COVID-19: Let’s Talk About Vaccines
by Raywat Deonandan, PhD
Epidemiologist & Associate Professor
University of Ottawa
(I add my credentials to these COVID-19 blog posts in case they get shared. I want readers to know that my opinion is supposedly an educated and informed one)
Revel in the miracle, my friends. And make no mistake: it is a miracle. Yes, it’s a human-fabricated miracle, but the arrival of efficacious vaccines against COVID-19 in less than a year since the declaration of pandemic is nothing short of a stupendous and near-supernatural achievement. I fully expect a few Nobel Prize nominations to come from this endeavour, and they will be well deserved.
Unsurprisingly, almost all the media questions I’ve been getting these past few days have concerned the vaccine. And while I think most people are pretty clear on what’s going on, I thought I would summarize some of the key points in this post.
So here we go.
What Are The Various Vaccine Options?
There are literally dozens of vaccine candidates coming down the pipeline. I’m not going to go through each one in detail. Instead, I’m going to focus on the three making the news right now, which happen to be the ones most likely to get into Canadian arms in the short term: the formulations made by Pfizer/Biontech, Moderna, and Oxford/Astra Zeneca.
So many conspiracy theories float around vaccine science, mostly having to do with the financial motivations of scientists like me. So let me get this out of the way. Yes, I own shares in both Pfizer and Astra Zeneca…. amounting to several hundreds of dollars. Yes, that’s it. I’m a hundredaire. Impressive, no? I’d intended to buy into Moderna back in February, when I first learned of (and was impressed by) their COVID vaccine platform; but I dragged my feet too long. And I might have done some consulting for Pfizer some decades ago; I really can’t remember.
In other words, I have no financial stakes in COVID vaccines. I wish that I did!
How Do They Work?
This is the cool part. All vaccines work the same way: they expose your body to a semblance of the pathogen (in this case a virus) to trigger your body to produce antibodies against that pathogen, so that when the real thing arrives, your body will already know how to fight it off. In other words, it’s target practice for your immune system.
Over the history of vaccinology, we’ve become more sophisticated in exposing our bodies to such ‘semblances’ of pathogens. First, we used to actually give people small doses of the actual virus. This is called “variolation.” In the early days of Small Pox immunization, variolation had a 2% chance of killing you. But Small Pox itself had a 30% chance of killing you. So it was thought to be a good gamble. (Though the best gamble is never being exposed to the disease in the first place.)
We got smarter after variolation, and instead attenuated (weakened) the pathogen before injecting it into a patient. The oral polio vaccine is an example of a live attenuated virus. It has a small but real chance of actually giving you the disease.
One level up from live attenuated vaccines is inactivated, or dead, pathogens. They cannot replicate or infect you. The rabies vaccine is an inactivated one.
Then we got smart and looked at ways of introducing a fragment of the pathogen into your cell. This way your body recognizes the fragment, produces antibodies against it, but cannot be infected by the fragment.
All of the COVID vaccines use this approach in some way. They are all focused on introducing your body to the “spike protein”, a fragment on the surface of the SARS-CoV2 virus. It’s like the licence plate of the virus if the virus were a car. You don’t need to drive the car to the police station for them to identify it; they just need to see the licence plate.
The cleverness is in how the vaccine manages to deliver that licence plate to your cell, because your body has a myriad of ways to keep things out. Viruses are just as clever at getting things in. Can vaccines be as clever as viruses?
The Oxford/AZ COVID vaccine delivers the licence plate –the spike protein– as a “Trojan horse”. It uses another virus called an “adenovirus”, which is like a mild common cold virus, commonly found in Chimpanzees. In other words, this adenovirus is highly unlikely to infect people; and if it does, it will give you a very mild cold. But the key thing about this adenovirus is that it has been engineered to deliver a fragment of the COVID spike protein –the licence plate– into your cell.
It’s pretty cool. But the Pfizer and Moderna vaccines are even cooler.
