Editor’s Note (9/4/20): The U.S. Centers for Disease Control and Prevention just alerted states to prepare for a novel coronavirus vaccine as early as November. In this story, Scientific American describes how the fast-track vaccine trials work and how they measure effectiveness and safety.

In late July, volunteers began receiving doses of a potential COVID-19 vaccine in the latest stage of a clinical trial at NYU Langone Health in New York City. The more than 1,000 names on the waiting list suggest the local response to the trial “has been outstanding,” says Mark Mulligan, an infectious disease specialist who directs NYU Langone’s Vaccine Center. “People are fed up with this disease and very motivated to help.”

The vaccine, which was co-developed by the pharmaceutical giant Pfizer and the German company BioNTech, is among front-runner efforts worldwide to develop immunizations for COVID-19 that are currently conducting or preparing to start phase III clinical trials—late-stage studies that test for efficacy and safety.* Six of these efforts are backed by Operation Warp Speed, a Trump administration program with the optimistic goal of beginning mass inoculations against the disease in the U.S. by January. During the trials, enrolled subjects will get experimental shots or a placebo, and investigators will observe whether those who received the vaccine develop infections and illness at lower rates. These assessments “will ultimately support regulatory approval and recommendations for how vaccines can be used,” says Penny Heaton, CEO of the Bill & Melinda Gates Medical Research Institute. The institute is not directly involved in the efforts to develop a vaccine against COVID-19, but it is working on vaccines for other viral diseases around the world.

Phase III clinical trials often take years to reach their conclusion. But vaccine developers now plan to test their candidates on rushed schedules that have sparked concerns over political meddling. (The concerns are not without merit: on August 11 Russia announced it had approved a vaccine despite the fact that the drug has not been tested in large-scale trials.) U.S. officials have insisted their own vaccines will be thoroughly vetted before approval. Experts say such trials should also include adequate representation from vulnerable subgroups at high risk from COVID-19, including the elderly, minority racial groups and individuals with underlying health problems. Adding to the challenge, a growing number of people have shown skepticism toward an eventual vaccine. And the trials have to answer key questions about how well human immune systems protect against SARS-CoV-2, the novel coronavirus behind the disease. Results from animal tests and early human safety studies look promising: vaccines generate encouraging immune responses, and the side effects they trigger—usually headache, arm pain, fatigue and fever—resolve quickly in most people. Yet only phase III clinical trials can show which vaccines—if any—will actually provide protection.

Strategizing for Speed

The trick to delivering fast answers on vaccine safety and efficacy is to enroll large numbers of people, says Peter Gilbert, a biostatistician at the Fred Hutchinson Cancer Research Center. Bigger study populations capture more incidences of viral exposure in a shorter amount of time than smaller ones, which are followed for longer periods. Each of the phase III clinical trials in the U.S. aims to enroll 30,000 individuals. This number is the lowest needed to rigorously show that 50 percent of people are protected from getting COVID-19 over six months—the Food and Drug Administration’s minimum bar for approval.

Investigators will monitor the vaccinated and placebo, or control, groups until the number of symptomatic infections between them reaches 150. If the researchers can show, with 95 percent statistical confidence, that cases in the vaccinated group add up to half of those in the control group or fewer, the vaccine will have met its primary target. “Still, none of us will really be happy with 50 percent,” says Gilbert, who leads the statistical center for the federal government’s COVID-19 Prevention Trials Network, an organization that is trying to recruit volunteers for the phase III studies. “We all want 90 to 95 percent protection.” Should a vaccine prove far more protective than the FDA’s minimum bar, he adds, there may be no need to wait for 150 cases. “We might look at 50 cases, and if the vaccine reduces disease rates by 80 percent, we might declare it successful and [apply] for approval within three to four months,” Gilbert says.

Crucially, FDA guidelines for COVID-19 vaccine developers call for ideally monitoring participants over an additional one to two years after approval to assess how long protection lasts in the general population and whether vaccinated people who become infected develop worse symptoms.

