Boosting Power of COVID mRNA Vaccines Hits Ceiling With Third Shot

(Reuters Health) – Studies of third and fourth doses of mRNA COVID vaccines suggest further boosting can maintain protection against severe disease, but the vaccines may never again offer the high efficacy against infection seen in clinical trials.

Studies in Europe and Israel found that third and fourth doses of mRNA vaccines boost overall antibody numbers to roughly the same levels. And while that increase includes antibodies capable of neutralizing new variants, there are too few to block infections or reduce viral loads as effectively as when the vaccines first rolled out, U.S. researchers note in another study.

Based on the composition of antibody-generating cells present after a third shot, the U.S. team suggests in a preprint posted on the bioRxiv website that there’s a limit on the extent to which antibody numbers and breadth can be increased. However, the “high quality” of the antibodies after a third dose should help stave off severe illness – including with variant viruses – and a fourth shot could replenish that, said study coauthor Theodora Hatziioannou, a research associate professor at Rockefeller University in New York City.

“It depends what your goal is, if your goal is to prevent severe disease, I think we’re there with three doses, but the memory component should stay,” Hatziioannou, a virologist, said in a phone interview. The antibody-generating memory B cells can respond within three to five days in a new infection, and “they’re really potent and broad.” But if the “really high level” of neutralization seen against the original version of the virus is what’s required, she said, “forget about it.”

The data also suggest that three doses are the minimum needed to get the vaccines’ full benefits, especially for those who have never been infected, said Dr. Rafael Delgado, of Hospital Universitario 12 de Octubre, in Madrid, Spain, senior author of one of the new studies, published ahead of peer review the medRxiv website.

The third shot is particularly important to get the benefit of further evolution of the antibody repertoire via B-cell affinity maturation, Dr. Delgado said in a phone interview. “Especially for Omicron, looking at the neutralizing results against Omicron, I think this idea to develop a potent and broad response in terms of covering variants, the third shot is really important. If you look at the results with Omicron, it’s very clear there is a huge difference.”

A fourth dose or an infection in a thrice-vaccinated person will also presumably contribute, Hatziioannou said, “but the effect is not going to be as impressive as with the third dose.”

With the U.S. Food and Drug Administration having approved a fourth dose of the Pfizer-BioNTech and Moderna mRNA vaccines for certain groups on Tuesday, and other governments moving ahead with fourth shots, researchers think it is certainly worthwhile for the elderly and other vulnerable populations to get the additional boost.

But high rates of breakthrough infection with high viral loads led Dr. Gili Regev-Yochay of Sheba Medical Center, in Tel Hashomer, Israel, and colleagues to conclude in The New England Journal of Medicine that “a fourth vaccination of healthy young health care workers may have only marginal benefits.”

The Israeli researchers studied immune responses and infections among 274 healthcare workers who received a booster dose of the Pfizer or Moderna vaccines at least four months after their third shot of the Pfizer vaccine and 426 age-matched controls who had received only three shots. In all participants, circulating antibodies had waned 7-9-fold from their peak following the third dose. After the fourth shot, titers of IgG antibodies against the virus’ receptor binding domain (RBD), and neutralizing antibodies, “were slightly higher than those achieved after the third dose, with no significant difference between the two vaccines,” the team reports.

Yet, 18.3% and 20.7% of the Pfizer and Moderna fourth-shot recipients, respectively, had Omicron breakthrough infections, compared with 25% of control subjects. Symptoms in all cases were mild, but most infected participants were potentially infectious, with relatively high viral loads.

“Our results suggest that maximal immunogenicity of mRNA vaccines is achieved after three doses and that antibody levels can be restored by a fourth dose,” the study team writes. Dr. Regev-Yochay did not respond to a request for comments.

In German healthcare workers, too, researchers saw only a small bump in neutralizing antibodies following a fourth mRNA vaccine dose and several breakthrough infections. “Neutralization of Omicron BA.1 and BA.2 was limited even after the 2nd booster vaccination indicating that an antibody-mediated protection against infection with this VOC is unlikely,” Katharina Grikscheit of the Institute for Medical Virology/University Hospital Frankfurt and colleagues write in a preprint on the Nature Portfolio In Review website.

Dr. Delgado’s team in Spain also saw responses to booster shots reach a ceiling when they compared 21 COVID-naïve and 21 previously-infected healthcare workers who had received the two-dose Pfizer vaccine in early 2021 and the 50-ug Moderna booster dose in December 2021.

In keeping with past research, previously-infected participants showed significantly higher antibody levels and neutralizing breadth after their second shot than the COVID-naïve subjects. Given that a third vaccine dose is really a fourth exposure in the previously-infected, researchers had expected their advantage over the COVID-naïve to persist with the booster, Delgado said. Instead, responses were largely the same in the two groups.

The third dose boosted Omicron-neutralizing antibody titers in the COVID-naïve to the level seen after the second shot in the previously-infected, and restored that level in the previously-infected. The same pattern held for other variants tested, including Alpha, Beta, Delta and Gamma. The only significant difference was in neutralizing antibodies against the SARS-CoV-1 virus: the previously-infected had double the titers seen in the COVID-naïve.

The additional neutralizing potency against SARS-CoV-1 shows there might still be a little room for improvement in people previously infected and vaccinated. “We think that the affinity maturation in the individuals infected with the real virus is more complete, the affinity maturation with vaccination is good, but with hybrid immunity it is superior, and one demonstration is those antibodies showing the capability to neutralize SARS-CoV-1.”

Affinity maturation may be the main reason vaccines based on the original Wuhan-hu-1 version of SARS-CoV-2 boost antibodies that neutralize newer variants at all, Hatziioannou said. When her group analyzed memory B cells present after a third mRNA vaccine dose, they found that 47% showed indicators of having undergone affinity maturation, as compared with just 33% of the cells present after the original two-dose vaccine series.

Memory B cells lacking the signs of affinity maturation also contributed to neutralization of variants, including Omicron, primarily by targeting conserved portions of the RBD, the researchers note.

Altogether, “more than 50% of the analyzed neutralizing antibodies in the memory compartment obtained from individuals receiving a 3rd mRNA vaccine dose neutralized Omicron,” the study team reports. Still, their prior work has shown that Omicron-neutralizing antibody titers “remain 10-20-fold lower than against Wuhan-Hu-1” and are often “insufficient to prevent infection,” they write.

“We won’t be able to prevent infection with this virus,” Hatziioannou said. “The evidence points towards the fact that we just don’t maintain the circulating levels of antibodies to stop infection.”

Hatziioannou nonetheless remains “more optimistic than pessimistic” about the prospect of further – even annual – booster shots against COVID-19. “What gave me hope is the data with the third dose,” she explained. “The antibodies are so much better. This is great, it means you can achieve immunity without having to experience an infection.”

SOURCES: NEJM, online March 16, 2022; In Review – Nature Portfolio, online March 30, 2022;, online March 20, 2022;, online February 15, 2022.

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