Protective effect of previous SARS-CoV-2 infection against Omicron BA.4 and BA.5 subvariants
To the editor:
Subvariants BA.4 and BA.5 of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) B.1.1.529 (omicron) variant have shown the ability to escape from neutralizing antibodies.1 These subvariants had a noticeable 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 prior 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 on SARS-CoV-2 laboratory tests, 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 performed in health care facilities in Qatar. Previous infection was defined as a positive test result at least 90 days before a new positive test result; subjects 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 by 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 by its occurrence in Qatar before 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 versus re-infection with BA.4 or BA.5 using determination of S gene target errors (SGTF) in PCR testing between 7 May and 28 July 2022 (Fig. S3). The SGTF designation indicates the deletion of codons 69 and 70 in the S gene, which is common to the omicron subvariants BA.1, BA.4, and BA.5. Since the presence 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 presence of other variants characterized by SGTF was negligible during the study. We also estimated efficacy based on the assumption that all diagnosed SARS-CoV-2 infections between June 8 and July 28, 2022 were BA.4 or BA.5 infections, as these were the predominant subvariants during this period. Details of 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); Efficacy against all BA.4 or BA.5 reinfections regardless of the presence of symptoms was 27.7% (95% CI, 19.3 to 35.2) (table 1). The efficacy of post-omicron infection against symptomatic BA.4 or BA.5 reinfection was 76.2% (95% CI, 66.4 to 83.1); efficacy against all BA.4 or BA.5 reinfections was 78.0% (95% CI, 75.0 to 80.7).
In the analysis of the effectiveness of previous infection where we assumed that all diagnosed infections were BA.4 or BA.5, we found results similar to those in the main analysis. An analysis of efficacy stratified by interval since previous infection showed waning protection over time (section S3 and table S3). Sensitivity analyzes 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). Analyzes categorized by vaccination status also confirmed the study results but suggested that efficacy might be slightly higher among vaccinated people. 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). The 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 due to more waning of immune protection over time and a greater ability to evade the immune system with the BA.4 and BA.5 subvariants.
Heba N. Altarawneh, MD
Hiam Chemaitelly, Ph.D.
Weill Cornell Medicine–Qatar, Doha, Qatar
Hossein H. Ayoub, Ph.D.
Qatar University, Doha, Qatar
Mohammad R. Hasan, Ph.D.
Sidra Medicine, Doha, Qatar
Peter Coyle, MD
Hamad Medical Corporation, Doha, Qatar
Hadi M. Yassine, Ph.D.
Hebah A. Al-Khatib, Ph.D.
Maria K. Smatti, M.Sc.
Qatar University, Doha, Qatar
Zaina Al-Kanaani, Ph.D.
Einas Al-Kuwari, MD
Andrew Jeremijenko, MD
Anvar H. Kaleeckal, M.Sc.
Ali N. Latif, MD
Riyazuddin M. Shaik, M.Sc.
Hamad Medical Corporation, Doha, Qatar
Hanan F. Abdul-Rahim, Ph.D.
Gheyath K. Nasrallah, Ph.D.
Qatar University, Doha, Qatar
Mohamed G. Al-Kuwari, MD
Primary Health Care Corporation, Doha, Qatar
Adeel A. Butt, MB, BS
Hamad Medical Corporation, Doha, Qatar
Hamad E. Al-Romaihi, MD
Mohamed H. Al-Thani, MD
Ministry of Public Health, Doha, Qatar
Abdullatif Al-Khal, MD
Hamad Medical Corporation, Doha, Qatar
Roberto Bertollini, MD, MPH
Ministry of Public Health, Doha, Qatar
Patrick Tang, MD, Ph.D.
Sidra Medicine, Doha, Qatar
Laith J. Abu-Raddad, Ph.D.
Weill Cornell Medicine–Qatar, Doha, Qatar
[email protected]
Supported by the Biomedical Research Program and Biostatistics, Epidemiology, and Biomathematics Research Core at Weill Cornell Medicine–Qatar; Qatar Ministry of Public Health; Hamad Medical Corporation; and Sidra Medicine. Qatar Genome Program and Qatar University Biomedical Research Center supported viral genome sequencing.
Disclosure forms provided by the authors are available with the full text of this letter at NEJM.org.
This letter was published on October 5, 2022 at NEJM.org.
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2. Ayoub HH, Tommy M, Chemaitelly Het al. Estimating protection conferred by previous infection to prevent reinfection: applying the test-negative study design. January 3, 2022 (https://www.medrxiv.org/content/10.1101/2022.01.02.22268622v1). oppression.
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