Kinetics of Anti-Sars-Cov-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2; A Prospective Study in 283 Health Workers

Abstract Background: Levels of neutralizing antibodies (NΑbs) against SARS-CoV-2 correlate with clinically relevant immune protection from COVID-19. However, a slight decline in antibody titers has become evident even at one month following the second BNT162b2 shot, whereas increased time since the second vaccine dose has been associated with decreased NAb activity against SARS-CoV-2 variants. The aim of this study was to investigate the kinetics of NAbs and anti-S-RBD IgGs after vaccination of health workers with the BNT162b2 mRNA vaccine over a period of up to three months after the second shot. The possible influence of comorbidities, characteristics of the subjects, co-medication, and adverse events was also investigated. Methods: All participants have been enrolled in a large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination. Main inclusion criteria for participation in this study were eligibility for vaccination according to the national program for COVID-19, age above 18 years, and ability to sign the informed consent form. Major exclusion criteria included the presence of active malignant disease, immunosuppressive therapy, and end-stage renal disease. According to National Immunization Program, access to the BNT162b2 mRNA vaccine was available to anyone 18 years of age or older. NΑbs and anti-S-RBD IgG titers were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111), using FDA approved methods, namely, cPass™ SARS-CoV2 NAbs Detection Kit (GenScript, Piscataway, NJ, USA) and Elecsys Anti-SARS-CoV-2 S assay (Roche Diagnostics GmbH, Mannheim, Germany), respectively. Results: In total, 283 health workers (median age 48 years) were included in this study. On D1, immediately before vaccination, the median neutralizing inhibition was 14.2%, while 29 individuals (10.2%) had inhibition levels above the positive threshold of the method (30%). NAbs showed a rapid increase from D8 to D36 on a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50 a slight decrease in NAbs values was detected and it became more prominent between D50 and D111, when the rate of decline was determined at -0.11 per day. The median (SD) NAbs titers at D111 were 92.7% (11.8). Paired grouped comparisons using the Wilcoxon signed ranks test showed statistically significant differences in inhibition levels between pairs: D36 vs. D50, D36 vs. D111, and D50 vs. D111 (for all three comparisons p<0.001) (Figure A). A similar pattern was also observed for anti-S-RBD antibodies. It is worth mentioning that compared to NAbs, the maximum anti-S-RBD levels were reached two weeks later, i.e., at D36. Interestingly, anti-S-RBDs showed a steeper increase during D22-D36 and a lower decline rate during D36-D111. All consecutive pairs comparison, using Wilcoxon's test, led to p-values<0.001 (Figure B). There was an almost linear relationship between NAbs and anti-S-RBD at D22 (Spearman's rho correlation coefficient equal to 0.718). However, their relationship became non-linear from D36; this is due to the steep increase in anti-S-RBD levels that was observed during the D22-D36 period, while the corresponding increase rate for NAbs was much lower. Also, the decline of anti-S-RBD titers was lower compared to that of NAbs. The composite effect of these functions led to a non-linear pattern. Furthermore, prior COVID-19 and younger age were associated with superior antibody responses over time. Regarding those with previous positive PCR for SARS-CoV-2, significantly higher levels were observed at the initial phase (D1, D8) (Mann-Whitney p-values<0.001) and at D111 (p=0.046). From D50 there was a trend for a slower decline rate for those with previous positive PCR. Younger individuals had higher antibody titers at D36, D50, and D111, which is due to a slower decline in NAbs compared to the older group of participants (for all three comparisons, Wilcoxon's p-values were<0.05). Conclusions: We found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals. Our longitudinal study is ongoing to determine the time point of NAbs reduction below the positivity threshold; then a booster vaccine dose might be necessary to maintain humoral immunity against SARS-CoV-2. Figure 1 Figure 1. Disclosures Terpos: Amgen: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; BMS: Honoraria; Sanofi: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria; Karyopharm: Honoraria; Genesis: Honoraria; Sanofi: Honoraria; GSK: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Dimopoulos: Takeda: Honoraria; Beigene: Honoraria; Amgen: Honoraria; BMS: Honoraria; Janssen: Honoraria.

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Kinetics of Anti-SARS-CoV-2 Antibody Responses 3 Months Post Complete Vaccination with BNT162b2; A Prospective Study in 283 Health Workers

Cells ◽

10.3390/cells10081942 ◽

2021 ◽

Vol 10 (8) ◽

pp. 1942

Author(s):

Evangelos Terpos ◽

Ioannis P. Trougakos ◽

Vangelis Karalis ◽

Ioannis Ntanasis-Stathopoulos ◽

Sentiljana Gumeni ◽

...

