Association of Host Factors With Antibody Response to Seasonal Influenza Vaccination in Allogeneic Hematopoietic Stem Cell Transplant Patients

Janina Linnik, Mohammedyaseen Syedbasha, Hans-Michael Kaltenbach, Dominik Vogt, Yvonne Hollenstein, Lukas Kaufmann, Nathan Cantoni, Sabine Ruosch-Girsberger, Antonia M S Müller, Urs Schanz, Thomas Pabst, Georg Stüssi, Maja Weisser, Jörg Halter, Jörg Stelling, Adrian Egli, Janina Linnik, Mohammedyaseen Syedbasha, Hans-Michael Kaltenbach, Dominik Vogt, Yvonne Hollenstein, Lukas Kaufmann, Nathan Cantoni, Sabine Ruosch-Girsberger, Antonia M S Müller, Urs Schanz, Thomas Pabst, Georg Stüssi, Maja Weisser, Jörg Halter, Jörg Stelling, Adrian Egli

Abstract

Background: Influenza vaccination efficacy is reduced after hematopoietic stem cell transplantation (HSCT) and patient factors determining vaccination outcomes are still poorly understood.

Methods: We investigated the antibody response to seasonal influenza vaccination in 135 HSCT patients and 69 healthy volunteers (HVs) in a prospective observational multicenter cohort study. We identified patient factors associated with hemagglutination inhibition titers against A/California/2009/H1N1, A/Texas/2012/H3N2, and B/Massachusetts/2012 by multivariable regression on the observed titer levels and on seroconversion/seroprotection categories for comparison.

Results: Both regression approaches yielded consistent results but regression on titers estimated associations with higher precision. HSCT patients required 2 vaccine doses to achieve average responses comparable to a single dose in HVs. Prevaccination titers were positively associated with time after transplantation, confirming that HSCT patients can elicit potent antibody responses. However, an unrelated donor, absolute lymphocyte counts below the normal range, and treatment with calcineurin inhibitors lowered the odds of responding.

Conclusions: HSCT patients show a highly heterogeneous vaccine response but, overall, patients benefited from the booster shot and can acquire seroprotective antibodies over the years after transplantation. Several common patient factors lower the odds of responding, urging identification of additional preventive strategies in the poorly responding groups.

Clinical trials registration: NCT03467074.

Keywords: categorical regression; graft-versus-host disease; hemagglutination inhibition titer; hematopoietic stem cell transplantation; immunosuppression; influenza; sequential model; seroconversion; vaccination.

© The Author(s) 2021. Published by Oxford University Press for the Infectious Diseases Society of America.

Figures

Figure 1.
Figure 1.
Overview of patient recruitment. All patients participated in only 1 of the seasons.
Figure 2.
Figure 2.
Antibody titers in hematopoietic stem cell transplant (HSCT) patients and healthy volunteers (HVs). A and B, Hemagglutination inhibition (HI) titers against 3 different influenza strains (A) in HSCT patients and (B) in HVs from 2 consecutive flu seasons. C, Average effect of vaccination on HI titer increase (relative to influenza strain- and season-specific baseline levels) in HSCT patients and HVs. Effects are expressed as the odds ratio for an increase in at least 1 titer level on days 7, 30, 60, and 180 compared to day 0. D, Estimated differences in vaccine response between time points, season, and influenza strains. Effects are expressed as the odds ratio for an HI titer increase by at least 1 level compared to the reference, specifically, day 60 vs day 30, season 2015/2016 vs 2014/2015 (by strain), A/California titers vs A/Texas titers, and B/Massachusetts titers vs others (by season).
Figure 3.
Figure 3.
Host factors associated with vaccine response in HSCT patients. A, Illustrative explanation of the compared models, the commonly used binary regression on seroconversion vs titer regression on HI titer levels. An effect inferred from binary logistic regression can be interpreted as the odds ratio between groups A and B for showing seroconversion. In contrast, an effect inferred from titer regression used in this study can be interpreted as the odds ratio for showing HI when HI has also been observed in all preceding dilution steps (ie, increase in HI titer by at least 1 level). Alternatively, effects can also be interpreted as a shift in antibody concentration between the compared subpopulations. Because all serum samples are diluted equally, this shift is the same at all dilution steps. For details on the regression models, see Supplementary Material. Note that we corrected for baseline titers when analyzing postvaccination titers because we want to infer effects on the relative HI titer increase, which means that we compared patients with the same baseline titer levels. In general, in the multivariable setting, an inferred effect gives the odds ratio between groups A and B for showing a higher HI titer/seroconversion/seroprotection when all the other variables are held constant. B, Variable importance in terms of contribution to the explained residual deviance of all investigated host factors. Results can only be compared within each model but not across models. ∗Only 3 patients received rituximab. C, Estimated effects for important patient factors. All inferred effects are shown in Supplementary Figure 5. Abbreviations: cGVHD, chronic graft-versus-host disease; CI, confidence interval; HI, hemagglutination inhibition; HSCT, hematopoietic stem cell transplantation.
Figure 4.
Figure 4.
Association of the time after transplantation (time post-HSCT) and absolute lymphocyte count with vaccination outcomes. A, Comparison of variable importance (in terms of contribution to the explained residual deviance) for HI baseline titers (day 0) vs HI titer response (days 30 and 60). While multiple host factors determined vaccine response, baseline titers were mostly explained by the time after transplantation. The association of time post-HSCT was significantly stronger for HI titers against B/Massachusetts compared to the influenza A strains (P=.001). There was no significant difference between A/California (H1N1) and A/Texas (H3N2) (P=.340). B, Scatterplot showing lymphocyte counts by time after transplantation for the investigated HSCT patient population. For patients with missing values, data show the mean and standard deviation of imputed values. Data were fitted by a smoothing spline. C, Association of absolute lymphocyte count with response and baseline titers. Normal lymphocyte counts range from 1000 to 4800 cells per μL blood. Shaded area indicates 95% confidence intervals in each graph. Abbreviations: cGVHD, chronic graft-versus-host disease; CI, confidence interval; HI, hemagglutination inhibition; HSCT, hematopoietic stem cell transplant.

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