Why we need booster shots against variants to help end the pandemic

Just as the coronavirus continues to mutate and evolve, so must the weapons used to fight it. To that end the National Institutes of Health began testing booster shots designed to target a new variant of the COVID-19 virus. First seen in South Africa, the strain known as B.1.351 is especially worrisome because it appears to spread, like some other variants, more easily than the original. Recent research also indicates it can evade the immune protections generated by vaccines or natural COVID-19 infections.

In an effort to get ahead of the virus, the National Institute of Allergy and Infectious Diseases (NIAID) is collaborating with Massachusetts-based Moderna to test a tweaked version of its vaccine. The shot has been retrofitted with genetic instructions that trigger the immune system to recognize and attack the South African variant. This new phase 1 trial, which involves 210 healthy adults, will show whether this booster shot is safe and effective.

“The mutations are just in the right place on the surface of the viral protein and cause some antibodies to not ‘see’ that protein,” says John Mascola, director of the vaccine research center at the NIAID. “These studies are being conducted to answer the question of whether a booster vaccine will induce a broader immune response.”

Modern’s variant vaccine candidate differs from their currently authorized vaccine. Rather than providing instructions for making the spike protein that was present on the original strain of SARS-CoV-2, it delivers the instructions for producing a spike protein incorporating the mutations present on B.1.351. This gives the immune system a preview of this South African variant.

Like Moderna and the NIH, Pfizer and BioNTech are exploring the possibility of variant specific vaccines. But they also have a second strategy in mind: simply giving people a third dose of their original vaccine, already authorized by the United States Food and Drug Administration. The hypothesis is that an additional shot might generate an even bigger blast of antibodies that would disarm these new strains.

Booster shots are part of a more comprehensive strategy to blunt the impact of the mutant strains. In February, the Biden administration earmarked $200 million to escalate surveillance and pay for an early warning system that will sequence SARS-CoV-2 samples across the nation in order to better identify and track emerging variants. This effort will be coordinated by a SARS-CoV-2 Interagency Group, within the Department of Health and Human Services. The goal of the project is to monitor and characterize emerging “variants of concern,” which pose the greatest threats because they’re more contagious, deadly, or able to evade the body’s protective mechanisms.

Watching evolution in real time

The massive scale of the still largely uncontrolled pandemic means that the virus has billions of hosts and thus trillions of opportunities to replicate and mutate.

In theory, that could translate into an infinite variety of variants, a few of which give the virus a selective advantage, making them virtually impossible to counteract, like a game of Whac-a-Mole. And there now appear to be more than a dozen distinct versions that have cropped up, not just in the U.K., South Africa, Brazil, and India, but also locally in California, Oregon, and New York.

Most variants are not a cause for concern, because their mutations are simply one-offs that disappear because they don’t give the virus any sort of advantage. It is only when the strain is either more contagious, makes us sicker, or enables the virus to elude our immune response that public health officials worry. Unfortunately, these factors describe the variants that are now circulating here in the U.S.

“What we’re seeing is the evolution of a virus in hyper-speed real time,” says Gregory Poland, an infectious disease expert and head of the Vaccine Research Group at the Mayo Clinic in Rochester, Minnesota. “Most mutations make the virus less fit for survival and infection. But natural selection is going to favor those mutations that are beneficial to the virus.”

The B.1.1.7 strain, for example, which was first detected in December 2020 and ravaged the U.K., is far more contagious and lethal than the original virus. It is now spreading rapidly across continental Europe and is poised to become the predominate strain here in the U.S. The South African strain, which first emerged in October and has now been detected in at least 25 states, and P.1, the variant that decimated Brazil and arrived in the U.S. in January 2021, could potentially reinfect people who’ve already had COVID-19 or are vaccinated because these variants contain a mutation that enables them to dodge the antibodies our immune system unleashes to fend off foreign intruders.

Scientists call the changes that allow the viruses to elude the reach of antibodies escape mutations. They occur when the virus faces natural selection pressures. The viruses that are able to keep infecting cells and reproducing are the ones that contain traits that enable them to evade the antibodies. Right now, the mutation scientists are most worried about is called E484K, which they believe is the main culprit behind the virus’s evasive maneuvers.

