Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients treated for lymphoid malignancies.

Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients treated for lymphoid malignancies. BACKGROUND: Immunocompromised patients such as patients with hematological malignancies have impaired immune response to two doses of BNT162b2 (Pfizer / BioNtech) vaccine against SARS-CoV-2. Evaluation of a repeated immune stimulation with a third vaccine dose is needed. METHODS: a vaccine monitoring observatory was conducted in outpatients who were treated for lymphoid malignancies (LM) to monitor both immune and cellular response measured the day of administration of the dose 3 of the mRNA vaccine BNT162b2 and again three to four weeks. Elecsys Anti-SARS-CoV-2 immunoassay was used to asses to the level of SARS-CoV-2 anti-Spike (S) antibodies (Abs) titer and SARS-CoV-2-specific T-cell responses were assessed by a whole blood Interferon-Gamma Release Immuno Assay (IGRA) (QuantiFERON Human IFN-gamma SARS-CoV-2, Qiagen). RESULTS: Among the 43 assessable patients (suffering from chronic lymphocytic leukemia (CLL) (n=15), indolent and aggressive B cell non-Hodgkin lymphoma (NHL) (n=14), and multiple myeloma (MM) (n=16)), 18 (41,8%) had no anti-S Abs before the dose 3 of BNT162b2 vaccine (n=9 CLL, n=8 NHL, n=1 MM), and they all 18 remained negative after the dose 3. Amongst the 25 patients with positive anti-S titers before dose 3, all patients remained positive and 23 patients increased their anti-S titer after dose 3. Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients, dose 3 of BNT162b2 vaccine significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3. CONCLUSIONS Dose 3 of BNT162b2 vaccine stimulated humoral immune response among patients with LM, in particular patients with MM (who had higher anti-S baseline titer after dose 2) and those with no anti-CD20 treatment history within a year. T-cell response was increased among patients in particular with no active chemotherapy regimen. Our data support the use of an early third vaccine dose among immunocompromised patients followed for LM though some of them will still have vaccine failure.

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Humoral and cellular responses after a third dose of BNT162b2 vaccine in patients with lymphoid malignancies

10.21203/rs.3.rs-727941/v1 ◽

2021 ◽

Author(s):

Daniel Re ◽

Barbara Seitz-Polski ◽

Michel Carles ◽

Vesna Brglez ◽

Daisy Graça ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Cellular Response ◽

Vaccine Dose ◽

T Cell Response ◽

Double Negative ◽

Immunocompromised Patients ◽

Ifn Gamma ◽

Lymphoid Malignancies ◽

Anti Cd20

Abstract BACKGROUND: Immunocompromised patients such as patients with hematological malignancies have impaired immune response to two doses of BNT162b2 (Pfizer / BioNtech) vaccine against SARS-CoV-2. Evaluation of a repeated immune stimulation with a third vaccine dose is needed.METHODS: a vaccine monitoring observatory was conducted in outpatients who were treated for lymphoid malignancies (LM) to monitor both immune and cellular response measured the day of administration of the dose 3 of the mRNA vaccine BNT162b2 and again three to four weeks. Elecsys ® Anti-SARS-CoV-2 immunoassay was used to asses to the level of SARS-CoV-2 anti-Spike (S) antibodies (Abs) titer and SARS-CoV-2-specific T-cell responses were assessed by a whole blood Interferon-Gamma Release Immuno Assay (IGRA) (QuantiFERON Human IFN-gamma SARS-CoV-2, Qiagen®).RESULTS: Among the 43 assessable patients (suffering from chronic lymphocytic leukemia (CLL) (n=15), indolent and aggressive B cell non-Hodgkin lymphoma (NHL) (n=14), and multiple myeloma (MM) (n=16)), 18 (41,8%) had no anti-S Abs before the dose 3 of BNT162b2 vaccine (n=9 CLL, n=8 NHL, n=1 MM), and they all 18 remained negative after the dose 3. Amongst the 25 patients with positive anti-S titers before dose 3, all patients remained positive and 23 patients increased their anti-S titer after dose 3. Patients with CLL and/or with previous anti-CD20 therapy treated within 12 months of administration of dose 3 had no significant increase of the humoral response. Among 22 available patients, dose 3 of BNT162b2 vaccine significantly increased the median IFN-gamma secretion. On eight (36.4%) patients who were double-negative for both immune and cellular response, five (22.7%) patients remained double-negative after dose 3.CONCLUSIONSDose 3 of BNT162b2 vaccine stimulated humoral immune response among patients with LM, in particular patients with MM (who had higher anti-S baseline titer after dose 2) and those with no anti-CD20 treatment history within a year. T-cell response was increased among patients in particular with no active chemotherapy regimen. Our data support the use of an early third vaccine dose among immunocompromised patients followed for LM though some of them will still have vaccine failure.

