Most people today are immune to SARS-CoV-2, the coronavirus that causes COVID-19, thanks to widespread vaccination campaigns and unplanned infection. Although this widespread immunity hasn't stopped new infections from happening, it has slowed the devastating spread of illness and death that the initial COVID-19 epidemic caused. As the virus evolves and produces novel strains that can partially dodge vaccines and antibodies created by past infections, it is imperative that this degree of protection be maintained.

Researchers observed that as new variations emerge, it is crucial to use booster vaccines aimed at increasing population protection. However, there is a catch: they point out that vaccinating people twice—first with the original SARS-CoV-2 strain and then with the new variant—may elicit a wide antibody response that can neutralize a range of variants, even ones that have not yet arisen. In order to stimulate the development of novel and varied antibody-producing cells, the booster vaccine must target a variant that is very divergent from the primary SARS-CoV-2 strain. The research titled "SARS-CoV-2 Omicron boosting induces de novo B cell response in humans" was published online in Nature.

The difficulty with COVID-19, according to Dr. Ali Ellebedy, associate professor of pathology and immunology at Washington University School of Medicine in St. Louis and co-corresponding author of the paper, is that the virus is always changing. That's not to say vaccine doesn't produce a long-lasting immune response. The difficulty is that the virus keeps evolving, rendering current antibodies ineffective. "In this study, we show that it is possible to build a booster vaccine against a specific variation that does more than just increase the effectiveness of preexisting antibodies. It also induces the production of brand new ones. Thus, even as this virus evolves, population-level protection could be maintained through routine booster vaccines against new strains.

More than 90% of serious infections and fatalities were prevented by the initial COVID-19 vaccines. The virus evolved, though. Breakthrough infections occurred because antibodies that worked well against the original SARS-CoV-2 strain failed to recognize and neutralize the developing variety. Ellebedy noted that updating the vaccine so that it targets the new strain was the reasonable next step, but that due to the initial vaccines' efficacy against the original SARS-CoV-2 strain, producing a successful booster vaccine against the variant became difficult.

"The goal of a booster vaccine against the new variant is to educate the immune system to recognize differences between the new variant and the original SARS-CoV-2 strain," Ellebedy remarked. "However, the new variant still shares many features with the original SARS-CoV-2 strain, and the response to these shared features is likely to dominate the response to the new features. A booster vaccine may end up simply activating already existing immune memory cells rather than creating new ones, which is what we need to defend against the new variant."

To measure the effectiveness of the booster vaccine in eliciting new antibodies, Ellebedy and colleagues studied people who received a COVID-19 vaccine against the original SARS-CoV-2 strain followed by a combination booster vaccine against two early variants—the Beta and Delta variants - or a booster vaccine against the newer Omicron variant.

Ellebedy noted that the first studies were discouraging. They looked at 39 people who were first vaccinated with Pfizer/BioNTech or Moderna COVID-19 vaccines followed by a combination booster vaccine for the Beta and Delta variants. All participants produced antibodies that neutralized the original SARS-CoV-2 strain as well as the Beta and Delta variants. However, none of the antibodies studied were unique to the Beta and Delta variants, and the absence of such antibodies suggests that the booster vaccines against the Beta and Delta variants failed to trigger the production of new detectable antibody-secreting B cells, Ellebedy said.

"It's disappointing, but not surprising," Ellebedy said. "If you look at the sequences of the stinger proteins of the Beta and Delta variants, they don't really differ that much from the original SARS-CoV-2 strain. If we saw this degree of variation between influenza virus strains, we would say there is no reason to update the vaccine every year. But the Omicron variant is a different issue."

The Omicron variant, which carries dozens of new mutations, was administered to eight people who had received either the Pfizer/BioNTech or Moderna COVID-19 vaccines, and Ellebedy and colleagues recruited them to administer a booster vaccine targeting only the Omicron variant.

More than 300 distinct antibodies neutralized the original SARS-CoV-2 strain or one or more variants, as determined by the investigators' analysis of blood samples submitted by these eight participants four months following the booster vaccination. This booster vaccine appears to have successfully induced the generation of new antibodies particularly against Omicron, as six of these antibodies were able to neutralize Omicron but not the initial SARS-CoV-2 strain. One of the new antibodies was able to neutralize BA.5, a widely-circulating subvariant of Omicron that was not present when this booster was created.

This booster vaccine activates the naive B cells and generates new memory cells, which means it expands people's immune repertoire, allowing them to respond to more variants," Ellebedy said. "Designing boosters to maintain immunity against these evolving viruses is not easy. The degree of variation between old and new variants is obviously important. However, if we choose carefully which variants to include in a booster vaccine, I think we can get ahead of these viruses."


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