Timing and Immune Status after Cellular Therapies Predict Response to COVID-19 Vaccines
Authors: Tamari Roni , Politikos Ioannis , Knorr David , Vardhana Santosha , Young Jennifer , Marcello Leeann , Doddi Sital , Devlin Sean M , Ramanathan Lakshmi , Pessin Melissa S. , Dunn Erica , Palazzo Meighan A. , Bravo Christina , Papanicolaou Genovefa A. , Kamboj Mini , Perales Miguel-Angel , Chung David J. , Shah Gunjan L 
Published: November 2021

Abstract
BACKGROUND
Cellular therapies (allogeneic hematopoietic cell transplantation, allo-HCT, autologous hematopoietic cell transplantation, auto-HCT, and chimeric antigen receptor T cell therapy, CAR T) render patients severely immunocompromised for extended periods post-therapy. Emerging data suggest reduced immune responses to COVID-19 vaccines among patients with hematologic malignancies, but data for cellular therapy recipients are sparse. We therefore assessed immune responses to mRNA COVID-19 vaccines among patients who underwent cellular therapies at our center to identify predictors of response.
PATIENT AND METHODS
In this observational prospective study, anti-SARS-CoV-2 spike IgG antibody titers and circulating neutralizing antibodies were measured at 1 and 3 months after the 1 st dose of vaccination. CD4, CD19, mitogen, and IgG levels from patient samples collected prior to initiation of vaccination in a subset of patients were used to assess immune recovery and association with response. A concurrent healthy donor (HD) cohort provided control response rates.
RESULTS
Allo-HCT (N=149), auto HCT (N=61), and CAR T (N=7) patients vaccinated between 12/22/2020- 2/28/2021 with mRNA vaccines and 69 HD participated in this study. At 3 months, 188 pts (87%) had a positive anti-SARS-CoV-2 spike IgG levels (median 5,379 AU/mL, IQR 451-15,750), and 139 (77%) had a positive neutralization Ab assay (median 93%, IQR 36-96%). All HD (100%) had a positive anti-SARS-CoV-2 spike IgG and a positive neutralization Ab assay with median levels of 8,011 AU/mL (IQR 4573-11,159) and 96% (IQR 78- 96%), respectively.
Time from vaccination to cellular therapy was associated with response; 67% of patients vaccinated in the first 12 months post-cellular therapy (N=42) mounted a serologic response, compared with patients vaccinated between 12-24 (89%) (N=45), 24-36 (91%) (N=32) and &gt;36 (93%) (N=98) months post-treatment, p= 0.001 (figure 1). Patients with immune parameters below the recommended threshold for vaccinations post-cellular therapies were also less likely to mount a response (figure 2): CD4+ T-cell count &lt; 200 vs &gt;200 cells/μL, 66% vs 87% (p=0.012); CD19+ B-cell count &lt;50 vs &gt;50 cells/μL; 33% vs 95% (p&lt;0.001), phytohemagglutinin mitogen response &lt;40% vs &gt;40%, 42% vs 89% (p&lt;0.001), and IgG &lt;500 vs &gt;500 mg/dl, 71% vs 91% (p=0.003). Patient age, gender, prior COVID-19 infection, treatment with IVIG, and type of mRNA COVID-19 vaccine were not associated with the likelihood of serologic response.
CONCLUSION
This largest cohort to date, demonstrates that COVID-19 vaccine responses of cellular therapy recipients are reduced compared to healthy control and response varies based on time interval from cellular therapy and immune function at the time of vaccination, underscoring the importance of monitoring immune status parameters, as well as qualitative measures (neutralizing Ab) of vaccine response, in informing clinical decisions, including the indication for booster vaccines.
Figure 1 Figure 1.

Disclosures
Politikos: Merck: Research Funding; ExcellThera, Inc: Other: Member of DSMB - Uncompensated. Vardhana: Immunai: Membership on an entity's Board of Directors or advisory committees. Perales: Equilium: Honoraria; Cidara: Honoraria; Sellas Life Sciences: Honoraria; Miltenyi Biotec: Honoraria, Other; Celgene: Honoraria; MorphoSys: Honoraria; Takeda: Honoraria; Incyte: Honoraria, Other; Karyopharm: Honoraria; Kite/Gilead: Honoraria, Other; Merck: Honoraria; NexImmune: Honoraria; Novartis: Honoraria, Other; Medigene: Honoraria; Omeros: Honoraria; Servier: Honoraria; Bristol-Myers Squibb: Honoraria; Nektar Therapeutics: Honoraria, Other. Shah: Amgen: Research Funding; Janssen Pharmaceutica: Research Funding.