Authors: Jacqueline Howard, CNN June 23, 2022

Omicron subvariants BA.4 and BA.5 appear to escape antibody responses among both people who had previous Covid-19 infection and those who have been fully vaccinated and boosted, according to new data from researchers at Beth Israel Deaconess Medical Center, of Harvard Medical School.

However, Covid-19 vaccination is still expected to provide substantial protection against severe disease, and vaccine makers are working on updated shots that might elicit a stronger immune response against the variants.

The levels of neutralizing antibodies that a previous infection or vaccinations elicit are several times lower against the BA.4 and BA.5 subvariants compared with the original coronavirus, according to the new research published in the New England Journal of Medicine on Wednesday.

“We observed 3-fold reductions of neutralizing antibody titers induced by vaccination and infection against BA4 and BA5 compared with BA1 and BA2, which are already substantially lower than the original COVID-19 variants,” Dr. Dan Barouch, an author of the paper and director of the Center for Virology and Vaccine Research at Beth Israel Deaconess Medical Center in Boston, wrote in an email to CNN.

“Our data suggest that these new Omicron subvariants will likely be able to lead to surges of infections in populations with high levels of vaccine immunity as well as natural BA1 and BA2 immunity,” Barouch wrote. “However, it is likely that vaccine immunity will still provide substantial protection against severe disease with BA4 and BA5.”

The newly published findings echo separate research by scientists at Columbia University.

They recently found that the BA.4 and BA.5 viruses were more likely to escape antibodies from the blood of fully vaccinated and boosted adults compared with other Omicron subvariants, raising the risk of vaccine-breakthrough Covid-19 infections.

The authors of that separate study say their results point to a higher risk for reinfection, even in people who have some prior immunity against the virus. The US Centers for Disease Control and Prevention estimates 94.7% of the US population ages 16 and older have antibodies against the coronavirus that causes Covid-19 through vaccination, infection, or both.

BA.4 and BA.5 caused an estimated 35% of new Covid-19 infections in the United States last week, up from 29% the week before, according to data shared by the US Centers for Disease Control and Prevention on Tuesday.

BA.4 and BA.5 are the fastest spreading variants reported to date, and they are expected to dominate Covid-19 transmission in the United States, United Kingdom and the rest of Europe within the next few weeks, according to the European Centre for Disease Prevention and Control.

‘COVID-19 still has the capacity to mutate further’

In the New England Journal of Medicine paper, among 27 research participants who had been vaccinated and boosted with the Pfizer/BioNTech coronavirus vaccine, the researchers found that two weeks after the booster dose, levels of neutralizing antibodies against Omicron subvariants were much lower than the response against the original coronavirus.

The neutralizing antibody levels were lower by a factor of 6.4 against BA.1; by a factor of 7 against BA.2; by a factor of 14.1 against BA.2.12.1 and by a factor of 21 against BA.4 or BA.5, the researchers described.

Among 27 participants who had previously been infected with the BA.1 or BA.2 subvariants a median of 29 days earlier, the researchers found similar results.

In those with previous infection – most of whom also had been vaccinated – the researchers described neutralizing antibody levels that were lower by a factor of 6.4 against BA.1; by a factor of 5.8 against BA.2; by a factor of 9.6 against BA.2.12.1 and by a factor of 18.7 against BA.4 or BA.5.

More research is needed to determine what exactly the neutralizing antibody levels mean for vaccine effectiveness and whether similar findings would emerge among a larger group of participants.

“Our data suggest that COVID-19 still has the capacity to mutate further, resulting in increased transmissibility and increased antibody escape,” Barouch wrote in the email. “As pandemic restrictions are lifted, it is important that we remain vigilant and keep studying new variants and subvariants as they emerge.”

A separate study, published in the journal Nature last week, found that Omicron may evolve mutations to evade the immunity elicited by having a previous BA.1 infection, which suggests that vaccine boosters based on BA.1 may not achieve broad-spectrum protection against new Omicron subvariants like BA.4 and BA.5.

