Timing and Immune Status after Cellular Therapies Predict Response to COVID-19 Vaccines

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 >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 < 200 vs >200 cells/μL, 66% vs 87% (p=0.012); CD19+ B-cell count <50 vs >50 cells/μL; 33% vs 95% (p<0.001), phytohemagglutinin mitogen response <40% vs >40%, 42% vs 89% (p<0.001), and IgG <500 vs >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.

Effect of Bruton Tyrosine Kinase Inhibitor on Serologic and Cellular Immune Responses to Recombinant Zoster Vaccine

Introduction The recombinant zoster vaccine (RZV) is effective in preventing herpes zoster reactivation in the general population. We previously showed that patients with chronic lymphocytic leukemia (CLL), particularly those receiving Bruton tyrosine kinase inhibitors (BTKis), have decreased humoral immune responses following vaccination. The impact of vaccination on cellular immune responses in CLL patients is not well characterized. Understanding the effect of humoral and cellular immunity in CLL patients who are treatment naïve or receiving BTKis can inform vaccination strategies in this immunosuppressed patient population. Methods In this phase II open-label study (NCT03702231), patients with CLL who were either treatment naïve (TN) or receiving a BTKi (ibrutinib or acalabrutinib) received 2 doses of RZV via intramuscular injection at baseline and 3 months. Subjects were followed for 6 months and assessed for serologic response at 3 and 6 months. Serologic response was defined as a ≥ four-fold rise in anti-glycoprotein E (anti-gE) IgG serum titer at the 6 month timepoint. Cellular immune response was assessed by intracellular cytokine staining and flow cytometric analysis of gE-specific CD4+ T cells expressing upregulation of ≥2 effector molecules (interferon-γ, interleukin-2, tumor necrosis factor-α, and/or CD40 ligand). Cellular response was defined as ≥ two-fold rise over baseline and ≥320 net gE-specific CD4(2+) cells per million CD4+ T cells. Descriptive statistics were used to report vaccine response rates. Mann-Whitney test and Fisher's exact test were used to compare titers and response rates between different groups. Spearman r was used to measure the correlation between vaccine responses and clinical characteristics. All subjects completed an adverse event (AE) diary documenting any local (injection site) or systemic AE that started within 7 days after receiving the first and second vaccine dose. Results 106 subjects had serologic response assessment at 6 months. Baseline characteristics are shown in Table 1. The serologic response rate to RZV was significantly higher in the TN cohort (76.8%, 95% CI, 64.2-85.9; n = 56) compared to patients receiving a BTKi (40.0%, 95% CI,27.6-53.8; n = 50; P = .0002). Cellular vaccine response was assessed in 94 subjects at 6 months. Similarly, the rate of cellular immunity was significantly higher in the TN cohort (69.4%, 95% CI,55.5-80.5; n = 49) compared to patients treated with a BTKi (40.0%, 95% CI,27.0-54.5; n = 45, P = .0067). Paired serologic and cellular responses were available in 93 subjects. 68.5% (95% CI,55.3-79.3; n = 54) of subjects with a serologic response also had a positive cellular immune response, whereas 35.9% (95% CI,22.7-51.6; n = 39) of subjects attained a cellular immune response in absence of a serologic response (P = .0029) (Figure 1). Among subjects with a negative serologic response and a positive cellular immune response, 42.9% were TN (n = 6) and 57.1% (n = 8) received a BTKi. There was no difference in serologic or cellular responses between patients treated with ibrutinib and acalabrutinib (P > 0.05). Serologic antibody titers and T cell responder frequencies were weakly positively correlated (r = 0.26; 95%CI .05-.44; P = .0127). Serologic titers and T cell responses were not correlated with age, beta-2 microglobulin, absolute lymphocyte count, absolute peripheral blood CD19+, CD3+, CD4+ or CD8+ counts or serum immunoglobulin levels (IgA, IgG, IgM) (all P > 0.05). The most frequent local and systemic AEs were injection site pain (98.3%), injection site reaction (97.4%), headache (51.7%), and generalized myalgias (51.7%). Most AEs were grade 1-2 and all AEs resolved or returned to baseline within 7 days of vaccine administration. Conclusions RZV is safe in CLL patients and can induce both humoral and cellular immune responses. BTKi treatment was associated with impaired serologic and cellular vaccine responses compared to TN patients. Although BTKi therapy may inherently decrease vaccine immunogenicity, TN CLL patients could be more immunocompetent because of less advanced disease, thereby permitting more effective immune responses. The majority of patients with a positive antibody response also developed virus-specific T cells following vaccination. Approximately one third of patients without a positive serologic response developed virus reactive T cells. Figure 1 Figure 1. Disclosures Laing: Curevo Vaccine: Consultancy; MaxHealth LLC: Consultancy. Wiestner: Acerta Pharma: Research Funding; Pharmacyclics LLC: Research Funding; Merck: Research Funding; Nurix: Research Funding; Verastem: Research Funding; Genmab: Research Funding. Koelle: Merck: Research Funding; Curevo Vaccine: Other: Scientific Advisory Board ; MaxHealth LLC: Other: Scientific Advisory Board ; Oxford Immunotec: Research Funding; Sensei Biotherapeutics: Research Funding; Sanofi Pasteur: Research Funding. Sun: Genmab: Research Funding.

