A fourth dose of a COVID-19 vaccine restores antibodies to levels observed after the third dose but provides only a modest boost in protection against infection, according to a small trial carried out in Israel1.
The study, posted on the medRxiv preprint server on 15 February without peer review, suggests that current mRNA vaccines hit a “ceiling of immunity” after the third dose, says Miles Davenport, a computational immunologist at the University of New South Wales in Sydney, Australia. Further doses will probably only recover the immunity lost over time owing to waning, he says.
“The third dose is really, really important,” says Gili Regev-Yochay, a physician and infectious-diseases researcher at Sheba Medical Center in Ramat Gan, who co-authored the study. But “people who are young and healthy and don’t have risk factors will probably not benefit much from a fourth dose” when faced with Omicron, she says.
Still, she and others say the fourth dose could be beneficial for people at higher risk of severe illness. Several countries, including Israel, Chile and Sweden, are offering fourth doses to older adults and other groups.
Starting in late 2021, Regev-Yochay and her colleagues enrolled 274 health-care workers in a clinical trial, in which they were given their fourth shot of an mRNA vaccine at least four months after their third. Some received the vaccine made by New York-based Pfizer with BioNTech in Mainz, Germany; others received that made by Moderna, based in Cambridge, Massachusetts.
Regardless of the vaccine brand, the fourth dose raised participants’ levels of ‘neutralizing’ antibodies, which can block viral infection of cells. But levels after the fourth dose did not surpass those observed shortly after the third dose, suggesting that the vaccines had hit an upper limit. “You can’t keep boosting antibody responses forever,” says Davenport.
The researchers also assessed the neutralizing antibodies from 25 participants for the antibodies’ power against several SARS-CoV-2 variants. They found that, after the third vaccine dose, participants’ antibodies could block Omicron from infecting cells — but not as well as they blocked the Delta variant. After the fourth dose, the antibodies’ potency against Omicron rose but also not more than their potency against Delta.
Those antibody data might explain why the fourth dose did not translate into substantial extra protection against infection with Omicron. A four-dose course of the Pfizer vaccine was 30% more protective against infection than a three-dose course; for Moderna, that extra efficacy was 11%.
That meant that, by the end of January, 52 participants who had received a fourth dose had tested positive for SARS-CoV-2 and 73 of the matched controls who had received only three doses had done so. Most of the infections were mild, and none of the participants in either the control group or the four-dose group developed severe COVID-19.
The relatively small increase in efficacy between the third and fourth doses is probably because protection offered by three doses is “already quite high”, says Davenport. Both vaccines offered slightly more protection against symptomatic disease than against infection.
Ran Balicer, a public-health physician at the Clalit Health Institute in Tel Aviv, notes that the trial’s efficacy estimates are based on a small sample size and have wide margins of uncertainty. Other observational studies2 from Israel have shown higher levels of protection against infection and severe disease. “This additional protection could make a large difference for high-risk groups during a surge,” says Balicer.
Ultimately, the study points to the need for new vaccines that can prevent infection with emerging variants, researchers say. The findings also highlight the importance of clarifying the optimal number of doses and time between doses for existing vaccines, says Gagandeep Kang, a virologist at the Christian Medical College in Vellore, India. “I don’t think chasing an ever-increasing number of doses is going to be the solution for Omicron or future variants.”