One-year breakthrough SARS-CoV-2 infection and correlates of protection in fully vaccinated hematological patients

Abstract

The long-term clinical efficacy of SARS-CoV-2 vaccines according to antibody response in immunosuppressed patients such as hematological patients has been little explored. A prospective multicenter registry-based cohort study conducted from December 2020 to July 2022 by the Spanish Transplant and Cell Therapy group, was used to analyze the relationship of antibody response over time after full vaccination (at 3-6 weeks, 3, 6 and 12 months) (2 doses) and of booster doses with breakthrough SARS-CoV-2 infection in 1551 patients with hematological disorders. At a median follow-up of 388 days after complete immunization, 266 out of 1551 (17%) developed breakthrough SARS-CoV-2 infection at median of 86 days (range 7-391) after full vaccination. The cumulative incidence was 18% [95% confidence interval (C.I.), 16-20%]. Multivariate analysis identified higher incidence in chronic lymphocytic leukemia patients (29%) and with the use of corticosteroids (24.5%), whereas female sex (15.5%) and more than 1 year after last therapy (14%) were associated with a lower incidence (p < 0.05 for all comparisons). Median antibody titers at different time points were significantly lower in breakthrough cases than in non-cases. A serological titer cut-off of 250 BAU/mL was predictive of breakthrough infection and its severity. SARS-CoV-2 infection-related mortality was encouragingly low (1.9%) in our series. Our study describes the incidence of and risk factors for COVID-19 breakthrough infections during the initial vaccination and booster doses in the 2021 to mid-2022 period. The level of antibody titers at any time after 2-dose vaccination is strongly linked with protection against both breakthrough infection and severe disease, even with the Omicron SARS-CoV-2 variant.

Fig. 1

Epidemiological distribution of reported SARS-CoV-2 breakthrough infections in the whole cohort according to the likelihood of SARS-CoV-2 variants.

Fig. 2. 1-year Incidence of SARS-CoV-2 breakthrough infection.

A In the whole cohort [cumulative incidence of 18% (95% confidence interval 95%, 16–20%)]. B According to the use of corticosteroids at the time of first vaccine dose. [Under corticosteroids cumulative incidence of 24.5% (95% confidence interval, 19–30%) vs without 16.7%, 95% C.I. 14–18 (p < 0.001)]. C According to the patient’s gender. [Male 19.6% (95% confidence interval, 17–22.4%) vs. female 15.5%, 95% C.I. 13–18 (p = 0.04)]. D According to development of COVID-19 before the first vaccine dose. [Prior COVID-19 11% (95% confidence interval, 6–17%) vs without 18.4%, 95% C.I. 16–20.5, (p = 0.04)]. E According to chronic lymphocytic leukemia vs others. [CLL 29% (95% confidence interval, 22–36%) vs. others16.8%, 95% C.I. 15–18.9 (p < 0.001)]. F According to timing of last therapy. [No treated 21% (C.I. 95%, 16–26%) vs. active therapy 20.5%, 95% C.I. 18–24 vs 6 months to 1 year 16% (C.I. 95%, 10–22) vs. >1 year 14% (95% C.I., 12–17) (p = 0.04)].

Fig. 3. Median anti-SARS-CoV-2 IgG reactive antibodies titers measured in binding antibody units/mL (BAU/mL) at 3–6 weeks, 3 months, 6 months and 1 year after the 2nd dose according to the development of breakthrough SARS-CoV-2 infection.

A Patients with breakthrough SARS-CoV-2 infection had a median of 202.57 BAU/mL (range 0–5714) vs those without SARS-CoV-2 infection median 937 BAU/mL (range 0–10400) (p < 0.001). B Q3-med means median interquartil 75%; Med-Q1, median interquartil 25%; m, mean. C Patients with breakthrough SARS-CoV-2 infection had a median of 70.14 BAU/mL (range 0–2126) vs those without SARS-CoV-2 infection median 379 BAU/mL (range 0–4746) (p < 0.001). D Patients with breakthrough SARS-CoV-2 infection had a median of 302 BAU/mL (range 0–5408) vs those with SARS-CoV-2 infection median 907 BAU/mL (range 0–11800) (p < 0.001). E Patients with breakthrough SARS-CoV-2 infection had a median of 1017 BAU/mL (range 0–6423) vs those without SARS-CoV-2 infection median 2080 (range 0–15600) (p < 0.001).

Fig. 4. Landmark analyses of cumulative incidence of SARS-CoV-2 breakthrough infection according to the vaccine dose status.

A Estimated from the time of third vaccine dose for booster cases and from median time between the 2nd and 3rd vaccine dose for the control group. [3rd dose 18% (95% confidence interval 16–21%) vs 2 doses 18%, 95% C.I. 12–25 (p = 0.1)]. B Estimated from December 26, 2021 in patients alive and without SARS-CoV-2 infection before the 3rd vaccine dose or before this date for the control group. [3rd dose 16% (95% confidence interval, 13–18%) vs 2 doses 23%, 95% C.I. 14–32 (p = 0.06)].