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COVID-19, Research
By Jill Coody Smits

COVID-19 Vaccines: What You Need to Know

With promising news about vaccines for COVID-19 coming in 2021, learn what’s involved in delivering them safely and effectively.

Doctors developing vaccines
Illustration by Jeannie Phan

As cases of the coronavirus continue to spike around the world and pandemic fatigue sets in, physicians and the general public are watching Operation Warp Speed (OWS), the United States' accelerated vaccine development initiative, with a mixture of hope and concern. They are hopeful a vaccine will allow life to return to normal but concerned that the aggressive pace may undermine public safety.

"I'm encouraged by how furiously the government and private sector have been working to develop a high-quality vaccine," says Jonathan Santoro, MD, director of neuroimmunology and demyelinating disorders at Children's Hospital Los Angeles. "But I need to see meaningful and transparent data from the government, US Food and Drug Administration [FDA], and pharmaceutical sponsors before recommending a vaccine to my vulnerable patients."

The goal of OWS is to produce and deliver 300 million COVID-19 vaccine doses, with initial doses available by January 2021, according to the US Department of Health and Human Services. The unprecedented pace is due to several factors: The genome sequence for SARS-CoV-2 (the virus that causes COVID-19) was published quickly; some researchers are using methods of vaccine delivery already investigated for other viruses, including Ebola; and the United States government has directed nearly $10 billion to vaccine-related efforts. To date, four trials OWS has funded either in researching, developing, manufacturing, or distributing are in phase 3.

Typically, it takes years for vaccines to make their way through the approval process at the FDA Center for Biologics Evaluation and Research. "Caution is important because you're giving vaccines to healthy people," says James J. Sejvar, MD, a neuro-epidemiologist with the US Centers for Disease Control and Prevention (CDC), "but some of the timelines the FDA has set out are archaically slow."

In preclinical trials, researchers test the viability of a drug or vaccine in cells and in living organisms. Once the drug or vaccine is deemed safe, a sponsor such as a drug company files an Investigational New Drug application that includes the method of manufacture, safety and efficacy data in animal testing, and a protocol for human studies. If the application is approved, the company can start a phase 1 clinical trial to determine safety and tolerability in small numbers of closely monitored healthy humans. If that goes well, the trial moves into a phase 2 study of dosing ranges in hundreds of subjects and then on to phase 3, which evaluates the medication's safety and efficacy among thousands of participants. Because vaccines will be administered to people of all ages, races, genders, and ethnic groups, the FDA gives priority to trials that include a diverse group of subjects.

A concerted push for a vaccine is nothing new, says David Jones, MD, PhD, professor of the history of medicine at Harvard. "There has always been strong motivation for developing vaccines," he says, "and the risk-benefit trade-off for them is better than almost any other area of medicine." He cites diseases like smallpox, tetanus, polio, and measles that have been mostly eradicated by vaccines as proof.

But rapid development has its own problems, especially if companies or governments cut corners in testing or manufacturing or release a vaccine prematurely, Dr. Jones says. Mistakes have been made in the past. In 1976, for example, President Gerald Ford responded to fears about swine flu by implementing a national immunization program through which 45 million Americans were vaccinated—unnecessarily, as it turned out. In the rush to deliver a vaccine, the government used a live virus, which can increase the risk of side effects in vulnerable groups, instead of an inactivated killed form. After being vaccinated, more than 450 people developed Guillain-Barre syndrome (GBS), a condition that causes the body to attack its own nerves. However, no cause-and-effect relationship was found, and the CDC now says a person is much more likely to develop GBS after having the flu than from a vaccine.

A similar event occurred in 1955, when the polio vaccine was introduced. Parents eagerly signed up their children to be "polio pioneers," and hundreds of thousands were vaccinated in a single month. Soon after, 40,000 children developed polio, 200 suffered paralysis, and 10 died. The culprit was a manufacturing mistake: A firm called Cutter Laboratories had produced doses with a live rather than an inactive virus.