Whereas Oxford/AZ actually delivers the licence plate into your cell, Pfizer and Moderna do something really space-age. They trick your cell into making the licence plate.
In your cells are tiny factories that make proteins. They do this by reading the RNA (genetic material) that were in turn made by your DNA (your central archive genetic material) and creating proteins according to the recipe of that RNA. These factories are essentially protein machines that read recipe cards.
The Moderna/Pfizer vaccines essentially insert a new recipe card into that factory, causing it to make the spike protein, the licence plate. Your immune system sees it and goes, “Holy shit! A spike protein!” and makes a bunch of antibodies to shoot at it. Voila: immunity.
So the Oxford/AZ vaccine is a “viral vector” that delivers the spike protein as the payload in a torpedo made from a Chimp adenovirus. And the Pfizer/Moderna vaccines are like Amazon packages that roll up to your cell’s front door, let themselves in, unpack themselves to reveal a recipe card (called messenger RNA), which is then read by your body to produce the spike protein.
That’s a lot of metaphors.
The important thing is that they all end up with spike proteins in your cells, and can NOT actually give you COVID. We know they cannot because they do not actually present you with the COVID virus.
The CDC has a short document explaining everything I just said, but with more science-y words.
Do They Work?
Yes, it seems so. The Oxford/AZ data is sketchy. They’re going to have to redo their phase 3 trial. But both Pfizer and Moderna show around 94-95% efficacy.
What does this mean? First, efficacy is how a thing works in somewhat controlled circumstances. Effectiveness is how it works in genuine real-world conditions. While I would argue that a phase 3 trial is pretty real-worldy, many people say that we don’t have true “effectiveness” until the vaccine is deployed widely, post-market. Whatever.
But I get ahead of myself. What are these clinical trial “phases” people keep talking about? Well, first scientists muck about with drugs in the lab, and often have controlled exposures using non-human animals as test subjects. (Yes, that hurts my vegan heart to think about. But this is the world in which we live.) Then we begin experimenting on humans in a phased manner…
Phase 0 — some trials (not all) use a Phase 0. It’s a very small trial, often using very low doses of the drug on a small number of people (10-15). It’s done really to confirm that the drug has an effect on human beings and has no obvious horrendous adverse effects.
Phase 1 — this is also done on 10-15 people, and is sometimes called a “dosing trial” because it establishes what the appropriate dose is to get the desired outcome. Another way to phrase the Phase 1 goal is that it’s meant to establish the highest dose that can be given to people without eliciting serious adverse events.
Phase 2 — if a drug is found to be safe in Phase 1, it progresses to Phase 2. In this phase, 20-100 people are typically recruited. Different arms (groups) of the study reflect different manifestations of the therapy (doses, schedules, cofactors, etc). Often, a placebo control is not used in Phase 2, but this is not a hard rule. As always, we are looking here for signs of effectiveness and poor safety.
Phase 3 — is the money trial. This phase involves many more people. In COVID trials, that means tens of thousands. Phase 3 is when we find out if the drug is safe and efficacious in a “real world” setting. One group receives the vaccine, and the other group receives a placebo. Then they are set free in society (often living in a high-COVID area) to experience the same behaviours and exposures as everyone else. We then wait to see which group is more likely to get COVID.
Maybe you’ve heard of a “challenge trial”? For ethical reasons we cannot simply take our vaccine group and our placebo group, put them in chairs, and have them French kiss a bunch of COVID-positive people. That’s what a challenge trial would be (probably minus the kissing): deliberate exposure of our groups to the virus.
Challenge trials are not considered ethical, because we have deemed it improper to deliberately try to infect people with a potentially lethal disease when we do not have a treatment and we do not yet know if the vaccines will work. You might disagree with this, and you would not be alone. A lot of work is being done right now on the ethics of challenge trials.
It’s because we have to wait for our Phase 3 group to become exposed and potentially infected naturally that the trial takes so long. Our candidates decided a priori that their trials would end when a total of a couple hundred or so COVID infections had been achieved. At that point, the investigators would compare the two groups to see in which one the majority of infections had been observed. And that’s how we know about their efficacy.
