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Science is supposed to capture the objective truth. But real life is messy and all-too-human. In the high-stakes pursuit of a COVID-19 vaccine, how do scientists and the laypeople participating in clinical trials overcome these contradictions?

A health worker in Rio de Janeiro holds a vial of the AstraZeneca/Oxford COVID-19 vaccine on Jan. 23. The drug had been approved for emergency use in Brazil days earlier, and in Britain a few weeks before that, after months of clinical trials.Bruna Prado/The Associated Press

Tiffany Cassidy is a Canadian freelance journalist in Britain.

It’s 10 months into the pandemic, and I’m in my kitchen in Oxford, England, washing my groceries.

It’s an irritating routine: bending over my grocery bags, placing cardboard packages in the corner for their quarantine, lathering the plastic packages in my sink and laying them on a towel on the kitchen floor. I try not to bicker with my husband as my discomfort with this now-regular procedure mounts, before I run upstairs for a shower.

Researchers have said the risks are much higher of catching COVID-19 from the air than from touching surfaces, and critics call this kind of obsessive cleaning “hygiene theatre.” I accept that. But I can’t help myself. I see it as a tolerable prevention tactic – even if I grant that it’s not exactly rational behaviour.

But what makes my insistence on this extra-cautious sanitizing process perhaps uniquely frustrating is that I know reducing my risk like this limits my usefulness to the scientific community.

In May, 2020, the University of Oxford’s Jenner Institute vaccinated me as part of the Phase 1 trial for a COVID-19 vaccine manufactured by AstraZeneca.

In the double-blinded trial, I received a needle that contained either an experimental coronavirus vaccine made of a modified and weakened version of a common-cold virus from chimpanzees, or a vaccine for meningitis and sepsis as a placebo – and neither I nor the researchers know which one I got.

And then, I went off to live my life.

When the trial participants came into contact with the coronavirus in their everyday life, and either developed COVID-19 or not, the trial team could discern whether the experimental vaccine offered real protection when compared with the control group (the people who got the placebo).

A volunteer in the AstraZeneca/Oxford trial takes a dose in Oxford on Nov. 19, 2020.Andrew Testa/The New York Times

The part that most would think of as “the trial” has been somewhat uneventful. For the 29 days after I received my vaccine in Phase 1 – whichever vaccine that was – I reported my symptoms in an electronic diary. They sent me home with a bag containing a thermometer to give my exact reading and a tape measure to check the precise size of any redness around the injection site. After the first day, I felt fine; there was nothing to report. These days, months into the trial, I only have to fill out a weekly online exposure questionnaire, with occasional appointments.

Those entries take no more than five minutes of my day. For the other 23 hours and 55 minutes, I mused about what more I could do. I wasn’t told to change my lifestyle, but I often think that if I truly wanted to help get a mass-produced coronavirus vaccine out there as quickly as possible, I would actually put myself at higher risk by interacting more with the world. Even Adrian Hill, the director of the Jenner Institute in Oxford, made clear that the trial can only work if people are exposed to the coronavirus: “We’re the only people in the country who want the number of new infections to stay up for another few weeks, so we can test our vaccine,” he told The New York Times in April.

Of course, when I (mostly) jokingly suggested being more cavalier about the coronavirus to my parents, my dad visibly winced on the video call.

But by participating in this trial, and remaining in it to this day – meaning I’m either moving through the world with a highly sought-after vaccine or completely vulnerable – I’ve found myself on the front lines of philosophical debates. What makes people sign themselves up for scientific experimentation? Why does science, which strives to be objective, rely so deeply on humans who are fretful and anxious or risk-seeking and blissfully unaware, and who are, on the whole, completely unpredictable? What do we owe to science? And on a personal level: How long should I continue to fly blind, before I find out once and for all whether I’m vaccinated?

Before this, the term “trial” used to make me think of a white, sterile lab where every detail was precisely controlled. But now – with the trials still under way, even though the Oxford/AstraZeneca vaccine got emergency approval in Britain just before New Year’s – what I’ve learned firsthand is that science is necessarily comprised of people doing the inherently messy act of living life, rationally or irrational.


