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4th jab can give higher immunity than initial booster – Cov-Boost trial

A fourth dose of a COVIF vaccine can ramp up the body’s immune defences beyond the peak achieved after a third dose, research suggests.

A second booster – often a fourth dose of a COVID vaccine – is currently offered in the UK to those aged 75 or over, people living in care homes for older people, and those older than 12 who are immunosuppressed.

Now researchers say they have found a fourth dose can rescue immune responses that have waned since a third jab, reports The Guardian.

“A fourth dose can produce a substantial boost to both the antibody and cellular immunity when you give them more than six months after the third dose,” said Prof Saul Faust, who led the trial and is director of the NIHR Southampton clinical research facility.

Writing in The Lancet Infectious Diseases, researchers involved in the UK-based Cov-Boost trial report how they measured immune responses in 166 participants who received a fourth COVID jab on average seven months after having had a Pfizer/BioNTech jab as their third dose. All participants had initially had either two doses of the Pfizer/BioNTech jab or two doses of the Oxford/AstraZeneca vaccine.

Half were randomly allocated to receive a full dose of the Pfizer/BioNTech COVID jab as their fourth vaccination, while the others were given half a dose of the Moderna jab. No serious adverse events were linked to the vaccines.

The team analysed data from 133 participants, finding that 14 days after receiving the fourth jab, there was a 1.6-fold increase in antibodies among those who received the Pfizer/BioNTech vaccine, and a more than twofold increase among those who received the half-dose Moderna jab, compared with 28 days after the third dose, when antibody levels were still at their peak. Increases were seen for those over and below 70 years of age.

In addition, levels of antibodies and T-cells increased substantially between the day before the fourth vaccination and 14 days after for both types of fourth jab.

“Our results for immunogenicity are also consistent with the little observational evidence on vaccine effectiveness available from Israel, which indicates increased protection against symptomatic infection and severe illness from a fourth-dose booster,” the team write.

Faust added that those who had little waning of their immune responses before their fourth dose gained only a limited increase in their immune responses as a result of the booster – with similar findings for others who had a recent history of a COVID infection.

“That indicates there may be a ceiling, a maximum antibody level with the T-cell response effects,” he said. Faust said it was up to the UK’s Joint Committee on Vaccination and Immunisation to decide whether a second booster should be offered more widely.

Some experts have suggested in the current circumstances those yet to reach middle age might never be offered another COVID jab.

But Prof Danny Altmann, an immunologist at Imperial College London, said Omicron still posed a serious threat, adding that the new study demonstrated the added value of a fourth dose.

“Just because our first-generation vaccines wane rapidly and offer rather permeable protection nowadays, does not suggest we should give up and have no further boosters,” he said.

“On the contrary, [given] many of us, even with high apparent antibody levels, actually show [very little] protective neutralisation of Omicron, there is all the more urgency to use [fourth] doses – in all age groups – to boost levels back up into the protective range.”

Study details

Safety, immunogenicity, and reactogenicity of BNT162b2 and mRNA-1273 COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial

Alasdair Munro, Shuo Feng, Leila Janani, Victoria Cornelius, Parvinder K Aley, Gavin Babbage, et al.

Published in The Lancet on 9 May 2022


Some high-income countries have deployed fourth doses of COVID-19 vaccines, but the clinical need, effectiveness, timing, and dose of a fourth dose remain uncertain. We aimed to investigate the safety, reactogenicity, and immunogenicity of fourth-dose boosters against COVID-19.

The COV-BOOST trial is a multicentre, blinded, phase 2, randomised controlled trial of seven COVID-19 vaccines given as third-dose boosters at 18 sites in the UK. This sub-study enrolled participants who had received BNT162b2 (Pfizer-BioNTech) as their third dose in COV-BOOST and randomly assigned them (1:1) to receive a fourth dose of either BNT162b2 (30 μg in 0·30 mL; full dose) or mRNA-1273 (Moderna; 50 μg in 0·25 mL; half dose) via intramuscular injection into the upper arm. The computer-generated randomisation list was created by the study statisticians with random block sizes of two or four. Participants and all study staff not delivering the vaccines were masked to treatment allocation. The coprimary outcomes were safety and reactogenicity, and immunogenicity (anti-spike protein IgG titres by ELISA and cellular immune response by ELISpot). We compared immunogenicity at 28 days after the third dose versus 14 days after the fourth dose and at day 0 versus day 14 relative to the fourth dose. Safety and reactogenicity were assessed in the per-protocol population, which comprised all participants who received a fourth-dose booster regardless of their SARS-CoV-2 serostatus. Immunogenicity was primarily analysed in a modified intention-to-treat population comprising seronegative participants who had received a fourth-dose booster and had available endpoint data. This trial is registered with ISRCTN, 73765130, and is ongoing.

Between Jan 11 and Jan 25, 2022, 166 participants were screened, randomly assigned, and received either full-dose BNT162b2 (n=83) or half-dose mRNA-1273 (n=83) as a fourth dose. The median age of these participants was 70·1 years (IQR 51·6–77·5) and 86 (52%) of 166 participants were female and 80 (48%) were male. The median interval between the third and fourth doses was 208·5 days (IQR 203·3–214·8). Pain was the most common local solicited adverse event and fatigue was the most common systemic solicited adverse event after BNT162b2 or mRNA-1273 booster doses. None of three serious adverse events reported after a fourth dose with BNT162b2 were related to the study vaccine. In the BNT162b2 group, geometric mean anti-spike protein IgG concentration at day 28 after the third dose was 23 325 ELISA laboratory units (ELU)/mL (95% CI 20 030–27 162), which increased to 37 460 ELU/mL (31 996–43 857) at day 14 after the fourth dose, representing a significant fold change (geometric mean 1·59, 95% CI 1·41–1·78). There was a significant increase in geometric mean anti-spike protein IgG concentration from 28 days after the third dose (25 317 ELU/mL, 95% CI 20 996–30 528) to 14 days after a fourth dose of mRNA-1273 (54 936 ELU/mL, 46 826–64 452), with a geometric mean fold change of 2·19 (1·90–2·52). The fold changes in anti-spike protein IgG titres from before (day 0) to after (day 14) the fourth dose were 12·19 (95% CI 10·37–14·32) and 15·90 (12·92–19·58) in the BNT162b2 and mRNA-1273 groups, respectively. T-cell responses were also boosted after the fourth dose (eg, the fold changes for the wild-type variant from before to after the fourth dose were 7·32 [95% CI 3·24–16·54] in the BNT162b2 group and 6·22 [3·90–9·92] in the mRNA-1273 group).

Fourth-dose COVID-19 mRNA booster vaccines are well tolerated and boost cellular and humoral immunity. Peak responses after the fourth dose were similar to, and possibly better than, peak responses after the third dose.


The Guardian article – Fourth Covid jab can give higher immunity than initial booster, study finds (Open access)


The Lancet article – COVID-19 vaccines given as fourth-dose boosters following two doses of ChAdOx1 nCoV-19 or BNT162b2 and a third dose of BNT162b2 (COV-BOOST): a multicentre, blinded, phase 2, randomised trial (Open access)


See more from MedicalBrief archives:


Fourth COVID jab gives 76% added protection against death – Israeli study


Warning from WHO and EU regulator against repeat COVID boosters


WHO’s vaccine head on why the rush for COVID booster jabs is premature



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