What is the efficacy of the fourth vaccination dose of mRNA against the Omicron variant?

In a recent study published in British Medical Journal (BMJ)Researchers evaluated the efficacy of a fourth dose of vaccine against coronavirus disease 2019 (COVID-19) among long-term care residents.

Study: Efficacy of a fourth dose of covid-19 mRNA vaccine against an omicron variant among residents of long-term care in Ontario, Canada: a negative design study test. Image Credit: Tequiero / Shutterstock

The long-term care (LTC) population is at increased risk of SARS-CoV-2 infection and severe outcomes. LTC Homes in Ontario, Canada, is publicly funded and provides medical, residential, personal, and nursing support for people with disabilities or neurocognitive disorders. LTC residents in Ontario have been disproportionately affected by COVID-19, accounting for about two-thirds of deaths during the pandemic’s first two waves.

The vaccinated LTC population had significantly lower infections and mortality compared to unvaccinated controls. A third vaccine dose (the first booster dose) was offered to LTC residents as of August 2021, and administration of the fourth vaccine (the second booster) began on December 30, 2021. Moderna Spikevax (mRNA-1273) was preferred for the second booster.

about studying

In this study, the researchers estimated the marginal efficacy of a fourth vaccine dose compared to a third dose. The authors implemented a negative test design and determined marginal efficacy (fourth versus third) and vaccine efficacy (for the fourth dose) among residents across 626 licensed LTC homes in Ontario. Subjects were excluded if they had received the second booster before December 30, 2021, or had tested positive for SARS-CoV-2 in the past 30 days.

Only those vaccinated with the mRNA vaccines (BNT162b2 [Pfizer] or mRNA-1273) for all four doses in the study. Evaluation of vaccine efficacy has been limited to SARS-CoV-2 Omicron. Spike(S)-target failure (SGTF) assay or whole genome sequencing was used to identify the variant. Delta cases were excluded. Regional datasets for COVID-19 testing, vaccination, and health management information were linked using unique coded identifiers.

Three outcomes were measured: infection (SARS-CoV-2 positive), symptomatic infection, and severe outcome. Populations were considered 1) cases if they tested positive at least once a week or 2) controls if they tested negative on all tests that week. The frequencies and means were calculated for the categorical and continuous variables, respectively.

Test negative controls were compared to test positive cases using standard differences. Those vaccinated with a third dose 84 days before the indicator test (the first positive SARS-CoV-2 test) were compared with those who received a third, second, first, or no vaccine dose less than 84 days and the fourth dose < or 7 days before the test .

the findings

More than 87% of LTC residents in Ontario were tested for SARS-CoV-2 from December 30, 2021 to April 27, 2022. There were 13,654 positive cases of Omicron and 20,862 negative tests. Most of the population (80.1%) was tested multiple times during the study period. More than half of the cases (58.1%) and the control group (53.3%) received only three doses of the vaccine, and a greater proportion of the controls (38.2%) received a second booster dose of cases (28%).

The marginal efficacy of the fourth dose 7 days after vaccination was 19% against infection, 31% against accidental infection, and 40% against severe outcomes compared with those vaccinated with a third dose 84 days before the index test. Corresponding estimates compared to residents vaccinated with a third dose less than 84 days prior to index testing were 16% against infection, 20% against symptomatic infection, and 29% against severe outcomes.

Seven days after the fourth dose, the vaccine was 49% effective against infection, 69% against symptomatic infection, and 86% against severe outcomes. Vaccine efficacy for the third dose given 84 days before testing was 37% against infection, 55% against symptomatic infection, and 77% against severe outcome. Vaccine efficacy was similar between the population receiving three doses of mRNA-1273 and those receiving two doses of BNT162b2 and one mRNA-1273 vaccine.

Most of the LTC population (95%) received the mRNA-1273 vaccine as the second booster, and similar vaccine efficacy against infection and severe outcomes were observed in all vaccination combinations. However, vaccine efficacy against symptomatic infection was higher among those who received four doses of mRNA-1273 or three doses of BNT162b2 and one dose of mRNA-1273 than among those who received two BNT162b2 vaccines and two mRNA-1273 vaccines.


The fourth vaccination provided a marginal increase in efficacy over the third dose (received 84 days before) against infection and symptomatic infection with severe outcomes. But the marginal efficacy was lower if the third dose was given less than 84 days earlier. This generally refers to the three-month period between the third and fourth doses.

Vaccine efficacy against asymptomatic infection and severe outcome was higher for the recipients of the second booster than the population that received the triple vaccination. In conclusion, a fourth vaccine for COVID-19 mRNA increased protection against outcomes measured among the LTC population during the Omicron-dominant phase, although the duration of protection should be investigated.

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