In weighing the pros and cons of a COVID-19 vaccine, scientists ponder several questions. How effective is effective enough for a vaccine to be put into widespread use? Which potential side effects would be acceptable if the vaccine could save hundreds of thousands of lives and allow the world to move freely again? Every week, more vaccine trials march forward, compiling additional data and revealing new information in the hopes of answering those questions.

In addition to OWS studies, more than 50 vaccine trials in phases 1 through 3 are being funded through the World Health Organization's COVAX initiative, foreign governments, private entities, and nongovernment organizations. One vaccine is already in use in Russia, although it has yet to enter phase 3 clinical trials. Scientists around the world say that rapid rollout leaves important information about the vaccine's safety and efficacy unknown.

While it's not yet clear which vaccine—or, more likely, vaccines—will eventually be used in an immunization program, the CDC says it probably won't be rolled out for the general public before the middle of 2021. Dr. Sejvar expects the process to be a huge undertaking, dependent on how quickly manufacturing can be ramped up and what format the vaccine takes and whether it needs to be refrigerated. All four OWS phase 3 trials use injections, and the logistics of keeping millions of vaccine doses frozen in transit across the country or the world is a challenge.

It's also unclear how many people would consider being inoculated once a vaccine is available. In September, a Pew Research Center report found that about half of Americans, citing concerns about efficacy and side effects, said they probably would not get vaccinated. "Political polarization, and distrust and disparagement of science and experts in general, mean scientists and pharmaceutical companies have to be even more transparent about whether a vaccine is going to work," says Dr. Jones. Overall, though, he is optimistic. "We have reason to believe these vaccines will be safe," he says. "I hope years from now there's a happy story about a vaccine that worked."

vaccine icon

The Status of Vaccine Trials

More than 150,000 people around the world are expected to be enrolled in four trials that Operation Warp Speed (OWS) is funding through research, manufacturing, or distribution. All are randomized, double-blind, placebo-controlled studies, which means some participants get the vaccine and others get a placebo, and neither researchers nor participants know who got what until the trial is complete. While some volunteers may test positive for COVID-19 from exposure in the community, none of the vaccines—all of which are delivered by injection—use live coronavirus, and no one is exposed to the virus as part of a trial.

The US Food and Drug Administration (FDA) says a vaccine will be widely used only if it is safe and at least "50 percent effective in a placebo-controlled trial." The FDA also has published guidelines on how and when a vaccine manufacturer can apply for "emergency use authorization" if trial data are positive. Here's the latest.

University of Oxford/AstraZeneca

  • What: This trial is looking into whether an adenovirus (one of the types of viruses that can cause the common cold) modified with a coronavirus gene can "trick" the immune system into developing antibodies that will fight off SARS-CoV-2.
  • When and where: The phase 3 trial launched August 31 at sites in the United States, Brazil, Great Britain, India, and South Africa. More than 20,000 people out of a projected 50,000 have been enrolled so far.
  • Complications: The trial was put on hold September 6 after a volunteer developed transverse myelitis, an inflammation of the spinal cord. The study resumed at most sites September 12. In the United States, the study resumed October 23 after the FDA investigated whether the condition was coincidental or a side effect of the vaccine and concluded that the trial was safe to continue. The trial was also paused in October when a volunteer in Brazil died of COVID-19, but the participant had received the placebo and not the vaccine, so the trial resumed.
  • Caveat: Pauses are a common and necessary part of the vaccine-approval process and suggest the companies are doing their due diligence. "Adverse events occur any time you analyze and assess several thousand people," says James J. Sejvar, MD, a neuro-epidemiologist with the US Centers for Disease Control and Prevention. "The question is whether it is occurring among participants more often."