A Clue to Better Select Chronic Lymphocytic Leukemia Patients with Optimal Response to BNT162b2 mRNA COVID-19 Vaccine

Given the immunosuppression of chronic lymphocytic leukemia (CLL), this disease represents a challenging model for assessing the extent of serologic response to mRNA vaccination against severe Acute Respiratory Syndrome Coronavirus-2 (SARS-CoV-2). In this perspective, we assessed the efficacy of the BNT162b2 mRNA COVID-19 vaccine in 70 CLL pts followed up at single hematological institution. The study was approved by the Institutional Review Board. Serologic testing for SARS Cov2 IgG was performed using the LIAISON® SARS-CoV-2 S1/S2 IgG test (DiaSorin; Saluggia, Italy), a chemiluminescence immunoassay for the quantitative determination of anti-S1 and anti-S2 specific IgG antibodies to SARS-CoV-2. Clinical sensitivity and specificity of assay were 98.7% and 99.5% respectively. Samples were considered negative for antibody titers below 13 AU/ml. Results were compared with those of an age-matched group of subjects with no hematological malignancy (n=57). Patient samples for serology testing were obtained after median time of 14 days (range, 14-28) from the second vaccine dose. Median age of CLL pts was 72 years (range, 63-88) and 71.4% were males. The median time from CLL diagnosis to vaccination was 82.5 mo. (range, 1-280). Twenty-three pts (32.9%) were treatment naïve (TN), 36 (51.4%) on active therapy (i.e., BTKi, 22; anti-BCL2 12; PI3Ki,1; cyclophosphamide,1) and 11 (15.7%) off-therapy (i.e., 8 in complete [CR] or partial remission [PR], and 3 in CLL relapse). Of note, 9 (25.7%) of 35 pts on therapy with a pathway inhibitor (PI) at the time of vaccination had been given an anti-CD20 antibody. The vaccine elicited an antibody-mediated response in 41 (58.5%) of the 70 CLL pts. An inferior response rate [RR] (58.5% vs 100%, OR, 0.012 [0.0007-0.206];P=0.02) and a lower antibody titers (median, 58 AU/ml; range, 1.8-800 vs. 284 AU/ml; range, 14-800; P< 0.0001) were observed in CLL pts in comparison to age-matched subjects with no hematological malignancy. The RR was higher in TN (87%) or off-therapy pts with sustained clinical response (87.5%) in comparison to pts on therapy at the time of vaccination (41.7%)(<0.0001). Similar results were observed when comparison was performed in terms of antibody titers (P=0.02;Kruskall-Wallis test; Fig 1). In comparison to pts treated with a PI as monotherapy, those who received an anti-CD20 antibody in association to PI had a lower antibody response to SARS-CoV-2 vaccine (11.1% vs 53.8%; OR,0.107 [0.011-0.984];P=0.04). In univariate analysis, the following variables were significantly associated with serological response to SARS-CoV-2 vaccination: early Rai stage (i.e.,0-I) (OR, 0.36 [0.13-0.97];P=0.04), mutated IGHV status (OR,0.30 [0.10-0.88]; P=0.02), lack of active therapy - which comprised TN and off-therapy pts with sustained response - (OR,0.09 [0.03-0.32];P<0.0001), and no anti-CD20 antibody exposure preceding vaccination (OR, 013 [0.01-1.23];P=0.04). Levels of immunoglobulins or absolute values of CD3,CD4,CD8, and CD16/CD56 cells measured before the first COVID-19 vaccination were not associated to vaccine response. Of note, in pts who experienced a serological response a concomitant increase of the absolute of CD16/CD56 positive cells was observed (P=0.02). Finally, Rai stage (OR, 0.19 [0.05-0.79]; P=0.02) and treatment status (OR, 0.06 [0.02-0.27]; P<0.0001) were independent predictors of response in multivariate analysis. We used these factors to build a score that identified pts with different pattern of response to vaccine. Serologic response to SARS-CoV-2 vaccination was 100% in pts with no factor (n=21), 45% in pts. with one factor (n=38) and 36% in pts with two factors (n=11) (P<0.0001). In agreement with results of recent studies (Herishanu et al, Blood 2021; Roeker et al, Leukemia 2021;Perry et al, Blood Cancer J. 2021; Benjamini O et al, Haematologica 2021 ) our findings suggest that antibody-mediated response to COVID-19 vaccination is significantly reduced in CLL and influenced by disease activity and treatment status. The serological response to SARS-CoV-2 vaccination observed in pts. with early disease with no need of therapy may help to identify CLL pts who are expected to achieve an optimal response to COVID-19 vaccine similarly to age- and sex-matched controls. Figure 1 Figure 1. Disclosures Molica: Astrazeneca: Honoraria; Abbvie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Incidence and Predictors of Sars-Cov-2 Antibody Responses Following COVID-19 Vaccination in Allogeneic Stem Cell Transplant Recipients