How the Oxford/AstraZeneca vaccine works

16/16

14/14

11/11

The Oxford University and AstraZeneca Covid-19

vaccine can prevent up to 90 per cent of people

contracting coronavirus when it is administered as

a half dose followed by a full dose

at least one month apart

Spike

protein

Spike protein:

Gene is cut from

Sars-CoV-2 genome

Virus

genome

Gene: Inserted into DNA

of adenovirus which acts

as vector in vaccine

Gene

Adenovirus:

Unable to

cause disease

Vaccine: Induces spike

protein antigen – triggers

antibody immune response

Antibodies

Human immune

system: Produces

antibodies against

spike proteins

Vaccine: Can be

stored in refrigerator

at 2-8°C. Two doses

of vaccine are

required

graphic news, SOURCE: Reuters; Oxford

Vaccine Trial; University of Oxford

16/16

14/14

11/11

The Oxford University and AstraZeneca Covid-19 vaccine

can prevent up to 90 per cent of people contracting

coronavirus when it is administered as a half dose

followed by a full dose at least one month apart

Spike

protein

Spike protein:

Gene is cut from

Sars-CoV-2 genome

Virus

genome

Gene: Inserted into DNA

of adenovirus which acts

as vector in vaccine

Gene

Adenovirus:

Unable to

cause disease

Vaccine: Induces spike

protein antigen – triggers

antibody immune response

Antibodies

Human immune

system: Produces

antibodies against

spike proteins

Vaccine: Can be

stored in refrigerator

at 2-8°C. Two doses

of vaccine are

required

graphic news, SOURCE: Reuters; Oxford Vaccine Trial;

University of Oxford

18/18

16/16

13/13

The Oxford University and AstraZeneca Covid-19 vaccine can prevent

up to 90 per cent of people contracting coronavirus when it is administered

as a half dose followed by a full dose at least one month apart

Spike protein

Adenovirus:

Unable to

cause disease

Gene

Virus genome

Spike protein:

Gene is cut from

Sars-CoV-2 genome

Gene: Inserted into DNA

of adenovirus which acts

as vector in vaccine

Antibodies

Vaccine: Induces spike

protein antigen – triggers

antibody immune response

Human immune

system: Produces

antibodies against

spike proteins

Vaccine: Can be

stored in refrigerator

at 2-8°C. Two doses

of vaccine are required

graphic news, SOURCE: Reuters; Oxford Vaccine Trial; University of Oxford


Scientific research methods have come a long way in the past two centuries. In a famous 1796 experiment, for instance, Edward Jenner – the namesake of the Jenner Institute, which runs my trial – inoculated an eight-year-old boy and then exposed him directly to smallpox. Fortunately, the boy survived, giving the world the basis for a smallpox vaccine.

The word “placebo,” meanwhile, first appeared in Western medicine in the early 1800s, as something the doctor could give “more to please than benefit the patient,” according to the 1811 Hooper’s Medical Dictionary. In 1863, a doctor designed the first clinical study that compared the effects of one treatment against a placebo remedy.

Some scientists began looking for ways to eliminate the biases of the participants in a given experiment, whose expectations around a given treatment could cause them to act differently and throw off the data. This led to blind experiments gaining traction in the early to mid-1900s. As it became clear that researchers could potentially assess participants and outcomes differently based on their own previously held beliefs, double-blind trials emerged to tackle observers’ biases.

Over the same time, scientific ethics have evolved. After the 1946 Nuremberg trials revealed that atrocious experiments had been performed on the prisoners in Nazi Germany concentration camps, the medical community began crafting a formal code of principles to guide treatment of and research on human subjects. This effort eventually led to the Declaration of Helsinki in 1964, which is now on its 10th version – and which declares, on placebo-control trials, that “extreme care must be taken to avoid abuse of this option.”

Indeed, while they’re seen by many as the gold standard, the debate over placebos’ ethics remains unresolved. Yes, they provide clear data baselines: In the case of the COVID-19 vaccine trials, they tell doctors how many people would catch the virus without a test vaccine, and they highlight differences in the levels of antibodies and T-cells. A group of World Health Organization experts even published an article arguing that trial participants should remain blinded after a COVID-19 vaccine receives emergency approval so scientists could gather information on the “longer-term safety and duration of protection.”

But if what is being tested works, the placebo group receives none of the benefits – to potentially deadly results. In the case of the Oxford vaccine trial, for instance, one participant in the placebo group died after being hospitalized with COVID-19. Much of the debate is framed this way: pitting the ethical duty to individuals against scientific endeavours working for the greater good.

