Stalling the virus

Dr. Amy Givler, 62, a family medicine doctor in Monroe, La., decided early in the COVID-19 pandemic that she wanted to participate in a vaccine trial if one was nearby. She and her husband, also a family medicine doctor, regularly treat patients with the coronavirus.

She learned a hospital in Shreveport would host the Pfizer/BioNTech phase 3 trial. She signed up and heard right away that the organizers wanted her in the trial. Then came a sinking feeling: “I said, ‘What have I done?’ That’s when I did a deep dive into mRNA vaccines.”

Vaccine trial participants like Givler, a member of the Christian Medical & Dental Associations, were nervous about trying a new kind of vaccine. But these volunteers were willing to put their health on the line to provide trials that were double the size of a normal vaccine trial, according to Peter Marks, who oversees vaccine safety at the Food and Drug Administration (FDA). Months after receiving doses, the volunteers are hopeful about how these mRNA vaccines could minimize loss of life in future pandemics.

Messenger RNA, or mRNA, forms the basis of two COVID-19 vaccines leading the pack, from Pfizer and Moderna. They’re the first FDA-approved mRNA vaccines. Both received U.S. funding through Operation Warp Speed and boast about 95 percent effectiveness, though questions remain about long-term effects and effectiveness. Scientists developed mRNA technology over the last 30 years to find an alternative to embryonic stem cells. And it might lead to more medical breakthroughs (see sidebar).

GIVLER ALREADY KNEW A LOT about vaccines. She describes herself as “one of those boring people” who watch the meetings of the Centers for Disease Control and Prevention’s Advisory Committee on Immunization Practices. But if she was going to be among the first Americans to take an mRNA vaccine, she wanted to know what she was getting into. She dug into the medical literature.

MRNA tells cells what proteins to make, and in these vaccines it gives cells the recipe for the spike protein that the coronavirus uses to enter cells. The cells then raise an immune response to the spike protein, so when a coronavirus enters the body, cells already have an immune defense and the virus can’t enter. The Moderna and Pfizer vaccines do not contain the virus, nor is it chemically possible for mRNA to enter a cell’s nucleus and alter a cell’s DNA. It only gives instructions for the one spike protein.

“The people who are making the vaccine, they don’t have to be in a special-level lab, because they’re not handling the virus,” Givler said. A single protein from the virus is less likely to cause the reactions some people experience with vaccines containing a version of a virus itself, she said.

Her research made her confident in going forward with the trial, which is a two-year commitment. She can drop out at any point but wants to stay in to provide long-term data on the vaccine.

Givler drove the hour and a half to Shreveport for her first dose of the Pfizer vaccine in September. She prayed she would get the vaccine, not the placebo. The trials are typically a “double blind” study: Organizers and participants don’t know who has the vaccine and who has the placebo. Doctors and staff administering the trial interviewed her in detail, took her vital signs, then gave her the first dose. She was hoping for a sore arm—a sign that she had gotten the vaccine—but only felt soreness from rubbing her arm so much to see if it hurt.

The second shot came a few weeks later, and Givler was suddenly fatigued. She lay on her couch a whole day with a low fever. She knows the placebo effect is strong, but she surmised she would have had placebo side effects on the first dose, not the second. She was sure she had gotten the vaccine.

Later she “cheated” and took an antibody test that showed she had strong antibodies to the virus.

Since getting the vaccine, she’s shared her experience with patients, encouraging them to plan to take a day off after getting the second dose in case they have reactions like hers.

“I say, ‘As soon as you get offered a vaccine, please get it.’ A lot of people just need to hear from their family doctor,” she said.

“To me it’s perfectly reasonable for someone to say in June, ‘No I wouldn’t get it if it was offered today. Let’s hear about it.’ [Dr. Anthony] Fauci was saying that,” Givler said. But now, she said, “it’s been tested.”

ABOUT HALF OF AMERICANS said they would take the coronavirus vaccine, according to a recent survey from the Associated Press-NORC Center for Public Affairs Research. Forty percent of black respondents and 33 percent of all adults under the age of 45 said they would not take the vaccine. Experts estimate the disease will start to come under control when 60 percent to 80 percent of the population is immunized.

AP’s survey found that about half of those who said they would not take the vaccine worried it would infect them. But that’s impossible for the first two vaccines to hit the U.S. market, since mRNA vaccines do not contain the virus.

During the summer, Dr. Reynold Verret, the president of Xavier University, the only historically black Catholic university, heard from his doctor that the Pfizer trial didn’t include many African Americans.

Verret, an immunologist, joined the phase 3 trial publicly, wanting to change that 40 percent of black Americans who say they won’t take the vaccine. Some of that mistrust is based on a long history of medical experiments performed on African Americans. The most well known is the Tuskegee study, a 40-year study on several hundred African American men. Researchers told them they’d receive medical treatment for syphilis, but they received placebos instead. Many died from illnesses that the researchers intentionally left untreated.

Verret mostly joined to see the vaccine’s efficacy, which varies more based on genetic background, he explained. Most people at Xavier know someone who has died of the virus, said Verret. He also lost family members to the virus: “I understood it was worth the risk.”

Dan Moore, 33, is a copywriter for a video game merchandise company in Tucson, Ariz. When the pandemic began, he thought experts overblew its severity. He began following the excess mortality statistics to prove his point. The numbers sobered him instead. In June he signed up for Moderna’s phase 3 trial in Tucson.

“I hate the lockdowns,” he said. “The vaccine for me is the way out of that.”

He and his wife, who are Catholic, haven’t been to Mass in about eight months, his baby daughter hasn’t been baptized, nor have his or his wife’s grandmothers met their great-granddaughter.