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2729. mRNA Vaccines Encoding Conserved Influenza Antigens Induce Robust and Durable Immunity in Rhesus Macaques

Open Forum Infectious Diseases ◽

10.1093/ofid/ofz360.2407 ◽

2019 ◽

Vol 6 (Supplement_2) ◽

pp. S961-S961

Author(s):

Jessica Flynn ◽

Kara Cox ◽

Sinoeun Touch ◽

Yangsi Ou ◽

Teresa Weber ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

Rhesus Macaques ◽

Vaccine Dose ◽

T Cell Responses ◽

Immune Recognition ◽

Serum Antibodies ◽

Ifn Gamma ◽

Cell Responses ◽

Lipid Nanoparticle

Abstract Background In response to immune pressure, influenza virus evolves, producing drifted variants capable of escaping immune recognition. One strategy for inducing a broad-spectrum immune response that can recognize multiple antigenically diverse strains is to target conserved proteins or protein domains. To that end, we assessed the immunogenicity of mRNA vaccines encoding the stem domain of hemagglutinin (HA) or nucleoprotein (NP) in nonhuman primates (NHPs). Methods Rhesus macaques were immunized three times intramuscularly, at 28 day intervals, with lipid nanoparticle-encapsulated mRNA encoding either HA stem (Yassine et al, 2015) or NP. Serum and PBMCs were collected up to 14 or 24 weeks, respectively, after the last vaccination. The magnitude and durability of humoral and cell-mediated immunity were evaluated. ELISA, competition ELISA, an in vitro antibody-dependent cell-mediated cytotoxicity (ADCC) reporter bioassay, and microneutralization assays were used to characterize serum immune responses. Intracellular cytokine staining (IFN-gamma and IL-2) was used to assess antigen-specific T-cell responses. Results HA stem-immunized NHPs developed a robust anti-stem binding titer after a single vaccine dose, and after two doses, serum antibodies recognized several antigenically distinct Group 1 HA proteins. This broad antibody response persisted for at least 14 weeks post-dose 3 (PD3). Serum antibodies showed ADCC activity and competed with a well-characterized broadly neutralizing antibody, CR9114, for binding to HA stem; however, the polyclonal serum had only minimal activity against a panel of H1N1 viruses in a microneutralization assay. HA-specific CD4+ T-cell responses were detectable PD3. A robust antibody binding response was also detected in NP-vaccinated NHPs, and titers remained high for at least 14 weeks PD3. Additionally, these animals developed robust NP-specific T-cell responses that persisted for at least 24 weeks PD3. On average, 0.5% of CD4+ and 4% of CD8+ T cells produced IFN-gamma in response to NP peptide stimulation at the peak of the response, 2 weeks after the last vaccine dose was administered. Conclusion Lipid nanoparticle-encapsulated mRNA vaccines encoding conserved influenza antigens induce a robust and durable immune response in NHPs. Disclosures All authors: No reported disclosures.

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Humoral and cellular responses to SARS-CoV-2 vaccination in patients with lymphoid malignancies

10.1101/2021.12.08.21266760 ◽

2021 ◽

Author(s):

Sean H. Lim ◽

Nicola Campbell ◽

Beth Stuart ◽

Marina Johnson ◽

Debora Joseph-Pietras ◽

...