Background Pharmacologic immunosuppression and incomplete immune reconstitution after allogeneic stem cell transplant (alloSCT) may impair a patient's ability to mount an immune response to vaccines, including currently available COVID-19 vaccines. Since immunocompromised patients are susceptible to severe COVID-19 and likely to respond poorly to vaccination, we sought to characterize SARS-CoV-2 antibody responses after vaccination in alloSCT patients to determine predictors of serologic response, which may inform timing of vaccine administration. Methods This retrospective analysis included adult patients who underwent alloSCT at the University of Pennsylvania between 1/1/2019 and 1/1/2021. Chart review identified patients who had received COVID-19 vaccines and had post-vaccination antibody titers drawn by July 2021 as part of routine care (n=63). Antibodies to SARS-CoV-2 spike protein receptor binding domain were detected using an assay developed at the Hospital of the University of Pennsylvania. Variables analyzed include interval between transplant date and initial vaccination, active GVHD, concurrent immunosuppressive therapy, absolute CD4 count greater than or equal to 200 cells/mm3 peri-vaccination, and total IgG greater than or equal to 400 mg/dL peri-vaccination. Immunosuppressive therapy was defined as tacrolimus, rituximab, ruxolitinib, prednisone 10 mg daily or greater, or extracorporeal photopheresis. Predictors of positive antibody response were assessed using a multivariate, binary logistic regression. Results Median transplant to vaccine interval was 458 days (range 125 to 813) for the 63 vaccinated patients with serologies available. GVHD was present in 23/63 (37%), and 19/63 (30%) were receiving immunosuppressive therapies at the time of vaccination. CD4 count greater than 200 cells/mm3 was observed in 49 patients (78%), and total IgG greater than 400 mg/dL was observed in 51 patients (81%). In total, 50/63 patients (79%) were positive for SARS-CoV-2 IgG antibodies. Positive serologies were observed in 41/49 (84%) with CD4 counts greater than 200 cells/mm3, compared to 9/14 (64%) with CD4 less than 200 cells/mm3. Our model found that peri-vaccination CD4 count greater than 200 cells/mm3 was a significant predictor of positive SARS-CoV-2 IgG serologies in this population (OR 2.14, 97.5% CI = 0.7 to 3.8, p= 0.005). Transplant to vaccine interval, total IgG levels, GVHD status, and immunosuppressive therapies were not significant predictors of serologic response. As of July 2021 no patients had developed COVID-19 after vaccination, regardless of serologic response. Conclusions This retrospective observational study demonstrates that the majority of alloSCT patients vaccinated against COVID-19 within 2 years of transplant, including those with active GVHD and on immunosuppressive therapies, can mount serologic responses. CD4 count greater than 200 cells/mm3 is a significant predictor of positive serologic response, though even among patients with CD4 counts under 200 cells/mm3 over 60% developed SARS-CoV-2 IgG antibodies. Disclosures Perry: Incyte: Consultancy, Speakers Bureau; Abbvie,: Speakers Bureau; Kadmon: Consultancy. Pratz: University of Pennsylvania: Current Employment; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Cellgene: Consultancy, Honoraria; Novartis: Consultancy; BMS: Consultancy, Honoraria; Agios: Consultancy; Millenium: Research Funding. Luger: Syros: Honoraria; Agios: Honoraria; Daiichi Sankyo: Honoraria; Jazz Pharmaceuticals: Honoraria; Brystol Myers Squibb: Honoraria; Acceleron: Honoraria; Astellas: Honoraria; Pfizer: Honoraria; Onconova: Research Funding; Celgene: Research Funding; Biosight: Research Funding; Hoffman LaRoche: Research Funding; Kura: Research Funding. Perl: Astellas: Consultancy, Research Funding; Loxo: Consultancy; AbbVie: Consultancy, Research Funding; Syndax: Consultancy; BMS/Celgene: Consultancy; Roche: Consultancy; Fujifilm: Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Forma: Consultancy; Arog: Research Funding; Genentech: Consultancy; Actinium: Consultancy; Onconova: Consultancy; Sumitomo Dainippon: Consultancy. Porter: ASH: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; DeCart: Membership on an entity's Board of Directors or advisory committees; Genentech: Current equity holder in publicly-traded company, Ended employment in the past 24 months; American Society for Transplantation and Cellular Therapy: Honoraria; Kite/Gilead: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; National Marrow Donor Program: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding; Tmunity: Patents & Royalties; Wiley and Sons Publishing: Honoraria. Hexner: Blueprint medicines: Membership on an entity's Board of Directors or advisory committees, Research Funding; PharmaEssentia: Membership on an entity's Board of Directors or advisory committees; Tmunity Therapeutics: Research Funding. Frey: Sana Biotechnology: Consultancy; Kite Pharma: Consultancy; Syndax Pharmaceuticals: Consultancy; Novartis: Research Funding.

