, so the vaccine seems to be highly effective even for older people (although unfortunately no data is provided for the very oldest people, aged 80+).
The results are even more impressive if we look only at people with severe covid. Among those getting the placebo, there were 30 cases. Among those getting the vaccine, not a single person developed a severe case of covid. So, just as with the previous two vaccines, the Moderna vaccine appears to be highly effective against covid-19.
What about safety?
1,0% of participants in the placebo group experienced a serious adverse event and 1,0% of participants in the vaccine group experienced a serious adverse event. Ideally we would like to see fewer serious adverse events in the vaccine group, but there weren’t enough cases of severe covid-19 for the vaccine to have any noticeable positive effect on the overall number.
If we look through the list of serious adverse events (yes, unlike Pfizer, Moderna actually provided this information), we see that there is nothing that could reasonably be thought to have been caused by the vaccine (unlike the transverse myelitis seen in the Astra-Zeneca study), and there is nothing that sticks out as being more common in the vaccine group than in the placebo group.
Overall, the Moderna vaccine does appear to be both effective and safe. Would I be willing to take it? Yes, I would, actually. There is a strong signal of benefit, and zero signal of harm. Considering that there were 15,000 people in the vaccine group, any serious side effects that can happen as a result of the vaccine are likely to be very rare (in those groups that were included in the study).
Ok, let’s wrap up. So all three vaccines appear to be highly effective at preventing covid-19, although both the Pfizer vaccine and the Moderna vaccine are clearly more effective than the Astra-Zeneca vaccine. In terms of safety, I have significant concerns about the Astra-Zeneca vaccine, considering that there is a signal suggesting that it increases your risk of developing transverse myelitis by a hundredfold or more. Future research will have to show whether that is a real risk or not. I also have concerns about the Pfizer vaccine, since there was a 73% increase in severe adverse events among those taking the vaccine, an issue that Pfizer hasn’t bothered to address at all, and I am also concerned about the fact that Pfizer does not provide a detailed breakdown of adverse events, which makes it impossible to see if there is anything in there that we should be worried about. The Moderna vaccine does appear to be safe however, based on the data available up to now.
One final point. None of these studies tell us whether the vaccines are safe and effective for children. It would be unethical to start vaccinating children without first having made sure that it’s safe, especially considering that the risk to children from covid is infinitesimal. The same applies to pregnant and breastfeeding women, people with immune disorders, and people with severe allergies. If you belong to one of these groups, you should probably think extra long and hard before getting vaccinated, because these groups were not represented in the studies, and it is therefore not clear that the benefits outweigh the harms.