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Fourth COVID-19 vaccine dose provides stronger immunity boost than third dose, shows study run in Leicester


COVID-19 vaccines given as fourth doses in the UK offer excellent boosting immunity protection, according to the latest results from a nationwide NIHR-supported study.

The latest results  from the COV-BOOST trial, run at the University Hospitals of Leicester NHS Trust, show that a fourth dose mRNA vaccine is safe and boosts antibody levels - higher than that of a third dose.

Researchers have published their findings today in The Lancet Infectious Diseases

Fourth doses of COVID-19 vaccines have been offered as a spring booster for those most vulnerable in the UK. This has been a precautionary strategy to maintain high levels of immunity prior to the study data being available. A wider group of people may be offered a fourth dose booster later this year.

The latest findings show that fourth dose mRNA booster vaccines for COVID-19 are well-tolerated in people who received Pfizer as a third dose. They are also effective at increasing both antibody and cellular immunity up to and above baseline and peak levels observed following third dose boosters.

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.”

The COV-BOOST study, led by University Hospital Southampton, provided the world’s first data on the safety, immune responses and side-effects of third dose in mix and match schedules. The study was key to shaping the UK’s autumn booster programme and gives vital evidence for global vaccination efforts.

In the fourth dose study, across 10 UK sites, 166 people who had received a third dose of Pfizer, following Pfizer or AstraZeneca initial doses in June 2021, were randomised to receive full dose Pfizer or half dose Moderna as a fourth dose. These were approximately seven months after their third dose.

Professor Lucy Chappell, Chief Scientific Adviser for the Department of Health and Social Care, Professor of Obstetrics at King’s College London and NIHR Chief Executive said: “These results show the benefits of having a fourth COVID-19 booster dose for those eligible, to top-up immunity.

“It is important to recognise the achievement of the COV-Boost study team, participants and all involved who have helped deliver this research to inform the best use of COVID-19 booster vaccines in the UK.

“The COV-Boost study, commissioned through the NIHR, is continuing to deliver world-leading research on booster vaccination.”

Professor Adrian Palfreeman, principal investigator for the Cov-Boost trial at Leicester’s Hospitals, said: “The findings from this study are reassuring for people who have received their fourth COVID-19 vaccine dose. We are grateful to the 41 volunteers who consented to be part of the trial here in Leicester and have played a significant role in helping us to overcome this virus.”

While pain at vaccination site and fatigue were the most common side effects, there were no vaccine-related serious adverse events and fourth doses were safe and well tolerated.

The two vaccines trialled in the fourth dose sub-study were those deployed in the UK NHS third dose booster campaign:

  • Pfizer (Pfizer-BioNTech)
  • Moderna (half dose – 50 micrograms)

Professor Andrew Ustianowski, NIHR Clinical Lead for the COVID-19 Vaccination Programme and Joint National Infection Specialty Lead said: "The COV-BOOST study has continuously supported the UK's booster vaccination programme and had further impact on how vaccines are administered globally. The study's latest results once again show the importance of sustained research into COVID-19 vaccines and how they are best used to keep the virus at bay. 

“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 provides the public with the confidence that fourth doses are both safe and even more effective than 3rd doses at boosting immunity against COVID-19.

"It is thanks to the endless efforts and contribution of study participants and staff across the UK that we can keep discovering more about the use of vaccines, and they continue to play a pivotal role just as they have done throughout the pandemic."

Current COV-BOOST sub-studies are investigating the interval between second and third doses, fourth doses of mRNA vaccines, an omicron variant vaccine and fractional dosing in young people aged 18-30 years.


This press release was issued by the NIHR Clinical Research Network: East Midlands. 

For more information, contact Steve Clapperton - steve.clapperton@nihr.ac.uk