Keyword(s):

Neutralizing Antibodies ◽

Health Workers ◽

Antibody Responses ◽

Healthy Individuals ◽

Younger Age ◽

Constant Rate ◽

Rate Of Decline ◽

A Prospective Study ◽

Kinetics Of ◽

Over Time

The aim of this study was to investigate the kinetics of neutralizing antibodies (NAbs) and anti-SARS-CoV-2 anti-S-RBD IgGs up to three months after the second vaccination dose with the BNT162b2 mRNA vaccine. NAbs and anti-S-RBD levels were measured on days 1 (before the first vaccine shot), 8, 22 (before the second shot), 36, 50, and three months after the second vaccination (D111) (NCT04743388). 283 health workers were included in this study. NAbs showed a rapid increase from D8 to D36 at a constant rate of about 3% per day and reached a median (SD) of 97.2% (4.7) at D36. From D36 to D50, a slight decrease in NAbs values was detected and it became more prominent between D50 and D111 when the rate of decline was determined at −0.11 per day. The median (SD) NAbs value at D111 was 92.7% (11.8). A similar pattern was also observed for anti-S-RBD antibodies. Anti-S-RBDs showed a steeper increase during D22–D36 and a lower decline rate during D36–D111. Prior COVID-19 infection and younger age were associated with superior antibody responses over time. In conclusion, we found a persistent but declining anti-SARS-CoV-2 humoral immunity at 3 months following full vaccination with BNT162b2 in healthy individuals.

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The Slower Antibody Response in Myelofibrosis Patients after Two Doses of mRNA SARS-CoV-2 Vaccine Calls for a Third Dose

Biomedicines ◽

10.3390/biomedicines9101480 ◽

2021 ◽

Vol 9 (10) ◽

pp. 1480

Author(s):

Fabio Fiorino ◽

Anna Sicuranza ◽

Annalisa Ciabattini ◽

Adele Santoni ◽

Gabiria Pastore ◽

...

Keyword(s):

Healthy Subjects ◽

Vaccine Dose ◽

Antibody Responses ◽

Inhibition Activity ◽

Specific Antibodies ◽

Slow Kinetics ◽

Binding Inhibition ◽

Specific Igg ◽

The Impact ◽

Kinetics Of

Immunization with mRNA SARS-CoV-2 vaccines has been highly recommended and prioritized in fragile subjects, including patients with myelofibrosis (MF). Available data on the vaccine immune response developed by MF patients and the impact of ruxolitinib treatment are still too fragmented to support an informed decision on a third dose for this category of subjects. Here, we show that 76% of MF patients develop spike-specific IgG after the second mRNA SARS-CoV-2 vaccine dose, but the response has a slower kinetics compared to healthy subjects, suggesting a reduced capability of their immune system to promptly react to vaccination. A reduced ACE2/RBD binding inhibition activity of spike-specific antibodies was also observed, especially in ruxolitinib-treated patients. Our results, showing slow kinetics of antibody responses in MF patients following vaccination with mRNA SARS-CoV-2 vaccines, support the need for a third vaccine dose.

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For Better or for Worse: COVID-19 Vaccination during or Early after (Immuno-) Chemotherapy or Hematopoietic Progenitor Cell Transplantation

Blood ◽

10.1182/blood-2021-150379 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 754-754

Author(s):

Sabine Haggenburg ◽

Birgit I. Lissenberg-Witte ◽

Robert S. Van Binnendijk ◽

Gerco Den Hartog ◽

Bhoekhan S. Michel ◽

...

Keyword(s):

