Immune escape and waning immunity of COVID-19 monovalent mRNA vaccines against symptomatic infection with BA.1/BA.2 and BA.5 in Japan

Background: Repeated emergence of variants with immune escape capacity and waning immunity from vaccination are major concerns for COVID-19. We examined whether the surge in Omicron subvariant BA.5 cases was due to immune escape or waning immunity through vaccine effectiveness (VE) evaluation. Methods: A test-negative case-control study was conducted in 16 clinics/hospitals during the BA.1/BA.2-dominant and BA.5-dominant periods. VE against symptomatic infection was estimated after adjusting for age, sex, comorbidity, occupation, testing frequency, prior infection, close contact history, clinic/hospital, week, and preventive measures. Absolute VE (aVE) was calculated for 2/3/4 doses, compared to the unvaccinated. Relative VE (rVE) was calculated, comparing 3 vs 2 and 4 vs 3 doses. Results: 13,025 individuals were tested during the BA.1/BA.2-dominant and BA.5-dominant periods with similar baseline characteristics. For BA.1/BA.2, aVE was 52 % (95 %CI:34–66) 14 days-3 months post-dose 2, 42 % (29–52) > 6 months post-dose 2, 71 % (64–77) 14 days-3 months post-dose 3, and 68 % (52–79) 3–6 months post-dose 3. rVE was 49 % (38–57) 14 days-3 months post-dose 3 and 45 % (18–63) 3–6 months post-dose 3. For BA.5, aVE was 56 % (27–73) 3–6 months post-dose 2, 32 % (12–47) > 6 months post-dose 2, 70 % (61–78) 14 days-3 months post-dose 3, 59 % (48–68) 3–6 months post-dose 3, 50 % (29–64) > 6 months post-dose 3, and 74 % (61–83) ≥ 14 days post-dose 4. rVE was 56 % (45–65) 14 days-3 months post-dose 3, 39 % (27–48) 3–6 months post-dose 3, 25 % (-2–45) > 6 months post-dose 3, and 30 % (-6–54) ≥ 14 days post-dose 4. Conclusions: Booster doses initially provided high protection against BA.5 at a level similar to that against BA.1/BA.2. However, the protection seemed shorter-lasting against BA.5, which likely contributed to the surge. Furthermore, rVE post-dose 4 was low even among recent vaccinees. These results support the introduction of variant-containing vaccines and emphasize the need for vaccines with longer duration of protection.