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A phase II randomized, placebo-controlled, multicenter trial to evaluate the efficacy of cytomegalovirus PepVax vaccine in preventing cytomegalovirus reactivation and disease after allogeneic hematopoietic stem cell transplant
Nakamura, R., La Rosa, C., Yang, D., Hill, J. A., Rashidi, A., Choe, H., Zhou, Q., Lingaraju, C. R., Kaltcheva, T., Longmate, J., et al
Haematologica. 2024
Abstract
Not available.
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2.
Immunogenicity and Tolerance of BNT162b2 mRNA Vaccine in Allogeneic Hematopoietic Stem Cell Transplant Patients
Ben Khlil, A. A., Zamali, I., Belloumi, D., Gdoura, M., Kharroubi, G., Marzouki, S., Dachraoui, R., Ben Yaiche, I., Bchiri, S., Hamdi, W., et al
Vaccines. 2024;12(2)
Abstract
BACKGROUND Allogeneic hematopoietic stem cell transplantation (ASCT) induces acquired immunodeficiency, potentially altering vaccine response. Herein, we aimed to explore the clinical tolerance and the humoral and cellular immune responses following anti-SARS-CoV-2 vaccination in ASCT recipients. METHODS A prospective, non-randomized, controlled study that involved 43 ASCT subjects and 31 healthy controls. Humoral response was investigated using the Elecsys(®) test anti-SARS-CoV-2. Cellular response was assessed using the QFN(®) SARS-CoV-2 test. The lymphocyte cytokine profile was tested using the LEGENDplex™ HU Th Cytokine Panel Kit (12-plex). RESULTS Adverse effects (AE) were observed in 69% of patients, encompassing pain at the injection site, fever, asthenia, or headaches. Controls presented more side effects like pain in the injection site and asthenia with no difference in the overall AE frequency. Both groups exhibited robust humoral and cellular responses. Only the vaccine transplant delay impacted the humoral response alongside a previous SARS-CoV-2 infection. Noteworthily, controls displayed a Th1 cytokine profile, while patients showed a mixed Th1/Th2 profile. CONCLUSIONS Pfizer-BioNTech(®) anti-SARS-CoV-2 vaccination is well tolerated in ASCT patients, inducing robust humoral and cellular responses. Further exploration is warranted to understand the impact of a mixed cytokine profile in ASCT patients.
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Immune reconstitution, vaccine responses, and rituximab use after ex-vivo CD34-selected myeloablative allogenic hematopoietic cell transplantation
Melica, G., Preston, E., Palazzo, M., Seier, K., Malard, F., Cho, C., Devlin, S. M., Maloy, M., Borrill, T., Maslak, P., et al
Bone marrow transplantation. 2024
Abstract
Myeloablative T cell depleted (CD34-selected) hematopoietic cell transplantation (HCT) is associated with less acute and chronic graft versus host disease (GVHD). We aimed to examine vaccine responses in relation to immune reconstitution and post HCT rituximab administration in this population. This single center retrospective study included 251 patients with hematological malignancies who received a first CD34-selected HCT between 2012 and 2015. Of 251 patients, 190 were alive 1 year after HCT. Among the entire population, 77 (30.7%) patients were vaccinated. After vaccine administration, 35/44 (80%), 30/75 (40%), 27/36 (75%), 33/65 (51%), 34/51 (51%), 22/28 (79%) and 20/34 (59%) of evaluable patients had protective antibody titers for haemophilus influenzae type B (Hib), Pneumococcus, Tetanus, Diphtheria, Pertussis, hepatitis A (HAV), and hepatitis B (HBV) respectively. Responders to the pneumococcal vaccine had a higher CD45RA T cell count than non responders, with 12/18 patients (66.7%) vs 11/32 (34.4%) p = 0.04. For pneumococcal vaccine, there was also a trend to higher total lymphocyte B cell count in responders vs non responders p = 0.06. Rituximab post HCT was given to 59/251 (23.5%) patients. No difference was found in immune reconstitution patterns for rituximab use between vaccine responders and not. Recipients of CD34-selected HCT may respond to vaccination, and T and B cell subsets could be useful to predict vaccine response.
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4.