A South African participant in the AstraZeneca/Oxford trial takes an injection last June.SIPHIWE SIBEKO/POOL/AFP via Getty Images

It’s not always clear what happens once the trials lead to an approved product, either. In April, the Times reported that once the Oxford/AstraZeneca trial knew its vaccine was effective, “Everyone who had received only the placebo would also be vaccinated immediately.” But when I reached out to the trial’s media team at the time, they couldn’t confirm the statement. And in the Pfizer trial, some placebo recipients complained that despite feeling like they’d stepped up for science, they were not given early access to the working vaccine.

One workaround is to provide the vaccine to the placebo group and the placebo to the vaccinated group after it’s been approved, so that people can remain blinded over the full course of the trial but still get the protection. Anthony Fauci, the director of the National Institute of Allergy and Infectious Diseases, has said this approach could fulfill ethical constraints while still providing new knowledge, including the longevity of vaccine protection. But even this has generated debate: Some believe that guaranteeing a vaccination for both groups could be seen as letting low-risk volunteers jump the queue for a working vaccine.

At the beginning of a pandemic, however, you just don’t have many ways to test efficacy other than blinded placebo trials. “When there are no other options, it’s perfectly reasonable to have a placebo, because otherwise you aren’t going to know the answer,” said Lisa Barrett, a clinician scientist in infectious disease and viral immunology at Dalhousie University who runs studies and trials for research on infectious diseases, including COVID-19. Science, after all, always exists in the context of a given society at a particular moment of time.

And so, scientists have to carefully lay out the potential risk to participants, but also rigorously assess the interests of those who do sign up. Dr. Barrett says trials screen for negative motivations and try to exclude anyone who may be coerced – for example, anyone giving the sense that they need the trial money.

Here, I should make it clear – lest you think I see myself as a hero – that self-interest absolutely fuelled my participation in the Oxford/AstraZeneca trial. Back in April, after I had my screening appointment, I wrote in my journal that, “I hope I get to participate in the study because it would make me feel useful to the cause.” I even remember worrying that too many eligible people would volunteer and I wouldn’t be chosen. I was overwhelmed by the state of the world and felt powerless to stop people from dying, and being asked to do this trial felt like I could win meaning in my life – a way for me to personally help the vaccine arrive as quickly as possible.

For disclosure, I also received £310 ($540) as compensation for my time. I didn’t know that I would be paid when I first offered to participate, and they don’t tell you the exact amount you’ll receive. Thankfully, that amount wasn’t essential to my income over the year and I didn’t expect it to be. But the pandemic hit during my first year of full-time freelancing, and all of my forthcoming projects had been cancelled or postponed. I doubt I was the only one in that position, and that’s hard to screen out.

Indeed, trials may never eliminate incentives entirely. In January, a family member introduced me to Kamal Ndousse, a 28-year-old AI researcher in San Francisco who joined the Oxford/AstraZeneca trials in Phase 3. He told me over video chat that – in true Silicon Valley form – he and his roommates use a risk calculator to analyze and manage their exposure risk analytically. When a vaccine trial became an option, he wanted to join to try to speed up the vaccine results for everyone, but he also had a personal incentive: Mr. Ndousse has asthma. He considered his risks of a serious reaction to COVID-19, and calculated that he wouldn’t likely be early in the line for an approved vaccine. He also read about the trial to that point, including early results and a deep sea of media reports. He knew he couldn’t be certain, but he did the math: His risk of adverse reaction seemed lower than the risk of getting COVID-19 with asthma and without a vaccine. “It just seemed like it was possible to make an extremely informed decision,” he said.

Trials are always being confronted with such human complexity. Recently, with approved vaccines more readily available, older, higher-risk people have increasingly exited blind trials; they’ve also been volunteering less to begin with so they can be assured of receiving a COVID-19 vaccine. This has led to diminished data around certain vaccines’ effectiveness for those older than 65. “As the trial goes on, more and more people are being lost,” Paul Heath, who led the British trials for Novavax’s vaccine, told The Globe and Mail. “This is clearly not ideal from a trial point of view, but we all knew this was going to happen.”

