Abstract
We estimated the vaccine effectiveness (VE) of second monovalent and bivalent booster vaccines containing Omicron BA.1 or BA.4/BA.5 and the protection conferred by natural immunity against SARS-CoV-2 infection in Luxembourg. We conducted a test-negative case-control study among residents aged 60 years or older by integrating national socio-demographic, COVID-19 vaccination, and testing data, achieving full population coverage. Using conditional logistic regression, we estimated absolute and relative VE of monovalent and bivalent boosters and natural immunity from prior infection. Our analysis included 5,390 test-positive cases and 11,048 test-negative controls matched by week of testing between September 2022 and April 2023. Absolute VE for monovalent and bivalent boosters decreased from 64.8% and 66.6% in the first month to 1.5% and 16.5% after 5-6 months, respectively. The bivalent was superior to the monovalent booster only in individuals without natural immunity (relative VE 25.7%, 95% confidence interval 11.4%; 37.7%). Natural immunity lasted longer than vaccine-induced immunity with 80.7% protected at 4-8 months and 44.9% at 15-25 months post-infection. Both second booster vaccines provided temporary protection against SARS-CoV-2 infection; bivalent boosters offered a slight benefit over monovalent boosters. Natural immunity appears to confer longer-lasting protection.