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To the Editor: The BA.4 and BA.5 subvariants of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant have shown the capacity of escaping from neutralizing antibodies.1 These subvariants had an appreciable presence in Qatar by early May 2022 (Fig. S1 in the Supplementary Appendix, available with the full text of this letter at NEJM.org) and had become the dominant subvariants by June 8 (Fig. S2). We estimated the effectiveness of previous SARS-CoV-2 infection in preventing reinfection with BA.4 and BA.5 subvariants using a test-negative, case–control study design (Section S1).2 We extracted data regarding SARS-CoV-2 laboratory testing, clinical infection, vaccination, and demographic details from the national SARS-CoV-2 databases, which include all results of polymerase-chain-reaction (PCR) and rapid antigen testing conducted at health care facilities in Qatar. Previous infection was defined as a positive test result at least 90 days before a new positive test finding; persons with negative results were used as controls.2 To control for differences in SARS-CoV-2 infection risk in Qatar, we matched cases and controls according to sex, 10-year age group, nationality, number of coexisting medical conditions, calendar week of testing, method of testing, and reason for testing.2 Previous infection was further categorized according to its occurrence in Qatar before the December 19, 2021, initiation of the omicron wave (pre-omicron infections) or after that date (post-omicron infections).3

ber of coexisting medical conditions, calendar week of testing, method of testing, and reason for testing.2 Previous infection was further categorized according to its occurrence in Qatar before the December 19, 2021, initiation of the omicron wave (pre-omicron infections) or after that date (post-omicron infections).3 In the main analysis, we estimated the effectiveness of previous infection against reinfection with BA.4 or BA.5 using the determination of S-gene target failure (SGTF) on PCR testing between May 7 and July 28, 2022 (Fig. S3). The SGTF designation indicates the deletion of codons 69 and 70 in the S gene, which is common to omicron subvariants BA.1, BA.4, and BA.5. Because the incidence of BA.1 was negligible during the study, as confirmed by sequencing (Section S2), SGTF was used as a proxy marker for BA.4 or BA.5 infection. The incidence of other variants that were characterized by SGTF was negligible during the study. We also estimated effectiveness on the assumption that all diagnosed SARS-CoV-2 infections between June 8 and July 28, 2022, were BA.4 or BA.5 infections, since these were the dominant subvariants during this period. Details regarding the study population are shown in Figures S3 and S4. The baseline characteristics of the study population are shown in Table S1. The study population was broadly representative of the population of Qatar (Table S2).

BA.4 or BA.5 infections, since these were the dominant subvariants during this period. Details regarding the study population are shown in Figures S3 and S4. The baseline characteristics of the study population are shown in Table S1. The study population was broadly representative of the population of Qatar (Table S2). The effectiveness of pre-omicron infection against symptomatic BA.4 or BA.5 reinfection was 35.5% (95% confidence interval [CI], 12.1 to 52.7); the effectiveness against any BA.4 or BA.5 reinfection regardless of the presence of symptoms was 27.7% (95% CI, 19.3 to 35.2) (Table 1). The effectiveness of post-omicron infection against symptomatic BA.4 or BA.5 reinfection was 76.2% (95% CI, 66.4 to 83.1); the effectiveness against any BA.4 or BA.5 reinfection was 78.0% (95% CI, 75.0 to 80.7).

BA.4 or BA.5 reinfection regardless of the presence of symptoms was 27.7% (95% CI, 19.3 to 35.2) (Table 1). The effectiveness of post-omicron infection against symptomatic BA.4 or BA.5 reinfection was 76.2% (95% CI, 66.4 to 83.1); the effectiveness against any BA.4 or BA.5 reinfection was 78.0% (95% CI, 75.0 to 80.7). In the analysis of the effectiveness of previous infection in which we assumed that all diagnosed infections were BA.4 or BA.5, we found results that were similar to those of the main analysis. An analysis of effectiveness that was stratified according to the interval since previous infection showed waning protection over time (Section S3 and Table S3). Sensitivity analyses that were performed after adjustment for vaccination status and after matching according to the number of vaccine doses confirmed the results of the main analysis (Tables S3 and S4). Analyses that were categorized according to vaccination status also confirmed the study results but suggested that effectiveness could be slightly higher among vaccinated persons. Limitations of the study design are discussed in Section S1.

of vaccine doses confirmed the results of the main analysis (Tables S3 and S4). Analyses that were categorized according to vaccination status also confirmed the study results but suggested that effectiveness could be slightly higher among vaccinated persons. Limitations of the study design are discussed in Section S1. Protection from a previous SARS-CoV-2 infection against BA.4 or BA.5 reinfection was modest when the previous infection had been caused by a pre-omicron variant but strong when it had been caused by a post-omicron subvariant (including BA.1 or BA.2). Protection of a previous infection against reinfection with a BA.4 or BA.5 subvariant was lower than that against reinfection with a BA.1 or BA.2 subvariant3-5 because of more waning of immune protection over time and a greater capacity for immune-system evasion with the BA.4 and BA.5 subvariants.