So What Do We Know?
As I noted, as of this date, the Oxford/AZ phase 3 trial is a little wonky. So I’m going to ignore that one for now.
We know that the Moderna vaccine trial ended after 196 COVID cases were detected. Among those 196, 94.1% were in the placebo group, which is its efficacy score. In addition, 100% of the severe COVID cases were in the placebo group, which is outstanding. It means that even though the vaccine doesn’t seem to prevent all cases of COVID, it does seem to prevent all serious cases.
While many people (under 10%) reported some pain and fever, no one reported any “serious” adverse events. Serious would be anything requiring hospitalization or discontinuation.
The Pfizer trial ended after 170 cases, 95% of which were in the placebo group.
Both vaccines showed high efficacy across all ages and ethnicities. But a key difference is that the Pfizer vaccine must be stored in an ultra-cold environment, much colder than most pharmacies are presently equipped for.
Both vaccines also require a booster shot, about 3 weeks after the initial shot.
What Don’t We Know?
To my mind, here are the great unknowns, in no specific order:
(1) As of today, we have yet to see the full safety data. Which subgroups are most likely to get which adverse reactions? How common were the reactions, and were they associated with comorbidities or other medications? A host of safety questions remain. Having said that, all signs point to these formulations being quite safe.
(2) All participants in both trials were 18 years of age or older. These formulations have not been tested on children. They might be, quite soon. But do not expect children to be vaccinated against COVID before the end of next year at the earliest.
(3) The efficacy scores are based on reported COVID symptoms confirmed with a PCR test. It is entirely possible that a host of participants were infected asymptomatically and had no reason to then seek PCR confirmation. So all we really know is that the vaccines prevent symptomatic COVID.
(4) Related to the above, we don’t know if the vaccines confer what we call sterilizing immunity. That’s when the virus is prevented from infecting the cells in the first place. All we can really say is that it seems to prevent the symptoms of infection from arising. To my mind, this is pretty important because we don’t know if infection, even asymptomatic infection, renders any subtle long term morbidity.
(5) Also related to the above, we don’t know if the vaccines prevent transmission. Now, this is very important. If the vaccine does not prevent transmission, then its ability to confer herd immunity is impaired. It means we’d likely have to inoculate a lot more people, closer to 100%, to ensure full protection for everyone. This is not a big deal if asymptomatic infection does not confer subtle morbidity and if all the vulnerable people at least are inoculated.
For what it’s worth, there was some indication in an earlier trial than the Moderna formulation does confer some sterilizing immunity, though only in mice. And the strong efficacy signal is highly suggestive of suppression of transmission. After more extensive deployment, the statistical epidemiological signals will better suggest to us if sterilizing immunity is being achieved. That will take some months to assess.
(6) We do not know what happens if you only get one shot and skip the booster. This is important because in the real world, it is highly likely that many people will fail to get a booster, for a number of logistical reasons. We need to know how immune such people really are.
(7) Lastly, and importantly, we do not know how long immunity lasts. Earlier clinical trials suggested that all candidates produce both humoral (i.e. antibody) immunity and cellular (e.g., T-cell) immunity. The latter tends to last much longer, so there is reason to believe that these vaccines might be effective for longer than a year; perhaps much longer.
What Happens Next?
Both Moderna and Pfizer have applied for “Emergency Use Authorization” (EUA) from the US government. The criteria for granting an EUA are four-fold:
(1) the need must be dire (life and death)
(2) the cost-benefit analysis must swing toward the benefit
(3) there is evidence of high efficacy
(4) there are no alternatives
Based on these criteria, it seems highly likely that both formulations will receive authorization quickly, which means shots in the arms of Americans by mid-December.
In Canada, our officials are monitoring the data in real time. This means that any delay in getting a vaccine will not be an administrative one. As soon as the last data point is revealed, our officials will be able to make a determination almost instantly. I anticipate they will reach the same conclusion as the Americans, which means Canada will be eager to receive both formulations ASAP, likely mid-January.