Board Of Directors ◽

Research Funding ◽

Booster Vaccination ◽

Steering Committee ◽

Antibody Responses ◽

Hematopoietic Progenitor Cell ◽

High Dose ◽

Advisory Committees ◽

Humoral Immune ◽

Antibody Titers

Abstract Background: Patients with hematologic conditions have a high mortality rate when infected with SARS-CoV-2 (Williamson, Nature 2020). Protection of this group from severe COVID-19 is therefore important. However, according to available vaccination guidelines, one should consider to postpone vaccination of patients on or early after chemotherapy, hematopoietic progenitor cell transplantation (HCT) or with graft versus host disease, because of anticipated poor efficacy. Based on previous (non-COVID-19) vaccination studies among hematology patients, we hypothesized that a significant group of patients may acquire sufficient protection following COVID-19 vaccination, despite disease and therapy related immunodeficiencies. Methods: We conducted a prospective cohort study with 17 cohorts of hematology patients of particular risk for severe COVID-19 who are considered to have no or limited benefit from vaccination. We evaluated humoral immune responses following 2 doses (28 days apart) of the mRNA-1273 vaccine (Moderna/Spikevax) in 722 patients, at baseline and 28 days after each vaccination as SARS-COV-2 S1- (spike)-specific serum IgG antibody concentrations by bead-based multiplex immune assay. The threshold for adequate antibody response is set at ≥300 binding antibody units (BAU)/ml according to the international WHO standard, and is associated with virus plaque reducing neutralization test titers of ≥40 PRNT 50. This study is registered as EudraCT 2021-001072-41, NL76768.029.21. Results: Patient cohorts and corresponding vaccine responses are depicted in Table 1. Vaccine efficacy, as measured by antibody concentration, 4 weeks after the 2 nd mRNA-1273 vaccination was available for 691 out of 722 participants. The majority of patients (389/691; 56%) obtained an S1 antibody titer that is considered adequate (≥300 BAU/ml). Twenty-nine percent of patients (198/691) did not seroconvert (S1 antibody titer <10 BAU/ml), while the remaining 15% (104/691) did seroconvert but not to sufficient levels (10-300 BAU/ml). Adequate responses were observed in the majority of patients with sickle cell disease using hydroxyurea, chronic myeloid leukemia (CML) receiving tyrosine kinase inhibitor therapy, acute myeloid leukemia (AML) on or early after high dose chemotherapy, patients with myeloproliferative disorders on ruxolitinib, patients with multiple myeloma (MM), including those on daratumumab and those early after high-dose melphalan and autologous HCT, patients with untreated chronic lymphocytic leukemia (CLL), and patients with chronic GvHD. Insufficient or absent antibody responses were observed in the majority of AML patients receiving hypomethylating agents, CLL patients on ibrutinib, patients with B-cell non-Hodgkin's Lymphoma (NHL) during or shortly after rituximab-chemotherapy or following BEAM chemotherapy and autologous HCT, allogeneic HCT recipients <6 months after transplantation, and CAR-T cell therapy recipients. However, even in these low-responder groups considerable numbers of patients did mount sufficient antibody titers. In others, titers increased after each of both vaccinations, suggesting that booster vaccination may enhance antibody titers to sufficient levels (Figure 1). Conclusion: Vaccination with mRNA-1273 had significant efficacy in severely immunocompromised hematology patients. Adequate humoral immune responses after two dose vaccination were reached in the majority of patients receiving therapy for sickle cell disease, MPD, MM, CML and AML, in patients early after HCT and in patients with GvHD. We are currently evaluating clinical and immunologic parameters that correlate with sufficient antibody responses, pseudovirus neutralization and SARS-COV-2-specific B and T cell numbers, phenotype and function. Per study design, all participants with absent or insufficient antibody responses (<300 BAU/ml) will receive a booster vaccination 5 months after initial vaccination, and antibody responses to booster vaccinations will be presented as well. Unlike currently available guidelines, COVID-19 vaccination should not be postponed. Moreover, as antibody titers increased after each of both vaccinations, booster vaccination of patients with absent or insufficient antibody responses seems warranted. Figure 1 Figure 1. Disclosures Mutsaers: AstraZeneca: Research Funding; BMS: Consultancy. Van Meerten: Janssen: Consultancy; Kite, a Gilead Company: Honoraria. Kater: BMS, Roche/Genentech: Other: Ad Board, , Research Funding; Janssen, AstraZeneca: Other: Ad Board, steering committee, Research Funding; Abbvie: Honoraria, Other: Ad Board, Research Funding; Genmab, LAVA: Other: Ad Board, Steering Committee. Zweegman: Oncopeptides: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Nijhof: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene/Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees.

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Antibody responses induced by trivalent inactivated influenza vaccine among pregnant and non-pregnant women in Thailand: A matched cohort study

PLoS ONE ◽

10.1371/journal.pone.0253028 ◽

2021 ◽

Vol 16 (6) ◽

pp. e0253028

Author(s):

Sutthichai Nakphook ◽

Jayanton Patumanond ◽

Manash Shrestha ◽

Kriengkrai Prasert ◽

Malinee Chittaganpitch ◽

...