Keyword(s):

Immune Response ◽

T Cell ◽

T Cell Responses ◽

B Cell Lymphoma ◽

Cellular Responses ◽

Response Monitoring ◽

Vaccine Response ◽

Humoral And Cellular Immunity ◽

Cell Responses ◽

Anti Cd20

SUMMARYSARS-CoV-2 vaccination protects against COVID-19. Antibodies and antigen-specific T-cell responses against the spike domain can be used to measure vaccine immune response. Individuals with lymphoma have defects in humoral and cellular immunity that may compromise vaccine response. In this prospective observational study of 457 participants with lymphoma, 52% of participants vaccinated on treatment had undetectable anti-spike IgG antibodies compared to 9% who were not on treatment. Marked impairment was observed in those receiving anti- CD20 antibody within 12 months where 60% had undetectable antibodies compared to 11% on chemotherapy, which persisted despite three vaccine doses. Overall, 63% had positive T-cell responses irrespective of treatment. Individuals with indolent B-cell lymphoma have impaired antibody and cellular responses that were independent of treatment. The significant reduction and heterogeneity in immune responses in these individuals emphasise the urgent need for immune response monitoring and alternative prophylactic strategies to protect against COVID- 19.

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Accelerated Progression of Disseminated Coccidioidomycosis Following SARS-CoV-2 Infection: A Case Report

Military Medicine ◽

10.1093/milmed/usab132 ◽

2021 ◽

Author(s):

Daniel S Krauth ◽

Christina M Jamros ◽

Shayna C Rivard ◽

Niels H Olson ◽

Ryan C Maves

Keyword(s):

Immune Response ◽

Case Report ◽

T Cell ◽

Cellular Response ◽

Cd8 T Cell ◽

Host Immune Response ◽

Cell Senescence ◽

Functional Exhaustion ◽

T Cell Senescence

ABSTRACT We describe a patient with subclinical coccidioidomycosis who experienced rapid disease dissemination shortly after SARS-CoV-2 infection, suggesting host immune response dysregulation to coccidioidomycosis by SARS-CoV-2. We hypothesize that disrupted cell-mediated signaling may result after SARS-CoV-2 infection leading to functional exhaustion and CD8+ T-cell senescence with impairment in host cellular response to Coccidioides infection.

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Cellular and humoral immunogenicity of the mRNA-1273 SARS-CoV-2 vaccine in patients with hematologic malignancies

Blood Advances ◽

10.1182/bloodadvances.2021006101 ◽

2021 ◽

Author(s):

Moraima Jiménez ◽

Elisa Roldan ◽

Candela Fernández- Naval ◽

Guillermo Villacampa ◽

Monica Martinez-Gallo ◽

...

Keyword(s):

T Cell ◽

Cellular Response ◽

Immunosuppressive Agents ◽

Immunosuppressive Treatment ◽

Humoral Response ◽

Hematologic Malignancies ◽

T Cell Response ◽

Cell Counts ◽

Immuno Assay ◽

Anti Cd20

Recent studies have demonstrated a suboptimal humoral response to SARS-CoV-2 mRNA vaccines in patients diagnosed with hematologic malignancies, however data about cellular immunogenicity is scarce. In this study we aimed to evaluate both the humoral and cellular immunogenicity one month after the second dose of the mRNA-1273 vaccine. Antibody titers were measured by the Elecsys and LIAISON Anti-SARS-CoV-2 S assay while T-cell response was assessed by Interferon-Gamma-Release-immuno-Assay technology. Overall, 76.3% (184/241) of patients developed humoral immunity and the cellular response rate was 79% (184/233). Hypogammaglobulinemia, lymphopenia, active hematological treatment and anti-CD20 therapy during the last 6 months were associated with an inferior humoral response. Conversely, age over 65 years, active disease, lymphopenia and immunosuppressive treatment for GvHD were associated with an impaired cellular response. A significant dissociation between humoral and cellular response was observed in patients treated with anti-CD20 therapy, being the humoral response of 17.5% whereas the cellular response was 71.1%. In these patients B-cell aplasia was confirmed while T cell counts were preserved. In contrast, humoral response was observed in 77.3% of patients under immunosuppressive treatment for GvHD, while only 52.4% had cellular response. The cellular and humoral response to the SARS-CoV-2 mRNA-1273 vaccine in patients with hematological malignancies is highly influenced by the presence of treatments like anti-CD20 therapy and immunosuppressive agents. This observation has implications for the further management of these patients.

