Updated COVID-19 vaccines boost protection, but may not beat original formula against BA.4 and BA.5, early studies suggest

By Brenda Goodman, CNN

The updated COVID-19 booster shots appear to work about as well against the BA.4 and BA.5 Omicron subvariants as the original boosters they replaced, according to two new studies from research teams at Harvard and Columbia universities.

The research suggests that our bodies have been well-trained to fight the original virus, which emerged from Wuhan, China, and that boosters mostly reinforce that response. Getting boosted this fall is still an important way to renew protection, even among people who were previously infected or vaccinated.

But the hope was that by tweaking the vaccine recipe to include currently circulating strains of the Omicron variant, it would help broaden immunity against those variants and perhaps offer better and longer-lasting protection.

When the researchers compared the immune responses of people who got a booster dose of the original shot to people who got the updated bivalent boosters, they looked about the same.

“We see essentially no difference” between the old boosters and the new about a month after the shot, said Dr. David Ho, professor of microbiology and immunology at Columbia, whose team authored one of the studies.

Immunologists say a vaccine against two strains may not be better than a single strain shot because of a phenomenon called immune imprinting. Scientists say imprinting may complicate efforts to stay ahead of new variants as the coronavirus continues to evolve, and it adds urgency to the development of new vaccine technologies to fight the virus.

When the US Food and Drug Administration issued emergency use authorizations for new bivalent COVID-19 vaccines from Pfizer and Moderna at the end of August, it did so on the basis of studies in mice and previous human trials with a different two-strain booster formulation. Little was known about the how protective the shots might be in people; full data from clinical trials testing the BA.4 and BA.5 bivalent vaccines in humans hasn’t yet been made public.

But modeling data suggested that getting the boosters out in September could save tens of thousands of lives if the country had another winter surge, so the FDA authorized the shots, ahead of results from clinical trials, in order to get them to the public more quickly.

The updated shots contain instructions that show cells how to make spike proteins from the original virus that caused COVID-19, as well as spikes from the BA.4 and BA.5 subvariants. These spikes get assembled by our cells and displayed to our immune system so it can make antibodies to fight the real thing during an active infection.

The original strain of the virus, sometimes called the ancestral or wild-type strain, is no longer circulating, however. When we boost, we are mostly boosting antibodies against a virus that’s long gone.

As the virus has evolved, the vaccines have not kept pace. Each new variant has become more and more resistant to the antibodies we make against it, increasing the risk of breakthrough infections, hospitalizations and deaths.

Right now, protection against infection begins to wane just a few months after each booster dose. Protection against severe outcomes — hospitalization or death from COVID-19 — lasts longer, but can also fade, especially for vulnerable groups such as people who are over 65, who have weakened immune systems or who have underlying medical conditions.

Similar immune responses

The studies have important limitations, and they aren’t the final word on the updated boosters.

Both studies were small. Ho’s study looked at the immune responses of 19 people who were boosted with a fourth dose of the original recipe vaccine and 21 people who got a fourth dose of the updated boosters. The other study, from Dr. Dan Barouch, a professor at Harvard and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center, looked at 15 people who got the original booster and 18 people who got bivalent shots.

Both reports were posted as preprints, before scrutiny by independent experts.

The studies also measured immune responses over a short period of time — about three to five weeks after the fourth doses. Ho says these results could change with time, as immune cells mature.

“We can’t say that a few months from now, there won’t be any difference,” he said. “We won’t know that until these individuals are followed for a longer period of time.”

Despite these caveats, experts who were not involved in the research say that two studies from well-regarded labs arriving at roughly the same conclusions about the vaccines gives them confidence that the results are correct.

“At least at this time point, there’s no discernible benefit” over the older boosters, Ho said.

Clinical trials being conducted by vaccine makers Pfizer and Moderna involve hundreds of people who have had the updated boosters and are being followed for longer periods of time. Data from those studies are still coming.

Both companies declined to comment on Ho and Barouch’s studies, citing company policies not to weigh in on research they have not been involved in.

In comparing the immune responses of people who got the old boosters with those who got the newer ones, the researchers found that neutralizing antibodies spiked after both shots to about the same high levels, which was good news.

In Barouch’s study, antibody concentrations were 15 times higher after the original boosters, rising from 184 to 2,829. They were 17 times higher after the updated shots, jumping from 211 to 3,693. The difference in antibody levels between shots didn’t pass a statistical test, however, so the results may have been due to chance.

More importantly, that slight difference in antibody levels probably wouldn’t protect people any better in the real world.

“We would not expect this to be clinically significant,” said Barouch, who worked on the development of the Johnson & Johnson COVID-19 vaccine.

But the bulk of the antibodies generated after either shot were ones that would bind the original virus, with fewer directed specifically against the BA.4 and BA.5 subvariants.