Keyword(s):

Influenza Vaccine ◽

Pregnant Women ◽

Study Groups ◽

Antibody Responses ◽

P Values ◽

Post Vaccination ◽

Vaccination Recommendations ◽

Influenza A H1n1 ◽

Antibody Titers ◽

Antibody Levels

Background We compared influenza antibody titers among vaccinated and unvaccinated pregnant and non-pregnant women. Methods During 1st June– 30th September 2018, four groups of cohort participants—vaccinated pregnant, unvaccinated pregnant, vaccinated non-pregnant, and unvaccinated non-pregnant women were selected by matching age, gestational age, and the week of vaccination. Serum antibody titers against each strain of 2018 Southern Hemisphere inactivated trivalent influenza vaccine (IIV3) were assessed by hemagglutination inhibition (HI) assay on Day 0 (pre-vaccination) and Day 28 (one month post-vaccination) serum samples. Geometric mean titer (GMT), GMT ratio (GMR), seroconversion (defined as ≥4 fold increase in HI titer), and seroprotection (i.e. HI titer ≥1:40) were compared across the study groups using multilevel regression analyses, controlling for previous year vaccination from medical records and baseline antibody levels. Results A total of 132 participants were enrolled in the study (33 in each of the four study groups). The baseline GMTs for influenza A(H1N1), A(H3N2), and B vaccine strains were not significantly different among all four groups (all p-values >0.05). After one month, both vaccinated groups had significantly higher GMT, GMR, seroconversion, and seroprotection than their unvaccinated controls (all p-values <0.05). The seroconversion rate was over 60% for any strain among the vaccinated groups, with the highest (88.8%) observed against A(H1N1) in the vaccinated pregnant group. Similarly, at least 75% of the vaccinated participants developed seroprotective antibody levels against all three strains; the highest seroprotection was found against A(H3N2) at 92.6% among vaccinated non-pregnant participants. Antibody responses (post-vaccination GMT, GMR, seroconversion, and seroprotection) were not significantly different between pregnant and non-pregnant women for all three strains of IIV3 (all p>0.05). Conclusions The 2018 seasonal IIV3 was immunogenic against all three vaccine strains and pregnancy did not seem to alter the immune response to IIV3. These findings support the current influenza vaccination recommendations for pregnant women.

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Robust spike antibody responses and increased reactogenicity in seropositive individuals after a single dose of SARS-CoV-2 mRNA vaccine

10.1101/2021.01.29.21250653 ◽

2021 ◽

Cited By ~ 4

Author(s):

Florian Krammer ◽

Komal Srivastava ◽

Viviana Simon ◽

Keyword(s):

Single Dose ◽

Antibody Response ◽

Vaccine Dose ◽

Antibody Responses ◽

Short Report ◽

The Past ◽

Antibody Titers

AbstractAn important question is arising as COVID-19 vaccines are getting rolled out: Should individuals who already had a SARS-CoV-2 infection receive one or two shots of the currently authorized mRNA vaccines. In this short report, we show that the antibody response to the first vaccine dose in individuals with pre-existing immunity is equal to or even exceeds the titers found in naïve individuals after the second dose. We also show that the reactogenicity is significantly higher in individuals who have been infected with SARS-CoV-2 in the past. Changing the policy to give these individuals only one dose of vaccine would not negatively impact on their antibody titers, spare them from unnecessary pain and free up many urgently needed vaccine doses.

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Humoral immunity to HIV-1: kinetics of antibody responses in chronic infection reflects capacity of immune system to improve viral set point

Blood ◽

10.1182/blood-2004-01-0251 ◽

2004 ◽

Vol 104 (6) ◽

pp. 1784-1792 ◽

Cited By ~ 31

Author(s):

A. Trkola

Keyword(s):

Immune System ◽

Humoral Immunity ◽

Chronic Infection ◽

Antibody Responses ◽

Set Point ◽

Kinetics Of ◽

Hiv 1

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Antibody responses induced by trivalent inactivated influenza vaccine among pregnant and non-pregnant women in Thailand: a matched cohort study

10.1101/2021.04.07.21255057 ◽

2021 ◽

Author(s):

Sutthichai Nakphook ◽

Jayanton Patumanond ◽

Manash Shrestha ◽

Kriengkrai Prasert ◽

Malinee Chittaganpitch ◽

...