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9-O-Acetylated Sialoglycoproteins Are Important Immunomodulators in Indian Visceral Leishmaniasis

Clinical and Vaccine Immunology ◽

10.1128/cvi.00453-08 ◽

2009 ◽

Vol 16 (6) ◽

pp. 889-898 ◽

Cited By ~ 10

Author(s):

Angana Ghoshal ◽

Sumi Mukhopadhyay ◽

Bibhuti Saha ◽

Chitra Mandal

Keyword(s):

Immune Response ◽

Visceral Leishmaniasis ◽

Cellular Response ◽

Mononuclear Cells ◽

Cellular Responses ◽

Immunoglobulin M ◽

Enzyme Linked Immunosorbent Assay ◽

Lymphoproliferative Response ◽

Th2 Response ◽

Peripheral Blood Mononuclear

ABSTRACT Overexpression of disease-associated 9-O-acetylated sialoglycoproteins (9-O-AcSGPs) on peripheral blood mononuclear cells (PBMC) of visceral leishmaniasis (VL) patients (PBMCVL) compared to their levels of expression in healthy individuals has been demonstrated using a lectin, achatinin-H, with specificity toward 9-O-acetylated sialic acid derivatives α2-6 linkage with subterminal N-acetylgalactosamine (9-O-AcSAα2-6GalNAc). The decreased presence of disease-associated 9-O-AcSGPs on different immune cells of parasitologically cured individuals after successful treatment relative to the levels in patients with active VL prior to treatment was demonstrated. However, their contributory role as immunomodulatory determinants on PBMCVL remained unexplored. Accordingly, 9-O-AcSGPs on PBMCVL were sensitized with achatinin-H, leading to their enhanced proliferation compared to that observed with different known mitogens or parasite antigen. This lymphoproliferative response was characterized by evaluation of the TH1/TH2 response by intracellular staining and enzyme-linked immunosorbent assay for secreted cytokines, and the results were corroborated by their genetic expression. Sensitized PBMCVL evidenced a mixed TH1/TH2 cellular response with a predominance of the TH1 response, indicating the ability of 9-O-AcSGPs to modulate the host cell toward a favorable response. Interestingly, the humoral and cellular responses showed a good correlation. Further, high levels of anti-9-O-AcSGP antibodies with an order of distribution of immunoglobulin M (IgM) > IgG1 = IgG3 > IgG4 > IgG2 > IgE could be explained by a mixed TH1/TH2 response. A good correlation of enhanced 9-O-AcSGPs with both the cell-mediated (r = 0.98) and humoral (r = 0.99) response was observed. In summary, it may be concluded that sensitization of 9-O-AcSGPs on PBMCVL may provide a basis for the modulation of the host's immune response by their controlled expression, leading to a beneficial immune response and influencing the disease pathology.

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Complementary Presence of HBV-Specific Humoral and T-Cellular Immune Response Provide the Long-Lasting Immune Protection After Neonatal Immunization

10.21203/rs.3.rs-436535/v1 ◽

2021 ◽

Author(s):

Yunmei Huang ◽

Yuting Yang ◽

Tingting Wu ◽

Zhiyu Li ◽

Yao Zhao

Keyword(s):

Immune Response ◽

T Cell ◽

Hepatitis B ◽

Cell Response ◽

Cellular Immune Response ◽

Cellular Response ◽

T Cell Response ◽

Hbv Infection ◽

Hepatitis B Vaccination ◽

Cellular Immune

Abstract Background: Hepatitis B vaccination is the most cost-effective way to prevent HBV infection. Currently, hepatitis B vaccine (HepB) efficacy was usually assessed by anti-HBs level, but there were little comprehensive analyses of humoral and cellular immune response to HepB in children after neonatal immunization. Methods: A total of 145 children with primary hepatitis B immunization history were involved in this study to evaluate the efficacy of HepB. Blood samples were obtained from 80 eligible children before one dose of HepB booster and 41 children post-booster. Children with anti-HBs at a low level (<10mIU/mL and [10,100) mIU/mL) were received one dose of HepB booster after informed consent. Subjects were be measured anti-HBs, HBsAg-specific T cell responses and frequency of B cell subsets before and after booster. Results: Among 80 subjects, 81.36% of children showed both T cell and anti-HBs responses positive at baseline. After one dose of booster, anti-HBs titer (P<0.0001), positive rate of HBsAg-specific T cell response (P=0.0036) and magnitude of SFCs (P=0.0003) increased significantly. Comparing preexisting anti-HBs titer <10mIU/mL with anti-HBs titer [10,100) mIU/mL, anti-HBs response (P=0.0005) and HBsAg-specific T lymphocyte response (P<0.0001) increased significantly. The change tendency of HBV specific humoral response is complementary to T cellular response with age. Conclusion: Protection from primary HBV immunization persists long on account of the complementary presence of HBV-specific humoral and T-cellular immune response. One dose of HepB booster is efficient enough to produce protective anti-HBs and enhance HBsAg-specific T cell response. In the HBV endemic areas, HepB booster immunization is still the most economical and effective way to prevent HBV infection, especially in children without anti-HBs.

