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4-Dose COVID-19 Vaccine Less Effective Beyond 90 Days


A new study has found that vaccine effectiveness against infection after 4 doses of the COVID-19 vaccine disappeared after 90 days for Omicron variants BA.2, BA.2.12.1, BA.4, and BA.5, although it remained effective against hospitalizations.

Vaccine effectiveness against SARS-CoV-2 infection had slipped by the 90-day mark post vaccination, according to a study published in Nature Communications. The vaccine, however, remained effective in preventing hospitalizations.

Omicron subvariants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5 have remained the dominant strains of the pandemic worldwide. Previous studies have found that vaccines have had less neutralization activity against BA.5 and BA.5 compared with previous strains. This study aimed to assess the effectiveness of the mRNA-1273 vaccine against infection and hospitalization in omicron subvariants.

The study used the Kaiser Permanente Southern California (KPSC) database to collect information on participants. The database can comprehensively capture all details of patient care, including vaccinations received outside of the KPSC network. Diagnostic testing for COVID-19 was performed routinely at KPSC for anyone who requested testing or prior to procedures or hospital admission.

A test-negative case-control study was used to evaluate the effectiveness of 3- and 4-dose vaccination against COVID-19 Omicron variants. Specimens were collected from January 1, 2022, to June 30, 2022. Participants were included if they were 18 years and older and had more than 12 months of KPSC membership before specimen collection.

Participants were excluded if they had a history of COVID-19 in the previous 90 days, had a dose of the mRNA-1273 vaccine less than 14 days prior to the collection date, had received 2 doses of mRNA-1273 less than 24 days apart or had more than 4 doses of mRNA-1273 before the collection date, or had received a COVID-19 vaccine other than mRNA-1273.

There were 123,236 participants included in this study: 30,809 were test-positive cases and 92,427 were test-negative controls. The median age of the population was 46 years, 18% were 16 years and older, 55.7% were female patients, and 45% identified as Hispanic.

Based on time since vaccination, vaccine effectiveness after a 3-dose vaccine ranged from 85.8% (95% CI, 82.7%-88.3%) against BA.1 in the 14 to 30 days after the third dose to 54.9% (95% CI, 35.6%-68.4%) more than 150 days after the third dose. Corresponding vaccine effectivness for the other subvariants were 61.0% (95% CI, 27.6%-79.0%) and –24.9% (95% CI, –32.3% to –16.7%) for BA.2, 82.7% (95% CI, 44.2%-94.7%) and –26.8% (95% CI, –34.6% to –18.0%) for BA.2.12.1, 72.6% (95% CI, –54.7% to 96.6%) and –16.4% (95% CI, –35.8% to 8.2%) for BA.4, and 90.6% (95% CI, 30.6%-98.7%) and –17.9% (95% CI, –29.6% to –4.2%) for BA.5.

For BA.2, effectiveness following a 4-dose vaccine was 64.3% (95% CI, 50.7%-74.2%) in the 14 to 30 days after the fourth dose and 17.3% (95% CI, –45.3% to 62.6%) after more than 90 days. The effectivenss for those time periods for the other subvariants was 64.4% (95% CI, 48.6%-75.4%) and 14.0% (95% CI, –48.4% to 61.9%) for BA.2.12.1, 75.7% (95% CI, 34.7%-91.0%) and 6.3% (95% CI, –66.3% to 70.4%) for BA.4, and 30.8% (95% CI, –9.2% to 56.5%) and 5.0% (95% CI, –56.9% to 61.1%) for BA.5.

Vaccine effectiveness against COVID-19 hospitalization for the 3-dose vaccine was 97.5% (95% CI, 96.3%-98.3%) for BA.1, 82.0% (95% CI, 64.5%-90.8%) for BA.2, and 72.4% (95% CI, 23.9%-90.0%) for BA.4/BA.5. For the 4-dose vaccine, the rates were 96.4% (95% CI, 88.4%-98.9%) for BA.2 and 88.5% (95% CI, 51.8%-97.2%) for BA.4/BA.5.

There were some limitations to this study. The results may not be generalizable to people who didn’t test for COVID-19 and didn’t seek testing in health care settings, and factors could have changed over time as subvariants evolved, which may affect the evaluation of vaccine effectiveness across all subvariants. Misclassification of test-positive and test-negative cases also could have been a source of bias.

The researchers concluded that although the effectiveness of mRNA-1273 is moderate and short lived against infection, the vaccine is still very effective in preventing hospitalizations for COVID-19.

"With the updated bivalent BA.4/BA.5–containing booster (mRNA-1273.222) available in the United States, it is imperative to continue to evaluate its effectiveness, durability, and impact on SARS-CoV-2 evolution," they emphasized.


Tseng HF, Ackerson BK, Bruxvoort KJ, et al. Effectiveness of mRNA-1273 vaccination against SARS-CoV-2 omicron subvariants BA.1, BA.2, BA.2.12.1, BA.4, and BA.5. Nat Commun. Published online January 12, 2023. doi:10.1038/s41467-023-35815-7

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