Who Gets It First?
This is not for me to decide, obviously. But if I have any say in the matter, the hierarchy of preference would be:
(1) health care workers –we need our best players to stay in the game
(2) the most vulnerable population (e.g., the extreme elderly, beginning in the nursing homes)
(3) first responders (police, firefighters, ambulance drivers, etc)
(4) people with a large number of daily contacts (teachers, transit workers, grocery clerks, etc)
(5) everyone else
Special attention must be given to the homeless, indigenous peoples, and incarcerated prisoners. These groups are particularly vulnerable and are administratively unique.
Another confounder is the global South. No one is safer until everyone is safe. A pandemic is not over until the hot zones of the world are extinguished. That means that it’s incumbent upon rich nations like Canada to ensure that poorer countries can get access to these vaccines. Otherwise, the pandemic will burn on for years.
What Barriers Will We Encounter
This is clearly the greatest public health logistics challenge in modern history. There are obvious challenges having to do with crowd management, communication, etc. But there are a couple of challenges that I think require special thinking.
(1) Cold storage. This is a big one, and many people are talking about it. The Pfizer formulation needs special refrigeration units for transportation and storage. This means additional expenses. It’s also unclear if you can re-refrigerate a dose once it’s been removed from the unit. This has great implications for wastage and management. Shipping this formulation to remote areas might be very difficult.
(2) Data management. Remember that everyone needs two doses. You can’t take the second dose from another formulation other than the one you initially received. So if you get the Moderna jab, you must get the Moderna booster. This is clear for most people. But many will forget which formulation they received. Heck, my elderly father thinks his blood test was a flu shot!
For the homeless and people without a family doctor, it might be chaotic keeping track of which dose is required. Also, how do we alert people when it’s their time for a booster? If we rely on people’s individual recognizance, I think we will struggle to achieve herd immunity.
Related to this is the great unknown of what happens if you fail to take your second dose. I sense that some might deliberately choose to eschew the second dose, especially if they had an adverse reaction to the first one.
Data management will also be essential to keep track of vaccine penetration through society and geographically, and to know how close we are to herd immunity. If it turns out we need a third shot (always possible), data will be essential.
When Will All Of This Be Over?
Back in March, I suggested that we might be in this for years. It’s unbelievable to me that I can see us getting through this crisis before this time next year. My God, I have to slap myself sometimes. I said then that we all know how this ends: with herd immunity, preferably with a vaccine.
We think herd immunity with an 95% efficacious vaccine will be achieved with 70-80% uptake, assuming that the vaccine prevents transmission. With a great societal effort, maybe we can get there by the end of 2021.
But as more and more people become inoculated, we can remove mitigation tools from the mix. Mask-wearing, distancing, and limits on gatherings will linger with us throughout the year, but will gradually fall away. As long as one or more of those strategies remain in play, the reproduction number is artificially depressed and the herd immunity threshold is also artificially lowered.
But as the vaccine uptake slowly increases, biological immunity will begin to replace NPI (non-pharmaceutical intervention) effects. Which will be the last to go? I think it will be social distancing.
So sometime in early 2022, I expect to give you all a great big French kiss. Yes, even you sociopaths who send me hate mail.
The pandemic is not fully over until the world achieves herd immunity. That means low income countries need the vaccine. They will likely be last to achieve sufficient penetration. So international travel will not be back to 2019 standards for some years.
But now we can truncate that schedule by hastening vaccine distribution and uptake. Now we have a plan.
But first we must persevere through the long, dark winter. The worst of the pandemic in North America is yet to come. The next couple of months might be horrific in some parts of the continent. So please do not let the good news of the vaccine distract us from what we must do now to protect each other.
As Dr Fauci said, the cavalry is coming. But that doesn’t mean we can stop shooting.
Due to several requests, I recorded a video of myself reading this blog post aloud: