I’m subject NL002-0060 and I’m dropping out of my COVID-19 vaccine trial | Science | #itsecurity | #infosec

A syringe containing either CureVac’s COVID-19 vaccine or a placebo is ready to be used at a trial site in Brussels on 2 March.

REUTERS/Yves Herman

Science’s COVID-19 reporting is supported by the Heising-Simons Foundation.

I’ve been wrestling with a dilemma the past few weeks: Do I stay in the COVID-19 vaccine trial I’ve been enrolled in for 4 months—and which I very much hope will be successful—or do I drop out, take an already proven vaccine, and protect myself sooner? It’s a question thousands of trial participants have faced over the past 6 months but that you don’t hear much about.

I knew I might face this dilemma since 21 January, the day I drove to a behemoth academic center in the southeastern part of Amsterdam, my hometown, to enroll in the HERALD study, a large efficacy trial of a candidate COVID-19 vaccine produced by the company CureVac. I sat down in a small basement room with an infectious diseases physician who provided some basic information about the study, gave me a consent form to sign, and carried out a physical examination.

Then came an important moment: I was going to be randomly assigned to receive either the experimental vaccine or a placebo. The researcher clicked a few buttons and looked at her screen. “The wheel of fortune is going to spin,” she said. Then she read a message that had popped up: “Thank you. The subject has been successfully randomized.”

Half an hour later, a nurse gave me an injection. Neither of us knew what was in it: 12 micrograms of RNA, packaged in tiny fatty bubbles, that might save me from getting sick or dying—or a few milliliters of saltwater.

It was a worthwhile gamble for me: I had a 50% chance of receiving a candidate vaccine at a time when case numbers in the Netherlands were high, the more transmissible variant that first emerged in the United Kingdom was taking over, and it might be many months before I was eligible for a proven vaccine, as doses were scarce in Europe. The chance at protection aside, I was happy to play a tiny part in one of the great scientific endeavors of my lifetime—and, with luck, help another vaccine cross the finish line.

CureVac looked promising enough. In 2020, scientists had shown it worked in hamsters and monkeys. A phase 1 study had found mostly moderate side effects, and the 12-microgram dose appeared to trigger a good immune response in human volunteers. Although a latecomer in the immunization race, the vaccine, named CVnCoV, has a potential advantage over the two other messenger RNA (mRNA) vaccines, developed by the Pfizer-BioNTech collaboration and Moderna, which require extremely low temperatures to remain stable. CVnCoV, in contrast, can be kept at 5°C, the temperature of an ordinary refrigerator, for at least 3 months, and 1 day at room temperature. That’s a huge advantage, especially in developing countries. (Pfizer and Moderna are working on less fragile formulations as well.)

CureVac, headquartered in Tübingen, Germany, seemed set to play a big role in Europe as well, if it managed to win authorization from the European Medicines Agency quickly. The European Commission ordered 225 million doses in November 2020, with an option for another 180 million. To help meet expected demand, the company teamed up with Bayer in January.

But first, the trial would have to show it worked. Launched in December 2020 in Germany, HERALD ultimately enrolled more than 35,000 people in four European and six Latin American countries.

No side effects

Being a research subject was uneventful. I had no side effects at all from that first shot or from the second one, 4 weeks later. My participation in the trial did not lead me to take more risks, a well-known phenomenon in vaccine studies. At times I even wondered how useful I was for a test of the vaccine’s ability to prevent infection, given my low exposure risk: I work at home and was cautious about social contacts. I did go back to the hospital for a COVID-19 test once, in February, when I had what seemed very mild symptoms. The test came back negative.

The written information I received about the study did not discuss the options should a participant become eligible for a proven vaccine. And initially, it looked like I might not have that choice. Vaccination in Europe has moved slowly, and the study would likely report the first data within a few months, the study team told me, before I became eligible for an authorized vaccine. CureVac planned to do the final analysis of its study after 185 confirmed COVID-19 infections had occurred, according to the clinical trial protocol, but the first interim analysis was scheduled after just 56 cases, which should not take long. (Efficacy is calculated by comparing the number of cases of symptomatic disease in the vaccine and placebo groups.)

If the trial reached a clear conclusion and was halted, I would be unblinded. If CVnCoV had been shown to work, as the researchers expected, I would have essentially two options: If I had received placebo shots, I would be offered the vaccine, and I’d be safe. If I had received CVnCoV, I had been safe all along and wouldn’t need anything else.

 A CureVac FAQ, still posted, says the company expects to announce its interim analysis in the first quarter of this year. But that deadline came and went, and in April, the pace of vaccination in my country began to pick up. Having started with people ages 90 and older, municipal health services were working their way down the birth cohorts, and as the weeks went by, it seemed increasingly likely that my year, 1964, would come up before any announcement from Tübingen.

If that happened, I could also be unblinded, the researchers had said, but it would open a different set of questions. If it turned out that I received CVnCoV shots, I could be altruistic and stay in the trial until its completion, knocking on wood that the vaccine worked as well as the other mRNA vaccines; or I could err on the side of safety, drop out, and get whatever the government had planned for me. If it turned out I had the placebo, I had the same two options but staying in would be dicier still, because I would be completely unprotected. (The trial would not give me the vaccine in that case, because its value had not yet been shown.)

I asked two scientists who had also volunteered in COVID-19 vaccine trials for advice. Florian Krammer, a virologist at the Icahn School of Medicine at Mount Sinai and a subject in Pfizer’s efficacy trial, says he was asked in an email in December 2020 whether he wanted to be unblinded, after an analysis of trial data showed the Pfizer vaccine was highly effective. “I was contemplating just staying blinded, because of course, I’m a data point,” Krammer said. “But there were a lot of COVID-19 cases back then.” Besides, if it turned out he had the placebo, Pfizer would offer Krammer the shot, and he would remain a data point, but as part of the trial’s other arm. Krammer chose to be unblinded, learned he had a placebo, and received the vaccine in January. He is still in the study.

My situation was different because CureVac did not have efficacy data yet. Krammer said staying in would be “noble” but that I should also think about myself. “Signing up for a trial is already a very, very helpful thing,” he said. “Nobody can expect you to stay in if there are vaccines available that will protect you from getting severe disease or from dying.” He pointed out that dropping out now would not void my participation altogether: The past 4 months were already part of the data. And this wasn’t just about me, he added: “What if you stay in the placebo group and you get infected and you infect somebody else and that person dies?”

Virologist John Moore of Weill Cornell Medical College faced a slightly different dilemma. He had volunteered for an efficacy study in the United States and Mexico of the vaccine produced by Novavax, which began in late December 2020. Moore says he decided to stay in the study even after he became eligible for a proven vaccine at his hospital at some point in February or March.

Interim data from a study in the United Kingdom in late January showed Novavax’s shot had 89% efficacy, and on 5 April, the company announced that both the U.K and U.S.-Mexican studies would switch to a “crossover design,” meaning all participants would be offered two more shots. Those who first received a placebo would now receive the vaccine, and vice versa, but everybody would remain blinded. For participants, the advantage is that they know they’re all protected; for the company, it’s a way to keep more people in the trial, allowing it, for example, to do better studies of duration of immunity and of the responses that correlate with protection.

Moore accepted the offer to cross over and received two more shots, the last one on 11 May; he feels confident that he’s protected now, but he remained unvaccinated for 4 to 6 weeks longer than he would have been if he had dropped out. “I didn’t think that delay would cost me very much,” he says. “But if it had been 4 to 6 months, then of course my dynamic would have been very different.”

CureVac has not said whether it will move to a crossover design. In fact, it has not said much at all about the dilemmas volunteers face. Moore, too, said I should make a decision based on my own circumstances: “You can leave a trial. It’s not a prison.”

Day 120

On 16 May, my age group became eligible for an mRNA vaccine. I went online right away to lock in appointments for the first and second doses. I had yet to make my decision but I figured I could always cancel them.

As it happened, I had a scheduled appointment with the trial team 4 days later, for a physical exam on day 120 after my enrollment. During the visit, my fourth, I told the researcher that my turn had come up, and we briefly ran through the possible scenarios. Then I asked her to unblind me. She swiveled her computer screen in my direction so I could see the steps it required. And there, suddenly, it was: “placebo.”

I didn’t have to think much longer. I’m looking forward to being safe from COVID-19. I want my 2019 life back—or something that resembles it. Summer is coming, and even with my two scheduled appointments, it will take until early July to be fully protected. “I’d like to drop out of the trial,” I said. The physician said she understood. It’s what most people in my situation did, she said.

Today, I biked to one of Amsterdam’s makeshift vaccination centers, inside a massive, empty conference center, and received my first Pfizer-BioNtech shot. The wheel of fortune had not given me what I had hoped for, but I still felt very lucky.

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