Johnson & Johnson's Janssen Pharmaceutical Companies

  • What: Volunteers get one single-dose injection. (In the other trials, volunteers get two single-dose injections.) Scientists are using an adenovirus to carry a coronavirus gene into a human cell in hopes it will produce a protective coronavirus antibody rather than the coronavirus itself. It is similar to a Johnson & Johnson Ebola virus vaccine approved late last year.
  • When and where: The phase 3 trial launched September 17 with the goal of enrolling 60,000 adults in nine countries.
  • Complications: The trial was halted October 12 due to a participant's "unexplained illness" but resumed 11 days later.

Moderna/National Institute of Allergy and Infectious Diseases

  • What: In this trial, messenger ribonucleic acid (mRNA) delivers to participants' cells a protein that simulates the coronavirus with the aim of prodding an immune response that would fight off the disease.
  • When and where: A phase 3 trial launched July 27 and enrolled about 30,000 participants at more than 80 US sites, with participants receiving two injections 28 days apart. In early October, Moderna released its protocol for safety and efficacy and announced that the vaccine would not be available for wide distribution before mid to late 2021, until sufficient data were collected and understood.
  • Caveat: No mRNA vaccines are currently in use, and none has ever been tested in phase 3 human trials.

Pfizer/BioNTech/Fosun Pharmaceutical

  • What: This trial also uses mRNA to prompt the immune system to recognize and fight off SARS-CoV-2.
  • When and where: The phase 2-3 trial launched July 27 in four countries, and more than 40,000 participants were enrolled by early November. In September, Pfizer announced that side effects were mostly mild to moderate. In November, the company said its vaccine was more than 90 percent effective with no serious side effects. However, in October the company said not enough volunteers had been exposed to COVID-19 to determine efficacy. Still, pending quality data and FDA approval, it plans to manufacture 1.3 billion doses by the end of 2021.

Why to Get Vaccinated

Vaccines are almost always a healthy choice, so why is there a backlash against them? "It comes down to two things," says James J. Sejvar, MD, a neuro-epidemiologist with the US Centers for Disease Control and Prevention. "Vaccines are a victim of their own success. Diseases like measles, mumps, and polio have basically been eradicated, and the perceived risk of severe illness is theoretical," he says. "And misinformation on social media takes on a life of its own."

In reality, he says, "vaccines undergo a tremendous amount of investigation into safety and efficacy before being released to the public, and side effects are very rare." If a person does have side effects—a sore arm, fever, or muscle aches—it's a sign that the immune system has kicked into gear, Dr. Sejvar says. "It absolutely is not a mild form of the disease itself."

Different Types of Vaccines

Vaccines, which are designed to provoke an immune response to fight off a virus, use different mechanisms to do that. For example, live-attenuated vaccines like those for measles, mumps, and rubella (MMR) use a weakened form of a virus to trigger a long-lasting immune response. Inactivated vaccines like flu shots use a dead germ to trigger a temporary immune response. They are weaker than live vaccines, making boosters necessary for continued immunity. Toxoid vaccines like tetanus shots use a disease-causing toxin to trigger the immune system to attack the toxin itself rather than the entire germ. Subunit vaccines like hepatitis B (and the Oxford/AstraZeneca and Johnson & Johnson COVID-19 vaccines) use part of a virus or bacterium, such as a protein or sugar, to trigger an immune response. There are subtypes within this sort of vaccine depending on what component (or antigen) is used.

People whose immune systems are suppressed should discuss specific vaccines with their physicians. Those with epilepsy may experience a lowered seizure threshold after taking a vaccine, says Jonathan Santoro, MD, director of neuroimmunology and demyelinating disorders at Children's Hospital Los Angeles. Anyone with a neurologic disorder is particularly vulnerable to diseases like influenza and COVID-19, and the protection afforded by vaccines often outweighs the risks, Dr. Santoro says. People will most likely still need to wear masks after being inoculated for COVID-19 and they may need yearly shots, says Gary Gronseth, MD, FAAN, vice chair of neurology at the University of Kansas.