Immunity boost from fourth COVID jab may exceed third dose effect, new data suggest

Findings from a recent study suggest that a fourth dose of COVID-19 vaccine can boost immunity to equal or greater levels than those seen 28 days after a third dose.

Close up image of an old man's arm being injected with a vaccine by a healthcare professional wearing a latex glove
Both the Pfizer-BioNTech vaccine and the Moderna vaccine may be employed as a fourth dose booster. | GETTY IMAGES

The COV-BOOST trial was designed to assess the efficacy of third-dose booster vaccines for COVID-19. In this extension study researchers aimed to assess the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19 administered approximately seven months following a third dose of BNT162b2 (Pfizer-BioNTech [Cominarty]).

Study participants were randomised to receive Cominarty (30 microgram/0.3ml; n=83) or the mRNA-1273 vaccine (Moderna [Spikevax] 50 microgram/0.25ml; n=83) as a fourth dose. Of the 166 participants, 88 had received two doses of the ChAdOx1 nCoV-19 vaccine (AstraZeneca [Vaxzevria]) plus a third dose of Cominarty, while the remaining 78 had received three doses of Cominarty.

Immunogenicity was compared at 28 days after the third dose versus 14 days after the fourth dose and at days 0 and 14 relative to the fourth dose. 

Significant boost in immunity

The geometric mean anti-spike protein IgG concentration increased from 23,325 ELISA laboratory units (ELU)/ml 28 days after a third dose to 37,460 ELU/ml at day 14 after a fourth dose of Cominarty, representing a significant fold change (geometric mean 1.59; 95% CI 1.41-1.78).

Similarly, there was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after a third dose to 14 days after a fourth dose of Spikevax (25,317 ELU/ml versus 54,936 ELU/ml with a geometric fold change of 2.19 [CI 1.90-2.52]).

The fold change in geometric mean anti-spike protein IgG concentration from day 0 to day 14 after the fourth dose was 12.19 (CI 10.37-14.32) for Cominarty and 15.90 (12.92-19.58) for Spikevax. The increase in immunogenicity between the two timepoints was observed regardless of initial vaccine schedule.

In addition, among participants with cellular response data available, similar T-cell responses were observed 14 days following the fourth dose compared with day 28 after the third dose.

Possible ceiling effect

The researchers report that some participants maintained high levels of humoral and cellular responses even before the fourth dose and had limited boosting from this dose, a finding that was replicated in participants with a history of SARS-CoV-2 infection.

The researchers state that this finding is important for policy makers as the benefit of a fourth dose may be less in people who already have high levels of immune responses from recent infection or vaccination. They add that this ceiling effect could be dependent on vaccine type and dose.

The fourth dose was well tolerated with fatigue, headache, malaise and muscle ache the most commonly reported systemic adverse effects.

So far, a fourth dose booster has been offered to those people in the UK population considered most vulnerable. Eligibility for this fourth dose may be widened later in the year.

Commenting on the study findings, Professor Saul Faust, trial lead and Director of the NIHR Southampton Clinical Research Facility, said: "These results underline the benefits of the most vulnerable people receiving current spring boosters and gives confidence for any prospective autumn booster programme in the UK, if the Joint Committee on Vaccination and Immunisation considers it needed at that time."

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