As for what all this means in the real world, Dr. Wesley Long, an experimental pathologist at Houston Methodist Hospital, told CNN that people should be aware that they could get sick again, even if they’ve had Covid-19 before.

“I think I’m a little bit worried about people who’ve had it maybe recently having a false sense of security with BA.4 and BA.5 on the increase, because we have seen some cases of reinfection and I have seen some cases of reinfection with people who had a BA.2 variant in the last few months,” he said.

Some vaccine makers have been developing variant-specific vaccines to improve the antibody responses against coronavirus variants and subvariants of concern.

“Reinfections are going to be pretty inevitable until we have vaccines or widespread mandates that are going to prevent cases rising again. But the good news is that we are in, I think, a much better spot than we were without the vaccines,” said Pavitra Roychoudhury, an acting instructor at the University of Washington’s Department of Laboratory Medicine and Pathology, who was not involved in the New England Journal of Medicine paper.

“There’s so much of this virus out there that it seems inevitable,” she said about Covid-19 infections. “Hopefully the protections that we have in place are going to lead to mostly mild infection.”

Efforts underway to update Covid-19 vaccines

Moderna’s bivalent Covid-19 vaccine booster, named mRNA-1273.214, elicited a “potent” immune responses against the Omicron subvariants BA.4 and BA.5, the company said Wednesday.

This bivalent booster vaccine candidate contains components of both Moderna’s original Covid-19 vaccine and a vaccine that targets the Omicron variant. The company said it is working to complete regulatory submissions in the coming weeks requesting to update the composition of its booster vaccine to be mRNA-1273.214.

“In the face of SARS-CoV-2’s continued evolution, we are very encouraged that mRNA-1273.214, our lead booster candidate for the fall, has shown high neutralizing titers against the BA.4 and BA.5 subvariants, which represent an emergent threat to global public health,” Stéphane Bancel, chief executive officer of Moderna, said in Wednesday’s announcement. SARS-CoV-2 is the coronavirus that causes Covid-19.

“We will submit these data to regulators urgently and are preparing to supply our next generation bivalent booster starting in August, ahead of a potential rise in SARS-CoV-2 infections due to Omicron subvariants in the early fall,” Bancel said.

The US Food and Drug Administration’s Vaccines and Related Biological Products Advisory Committee is meeting next week to discuss the composition of Covid-19 vaccines that could be used as boosters this fall.

The data that Moderna released Wednesday, which has not been published in a peer-reviewed journal, showed that one month after a 50-microgram dose of the mRNA-1273.214 vaccine was administered in people who had been vaccinated and boosted, the vaccine elicited “potent” neutralizing antibody responses against BA.4 and BA.5, boosting levels 5.4-fold in all participants regardless of whether they had a prior Covid-19 infection and by 6.3-fold in the subset of those with no history of prior infection. These levels of neutralizing antibodies were about 3-fold lower than previously reported neutralizing levels against BA.1, Moderna said.

These findings add to the data that Moderna previously released earlier this month, showing that the 50-microgram dose of the bivalent booster generated a stronger antibody response against Omicron than the original Moderna vaccine.

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Moderna’s data suggest that “the bivalent booster might confer greater protection against the BA.4 and BA.5 omicron strains than readministering the original vaccine to increase protection across the population. Although the information is based on antibody levels, the companies comment that similar levels of antibody protected against clinical illness caused by other strains is the first suggestion of an emerging ‘immune correlate’ of protection, although it is hoped that this ongoing study is also assessing rates of clinical illness as well as antibody responses,” Penny Ward, an independent pharmaceutical physician and visiting professor in pharmaceutical medicine at King’s College London, said in a statement released by the UK-based Science Media Centre on Wednesday. She was not involved in Moderna’s work.

“It has been reported previously that the bivalent vaccine is well tolerated with temporary ‘reactogenic’ effects similar to those following the univalent booster injection so we can anticipate that this new mixed vaccine should be well tolerated,” Ward said in part. “As we head towards the autumn with omicron variants dominating the covid infection landscape, it certainly makes sense to consider use of this new bivalent vaccine, if available.”