The majority of people now have some immunity against the virus that causes COVID-19 thanks to natural infection and a widespread vaccination program. Although it hasn’t prevented infections, the massive waves of sickness and fatalities that shook the world in the early years of the pandemic have been tempered by this widespread immunity. Maintaining this level of immunity is necessary for controlling the virus, but it is challenging due to the virus’s continuous production of new variants that can partly evade the antibodies produced by vaccinations and prior infections.
However, there is a caveat. According to a recent study from Washington University School of Medicine researchers in St. Louis, updated booster shots will be crucial for boosting population immunity as new variants appear.
Their study, which was published on April 3 in Nature, demonstrates that immunizing people against the primary virus strain and then giving them a booster shot that targets a new variant can cause a broad antibody response that can neutralize a variety of variants, even ones that have not yet appeared. The key is to choose a booster variant that differs from the virus’s initial strain enough to cause the maturation of numerous new and diverse antibody-producing cells.
“The challenge with COVID-19 is that the virus keeps mutating,” said senior author Ali Ellebedy, Ph.D., an associate professor of pathology & immunology, of medicine, and molecular microbiology. “It’s not that the vaccines don’t elicit a lasting antibody response. They do. The problem is that the virus changes and the existing antibodies become irrelevant. Here we showed that it’s possible to design a variant-specific booster that doesn’t just strengthen the antibodies people already have but elicits new antibodies. This means that periodically giving boosters targeting new variants would allow population-level protection to be maintained even as the virus evolves.”
The chance of serious illness and death was reduced by more than 90% with the first COVID-19 vaccines. However, the pathogen later evolved. Breakthrough infections resulted from the antibodies’ reduced ability to recognize and neutralize emerging variants, which had previously performed so well against the original strain. The obvious answer was to update the vaccines to target the new variants, but Ellebedy noted that because the initial vaccines were successful in protecting against the original strain, creating an efficient variant booster shot proved challenging.
“The whole point of making boosters against new variants is to teach the immune system to recognize features in the new variants that are different from the original strain,” Ellebedy said. “But the new variants still share a lot of features with the original strain, and it’s possible that the response to these shared features could dominate the response to new features. The boosters could end up just engaging immune memory cells that are already present rather than creating new memory cells, which is what we need for protection against new variants.”
Ellebedy and colleagues examined individuals who received a COVID-19 vaccine that was directed against the original strain, followed by a combined booster that targeted two of the early variants—beta and delta—or a booster that targeted the more recent omicron variant. Co-corresponding author and pathology & immunology instructor Jackson Turner, Ph.D., and co-first authors Wafaa B. Alsoussi, a graduate student, and Sameer Kumar Malladi, Ph.D., both working in Ellebedy’s lab, were also part of the study team.
Ellebedy observed that the initial studies were discouraging. The study examined 39 individuals who had gotten the Pfizer/BioNTech or Moderna COVID-19 vaccines in a two-shot primary sequence, followed by an experimental booster injection that targeted the beta and delta variants.
The initial virus strain as well as its beta and delta variants were both neutralized by the antibodies that each participant generated. However, none of the examined antibodies were specific to beta or delta. According to Ellebedy, the lack of these antibodies suggests that the variation booster did not successfully promote the emergence of appreciable new antibody-producing cells.
“This was disappointing but not surprising,” said Ellebedy, who is also an expert on influenza vaccines. “If you look at the sequences for the beta and delta spike proteins, they are not really very different from the original strain. If we saw this degree of difference among influenza strains, we would say there’s no reason to update the annual vaccine. But the omicron variant is a different matter.”
In comparison to the virus’s initial strain, the omicron variant, which has dominated the globe since late 2021, has undergone dozens of new mutations. Eight recipients of the COVID-19 vaccine from Pfizer/BioNTech or Moderna were chosen by Ellebedy and coworkers, and they were given a booster shot that was only effective against the omicron variant. Later, the CDC advised the use of updated boosters that are effective against both the initial strain and the omicron variant. These bivalent boosters, produced by both Pfizer/BioNTech and Moderna, went on sale to the general public in the autumn of 2022.
Four months after the booster shots, the subjects’ blood samples were examined by the researchers, who found more than 300 unique antibodies that could neutralize the original strain or one or more of the variants.
Six of them were able to neutralize omicron but not the original strain, showing that the booster was effective in stimulating the production of fresh antibodies that were tailored for omicron. Even BA.5, a subvariant of omicron that is now broadly spread but was not yet present when the booster was created, was neutralized by one of these novel antibodies.
“This booster engaged naive B cells and created new memory cells, which means it expanded people’s immune repertoire and equipped them to respond to a greater diversity of variants,” Ellebedy said. “Designing boosters to maintain immunity to the evolving virus is not going to be easy. The extent of the difference between the old and the new variants is clearly important. But if we are careful about how we choose which variants to include in boosters, I think we can stay ahead of this virus.”
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