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Omicron-targeting bivalent boosters likely conferred no extra protection against COVID-19 over the original mRNA products due to immune imprinting, according to vaccine expert Paul Offit, MD, of the Children's Hospital of Philadelphia.

And by the time 10% of the U.S. population had received one of the newly authorized boosters, which were designed to target the ancestral SARS-CoV-2 strain along with BA.4 and BA.5, newer more immune-evasive variants were already outpacing the BA.4/5 Omicron subvariants, Offit pointed out in a (NEJM) perspective piece.

Offit, who early last summer was one of just two members of FDA's Vaccines and Related Biological Products Advisory Committee (VRBPAC) to vote against the updated boosters, cited lab data from a pair of studies published simultaneously in the NEJM demonstrating that antibody responses against BA.4/5 on pseudovirus assays were not significantly greater with a bivalent booster when compared with an additional dose of an original mRNA vaccine.

So why did the strategy for increasing BA.4 and BA.5 neutralizing antibodies with a bivalent vaccine fail? "The most likely explanation is imprinting," said Offit.

"The immune systems of people immunized with the bivalent vaccine, all of whom had previously been vaccinated, were primed to respond to the ancestral strain of SARS-CoV-2," he explained. "They therefore probably responded to epitopes shared by BA.4 and BA.5 and the ancestral strain, rather than to new epitopes on BA.4 and BA.5."

In the , David Ho, MD, of Columbia University Vagelos College of Physicians and Surgeons in New York City, and colleagues, collected serum samples from 40 individuals who received three monovalent mRNA shots plus either a fourth dose (with either the bivalent or monovalent vaccine) and compared neutralizing-antibody levels against the ancestral strain and a host of Omicron subvariants. Across all strains, including BA.4/BA.5, Ho's group found that the bivalent boosters "did not elicit a discernibly superior virus-neutralizing peak antibody response as compared with boosting with the original monovalent vaccines."

Similarly, a involving 33 participants from Dan Barouch, MD, PhD, of Beth Israel Deaconess Medical Center in Boston, and colleagues reported on immunogenicity against BA.5 in 33 people, finding that "median BA.5 neutralizing antibody titer was similar after monovalent and bivalent mRNA boosting, with a modest trend favoring the bivalent booster by a factor of 1.3."

The two research groups also offered immune imprinting as a possible hurdle to success with variant-specific vaccines.

According to Barouch's group, "immune imprinting by previous antigenic exposure may pose a greater challenge than is currently appreciated for inducing robust immunity against SARS-CoV-2 variants."

Offit suggested that using BA.4/5 mRNA components alone, or with a greater quantity of BA.4/5-targeted mRNA, may have better elicited the intended goal. He cited on the companies' Omicron BA.1-containing vaccines (which VRBPAC rejected) that showed greater BA.1-specific neutralizing-antibody responses with monovalent BA.1 vaccines or with a higher-dose (60 μg) bivalent vaccines compared to a lower-dose (30 μg) bivalent shot.

"Fortunately," he said, "SARS-CoV-2 variants haven't evolved to resist the protection against severe disease offered by vaccination or previous infection. If that happens, we will need to create a variant-specific vaccine."

"Although boosting with a bivalent vaccine is likely to have a similar effect as boosting with a monovalent vaccine, booster dosing is probably best reserved for the people most likely to need protection against severe disease -- specifically, older adults, people with multiple coexisting conditions that put them at high risk for serious illness, and those who are immunocompromised," Offit argued. "In the meantime, I believe we should stop trying to prevent all symptomatic infections in healthy, young people by boosting them with vaccines containing mRNA from strains that might disappear a few months later.

Infectious disease specialist and epidemiologist Celine Gounder, MD, ScM, a senior fellow at the Kaiser Family Foundation, told 麻豆传媒 that "there may be value in giving a booster to certain populations at certain times of year, or in certain settings to reduce the risk of infection and transmission.

"While COVID vaccination doesn't prevent infection and transmission 100%, even a 20% reduction in risk can be profound in the right population, at the right time, and in the right place," Gounder said.

According to the science presented in these studies, she added, two full-doses of an Omicron-specific monovalent vaccine would be much more effective than the single half-dose that's in the bivalent booster. "This might have been a good option for vulnerable populations in need of the strongest practically achievable protection."

Imprinting deserves greater attention, Gounder added. "Because the bivalent boosters are a 50-50 blend of the ancestral and BA.4/5 vaccines," she said, "only a half-dose of Omicron-specific vaccine is being administered."

"These points are why we and colleagues have argued that the updated boosters may be at best minimally better at eliciting neutralizing antibodies against BA.4/5 compared to the original vaccines," said Gounder.