Background and Objective:
In Luxembourg, bivalent mRNA booster vaccines containing Omicron BA.1 or BA.4/BA.5 were introduced in September 2022 mainly targeting persons aged 60 years and older. The protection conferred by bivalent booster doses or by natural immunity due to prior infections against Omicron infections is unknown. We evaluated the effectiveness of a fourth bivalent Omicron-containing booster dose and natural immunity due to prior infection against laboratory confirmed SARS-CoV-2 infection.

Method:
We conducted a test-negative matched case-control study in persons aged 60 years and older in Luxembourg during a time period when SARS-CoV-2 Omicron lineage BA.5 and its sub lineages predominated. Matching was based on age group, sex and week of test. Effectiveness was assessed using conditional logistic regression adjusting for nursing home residency, time since last dose of vaccine, geographic region, and immigration background.

Results:
Data from 4714 cases and 9881 matched negative controls from September 22 through December 7 2022 were included in the analysis. The effectiveness of the fourth bivalent booster dose was 54% (95% CI 35%-67%) compared to no vaccination and 38% (95% CI 15%-55%) compared to three and 36% (95% CI 14%-52%) compared to four monovalent booster doses. Effectiveness for BA.1 and BA.4/BA.5 containing vaccines were similar (p>0.05). Effectiveness of prior Omicron and pre-Omicron infection were 80% (95% CI 77%-82%) and 45% (95% CI 37%-52%), respectively. Effectiveness of prior Omicron infections and bivalent booster vaccination was 87% (95% CI 72%-94%).

Conclusion:
Bivalent Omicron-containing boosters were more protective against Omicron infection than monovalent boosters. Prior infection with Omicron provided a high protection, significantly better than prior infection from the pre-Omicron era. Hybrid immunity with Omicron infections and bivalent booster vaccination conferred the highest levels of protection.