Since emerging in December, the 2019 novel coronavirus — severe acute respiratory syndrome coronavirus 2, or SARS-CoV-2 — has been confirmed in more than 800,000 people worldwide.

In early March, Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, estimated that developing an effective vaccine for SARS-CoV-2 would take “a year, a year-and-a-half, at least.”

With the help of Eric Weaver, an associate professor of biological sciences at the University of Nebraska–Lincoln who is working to develop a long-term, universal vaccine against influenza viruses, Nebraska Today is exploring some common questions surrounding the race to create a SARS-CoV-2 vaccine.

How do vaccines work, again?

Vaccines work by mimicking a viral or bacterial infection, effectively tricking the body into developing immunity against the disease(s) caused by those agents.

Leftover bits, or antigens, of invading germs will stimulate the production and mobilization of large molecules, called antibodies, that seek and destroy the antigens. Even after a wave of invading germs is eliminated, the body will (ideally) retain some T-cells that never forget the face of those invaders and will mobilize a fresh defense if they return. This, in essence, is immunity: the vigilant long-term memory of the immune system.

But not all vaccines are made of the same stuff. Most viral vaccines, including those being developed for SARS-CoV-2, fall into one of a few broad categories:

• Live-attenuated vaccines contain weakened but still-active forms of a virus. These vaccines closely imitate actual infections, stimulating the production of both antibodies and T-cells. That combination confers strong, long-lasting immunity, yet the vaccines are also easier and cheaper to produce than other types, Weaver said. Because live-attenuated viruses retain the ability to replicate, though, they do pose a risk of reverting to their virulent, disease-causing forms, especially in people with compromised immune systems.

• Inactivated vaccines consist of viruses that have been “killed” (the question of whether viruses are living organisms is still debated), usually by heat or chemicals. These vaccines can still induce the production of antibodies, and their inactivation eliminates any risk of the viruses replicating and infecting the body. But the lack of replication also means that the vaccines mobilize fewer T-cells, sometimes reducing their effectiveness or requiring multiple doses to build up sufficient immunity.

• Subunit vaccines contain just the parts, or antigens, of the virus that are essential to stimulating an immune response. That precision tends to reduce the risk of side effects (which do not include autism) that can sometimes accompany vaccines. Removing the inessential bits from the essential ones, however, can be a laborious and time-consuming process.

• Some newer, more-experimental vaccines are composed of DNA or messenger RNA: genetic instruction manuals that normally help cells build their life-sustaining machinery. Unlike conventional vaccines, this approach doesn’t directly trigger an immune response by presenting the body with viral antigens. Instead, the injected DNA or mRNA instructs the body’s cells to build the antigens, which then induce an immune response. Moderna, one of the higher-profile companies working on a SARS-CoV-2 vaccine, has adopted the mRNA approach, which requires smaller amounts of the virus but is relatively unproven.

“The main advantage of (attenuated and inactivated) vaccines is that they are tested and approved vaccine platforms,” Weaver said. “They’re less expensive than contemporary vaccines and can be easily scaled up for high-level production. Unfortunately, one of the biggest drawbacks is speed.

“If I had to make a vaccine as fast as possible, I would have made it the same way that Moderna has. … Ultimately, though, the vaccine that is used globally will likely be a more traditional, less expensive, more stable vaccine platform.”

What’s the typical process for developing a vaccine? How long does it usually take?

The fastest-developed vaccine on record — created to protect against a strain of Ebola virus after a 2014 outbreak in Africa — took about five years.

That’s partly because viruses have evolved staggeringly sophisticated ways of infecting and commanding cells to churn out copies of themselves. That sophistication usually requires many minds, working in concert, to fully unravel. And understanding the process is essential to defending against it.

After creating a vaccine prototype, researchers begin testing its effectiveness and safety in animals before moving on to human trials, which generally last years. In non-pandemic scenarios, those human trials include three phases:

• Phase I: An initial test of safety and side effects that typically consists of fewer than 100 people.
• Phase II: A larger-scale test of the vaccine’s ability to generate immunity.
• Phase III: A significant scale-up that assesses the vaccine’s safety and effectiveness in thousands of people by comparing a placebo group against one receiving the vaccine candidate.

If human trials go well, the vaccine gets submitted for regulatory approval. In the United States, that approval is granted or denied by the Food and Drug Administration. Approval leads to mass production of the vaccine, with public health officials then helping to decide which populations should receive the vaccine first.

But in the midst of a pandemic, researchers will sometimes fast-track the process by streamlining prototype development and even skipping certain steps — phases II and III of human trials, for instance — on the way to submitting a vaccine candidate for regulatory approval.

That’s already happening with some SARS-CoV-2 vaccine candidates. Of the 40-plus candidates currently reported by the World Health Organization, at least two are already moving to phase I of human trials — an unprecedented pace. The development of those vaccine prototypes was accelerated by Chinese researchers who managed to sequence the entire genetic code of a SARS-CoV-2 strain in mid-January. Informed by that genetic code, computational models have since identified sites on the virus that could be especially promising targets for vaccines or pharmaceutical drugs.

So how realistic is that proposed 12- to 18-month timeline?

Even considering the fast start, Weaver said meeting the timeline would demand an “incredibly fast pace.”

“I would say that it’s a very, very optimistic timeline,” he said. “It’s doable, but it comes with risks.”

Among those risks is the possibility that a vaccine candidate will actually make its recipients more susceptible to a virus that infects them later. That scenario played out in the 1960s, Weaver said, when researchers developed an inactivated vaccine for respiratory syncytial virus, or RSV, which can cause asthma and other severe respiratory issues in children.

“They gave this vaccine to children, and all it did was make the disease worse,” he said of human trials conducted in the United States. “Some children died, and it put about 80% of them in the hospital.”

Along with the immediate human costs, the incident did untold damage to the development of an RSV vaccine, Weaver said.

“There’s still no FDA-approved vaccine for it,” he said. “It (still) circulates and causes disease in our children all the time.”

Weaver said that cautionary tale and others have, much like immunity itself, imprinted themselves in the long-term memory of vaccinology. That vigilance has served to temper expectations and consistently remind researchers about the importance of putting vaccines through their proper paces, he said.

“There’s a real precedent, a real history, of respiratory diseases being enhanced by vaccines,” Weaver said. “So it’s not something that people want to take lightly. These decisions could have huge outcomes.

“I’m hopeful that they can make a coronavirus vaccine on that timeline, but that’s a lot of risk to put on somebody’s shoulders.”

If a SARS-CoV-2 vaccine is developed, will it still be administered after the pandemic has subsided?

“I would expect to see vaccinations continue even after the pandemic,” Weaver said. “We don’t tend to develop long-term memory to respiratory infections, and mucosal antibodies tend to wane rapidly. In addition, not everyone will get infected with the coronavirus this year, and we may see it re-emerge in later years.”

Will SARS-CoV-2 mutate into new strains of the virus?

All viruses mutate, and some of those mutations persist because they make viruses better at infecting, replicating or simply surviving. The good news? Early research suggests that SARS-CoV-2 is mutating slowly, especially in comparison to the fiendishly adaptable influenza viruses, which mutate into substantially different strains on an annual basis.

Even if SARS-CoV-2 did eventually mutate to the point of resisting an existing vaccine, Weaver said it probably wouldn’t pose a major issue.

“I think if we figure out how to make an effective coronavirus vaccine, modifying it for strain-specific immunity will be very doable,” he said. “If we figure out how to do it right one time, it’ll hopefully be relatively simple to modify for any new strains, in the same way that we make new flu vaccines every year.”