This mutation changes the shape of the spike protein that decorates the surface of the coronavirus; this virus normally uses the spike to attach itself to the receptors on the surface of human cells and enter them. The current vaccine arsenal stimulates the production of antibodies that latch on to the original spike protein and block it from entering a human cell—like the way sticking chewing gum on a key blocks it from turning a lock and entering a house.

But there are still many unknowns. For example, scientists don’t yet know how fast SARS-CoV-2 mutates. That matters because every time there is a mutation, the effectiveness of the authorized vaccines that effectively combat the original COVID-19 virus may become less effective.

That is quite different from the case of the measles virus. When it mutates the new strain is still unable to evade the vaccines’ neutralizing antibodies. That’s why we don’t need a booster shot every year or need to change the formulation. “The measles vaccine was introduced in 1963, and we’re using pretty much the same vaccine today,” says Cody Meissner, chief of pediatric infectious diseases at Tufts Children’s Hospital in Boston. “But if you look at influenza, we have new strains that need new vaccines every year. We don’t know where COVID-19 is going to fall between these two extremes. That’s why people are exploring all these different approaches. We just don’t know.”

Convergent evolution is good news

Although it may seem from preliminary studies like the world will forever be playing a game of catch-up with this virus, recent research suggests that the news isn’t all bad. Growing evidence indicates the most worrying variants contain certain common traits or mutations. For example, the South African variant, Brazil’s P.1 strain, and the B.1.1.7 strain that’s overwhelming Europe all contain the E484K mutation.

That’s actually a good thing. Scientists call this convergent evolution, a phenomenon that occurs when the same mutation emerges independently over time in different parts of the world because it’s an adaptation that helps with viral transmission and reproduction. “If you look at the mutation the gives the virus the most capacity, we see the same mutation in the South African and in the Brazilian variant,” says Alessandro Sette, an immunologist at the La Jolla Institute for Immunology. “This is important because at two points in time, on two different continents, that bad variant has the same mutation. In other words, the virus has a limited repertoire to be bad.”

This limited bag of tricks suggests that retrofitting vaccines with new genetic instructions encoding specific mutations might effectively target multiple worrying variants simultaneously.

Although the vaccine elicited antibodies may not be able to completely neutralize the South African variant, the vaccine is not a complete loss. In clinical trials in South Africa where the variant is prevalent, while one vaccine was less effective in stopping infection, it was still 100 percent effective in preventing death and hospitalization. That is because the sheer number of neutralizing antibodies stimulated by the vaccines were enough to compensate for the loss of efficacy. “The wall is still there,” says Sette. “It’s just not as effective in keeping the virus away.”

Killer T cells to the rescue?

As concerns mount over the variants, it’s critical to remember that vaccines and antibodies are not the only defense. Individuals who’ve previously been infected or fully vaccinated have another ally if they become reinfected with the virus or a new variant. The immune system’s so-called “killer” T cells may swing into action if the virus overwhelms the antibodies. T cells help by recognizing and destroying infected cells. “If the wall is breached and the virus gets inside the cell,” says Sette, “the killer T cells are important for controlling and eliminating the infection.”

In a study released in late March, researchers from the NIH analyzed blood cell samples from 30 people who had recovered from COVID-19 prior to the emergence of the variants. When one type of T cell from these samples was exposed to these variants, they found the CD8+ T cells recognized all of them, even the South Africa variant. “The areas that the T cells target are largely not affected by the mutations in the new variants,” says Andrew Redd, a staff scientist in the laboratory of immunoregulation at the NIAID. In the vast majority of cases, he says, the T cell response should prevent disease, even if the virus can dodge the neutralizing antibodies.

The NIH hopes to complete enrollment of the booster shot tests by the end of April. As the FDA has signaled that it will grant emergency approval for vaccines devised to combat the variants, the new shot could be deployed quickly. Yet despite all these reassuring developments, we need to remain vigilant. “We’re still at an early stage and if people get ‘tired’ of COVID for economic or political reasons, it’s like throwing gas on a smoldering fire,” says Gerald Poland of the Mayo Clinic. “We’re potentially at the beginning of an exponential surge of a highly transmissible variant. No one can predict what will happen next week.”