The Oxford/AstraZeneca trials, for their part, didn’t even include participants older than 60 until the vaccine was tested in younger people. While it’s been approved in Britain and elsewhere for the older age group, governments in Germany and France are among those who have voiced concern there’s not enough data to know whether it’s safe and effective for seniors.


Biologist Joana Angelica Barbosa, 68, holds up her vaccination card as she celebrates having recieved a dose of the AstraZeneca/Oxford vaccine in Rio de Janeiro.Silvia Izquierdo/The Associated Press


In the past few months, I’ve swayed between hoping that I had the experimental vaccine or the placebo. There were risks in both. But then, slowly but surely, I started considering adding some very real risk to the trial itself: I started guessing which vaccine I received.

I couldn’t help myself. When the first Phase 1 results were published in the scientific journal The Lancet – and it should be said that the amount of data available to the public is atypical of how continuing trials usually go, but this is a pandemic, after all – I decided to pore over the compiled data. I read that the group that received the COVID-19 vaccine reported higher amounts of almost every symptom experienced, including chills, fatigue, fever and muscle ache. I remembered no such symptoms.

So I had a guess, even if it was a weak one, of which I had received: the placebo. And my instinct was to be more careful, an undesirable outcome for the trial. But when I asked Dr. Barrett to go over the figures with me, she pointed out that it was hard to extrapolate a clear answer from the way the data were presented. I have no way of knowing if many people in the vaccine group had one symptom, or if the people who reported fever also had many of the other symptoms. Typically, she said, in a trial the people who get more significant symptoms get many different symptoms.

What is certain is that if I make a guess, even a bad guess, and it influences my behaviours, the trials don’t specifically account for that. (Randomization and a large enough trial size means that if people in the placebo group are reviewing data to guess their allocation, the same number of people doing that should be in the vaccine group.) So I asked Dr. Barrett outright: Was I a bad participant for trying to dig for clues in the study?

“You can’t be a bad person, you’re doing a trial,” she said. There is a level of expectation that people will want information, she assured me, and she would never tell her own participants they can’t read anything. But then she added, nicely: “If you think that you’re influencing yourself, you might decide to self-regulate a little bit.”

My internal roller-coaster ride reflected the way human behaviour is ultimately impossible to direct, as hard as clinicians might try. And they do try: In November, the trial team sent an exasperated e-mail answering some recently asked questions from trial participants. The first one was telling in its belligerence: “Why do I have to contact you every time I get a slight cough? I can tell that I just have a cold!” (The answer was that it was the only way to measure whether the vaccine works, and that “contacting us if you have any symptoms, however mild, is the most important thing you can do for the trial.” The last few words were underlined.)

So trying to peek over my blinders isn’t ideal for the trial – but much like my instinct for hygiene theatre, it was hard to help myself. I’m only human. And while I can’t fathom people thinking that they shouldn’t get tested in a trial, the reality was clear: Lives are complex.

I was reminded of that again in late November, when my husband and I found out that the British work visa he needed could only be applied for from Canada. We frantically packed and bought plane tickets. We made a game plan for staying safe: We wore badminton goggles on top of our masks on the train to the airport until they fogged over and used alcohol wipes on the airplane seats. I pointed the plane’s air vent directly toward me to try and create the “air barrier” I’d read about. Then we quarantined for two weeks in a sectioned-off portion of my parents’ home.

It was only several days into quarantine that I realized that, thanks to this messy, stressful situation, I was probably giving the trial the best data I ever had.

While I’m free to leave the trial at any time, the team is asking participants to stay blinded and in the trial until Britain’s National Health Service offers us an approved vaccine. I’ve agreed to remain. I have more follow-up appointments where they’ll take my blood samples to look for signs of an immune response. Who knows – maybe, despite my best guess, I’ve been vaccinated against COVID-19 all along.

But I do know this: When I eventually look back on this historical event, I’ll think about how science was once again able to forge miraculous vaccines out of the unpredictable, irrational behaviours of myself and other people who, for one reason or another, decided to leap, literally blindly, into a situation that invited risk during a pandemic already defined by it.


Vaccines vs. variants explained

Watch: Globe and Mail science reporter Ivan Semeniuk explains how vaccines may not be as effective against mutant forms of the virus that causes COVID-19, making it a race to control and track the spread of variants before they become dangerous new outbreaks.

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