Barouch’s team also looked specifically at T cells, which help the body hold the memory of germs it has been exposed to. These cells are thought to play a key role in how long immune protection lasts. Antibody levels naturally drop off over time, but T cells stick around.

The numbers of T cells didn’t budge much after either vaccine.

“Unfortunately, neither one increased T-cell responses very much, and we believe that T-cell responses in addition to antibody responses are important for protection against severe disease,” Barouch said.

‘A booster is a booster’

Dr. Eric Topol, who directs the Scripps Research Translational Institute, said the study results “can be considered a disappointment,” especially because the US government raced to make them available and because there had been high hopes for an improved vaccine in time for a predicted winter COVID-19 surge.

Topol also said it would be a mistake to skip these shots. They still work; they just may not be much of an improvement over the older ones.

“A booster is a booster until proven otherwise and we are in great need of getting more of them in the US,” Topol, who was not involved in the new studies, wrote in an email to CNN.

Fewer than 20 million people — less than 10% of the population ages 5 and up — have gotten the updated booster, according to data from the US Centers for Disease Control and Prevention.

After waiting the recommended three months since his last COVID-19 infection, President Joe Biden got an updated booster Tuesday and urged eligible Americans to do the same.

“Your old vaccine or your previous COVID infection will not give you maximum protection,” Biden said.

Public health officials had hoped that the rollout of the updated boosters would mark a turning point, where Americans might be able to get annual COVID-19 shots instead of boosters every few months.

Dr. Peter Marks, director of the FDA’s Center for Biologics Evaluation and Research, recently told Stat that he wasn’t sure whether the country had reached that point.

“I would be lying to you if [I said] it doesn’t keep me up at night worrying that there is a certain chance that we may have to deploy another booster — at least for a portion of the population, perhaps older individuals — before next September, October,” he said.

“I’m not saying that’s what’s going to happen, but it’s what keeps me up at night, because we see how fast this virus is evolving.”

Imprinting may complicate quest for better immunity

The studies probably didn’t find any difference between the new and old boosters because of immune imprinting, says Michael Worobey, a professor at the University of Arizona who studies the evolution of viruses and the origins and control of pandemics.

“Your body is on a hair trigger to create more antibodies of what it has a good memory of,” said Worobey, who was not involved in the new research.

At the beginning of the pandemic, our immune systems were blank slates when it came to the coronavirus. By now, most of us have been exposed to one version of the virus or another through the vaccine, an infection or both. That exposure programs cells called B cells to make specific kinds of antibodies, and more B cells get this programming during their first exposure to the virus than they do in subsequent brushes with it.

That’s the reason some strains of the flu may hit certain age groups harder than others, too. When viruses look more similar to the first infection or vaccine you had, your body tends to do a better job fighting them off.

Worobey said that both new studies have limitations, “but I think when you put them together, they paint a pretty clear picture that that antigenic imprinting is causing issues here, for sure.”

It’s possible to break through immune imprinting, he said. Certain kinds of vaccine ingredients, or adjuvants — “things that just happen to really wake up the immune system” — can do it.

But it’s not easy to add the kind of adjuvants he’s thinking about to mRNA vaccines like Pfizer and Moderna’s. In this case, he says, judging by the study findings, it probably would have been better to update the vaccine by including only the components against BA.4 and BA.5.

“For me, the take-home message is, if you want to boost and provide protection against Omicron, leave the original variant out of the vaccine.”

Dr. Paul Offit, director of the Vaccine Education Center at the Children’s Hospital of Philadelphia and a member of the FDA’s vaccine advisory committee, says the new studies bear out data that was presented to the FDA’s advisers in June.

He says it’s one of the reasons he voted against the FDA requiring companies to add an Omicron strain to the boosters used in the US.

“Certainly, the hope that this would be significantly better in terms of protection against the circulating strains, I think, is unlikely to be realized,” said Offit, who was not involved in the new studies.

Worobey says that when the strains are combined as they are in the updated boosters, they actually end up competing. The body’s response to the original strain is so strong, it will end up blocking the updated portion of the vaccine from stimulating those blank slate B cells against the newer variants and reshaping the immune response.

Thus, imprinting will complicate efforts to keep up with the virus, he says. We may need different kinds of vaccine technologies if the virus ever changes so much that it outcompetes our immunity altogether.

That’s something the FDA’s Marks has considered, too.

“I would love to see us have a very ecumenical look over all of the available vaccines and all of the vaccines in development to try to see what’s best moving forward,” he told Stat. “Not to diss the current mRNA vaccines but because we owe it to the population to see what might provide the greatest breadth, depth and duration of immunity against COVID-19.”

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CNN’s Jamie Gumbrecht and Jacqueline Howard contributed to this report.