Immune footprint and protection against repeated SARS-CoV-2 reinfection |  NEJM

Immune footprint and protection against repeated SARS-CoV-2 reinfection | NEJM

For the editor:

More than 2 years after the onset of the coronavirus disease 2019 (Covid-19) pandemic, the global population carries heterogeneous immune histories derived from various exposures to infection, viral variants and vaccination.1 Evidence at the level of binding and neutralizing antibodies and B-cell and T-cell immunity suggests that a history of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may have a negative effect on subsequent protective immunity.1 In particular, the immune response to the B.1.1.529 (omicron) subvariants might be compromised by differential immune imprinting in people who have had previous infection with the original virus or the B.1.1.7 variant ( alpha).1

We investigated the epidemiological evidence for immune fingerprinting in people with specific immune histories related to natural infection. We assessed the incidence of repeat reinfection in the national cohort of people in Qatar who had documented reinfection with omicron BA.1 or BA.2 after a primary infection with non-omicron SARS-CoV-2 (the “cohort “ double priming”) compared to the incidence of reinfection in the national cohort of people who had a documented primary infection with omicron BA.1 or BA.2 (the “omicron primed” cohort).2 This analysis was performed as a matched retrospective cohort study (Section S1 of the Supplementary Appendix, available with the full text of this letter on NEJM.org).

Data on SARS-CoV-2 laboratory testing, clinical infection, vaccination and demographic characteristics were extracted from the Qatar national SARS-CoV-2 databases. Individuals in the two cohorts were exactly matched in a 1:3 ratio by gender, 10-year age group, nationality, number of coexisting conditions, and calendar week of infection with the omicron subvariant . The follow-up period began 90 days after documentation of infection with the omicron subvariant. Vaccinated persons were excluded. Associations were estimated using Cox proportional hazards regression models. Relative risks were adjusted for the factors used for matching.

Figure S1 in the Supplementary Appendix shows the population selection process, and Table S1 shows the baseline characteristics of complete and matched cohorts. The matched cohorts included 7,873 people in the dual-primed cohort and 22,349 people in the omicron-primed cohort. The study population was representative of the unvaccinated population of Qatar with respect to demographic characteristics and history of SARS-CoV-2 infection (Table S2).

Incidence of SARS-CoV-2 reinfection in dual-primed and Omicron-primed cohorts.

The dual-boot cohort included individuals with documented reinfection with B.1.1.529 (omicron) BA.1 or BA.2 subvariant after primary infection with pre-omicron severe acute respiratory syndrome coronavirus 2 ( SARS-CoV-2), and the omicron-primed cohort included people with a documented primary infection with an omicron BA.1 or BA.2 subvariant. The inset in panel A shows the same data on an expanded y-axis. The primary analysis included the full matched cohorts; in an additional analysis (panel B), the dual-boot cohort included only individuals whose primary infection was caused by the original virus or the B.1.1.7 (alpha) variant. Relative risks were adjusted for the factors used for matching. This study was conducted in Qatar between December 19, 2021 and August 15, 2022. Follow-up began 90 days after documentation of reinfection. The median duration of follow-up was 125 days (interquartile range, 114 to 132) in each cohort.

During follow-up, 63 reinfections occurred in the dual-primed cohort and 343 in the omicron-primed cohort; none of the infections progressed to severe, critical, or fatal Covid-19 (Fig. S1). At 135 days after the start of follow-up, the cumulative incidence of reinfections was 1.1% (95% confidence interval [CI]0.8 to 1.4) in the dual-prime cohort and 2.1% (95% CI, 1.8 to 2.3) in the omicron cohort (Figure 1A). In the comparison of the dual-primed fully matched cohort with the omicron-primed cohort, the adjusted hazard ratio for reinfection was 0.52 (95% CI, 0.40 to 0.68). In an analysis of the subset of people from the dual-primed cohort whose primary infection was due to the original virus or the alpha variant versus the omicron-primed cohort, the adjusted hazard ratio for infection was 0.59 (95% CI 0.40 to 0.85) (Figure 1B).

During the first 70 days of follow-up, when infections were dominated by the BA.2 subvariant,2.3 the adjusted relative risk for infection was 0.92 (95% CI, 0.51 to 1.65). However, the cumulative incidence curves diverged when the BA.4 and BA.5 subvariants were introduced and then dominated4 (adjusted relative risk, 0.46; 95% CI, 0.34 to 0.62) (Figure 1A).

The limitations of the study are discussed in section S1. A potential limitation was the difference in testing frequency between the two cohorts, but a sensitivity analysis with adjustment for these differences showed similar results to the main analysis.

Omicron infection induces strong protection against subsequent omicron infection.2.4 In the present cohort study, additional prior infection with non-omicron SARS-CoV-2 was found to enhance this protection against subsequent omicron infection. Previous pre-omicron infection may have broadened the immune response against a future reinfection challenge.

Hiam Chemaitelly, Ph.D.
Weill Cornell Medicine–Qatar, Doha, Qatar
[email protected]

Houssein H. Ayoub, Ph.D.
Qatar University, Doha, Qatar

Patrick Tang, MD, Ph.D.
Mohammad R. Hasan, Ph.D.
Pulmonary 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-Chanani, 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 Healthcare Society, 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

Laith J. Abu-Raddad, Ph.D.
Weill Cornell Medicine–Qatar, Doha, Qatar
[email protected]

Supported by the Biomedical research program and research core in biostatistics, epidemiology and biomathematics at Weill Cornell Medicine–Qatar; the Qatar Ministry of Public Health; Hamad Medical Corporation; and medicine Sidra. The Qatar Genome Program and Qatar University Biomedical Research Center supported viral genome sequencing.

The disclosure forms provided by the authors are available with the full text of this letter on NEJM.org.

This letter was published on October 12, 2022 on NEJM.org.

  1. 1. CJ Reynolds, Pade C, JM Gibbons, et al. Immune enhancement by B.1.1.529 (omicron) depends on prior exposure to SARS-CoV-2. Science 2022;377(6603):eabq1841eabq1841.

  2. 2. Chemaitelly H, Ayoub HH, Coyle P, et al. Protection of infection of the omicron subline against reinfection by another omicron subline. Nat Common 2022;13:46754675.

  3. 3. Altarawneh HN, Chemaitelly H, Ayoub HH, et al. Effects of prior infection and vaccination on symptomatic omicron infections. N English J med 2022;387:2134.

  4. 4. Altarawneh HN, Chemaitelly H, Ayoub HH, et al. Protective effect of prior SARS-CoV-2 infection against omicron BA.4 and BA.5 subvariants. N Engl J Med. DOI: 10.1056/NEJMc2209306.

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