A new study from the COV-BOOST trial has found that a fourth dose of a COVID-19 vaccine provides a substantial boost to both antibody and cellular immunity

Production line for COVID-19 vaccine vials

A fourth dose of a COVID-19 mRNA booster vaccine is well tolerated and boosts cellular and humoral immunity, according to a new study from the COV-BOOST trial.

The UK-wide study was led by Professor Saul Faust, COV-BOOST Chief Investigator and National Immunisation Schedule Evaluation Consortium Co-Investigator. Professor Faust is also Director of the National Institute for Health and Care Research (NIHR) Southampton Clinical Research Facility, and Professor of Paediatric Immunology and Infectious Diseases at the University of Southampton.

‘Fourth doses of COVID-19 vaccines provide a substantial boost to both antibody and cellular immunity when administered at least 6 months after a third dose booster’, said Professor Faust, adding: ‘Antibody levels after the fourth dose of full-dose Pfizer or half-dose Moderna vaccines were higher than the peak level following the third dose of the Pfizer vaccine.’

The Secretary of State for Health and Social Care, Sajid Javid, said: ‘This is further evidence underlining the importance of people coming forward for their booster as soon as they are eligible.

‘We’re able to live with COVID thanks to the protection provided by our phenomenal vaccine programme, and a booster dose will top up your immunity.’

The ongoing COV-BOOST trial provided the first data on the safety and immunogenicity of a third dose in mix-and-match schedules, and underpinned the autumn 2021 booster roll-out.

The latest study data, published in Lancet Infectious Diseases, reported on fourth-dose responses (safety, antibodies, and T cells) of full-dose Pfizer-BioNTech (BNT162b2) or half-dose Moderna (mRNA-1273) vaccines, compared with those of the third dose, in healthy adults.

Fourth doses of COVID-19 vaccines have only been offered as a spring booster for those most vulnerable in the UK. It is not yet known if or when the rest of the population will be offered a fourth dose of a COVID-19 vaccine. The Joint Committee on Vaccination and Immunisation (JCVI) will consider the data and make a decision in due course.

Professor Andrew Ustianowski, NIHR Clinical Lead for the COVID-19 Vaccination Programme and Joint National Infection Specialty Lead, said: ‘We knew that it was important to offer a fourth dose to those most vulnerable earlier in the year. These new study findings support that decision and provide the public with the confidence that fourth doses are both safe and even more effective than third doses at boosting immunity against COVID-19.’

Fourth dose either Pfizer or Moderna after third dose of Pfizer

A total of 166 COV-BOOST participants who had previously received the Pfizer-BioNTech vaccine as their third dose were randomised to receive a fourth dose of either Pfizer-BioNTech vaccine (30 µg in 0.30 ml; full dose) or mRNA-1273 (Moderna; 50 µg in 0.25 ml; half dose). Of these, 88 had received AstraZeneca first and second doses, and 78 had received Pfizer-BioNTech first and second doses.

The outcomes were safety and reactogenicity (excessive immune response and adverse reactions), and immunogenicity (immune response against severe acute respiratory syndrome coronavirus-2), which comprised anti-spike protein immunoglobulin G titres as well as cellular immune response against the wild-type (original or Wuhan) variant.

Specifically, immunogenicity was assessed 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.

The average age of the participants was 70 years, and 86 of the 166 participants were women. The average interval between the third and fourth doses was 208.5 days (approximately 7 months).

Pain was the most common local adverse event, whereas fatigue was the most frequent systemic event after booster doses of both the Pfizer-BioNTech and Moderna vaccines. No serious adverse events reported after a fourth dose of the Pfizer-BioNTech vaccine were related to the vaccine.

‘Similar side effects were seen, whatever the first two vaccines, and they were manageable and probably a bit less than side effects seen with the third dose’, said Professor Faust. ‘Pain was mostly mild or moderate in severity, while fatigue, headache, and malaise were the most common systemic side effects.’

In the group that received a fourth dose of the Pfizer-BioNTech vaccine, mean immunogenicity 28 days after the third dose was 23,325 enzyme-linked immunosorbent assay laboratory units (ELU)/ml (95% confidence interval [CI] 20,030–27,162), and this increased to 37,460 ELU/ml (95% CI 31,996–43,857) a fortnight after the fourth dose, representing a mean fold-change of 1.59 (95% CI 1.41–1.78).  Likewise, in the group that received a fourth dose of the Moderna vaccine, mean immunogenicity 28 days after the third dose (Pfizer) was 25,317 ELU/ml (95% CI 20,996–30,528), and this increased to 54,936 ELU/ml (95% CI 46,826–64,452) a fortnight after the fourth dose, representing a mean fold-change of 2.19 (95% CI 1.90–2.52).

The changes in immunogenicity from immediately before the fourth dose (day 0) to 14 days after were 12.19-fold (95% CI 10.37–14.32) and 15.90-fold (95% CI 12.92–19.58) in the Pfizer-BioNTech and Moderna groups, respectively. T-cell responses were also boosted from before to after the fourth dose: 7.32 (95% CI 3.24–16.54) in the Pfizer-BioNTech group and 6.22 (95% CI 3.90–9.92) in the Moderna group.

Professor Faust added that some participants maintained high antibody and cellular responses even before the fourth dose, and that these people had limited boosting for the fourth dose: ‘This phenomenon was also seen in participants with a history of COVID-19 infection, indicating there might be a ceiling or maximum antibody level and T-cell response effects … this may be due to host immunity, the vaccine, or vaccine dose that needs to be explored in further trials and analyses.’

‘These results … give confidence for any prospective autumn booster programme in the UK, if the JCVI considers it needed at that time’, said Professor Faust.

This article originally appeared on Medscape, part of the Medscape Professional Network.


Lead image: James Thew/stock.adobe.com

Image 1: James Thew/stock.adobe.com