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Effect of Dose on Immune Response in Patients Vaccinated With an HER-2/neu Intracellular Domain Protein—Based Vaccine

Journal of Clinical Oncology ◽

10.1200/jco.2004.09.005 ◽

2004 ◽

Vol 22 (10) ◽

pp. 1916-1925 ◽

Cited By ~ 105

Author(s):

Mary L. Disis ◽

Kathy Schiffman ◽

Katherine Guthrie ◽

Lupe G. Salazar ◽

Keith L. Knutson ◽

...

Keyword(s):

Ovarian Cancer ◽

Immune Response ◽

T Cell ◽

Vaccine Dose ◽

T Cell Immunity ◽

Protein Vaccine ◽

Intracellular Domain ◽

Specific Immunity ◽

Cell Immunity ◽

Her 2

Purpose To evaluate the safety of an HER-2/neu intracellular domain (ICD) protein vaccine and to estimate whether vaccine dose impacts immunogenicity. Patients and Methods Twenty-nine patients with HER-2/neu—overexpressing breast or ovarian cancer and with no evidence of disease after standard therapy received a low- (25 μg), intermediate- (150 μg), or high-dose (900 μg) HER-2/neu ICD protein vaccine. The vaccine was administered intradermally, monthly for 6 months, with granulocyte-macrophage colony-stimulating factor as an adjuvant. Toxicity and both cellular and humoral HER-2/neu—specific immunity was evaluated. Results The vaccine was well tolerated. The majority of patients (89%) developed HER-2/neu ICD-specific T-cell immunity. The dose of vaccine did not predict the magnitude of the T-cell response. The majority of patients (82%) also developed HER-2/neu—specific immunoglobulin G antibody immunity. Vaccine dose did not predict magnitude or avidity of the HER-2/neu—specific humoral immune response. Time to development of detectable HER-2/neu—specific immunity, however, was significantly earlier for the high- versus low-dose vaccine group (P = .003). Over half the patients retained HER-2/neu—specific T-cell immunity 9 to 12 months after immunizations had ended. Conclusion The HER-2/neu ICD protein vaccine was well tolerated and effective in eliciting HER-2/neu—specific T-cell and antibody immunity in the majority of breast and ovarian cancer patients who completed the vaccine regimen. Although the dose of vaccine did not impact the magnitude of T-cell or antibody immunity elicited, patients receiving the highest dose developed HER-2/neu—specific immunity more rapidly than those who received the lowest dose.

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Co-Prevalence of Pre-Existing Immunity to Different Serotypes of Adeno-Associated Virus (AAV) in Adults with Hemophilia

Blood ◽

10.1182/blood-2019-123666 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3349-3349

Author(s):

Kavitha Rajavel ◽

Mila Ayash-Rashkovsky ◽

Ying Tang ◽

Bagirath Gangadharan ◽

Maurus de la Rosa ◽

...