Dynamics of the COVID-19 Clinical Findings and the Serologic Response

The factors affecting the dynamics of lengthening of symptoms and serologic responses are not well known. In order to see how the serologic responses change in relation to the clinical features, we selected a group of 472 adults with a positive IgM/IgG antibody test result from a baseline study of the anti-SARS-CoV-2 seropositivity, assessed their COVID-19 and past medical histories, and followed them up in about 3 months. Nearly one-fourth of the subjects were asymptomatic at the baseline; 12.8% subjects became symptomatic at the follow-up (FU) when 39.8% of the subjects had some persisting symptoms. At the baseline, 6.1% showed anti-SARS-CoV-2 IgM positive, 59.3% only for IgG, and 34.5% for both. At the FU, these figures declined to 0.6, 54.0, and 4.4%, respectively, with the mean IgM and IgG levels declining about 6.3 and 2.5 folds. Blood group A was consistently linked to both sustaining and flipping of the gastrointestinal (GI) and respiratory symptoms. The baseline IgM level was associated with GI symptoms and pre-existing cirrhosis in multivariate models. Both of the baseline and FU IgG levels were strongly associated with age, male, and lung involvement seen in chest computed tomography (CT)-scan. Finally, as compared with antibody decayers, IgM sustainers were found to be more anosmic [mean difference (MD): 11.5%; P = 0.047] with lower body mass index (BMI) (MD: 1.30 kg/m2; P = 0.002), while IgG sustainers were more commonly females (MD: 19.2%; P = 0.042) with shorter diarrhea duration in the FU (MD: 2.8 days; P = 0.027). Our findings indicate how the anti-SARS-CoV-2 serologic response and COVID-19 clinical presentations change in relation to each other and basic characteristics.

Impact of Diabetes Status on Immunogenicity of Trivalent Inactivated Influenza Vaccine in Older Adults

Individuals with type 2 diabetes mellitus experience high rates of influenza virus infection and complications. We compared the magnitude and duration of serologic response to trivalent influenza vaccine in adults aged 50-80 with and without type 2 diabetes mellitus. Serologic response to influenza vaccination was similar in both groups: greater fold-increases in antibody titer occurred among individuals with lower pre-vaccination antibody titers. Waning of antibody titers was not influenced by diabetes status.