Cellular and humoral immune response to SARS-CoV-2 vaccination and booster dose in immunosuppressed patients: An observational cohort study

Abstract

Background: Humoral and cellular immune responses to SARS-CoV-2 vaccination among immunosuppressed patients remain poorly defined, as well as variables associated with poor response.

Methods: We performed a retrospective observational cohort study at a large Northern California healthcare system of infection-naïve individuals fully vaccinated against SARS-CoV-2 (mRNA-1273, BNT162b2, or Ad26.COV2.S) with clinical SARS-CoV-2 interferon gamma release assay (IGRA) ordered between January through November 2021. Humoral and cellular immune responses were measured by anti-SARS-CoV-2 S1 IgG ELISA (anti-S1 IgG) and IGRA, respectively, following primary and/or booster vaccination.

Results: 496 immunosuppressed patients (54% female; median age 50 years) were included. 62% (261/419) of patients had positive anti-S1 IgG and 71% (277/389) had positive IGRA after primary vaccination, with 20% of patients having a positive IGRA only. Following booster, 69% (81/118) had positive anti-S1 IgG and 73% (91/124) had positive IGRA. Factors associated with low humoral response rates after primary vaccination included anti-CD20 monoclonal antibodies (P < 0.001), sphingosine 1-phsophate (S1P) receptor modulators (P < 0.001), mycophenolate (P = 0.002), and B cell lymphoma (P = 0.004); those associated with low cellular response rates included S1P receptor modulators (P < 0.001) and mycophenolate (P < 0.001). Of patients who had poor humoral response to primary vaccination, 35% (18/52) developed a significantly higher response after the booster. Only 5% (2/42) of patients developed a significantly higher cellular response to the booster dose compared to primary vaccination.

Conclusions: Humoral and cellular response rates to primary and booster SARS-CoV-2 vaccination differ among immunosuppressed patient groups. Clinical testing of cellular immunity is important in monitoring vaccine response in vulnerable populations.

Keywords: COVID-19; IGRA; Immunosuppression; SARS-CoV-2; Serology; Vaccination.

Fig. 1

Subgroup analysis of immunosuppressed patients following primary vaccination. A)Vaccine response rates in transplant recipients not on antimetabolites and those on antimetabolites (61 on mycophenolate, 1 on azathioprine). Only transplant recipients on a calcineurin inhibitor, mTOR inhibitor, mycophenolate, or other antimetabolites are plotted. B) Vaccine response rates of autoimmune disease patients, without other immunosuppressive conditions, on monotherapy with various ISMTs. Only ISMTs that apply to three or more patients are plotted. C) Vaccine response rates of immunoglobulin deficiency patients, without other immunosuppressive conditions, stratified by immunoglobulin use and sex. D) Vaccine response rates of patients with active and inactive heme malignancy, without other immunosuppressive conditions, stratified by disease subcategory and therapy status. Only disease subcategories that apply to three or more patients are plotted. E) Vaccine response rates of all patients with a history of HSCT, stratified by time between HSCT and vaccination, and activity of the malignancy. Patients with inactive disease include nine patients with primary anemia and one patient with germ cell tumor. ns, not significant; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 for pairwise comparisons as indicated; *P < 0.05, **P < 0.01, ***P < 0.001 compared to NISP, Fisher exact test. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)

Fig. 2

Change in vaccine response rates over time and after booster vaccination. A) Comparison of the change in natural log transformed anti-S1 IgG and IGRA values over time in HCW, NISP, and ISP cohorts. Error bars, mean ± standard deviation. B) Linear model fitted to the change in natural log transformed vaccine response over time versus the initial vaccine response (using the value of the assay performed closest to the vaccination date). Dotted lines denote the 95% confidence interval (CI) of the linear model mean and intercept. Note the 95% CI for slope includes 0 in both cases. C) Predicted decline in vaccine response over time (Supplementary Methods), at various starting (i.e. theoretical peak) response values after primary vaccination. D) Determination of anamnestic booster response given primary vaccination (primary dose) response (Star), based on the expected rate of change in response over time after primary vaccination (dashed line), with confidence intervals (CI) (Supplementary Methods). Booster responses that fall above the upper bound of the 70% CI (pink region) are determined to be anamnestic, while those that fall below the lower bound (blue region) are determined to be poor. E) ISP (n = 52) cohort with low anti-S1 IgG after primary vaccination separated into non-anamnestic (poor and expected) booster response (n = 34) and anamnestic booster response (n = 18), showing both the response after primary vaccination (orange dots) and after booster (blue dots). F) Distribution of age and days between primary vaccination and booster in non-anamnestic and anamnestic booster response patients. G) Anamnestic booster response rates in patients stratified by the likely primary cause of low humoral (anti-S1 IgG) response after primary vaccination (disease: heme malignancy and primary immunodeficiency patients, ISMT: solid malignancy, solid organ transplant, and autoimmune disease patients) H) Anamnestic booster response rates in patients stratified by whether there was a decrease in ISMT dosage around the time of booster vaccination. Only patients on ISMT during the primary doses are included. Panels A and B: n = 12 HCWs, 2 NISPs, 52 ISPs (IgG) and n = 15 HCWs, 1 NISP, 15 ISPs (IGRA). Panels F-H: only patients with low anti-S1 IgG after primary vaccination are included. ns, not significant; ^#P < 0.05, ^##P < 0.01, ^###P < 0.001 for pairwise comparisons as indicated, Fisher exact test. (For interpretation of the references to colour in this figure legend, the reader is referred to the web version of this article.)