Enrolling a Diverse Group

The guidelines also encourage—but do not require—that vaccine developers enroll subpopulations most affected by COVID-19, such as Black and Latino people, who are far more likely to become infected and die of the disease. Doing so may not be easy. Black Americans, in particular, have reason to be distrustful of clinical research, partly as a consequence of the Tuskegee study. (That 40-year experiment was as an investigation of untreated syphilis. When an effective penicillin treatment became available, the researchers unethically withheld it.) To recruit more people of color, “we have to engage them by reaching out to community-based organizations, such as churches, neighborhood groups, barbershops and stylists, and Black colleges,” says Patricia Whitley-Williams, a pediatrician who specializes in infectious diseases at Rutgers Robert Wood Johnson Medical School. “It’s essential that we tell our people of color that they’ve been sufficiently represented in the COVID-19 clinical trials.”

Kathrin Jansen, who leads vaccine research and development at Pfizer, agrees on the need to increase the representation of racial minorities in the company’s ongoing vaccine trial, which is enrolling people between the ages of 18 and 85 at sites across the U.S., Europe and South America. “This is something we’re actively looking into,” she says. Most of the people enrolled during Pfizer and BioNTech’s earlier-phase trials were white, NYU Langone’s Mulligan says. “But we’re hoping to significantly change that for the phase III,” Jansen says. The study does not set quantitative targets for minority recruitment, “but it will be monitored centrally, and feedback will be provided to each of the participating locations," Mulligan says. “We are committed to enrolling those most affected.”

Defining Markers of Protection

Trial investigators will not only assess whether vaccines lower COVID-19 disease rates; they will go a step further by probing the specific “correlates of protection” in blood samples that show if someone is, in fact, immune to the disease. Preliminary research suggests that so-called neutralizing antibodies play outsize roles in protection. These roving molecules deflect SARS-CoV-2 from attaching to its host cell receptor, preventing infection. A July study reported that another Warp Speed vaccine contender, co-developed by Johnson & Johnson, elicited neutralizing antibodies that were detected at high levels in macaque monkeys. When the researchers then exposed the animals to COVID-19, they were totally protected after a single vaccine dose. The company plans to launch its phase III clinical trial in September. Among the other Operation Warp Speed companies, Moderna and the National Institute of Allergy and Infectious Diseases are already conducting a phase III trial of their vaccine, and Novavax is set to start one in the fall. Legal agreements with each company stipulate how many millions of vaccine doses, at a minimum, the U.S. government will buy (it aims to deliver 300 million by January). The government has the option to purchase millions of additional doses, but it is not obligated to buy them if a vaccine is not approved.

Questions remain about the durability of the protection any vaccine will afford people, however. Antibody levels can fall off soon after recovery, and that possibility has raised fears that COVID-19 immunity might wane quickly in those who have recovered from the illness or been vaccinated. Yet Heaton strikes a more positive tone. “Ideally, you’ll get immunological memory, so that even if your antibodies wane, they’ll shoot back up when you’re reexposed to the virus,” she says. Phase III studies will monitor antibodies over time, Heaton adds, along with the actions of another key immune component, T cells, which might provide reinforcements. Killer T cells, in particular, eliminate infected cells, destroying their viral invaders in the process. But the response can cut two ways: these cells might also contribute to hyperactive immune reactions that are deadly for some patients. “We still need a much better understanding of how T cells respond to SARS-CoV-2 infection,” says Avery August, an immunologist at Cornell University’s College of Veterinary Medicine, who studies T cell responses to COVID-19 infections. “But overall, I’m optimistic about the vaccine candidates going into phase III. We have a lot more to learn, but the immune responses so far look promising.”

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*Editor’s Note (8/25/20): This sentence was edited after posting to correct a reference to the number of front-runner efforts.