Keyword(s):

Influenza Vaccine ◽

Pregnant Women ◽

Study Groups ◽

Antibody Responses ◽

P Values ◽

Post Vaccination ◽

Vaccination Recommendations ◽

Influenza A H1n1 ◽

Antibody Titers ◽

Antibody Levels

AbstractBackgroundWe compared influenza antibody titers among vaccinated and unvaccinated pregnant and non-pregnant women.MethodsDuring 1st June – 30th September 2018, four groups of cohort participants - vaccinated pregnant, unvaccinated pregnant, vaccinated non-pregnant, and unvaccinated non-pregnant women were selected by matching age, gestational age, and the week of vaccination. Serum antibody titers against each strain of 2018 Southern Hemisphere inactivated trivalent influenza vaccine (IIV3) were assessed by hemagglutination inhibition (HI) assay on Day 0 (pre-vaccination) and Day 28 (one month post-vaccination) serum samples. Geometric mean titer (GMT), GMT ratio (GMR), seroconversion (defined as ≥4 fold increase in HI titer), and seroprotection (i.e. HI titer ≥1:40) were compared across the study groups using multilevel regression analyses, controlling for previous year vaccination from medical records and baseline antibody levels.ResultsA total of 132 participants were enrolled in the study (33 in each of the four study groups). The baseline GMTs were similar for influenza A(H1N1), A(H3N2), and B vaccine strains among all four groups (all p-values >0.05). After one month, both vaccinated groups had significantly higher GMT, GMR, seroconversion, and seroprotection than their unvaccinated controls (all p-values <0.05). The seroconversion rate was over 60% for any strain among the vaccinated groups, with the highest (88.8%) observed against A(H1N1) in the vaccinated pregnant group. Similarly, at least 75% of the vaccinated participants developed seroprotective antibody levels against all three strains; the highest seroprotection was found against A(H3N2) at 92.6% among vaccinated non-pregnant participants. Pregnant women had similar antibody responses (post-vaccination GMT, GMR, seroconversion, and seroprotection) to non-pregnant women for all three strains of IIV3 (all p>0.05).ConclusionsThe 2018 seasonal IIV3 was immunogenic against all three vaccine strains and pregnancy did not seem to alter the immune response to IIV3. These findings support the current influenza vaccination recommendations for pregnant women.

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Poor Neutralizing Antibody Responses in Patients with CLL, NHL and HL after Vaccination Against Sars-Cov-2; A Prospective Study in 132 Patients

Blood ◽

10.1182/blood-2021-145110 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3752-3752

Author(s):

Evangelos Terpos ◽

Maria Gavriatopoulou ◽

Despina Fotiou ◽

Chara Giatra ◽

John V. Asimakopoulos ◽

...

Keyword(s):