“I work at a company that sells video game merchandise, not the most socially critical mission, so it’s good to feel I did something of some value,” he said with a laugh. “Selfishly, I want to watch sports, I want to go to concerts, I want to sit inside a Wendy’s and read a book.”

But before he took the doses he needed to do research. Moore’s uncle had a swine flu vaccine in 1976 when there was a rush to vaccinate the nation. He had a Guillain-Barré reaction, in which the immune system attacks the nervous system, but recovered. Moore also looked up the “Cutter incident,” where the first batches of the polio vaccine accidentally contained the live virus. He concluded an mRNA vaccine wouldn’t have such problems: “You get cold feet after you sign up for something like that, naturally.”

He went forward with the two doses in the summer, and none of his vaccine-skeptical family members criticized his participation in the trial: “Because I made this decision myself it’s, ‘Oh, that’s a cool thing you’re doing.’” He thinks skepticism about a new vaccine will melt away as people gradually see others around them getting the vaccine.

Dr. Tim Millea, in Davenport, Iowa, was working in a hospital during the 1976 swine flu outbreak and remembered seeing several patients with the Guillain-Barré reaction to the vaccine. He is a member of the Catholic Medical Association and on the U.S. Conference of Catholic Bishops’ panel to consider the pro-life implications of the new vaccines. He examined the data and found the rate of Guillain-Barré was no higher than before the swine flu epidemic.

“This association by coincidence is something we have to look out for as well,” he said. “God bless [skeptics] for asking questions … [but] I don’t think we’re wrong. There are enough checks and balances in the approval process. People in the FDA, DEA [Drug Enforcement Administration], and the CDC, they’ve been in this rodeo before.”

PEOPLE LIKE THE FDA’S MARKS and Dr. Peter Hotez, whose team at Baylor College of Medicine is working on a COVID-19 vaccine in trials in India, are still waiting for data on several fronts: whether the vaccines prevent asymptomatic transmission (the 95 percent effectiveness of the vaccine is in preventing COVID-19 symptoms, not necessarily the coronavirus’ infectiousness), how long the vaccine is effective before more doses are necessary, and whether the coronavirus will mutate in such a way as to require a new vaccine each year like the flu. Later studies will examine the effects of the vaccine on children, pregnant women, and the immunocompromised.

Trials show no serious side effects from the Pfizer or Moderna vaccines, other than what’s typical of vaccines that stimulate the immune system: fatigue, a low-grade fever, or soreness at the jab site. Some small number of recipients, like two recipients of the COVID-19 vaccine in the United Kingdom, will have allergic reactions as with any vaccine or drug like ibuprofen. Marks acknowledges researchers don’t have long-term safety data on the vaccines yet, but said “we’re not going to let something out there that we aren’t comfortable taking ourselves.”

Much of the U.S. safety regimen for vaccines deals with ensuring production quality, according to Hotez. Part of the reason for extra months of delay in the AstraZeneca and Sanofi vaccines is because of quality issues in the supply lines that created dosing errors during the trials.

“We’ve known for years the spike protein was the weak link for coronaviruses in general,” Hotez said in an event about the new vaccines at the Baker Institute. “It was never a heroic scientific accomplishment. The hard part was doing all of this with quality control, quality assurance, good clinical trials … that’s the differentiator with vaccines coming out of the United States versus Russia … and that’s what the U.S. taxpayers have been paying for all along.”

“They should win a Nobel Prize”

The Charlotte Lozier Institute’s Dr. David Prentice, an expert on stem cells, said the mRNA technology at the heart of the two main COVID-19 vaccines is “a big deal” in the world of alternatives to embryonic stem cells. Prentice has long advocated for alternatives to embryonic stem cells. (WORLD has published several articles detailing the use of fetal cell lines in vaccine research, and the Charlotte Lozier Institute has an explanation on each vaccine.)

Neither the Pfizer nor the Moderna vaccine used fetal abortion–derived cell lines during development or production, but both used abortion-derived cell lines in some “confirmatory lab tests.”

Derrick Rossi, one of the founders of Moderna who has since left, started the company a decade ago with the idea that mRNA (Get it? Modified RNA, or Moderna) technology could make imitation stem cells, what scientists call induced pluripotent stem (iPS) cells. He thought the technology could help scientists avoid the controversy of embryonic stem cells.

Previous iPS technology altered genetic material directly in cells, creating threats inside the cell later on, like cancer. Using mRNA solves that problem because it doesn’t alter DNA. MRNA is fragile (partly why the vaccines have to be kept at such low temperatures) and, when introduced from the outside, can be destroyed by a cell’s defense systems before it gets a chance to do its work. But Rossi, building on similar research from other scientists like Katalin Karikó, who now oversees mRNA research at BioNTech, found a way to slip custom mRNA into cells.

“MRNA has a lot of uses other than that, but that was its first big hit, to make these ethically derived stem cells,” said Prentice. “They look and act like an embryonic stem cell. No one has to die to get this stem cell. This was a big deal.”

The mRNA technology is just now “coming into its own,” said Prentice, but he sees many therapeutic uses. That’s what Rossi envisioned too: an entirely new genre of treatment for every illness from heart disease to cancer.

Before its COVID-19 vaccine, Moderna had not produced any officially approved treatments with its mRNA technology, but Prentice said he thinks there is a good chance that the research on these mRNA vaccines might lead to more breakthroughs for other mRNA uses, “not just for a future pandemic.”

Prentice said celebrating scientists and companies who move away from using embryonic cell lines for research and treatment “puts pressure on those not using the ethical tools.”

“At some point in time I think Rossi and the other scientists who came up with this way … should win a Nobel Prize for that kind of work,” he said. —E.B.