As COVID-19 cases resulting from infection with SARS-CoV-2 variants accumulate in the US and around the world, one question looms large:

How well do the COVID-19 vaccines developed so far protect against these novel coronavirus spinoffs?

“The virus is telling us it’s going to throw out a lot of mutations,” infectious disease specialist Jesse Goodman, MD, MPH, who, as then-chief scientist at the US Food and Drug Administration (FDA), led the agency’s response to the H1N1 influenza A pandemic, said in an interview. “Even if we don’t have a critical situation right at the moment…there’s a realistic possibility that variants will continue to evolve that have potential to avoid vaccine immunity.”

That’s to be expected, Anthony Fauci, MD, director of the National Institute of Allergy and Infectious Diseases (NIAID), told JAMA Editor in Chief Howard Bauchner, MD, in a February 3 podcast. Regardless of the platform on which the vaccine is based, Fauci said, “you still have a fixed immunogen and a virus that’s changing. Sooner or later, you’re going to get a mutant that evades that.”

One reason SARS-CoV-2 is throwing out variants and will continue to do so is because relatively few people globally have been vaccinated, Norman Baylor, PhD, a former director of the FDA’s Office of Vaccines Research and Review, noted in an interview. “This virus is like, ‘Yep, I’ve got plenty of people I can infect, and the more I replicate, the more I can mutate,’” Baylor said.

Some scientists have used the term vaccine resistance to describe the reduced efficacy of COVID-19 vaccines against some variants. But that confuses matters by suggesting vaccines are analogous to antibiotics, University of Washington biologist Carl Bergstrom, PhD, who studies evolution and medicine, said in an interview. “The key point for me is that in antibiotic resistance, the changes happen in people who are on antibiotics,” he said, while antigenic escape by SARS-CoV-2 occurs in people who haven’t been vaccinated.

When viruses replicate, Penn State biologist David Kennedy, PhD, explained in an interview, the cycle is like a classic childhood game. “Viruses copying themselves, it’s almost like a game of telephone,” said Kennedy, who studies pathogen evolution. “They repeat what they thought they heard, so they make mistakes all the time.”

Despite those many mistakes, Kennedy noted, he’s unaware of any vaccines against viral diseases other than seasonal flu that have had to be updated because of changes in the virus. Hepatitis B virus developed “vaccine escape mutations,” but they posed no health risks, he said.

Good Enough?

Current COVID-19 vaccines are based on the SARS-CoV-2 spike protein, which the virus uses to bind to and infect host cells, of the original Wuhan-hu-1. But the emerging “variants of concern”—deemed so because they appear to be more transmissible or deadlier than the wild-type SARS-CoV-2—contain mutations in the spike protein, spurring vaccine efficacy concerns.

Trials of the Novavax, Janssen/Johnson & Johnson, and AstraZeneca vaccines in South Africa, where the B.1.351 variant of concern represents virtually all of the circulating SARS-CoV-2, seemed to justify those concerns. The South Africa trials found lower vaccine efficacy compared with trials in other countries where B.1.351 wasn’t dominant.

The pivotal trials of the Pfizer-BioNTech and Moderna vaccines, the first 2 authorized by the FDA, were conducted mainly in the US before any cases of infection by B.1.351 or other variants of concern had been detected in the country.

Much of the current data on the messenger RNA (mRNA) vaccines’ efficacy against SARS-CoV-2 variants has come from laboratory studies in which researchers exposed serum samples from immunized individuals to genetically engineered versions of concerning variants and then measured neutralizing antibody titers. Such studies repeatedly have shown the vaccines elicit lower levels of neutralizing antibodies against SARS-CoV-2 variants than against older, more common isolates.

For example, in a February 17 letter to the editor in The New England Journal of Medicine, scientists described testing serum samples from individuals immunized with 2 doses of the Pfizer-BioNTech vaccine against recombinant viruses containing some or all of the spike protein mutations found in the B.1.351 variant. Neutralization of B.1.351 was approximately two-thirds lower than that of USA-WA1/2020, an early SARS-CoV-2 isolate.

In another letter published the same day, researchers reported measuring neutralizing antibody activity in serum samples from participants in the phase 1 trial of the Moderna COVID-19 vaccine. One week after the participants received the second dose, neutralizing antibody titers induced by a recombinant virus bearing the B.1.351 spike protein were 6-fold lower than those induced by a recombinant virus bearing the original Wuhan-Hu-1 spike protein.

However, that still might be sufficient to protect against COVID-19, or at least severe COVID-19.

“Fortunately, neutralization titers induced by vaccination are high, and even with a 6-fold decrease, serum can still effectively neutralize the virus,” Fauci and 2 NIAID colleagues wrote in a JAMA editorial posted February 11. And, they noted, lower vaccine efficacy in the South African clinical trials could be related to geographic or population differences.

Although serum antibody levels correlate well with protection for many infectious diseases, protective levels haven’t yet been determined for SARS-CoV-2. They may never be established, Baylor said. “With some organisms, it’s very difficult to pinpoint exactly what level of [antibody] response is needed,” he said, citing the bacterium that causes pertussis as one such microbe.

In addition to neutralizing antibodies, mRNA vaccines also induce virus-specific helper T cells and cytotoxic T cells that might help protect against infection, Paul Offit, MD, director of the Children’s Hospital of Philadelphia’s Vaccine Education Center, and John Moore, PhD, a microbiologist and immunologist at Weill Medical College of Cornell University, noted in a JAMA viewpoint published recently.

Assays of serum samples from participants in the phase 1 and phase 3 trials of Johnson & Johnson’s adenovirus-based vaccine, which the FDA authorized for emergency use on February 27, suggest that neutralization correlates with protection but probably is not the only biomarker that does, Johan Van Hoof, MD, who oversees vaccine research and development at Janssen, a Johnson & Johnson subsidiary, said February 26 during an FDA advisory committee meeting.