Fourth doses of mRNA COVID-19 vaccines are effective and well tolerated but responses may be muted in people who have maintained robust immunity from earlier vaccination or COVID-19 disease, research shows.

According to the latest data from the UK COV-BOOST trial, a fourth COVID vaccine dose substantially boosted both cellular and humoral immunity when given more than six months after the first dose, with peak responses found to be similar to, and in some cases stronger than, those observed after a third dose.

However, the study investigators said noted that in some people who maintained high antibody and cellular responses before the fourth dose, including those with a history of COVID, the boosting effect of the fourth dose was limited.

“This suggests that there may be ceiling or maximum antibody level and T-cell response effects and that the fourth dose might not boost antibodies and cellular responses if the baseline level is high” said Professor Saul Faust, trial lead and Director of the NIHR Southampton Clinical Research Facility.

“If the ceiling effect is replicated in other datasets, it may be due to host immunity, the vaccine or the vaccine dose, which needs to be explored in further trials and analyses,” he added.

For the study, 166 participants were randomly assigned to receive either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose, administered around 7 months after a third dose.

Results, published in Lancet Infectious Diseases, showed a significant mean change in geometric mean anti-spike protein IgG concentration flowing a fourth dose of Pfizer’s BNT162b2, which rose from 23,325 ELU/mL after the third dose to 37,460 ELU/mL 14 days after the fourth dose. There was a significant increase after a fourth dose of Moderna, for which the respective figures were 25,317 ELU/mL to 54,936 ELU/mL.

Also, the fold changes in anti-spike protein IgG titres from before to after the fourth dose were 12.19 in the Pfizer group and 15.9 in the Moderna group, while T cell responses were also boosted after the fourth dose, the researchers noted.

Regulators are now assessing data from the study to inform future vaccination policy, Prof Faust said.

“The key data is going to be the reinfection, hospitalisations and death rates in people who have received either two or three doses, and that is a UK HPA data set that is being well maintained and reported separately by UKHSA to JCVI,” he noted.