Antibody Response ◽

Prospective Study ◽

Active Treatment ◽

Research Funding ◽

Hematological Malignancies ◽

Viral Inhibition ◽

Age And Gender ◽

And Gender ◽

Humoral Responses ◽

Kinetics Of

Abstract Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies, especially under therapy with monoclonal antibodies targeting B-cells. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with chronic lymphocytic leukemia (CLL), Non-Hodgkin Lymphoma (NHL) and Hodgkin's Lymphoma (HL) after vaccination with the mRNA BNT162b2 vaccine, up to 50 days post their first vaccine dose. Methods: This is a large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and patients with hematological malignancies. We report here the results in CLL, NHL and HL patients in comparison to age- and gender-matched controls who were vaccinated at the same time period (January to May 2021). After vein puncture, the serum of both patients and controls was collected on day 1 (D1; before the first BNT162b2 dose), on day 22 (D22; before the second dose of the BNT162b2) and on day 50 (D50; 3 weeks post second dose of the BNT162b2). Serum was separated within 4 hours from blood collection and stored at -80°C until the day of measurement. NAbs against SARS-CoV-2 were measured using FDA approved methodology (ELISA, cPass™ SARS-CoV-2 NAbs Detection Kit; GenScript, Piscataway, NJ, USA) on the abovementioned timepoints. A NAb titer of at least 30% is considered as positive, according to manufacturer, whereas a NAb titer of at least 50% has been associated with clinically relevant viral inhibition [Walsh et al. N Engl J Med 2020, 383, 2439-50]. Samples of the same individual were measured in the same ELISA plate. Results: We evaluated 132 patients with CLL/Lymphomas after vaccination with the BNT162b2. Patient population included 53 with CLL, 57 with NHL and 22 with HL, while 214 healthy controls, of similar age and gender, were also studied. At the time of vaccination, 30% (n=40) of patients had asymptomatic disease and out of 92 symptomatic patients, 49% (n=45) were on active treatment. Vaccination with two doses of the BNT162b2 led to lower production of NAbs against SARS-CoV-2 in patients compared with controls, both on day 22 and on day 50 (P<0.001 for all comparisons) for all subgroups. After the first dose of the vaccine, on D22, the patient group had lower NAb titers compared with controls: the median NAb inhibition titer was 18% (IQR: 8.5-29%) for patients versus 41.6% (IQR: 25.3-59%) for controls; p<0.001. On D50, the median NAb inhibition titer was 32.5% (IQR: 13.5-93%) for patients versus 94.7% (IQR: 89-97%) for controls; p<0.001. More specifically, only 50.8% (67/132) of the patients versus 98.1% (210/214) of the controls developed NAb titers ≥30% and 43.9% (58/132) of patients versus 95.3% (204/214) titers ≥50% (high protective titers) at day 50 (p<0.0001 for all comparisons; Figure-left part). Importantly, active treatment (which included anti-CD antibodies, Bruton's tyrosine kinase inhibitors, a combination of the above, chemotherapy-only regimens or Bcl-2 inhibitors) was an independent prognostic factor for suboptimal antibody response at day 50 (<50%) in the patient subgroup (p<0.001). Rituximab administration in the last 12 months correlated with decreased antibody response at day 50 (p<0.01). Patients with HL were more likely to achieve humoral responses (>50% at day 50) compared to other disease types (p<0.05; Figure-right part). Disease-related immune dysregulation and therapy-related immunosuppression were therefore involved in the low humoral responses seen in patients. Regarding adverse events, 9% and 9.8% patients reported mild reactions after the first and second dose of the BNT162b2 vaccine, respectively. Conclusion: Patients with CLL/NHL/HL have a low humoral response following SARS-CoV-2 vaccination, particularly patients who are on active treatment with rituximab or BTK inhibitors. These patient subgroups therefore should continue utilizing protective measures against SARS-CoV-2 (masks, social distancing, etc) as they are at high risk for COVID-19. Further studies on the kinetics of immune subpopulations following COVID-19 vaccination will elucidate the underlying immune landscape and determine the potential need for additional booster vaccine doses or protective administration of antibodies against SARS-CoV-2 in CLL/NHL/HL patients with poor response after full vaccination. Figure 1 Figure 1. Disclosures Terpos: Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria; GSK: Honoraria; Genesis: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Karyopharm: Honoraria. Baltadakis: Amgen: Honoraria; Bristol-Myers Squibb: Honoraria; Alexion: Honoraria; Astellas: Honoraria; Pfizer: Honoraria, Other: Travel Grants; Gilead: Honoraria; Novartis: Honoraria; Abbvie: Honoraria; Genesis Pharma: Other: Travel Grants; Gilead: Other: Travel Grants; WinMedica: Other: Travel Grants; Baxalta Hellas: Other: Travel Grants. Dimopoulos: BMS: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Takeda: Honoraria; Beigene: Honoraria.

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Patients with Multiple Myeloma on Anti-CD38 or Anti-BCMA Based Regimens and Patients with Waldenstrom's Macroglobulinemia Under Rituximab or BTK Inhibitors Have a Poor Humoral Response Following COVID-19 Vaccination

Blood ◽

10.1182/blood-2021-144856 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3791-3791

Author(s):

Evangelos Terpos ◽

Maria Gavriatopoulou ◽

Ioannis Ntanasis-Stathopoulos ◽

Alexandros Briasoulis ◽

Sentiljana Gumeni ◽

...

Keyword(s):

