COVID-19 Booster Vaccination Effective Despite Possible Negative Immune Imprinting

COVID-19 booster vaccination conferred significant protection against incident infection, though waning protection beginning 7 months after receipt suggests the possibility of negative immune imprinting.

Although waning protection against the Omicron variant was observed at 7 months after COVID-19 booster vaccination, COVID-19 vaccine boosters conferred significant protection against severe infection for up to 1 year. These study results were published in The Lancet Infectious Diseases. 

Researchers conducted a matched, retrospective cohort study in Qatar between January 2021 and October 2022. Data were analyzed from 2,228,686 patients following pCOVID-19 primary series (2 dose) vaccination. Of the total patient population, 658,947 (29.6%) received a COVID-19 mRNA vaccine booster. The researchers aimed to compare the effectiveness of primary series vaccination alone vs booster vaccination against incident infection and severe, critical, and fatal COVID-19 infection. Outcomes among patients who received a third COVID-19 vaccine dose (booster) were compared against a national cohort of individuals who received only 2 vaccine doses (primary series).

The cohorts were matched 1:1 on the basis of sex, age, nationality, number of comorbid conditions, vaccine type, calendar week of receipt of the second vaccine dose, and previous infection status. The matched cohorts each included 304,091 patients. The cumulative incidence of infection was analyzed with the Kaplan-Meier method. A Poisson log-likelihood regression model was used to estimate the incidence rate of infection, and hazard ratios were calculated via Cox regression models. The median duration of follow-up was 203 (IQR, 59-262) and 190 (IQR, 45-256) days for patients in the booster and primary series cohorts, respectively. 

Among matched patients who received booster vaccination, 20,528 incident infections were observed, 7 of which progressed to severe COVID-19 infection. There were 30,771 incident infections observed among patients in primary series cohort, of which 25 progressed to severe infection, 3 progressed to critical infection, and 3 progressed to fatal infection. The cumulative incidence of infection was 12.9% (95% CI, 12.5%-13.3%) among patients in the booster cohort and 15.1% (95% CI, 14.7%-15.4%) among those in the primary series cohort (P <.0001). Further analysis showed that the relative effectiveness of COVID-19 booster vaccination to that of primary series vaccination was 26.2% (95% CI, 23.6%-28.6%) against incident infection and 75.1% (95% CI, 40.2-89.6) against severe, critical, or fatal infection.

The researchers assessed the effectiveness of booster vaccination on the basis of prior infection status and vulnerability to COVID-19 infection in subgroup analyses. Of patients with no previous infection, booster effectiveness was 26.3% (95% CI, 23.6%-28.8%) against incident infection and 74.4% (95% CI, 38.3%-89.4%) against severe, critical, or fatal COVID-19 infection.

Although the imprinting is a theoretical concern, it is unlikely to negate the public health value of the booster vaccination.

Among patients previously infected with the Omicron or pre-Omicron variant, booster effectiveness was 62.8% (95% CI, 52.8%-93.4%). Of patients at increased risk for COVID-19 infection, booster effectiveness was 34.2% (95% CI, 27.0%-40.6%) against incident infection and 76.6% (95% CI, 34.5%-91.7%) against severe, critical, or fatal COVID-19 infection.

Booster vaccination conferred the highest protection against incident COVID-19 within the first month of receipt (61.4%; 95% CI, 60.2%-62.6%). However, at 6 months after receipt, only modest protection was observed 15.5% (95% CI, 9.3%-22.2%). The researchers noted that this waning in protection may suggest the possibility of negative immune imprinting.

Irrespective of previous infection status, COVID-19 vulnerability, or vaccine type, protection conferred by booster vaccination against incident was found to wane gradually throughout the follow-up period. Of note, protection against severe infection remained high at 1 year.

Limitations of this study include the low number of patients with severe COVID-19 infection, differences in testing frequency between the cohorts, potential misclassification in variant and subvariant status of previous infections, and the observational design. 

“Although the imprinting is a theoretical concern, it is unlikely to negate the public health value of the booster vaccination,” the researchers concluded.

Disclosures: One study author declared affiliations with industry. Please see the reference for a full list of disclosures.


Chemaitelly H, Ayoub HH, Tang P, et al. Long-term COVID-19 booster effectiveness by infection history and clinical vulnerability and immune imprinting: a retrospective population-based cohort study. Lancet Infect Dis. Published online, March 10, 2023. doi:10.1016/ S1473-3099(23)00058-0