Keyword(s):

Gene Therapy ◽

Immune Response ◽

T Cell ◽

Immune Responses ◽

Peripheral Blood ◽

Cellular Response ◽

Employment Equity ◽

Adeno Associated Virus ◽

Peptide Antigens ◽

Equity Ownership

Background: Recombinant and synthetic adeno-associated virus (AAV) vectors are in development for gene transfer in patients with hemophilia A (HA) or hemophilia B (HB). These include liver-directed recombinant AAV8 vectors BAX 888/SHP654/TAK-754 factor VIII (FVIII) gene therapy (GT) for severe HA, and SHP648/TAK-748 factor IX (FIX) GT for HB (Baxalta US Inc., a Takeda company, Lexington, MA, USA). However, environmental exposure to wild-type AAVs can result in individuals developing antibodies and cell-mediated immune responses to the naturally occurring AAV. While natural exposure to AAV does not result in any known disease in humans, presence of preexisting immunity can block delivery and prevent sustained expression of the transgene by an AAV-based vector in a gene therapy setting. Of the AAV serotypes, AAV2 is the most frequently encountered natural human infection and AAV5 and AAV8 have been the most commonly used vectors for hemophilia GT. Therefore, it is important to assess the prevalence and co-prevalence of antibody and T cell-mediated responses against each of these AAV serotypes and to better characterize the association between humoral and cellular immunity in people with hemophilia. Aims: To determine the prevalence of preexisting antibody-mediated immunity against AAV2, AAV5 and AAV8 and the association between AAV8-specific humoral and cell-mediated responses in adult patients with HA and HB in an international prospective, epidemiological study. Methods: This ongoing seroprevalence study involved adult male patients (18-75 years of age) with severe HA (<1% plasma FVIII activity) or severe/moderate HB (≤2% plasma FIX activity) recruited from hemophilia treatment centers in the United States and Europe (NCT03185897). Participants consented to collection of peripheral blood at either a single or multiple annual outpatient study visits, in order to explore fluctuations of the immune response over time. Local ethics committee approval was obtained. Titers for anti-AAV2, anti-AAV5 and anti-AAV8 neutralizing antibodies (NAbs) were determined using a cell-based transduction inhibition assay, with seropositivity defined as a titer ≥1:5. Titers for anti-AAV2, anti-AAV5 and anti-AAV8 binding antibodies (BAbs) were quantitated by indirect enzyme-linked immunosorbent assay (ELISA), with seropositivity defined as a titer ≥1:80. Cell-mediated immune responses to AAV8 peptide antigens were measured in peripheral blood mononuclear cells using an interferon-γ enzyme-linked immunospot (ELISpot) assay. Samples with a signal ≥3 times background and >60 spots per million cells were defined as positive. Results: Here we present data from patients who completed at least a single visit at the time of the interim, one year data cut (November 9, 2018). Of 242 patients enrolled (mean ± SD age: 35.3 ± 11.4 years), 194 patients had HA and 48 patients had HB. The overall co-prevalence of NAbs and BAbs to AAV2, AAV5 and AAV8 was 39.7% (HA: 38.1%, 72/189; HB: 45.8%, 22/48) and 16.1% (HA: 16.5%, 31/188; HB: 14.6%, 7/48) respectively, with further details shown in Table 1. Overall, 38.3% of patients (82/214) exhibited a T cell-mediated immune response to AAV8 peptide antigens (HA: 35.9%, 61/170; HB: 47.7%, 21/44). Among patients with AAV-8-specific NAbs, 37.9% (39/103) demonstrated positive AAV8-specific ELISPOT results. (HA: 35.7%, 30/84; HB: 47.4%, 9/19). Conclusion: The findings from this ongoing study demonstrate that approximately 50% of patients with hemophilia have preexistent NAb responses to AAV2, AAV5 or AAV8 with 40% demonstrating co-prevalence to all 3 evaluated AAV serotypes. Similar percentages of patients exhibited a positive cellular response to AAV8 antigens. Further, patients with HB demonstrated a slightly higher co-prevalence and a higher cellular response than patients with HA. In the combined HA and HB cohorts, co-prevalence was almost 40% for AAV8-specific humoral and T-cell mediated immunity. These data will add to our appreciation of preexisting AAV immunity that prevent patient participation in gene therapy trials. Disclosures Rajavel: Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Ayash-Rashkovsky:Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Tang:Baxalta US Inc., a Takeda company: Employment, Equity Ownership. Gangadharan:Baxalta Innovations GmbH, a Takeda company: Employment. de la Rosa:Baxalta Innovations GmbH, a Takeda company: Employment. Ewenstein:Baxalta US Inc., a Takeda company: Employment, Equity Ownership, Other: a Takeda stock owner.

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