Antibody Response ◽

Active Treatment ◽

Neutralizing Antibodies ◽

Research Funding ◽

Hematological Malignancies ◽

Kinase Inhibitors ◽

Viral Vector ◽

Vaccine Dose ◽

Humoral Response ◽

Kinetics Of

Abstract Introduction: Recent data suggest a suboptimal antibody response to COVID-19 vaccination in patients with hematological malignancies. Herein, we evaluated the development of neutralizing antibodies (NAbs) against SARS-CoV-2 in patients with plasma cell neoplasms (PCNs) after vaccination with either the mRNA BNT162b2 or viral vector AZD1222 vaccine, up to 50 days post their first vaccine dose. Methods: This is an ongoing large prospective study (NCT04743388) evaluating the kinetics of anti-SARS-CoV-2 antibodies after COVID-19 vaccination in healthy subjects and in patients with hematological malignancies or solid tumors. Here we present the data on patients with PCNs in comparison to controls of similar age and gender, who were vaccinated during the same time period (January to March 2021) in Athens (Greece). Major exclusion criteria for both patients and controls included the presence of: (i) autoimmune disorder under immunosuppressive therapy or other active malignant disease; (ii) HIV or active hepatitis B and C infection, (iii) end-stage renal disease and (iv) prior diagnosis of COVID-19. Serum was collected on day 1 (D1; before the first vaccine dose), on day 22 (D22; before the second dose of the BNT162b2 or 3 weeks post the first AZD1222 dose) and on day 50 (D50; 4 weeks post second dose of the BNT162b2 or 7 weeks post the first AZD1222 dose). NAbs against SARS-CoV-2 were measured using an FDA approved-ELISA methodology (cPass™ SARS-CoV-2 NAbs Detection Kit, GenScript, Piscataway, NJ, USA). Results: We evaluated 382 patients with PCNs after vaccination with either the BNT162b2 or the AZD1222 vaccine. Patients with MM (n=213), WM (n=106), SMM (n=38) and MGUS (n=25) and 226 healthy controls were enrolled in the study. Of MM/SMM/MGUS patients, 215 (77.9%) were vaccinated with the BNT162b2 and 61 (22.1%) with the AZD1222 vaccine, while out of 106 WM patients 90 (84.9%) were vaccinated with the BNT162b2 and 16 (15.1%) with the AZD1222 vaccine. Vaccination with either two doses of the BNT162b2 or one dose of the AZD1222 vaccine led to lower production of NAbs against SARS-CoV-2 in patients compared with controls both on day 22 and on day 50 (P<0.001 for all comparisons). After the first dose of the vaccine, on D22, the patient group had lower NAb titers compared with controls: the median NAb inhibition titer was 27% (IQR: 15.3-42%) for MM/SMM/MGUS versus 20.5% (IQR: 10-37%) for WM patients versus 38.7% (IQR: 22-54.3%) for controls (P<0.001 for all comparisons). On D50 the median NAb inhibition titer was 62.8% (IQR: 26-88.9%) for MM/SMM/MGUS versus 36% (IQR: 18-78%) for WM patients versus 90% (IQR: 58-96.4%) for controls (P<0.001 for all comparisons). 57.3% MM/SMM/MGUS, 42% WM patients and 81% controls developed NAb titers ≥50% (p<0.001 for patients versus controls). Furthermore, MM patients showed an inferior NAb response compared with MGUS on day 22 (p=0.009) and on day 50 (p=0.003). Importantly, active treatment with either anti-CD38 monoclonal antibodies or belantamab mafodotin and lymphopenia at the time of vaccination were independent prognostic factors for suboptimal antibody response following vaccination in MM (p<0.05). Disease-related immune dysregulation and therapy-related immunosuppression were involved in the low humoral response in patients with WM. Importantly, active treatment with either rituximab or Bruton's Tyrosine Kinase inhibitors (BTKIs) was proven as an independent prognostic factor for suboptimal antibody response following vaccination in WM (p<0.05). Regarding adverse events, 33% and 31.6% patients reported mild reactions after the first and second dose of the BNT162b2 vaccine, respectively; 32.8% patients vaccinated with the first dose of AZD1222 also presented with local reactions. Conclusion: Patients with MM and WM have a low humoral response following SARS-CoV-2 vaccination, especially those who are under treatment with anti-CD38-, anti-BCMA-, anti-CD20- or BTKIs-based regimens. This result suggest that these patients have to continue the protective measures against SARS-CoV-2 as they are at high risk for COVID-19. Further studies on the kinetics of immune subpopulations following COVID-19 vaccination will elucidate the underlying immune landscape and determine the potential need for additional booster vaccine doses or protective administration of antibodies against SARS-CoV-2 in MM/WM patients with poor response after full vaccination. Disclosures Terpos: Janssen-Cilag: Consultancy, Honoraria, Research Funding; BMS: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Genesis: Consultancy, Honoraria, Research Funding; GSK: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Amgen: Consultancy, Honoraria, Research Funding. Gavriatopoulou: Janssen: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Karyopharm: Honoraria; Genesis: Honoraria; GSK: Honoraria; Amgen: Honoraria. Kastritis: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Genesis: Honoraria; Takeda: Honoraria; Pfizer: Honoraria. Dimopoulos: Janssen: Honoraria; BeiGene: Honoraria; Takeda: Honoraria; Amgen: Honoraria; BMS: Honoraria.

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Humoral Immunity and Plasma Cell Changes in Patients Responding to CD19-Specific Chimeric Antigen Receptor (CAR)-Modified T-Cell Adoptive Immunotherapy

Blood ◽

10.1182/blood.v124.21.1110.1110 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1110-1110

Author(s):

Vijay Bhoj ◽

Michael C Milone ◽

Carl H. June ◽

David Porter ◽

Stephan A. Grupp ◽

...

