In the spring of 2020, when the COVID-19 pandemic was just taking off, some of the first US patients to recover donated blood samples to the National Institute of Allergy and Infectious Diseases (NIAID). Researchers there used some of the convalescent serum samples to study antibody responses to SARS-CoV-2 infection. Late last year, when viral variants began to emerge, they thawed out the stored antibodies to investigate how those from individuals infected in the first wave would defend against the evolving pathogen.
At least a few of the patients, all of whom had mild to moderate disease, produced 4 particularly potent antibodies against the strain that infected them and a diverse range of variants that since have been detected. Two of the antibodies were “ultrapotent” at tiny concentrations across all 23 of the variants the scientists tested, including the highly transmissible B.1.1.7 (alpha), B.1.351 (beta), and B.1.617.2 (delta) versions, the researchers recently reported in Science. Combinations of some of these antibodies mitigated viral escape in laboratory experiments, a feature that could slow resistant strains from emerging in patients treated with the cocktails.
The newly identified antibodies and others like them could hold the key to COVID-19 therapeutics and vaccines that can stand the test of time. “The work shows the potential of the human immune system to generate antibodies broadly reactive against SARS-CoV-2 variants,” study coauthor Nancy Sullivan, PhD, chief of the Biodefense Research Section at NIAID’s Vaccine Research Center (VRC), wrote in an email to JAMA. “The antibodies will add to the possibilities for therapeutic intervention and…provide a basis for rational structure-based vaccine design against variants of concern.”
Sidestepping the Hotspots
The discovery comes at a critical moment. After plummeting earlier this year, SARS-CoV-2 cases are rising again with the spread of the delta variant, relaxed restrictions, and pockets of low vaccination uptake. Just months after the first vaccine doses became available in the US, talk of boosters is dominating the public conversation.
The virus has already sidelined 2 monoclonal antibody therapies. Lilly’s bamlanivimab was the first to receive US Food and Drug Administration (FDA) Emergency Use Authorization for mild to moderate COVID-19. After resistant variants arose, the company transitioned to a combination of bamlanivimab plus etesevimab. But the proliferation of the beta and P.1 (gamma) variants, which have reduced susceptibility to the 2 drugs, led the National Institutes of Health (NIH) to recommend against the cocktail’s use. Only 2 therapies with FDA Emergency Use Authorization are now generally recommended for treating mild to moderate COVID-19 in outpatients at high risk of severe disease: Regeneron’s casirivimab plus imdevimab cocktail and sotrovimab from GlaxoSmithKline and Vir Biotechnology.
“The past few months have highlighted how SARS-CoV-2 evolution and continually emerging variants of concern can render monoclonal antibodies and even their cocktails ineffective,” Tyler Starr, PhD, a postdoctoral fellow at the Fred Hutchinson Cancer Research Center, who was not involved in the new study, wrote in an email. He noted that it’s unknown how mutations will continue to accrue over time or which virus surface regions that can illicit an immune response might change next. It’s therefore important to continue developing antibodies that target different epitopes, as these regions are known. “This paper works toward that aim by identifying antibodies that are robust to existing SARS-CoV-2 variation,” Starr wrote.
His own recent work goes beyond even that variation. His team, along with scientists at Vir and the University of Washington in Seattle, among other collaborators, have discovered SARS-CoV-2 antibodies with broader activity across the larger SARS-related coronavirus lineage, including some highly resistant to viral escape. These features derive from targeting regions that are “conserved,” or stable, across the related viruses, the researchers reported in 2 articles in Nature.
Such highly conserved regions also turned up in the NIAID study, according to John Misasi, MD, an NIH staff clinician who led the work at the VRC. “When we started looking at the variants back at the end of last year, we took all of these antibodies and tested them using serum neutralization assays,” Misasi said in an interview. “We noted that these 2 antibodies in particular were 5- to 10-fold more potent than anything we had tested so far. As new variants came out, we kept saying, ‘Well, they’re still good.’ That led us to say, ‘Okay, let’s do these structural studies so that we can learn why they are so much better.’”
Misasi explained that the SARS-CoV-2 spike protein’s receptor-binding domain (RBD) flips between up and down positions. Using cryogenic electron microscopy, the researchers visualized the 2 most potent antibodies—dubbed A23-58.1 and B1-182.1—enveloping a hook-like structure on the RBD tip in its up position. In doing so, the antibodies skirted around key locations lower on the tip that appear to be mutational hotspots for the virus. “These two antibodies avoid those hotspots,” Misasi said.
As infectious disease and virology expert Michael Diamond, MD, PhD, a professor of medicine at the Washington University School of Medicine in St Louis, who was not involved in the work, explained in an interview, “They were able to identify sites that are highly, highly conserved on the SARS-CoV-2 spike that are not appreciably affected by a number of the key variants and likely not to be affected by many variants going forward.”
Monoclonals and Vaccines to Come
To test whether the antibodies would suppress future mutational escape, the researchers incubated a nonreplicating vesicular stomatitis virus engineered with the SARS-CoV-2 spike protein with round after round of increasing antibody concentrations, putting pressure on it to generate so-called escape mutants.
The experiments suggested that combining B1-182.1, the most potent of the candidates, with either of 2 other strong neutralizers stopped antibody-resistant mutations from emerging. “Two of the antibodies working together appear to be better at mitigating escapes than just a single antibody alone,” Misasi said.
He emphasized that the report is an early one and that further research is needed to demonstrate that the laboratory findings will translate to the clinic. But he and others were optimistic that the discovery of SARS-CoV-2 überantibodies will play a role in the pandemic’s next chapter.
“Going forward, we are going to need to adjust our antibody therapies because some of them will become obsolete due to escape,” said Diamond, who also is working to identify broadly neutralizing SARS-CoV-2 antibodies and expects to publish findings soon. As the discoveries accrue, the armamentarium of COVID-19 treatments should expand, he said. Potent, broadly reactive monoclonal antibody cocktails that are resistant to viral escape could be put to use right off the bat. Or the individual antibodies could be stockpiled and substituted into existing combination therapies as resistance against them develops.
According to David Montefiori, PhD, director of the Laboratory for HIV Vaccine Research and Development at Duke University Medical Center, who was not involved in the VRC study, the work provides insights into the types of neutralizing antibodies the virus cannot escape. “These are ideal antibodies to induce with vaccines,” he wrote in an email. “The next step is to determine whether similar antibodies are already induced by vaccination, and whether additional boosting will improve the potency and durability of the response.”
Knowing which spike protein regions are highly conserved across variants could potentially enable the design of a universal SARS-CoV-2 vaccine. The available shots are based on the original spike configuration, and researchers are studying boosters that use variant spikes. This arms race between virus and vaccine could continue indefinitely. But instead of perpetually staying 1 (or more) steps behind the virus, third-generation vaccines could be designed to induce or deliver only the spike epitopes that at least so far have remained stable.
Such vaccines would avoid the virus’ mutational hotspots, which also are where the immune system focuses most of its response. In theory, removing that distraction would redirect a potent antibody response to the conserved regions of the virus. Ideally, Misasi said, these vaccines would have “breadth right from the get-go, as opposed to trying to chase every single variant that comes down the line.”
However, developing a vaccine that drives people to make antibodies that recognize a particular viral protein epitope is not a simple leap, Diamond cautioned. “That is the field of reverse vaccinology,” he said. “There are a couple of different strategies to do this, but it is not trivial, and so this will require a bit of work. But that’s the goal.”