Keyword(s):

Bone Marrow ◽

Flow Cytometry ◽

B Cells ◽

B Cell ◽

Plasma Cell ◽

Humoral Immunity ◽

Research Funding ◽

Plasma Cells ◽

Flow Cytometric ◽

Antibody Titers

Abstract Introduction: T cells engineered to express chimeric antigen receptors (CARs) recognizing CD19 (CART19) can eliminate malignant cells in acute lymphoblastic leukemia (ALL) and chronic lymphocytic leukemia (CLL). We and other groups have shown that persistent tumor eradication by CD19-specific T cell immunotherapy is accompanied by normal B-cell aplasia. It is assumed that responding patients cannot make new antibody responses post-successful CART19 treatment; however, the status of previously established humoral immunity in these patients is currently unknown. Understanding the consequence of successful CART19 therapy on established humoral immunity has implications for both the clinical management of CART19-treated patients as well as the potential application of this therapy to non-malignant diseases such as autoimmunity and transplantation. Methods: We performed a prospective, observational study of adult and pediatric patients with ALL and adults with relapsed/refractory CLL, who were enrolled in clinical trials of CART19 at our institution. Serum antibody titers to previously-generated vaccine or vaccine-related pathogens (Streptococcus pneumoniae, Tetanus toxoid, Hemophilus influenza type-B (HIB), Measles, Mumps, and Rubella) were determined along with a quantitative assessment of B-cell and plasma cell frequencies in blood and bone marrow aspirates. Specimens were collected during pre-established study assessments or additional time points when collected as required for clinical management. Due to the challenges of assessing plasma cells, multiple methods were employed for their quantification in fresh specimens including flow cytometry and immunohistochemistry (IHC). Flow cytometric assessment of plasma cells was performed on freshly obtained marrow samples. Only patients with at least 3 months of B-cell aplasia in the absence of regular intravenous immunoglobulin (IVIg) infusions were included in the study. Results: All patients had no evidence of leukemia or peripheral B cells post-CART19 infusion at the time of this study. Compared to pre-CART19 serum titers, antibodies to S. pneumoniae remained stable or increased in 9 of 12 patients despite lack of circulating B-cells. Antibody titers to Tetanus toxoid were stable or increased in 13 of 14 patients. Anti-HIB levels were stable or increased in 9 of 11 patients and antibodies to Measles, Mumps and Rubella were stable or increased in 12 of 13, 11 of 13, and 12 of 13 patients, respectively. Flow cytometric analysis of bone marrow aspirates after CART19 infusion revealed three patients with persistence of CD38+ CD138+ plasma cells (at 1, 3 and 9 months post infusion, respectively) despite a complete absence of peripheral CD19+ B cells. In 9 patients, CD20 and CD138 IHC analysis of bone marrow core biopsies revealed a decrease in plasma cell (ranges: 1-5% pre-CART19, 0-<1% post-CART19), consistent with our previously published data. Finally, in another subset of patients, neither B cells nor plasma cells were detectable by flow cytometry of aspirate material or IHC of core biopsies collected either pre- or post-CART19 treatment. Conclusions: The stable or increased titers of antibodies to previous vaccines are surprising and may, in part, reflect improved marrow function as a result of leukemia eradication. The demonstration of plasma cells in a subset of patients in the absence of detectable tumor or normal B cells provides strong evidence for the existence of a population of plasma cells that are resistant to lysis by CART19 cells. This is consistent with antibody titers to previously generated vaccine antigens, which remain stable despite effective CART19 treatment. The additional finding of a decrease in CD138+ cells in several patients by IHC suggests that some populations of plasma cells are either targeted directly by CART19 or have a short half-life (e.g. plasmablasts); CD138 is not sufficient to distinguish these populations. Overall, these results indicate that long-lived plasma cells are resistant to CART19, likely due to a loss of CD19 during plasma cell differentiation. Continued analysis of remaining plasma cells in the absence of ongoing B-cell maturation as a result of CART19 persistence may provide important information on turnover rates of these long-lived cells in humans. Disclosures Bhoj: Novartis: Research Funding. Milone:Novartis: Patents & Royalties, Research Funding. June:Novartis: Research Funding, Royalty income Patents & Royalties. Porter:Novartis: Patents & Royalties, Research Funding. Grupp:Novartis: Research Funding. Melenhorst:Novartis: Research Funding. Lacey:Novartis: Research Funding. Mahnke:Novartis: Research Funding.

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