Third BNT162b2 mRNA SARS-CoV-2 Vaccine Dose Significantly Enhances Immunogenicity in Recipients of Allogeneic Hematopoietic Stem Cell Transplantation
Henig, I., Isenberg, J., Yehudai-Ofir, D., Leiba, R., Ringelstein-Harlev, S., Ram, R., Avni, B., Amit, O., Grisariu, S., Azoulay, T., et al
Vaccines. 2023;11(4)
Abstract
COVID-19-related mortality among hematopoietic stem cell transplantation (HSCT) recipients in the pre-vaccine era ranged between 22 and 33%. The Pfizer/BioNTech BNT162b2 vaccine demonstrated significant immunogenicity and efficacy in the healthy population; however, its long-term effects on allogeneic HSCT recipients remained unclear. Our study longitudinally evaluated humoral and cellular responses to the BNT162b2 vaccine in adult allogeneic HSCT patients. A positive response was defined as antibody titers ≥ 150 AU/mL post-second vaccination. Among 77 included patients, 51 (66.2%) responded to vaccination. Response-associated factors were female gender, recent anti-CD20 therapy, and a longer interval between transplant and vaccination. Response rates reached 83.7% in patients vaccinated >12 months post-transplant. At 6 months post-second vaccination, antibody titers dropped, but were significantly increased with the booster dose. Moreover, 43% (6/14) of non-responders to the second vaccination acquired sufficient antibody titers after booster administration, resulting in an overall response rate of 79.5% for the entire cohort. The BNT162b2 vaccine was effective in allogeneic transplant recipients. Although antibody titers decreased with time, the third vaccination led to their significant elevation, with 93% of third-dose responders maintaining titers above 150 AU/mL at 3 months post-administration.
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5.
Long-term immunity against tetanus and diphtheria after vaccination of allogeneic stem cell transplant recipients
Einarsdottir, S., Sverrisdottir, I., Vaht, K., Bergström, T., Brune, M., Andersson, P. O., Wenneras, C., Ljungman, P.
Transplantation and cellular therapy. 2023
Abstract
BACKGROUND Revaccination against tetanus and diphtheria after allogeneic hematopoietic stem cell transplant (HCT) is usually effective, but the duration of the immunity is unknown. OBJECTIVE To study humoral immunity to tetanus and diphtheria in long-term survivors and to provide knowledge regarding the need for boosters. STUDY DESIGN The median time from transplantation to blood sampling was 14 years (min-max: 8-40). All patients had received at least 3 doses of vaccines, against both tetanus and diphtheria, either monovalent or combination vaccines containing a full dose of the diphtheria toxoid component (D). In addition, one or more booster doses were administered to 21/146 (14 %) of the patients. Enzyme-linked immunosorbent assays (ELISA) were used where levels below <0.1 IU/mL for diphtheria and <0.01 IU/mL for tetanus were considered "low" or "seronegative". Values between 0.01-0.5 IU/mL for tetanus and 0.1-1.0 IU/mL for diphtheria were considered to represent "partial protection" and levels above 0.5 and 1.0 IU/mL, respectively were considered "high" and protective. RESULTS In all, 39% were seronegative against diphtheria, 52% had "some protection" and 9% had a high titer. In contrast, no patient had become seronegative to tetanus, 32% had "partial protection" against tetanus and 68% had a high titer. In multivariate analysis active Graft-versus-host-disease (GvHD), gender or time from sampling did not affect the probability of becoming seronegative or seropositive. Younger age was associated with lower antibody levels to tetanus toxoid, but age was not correlated with antibody levels against diphtheria toxoid. CONCLUSION Tetanus immunity was maintained after vaccination in most long-term survivors, but immunity against diphtheria was poor and boosters should be considered.
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A phase 3 randomized, double-blind, comparator-controlled study to evaluate safety, tolerability and immunogenicity of V114, a 15-valent pneumococcal conjugate vaccine, in allogeneic hematopoietic cell transplant recipients (PNEU-STEM)
Wilck, M., Cornely, O. A., Cordonnier, C., Velez, J. D., Ljungman, P., Maertens, J., Selleslag, D., Mullane, K. M., Nabhan, S., Chen, Q., et al
Clinical infectious diseases : an official publication of the Infectious Diseases Society of America. 2023
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Editor's Choice
Abstract
BACKGROUND Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk for pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE™), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients. METHODS Participants received 3 doses of V114 or PCV13 in one-month intervals starting 3-6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAXTM 23 or a fourth dose of PCV (if they experienced chronic graft versus host disease). Safety was evaluated as the proportion of participants with adverse events (AEs). Immunogenicity was evaluated by measuring serotype-specific immunoglobulin G (IgG) geometric mean concentrations (GMCs) and opsonophagocytic activity (OPA) geometric mean titers (GMTs) for all V114 serotypes in each vaccination group. RESULTS A total of 274 participants were enrolled and vaccinated in the study. The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90. CONCLUSIONS V114 was well tolerated in allo-HCT recipients with a generally comparable safety profile to PCV13. V114 induced comparable immune responses to PCV13 for the 13 shared serotypes, and higher for V114 serotypes 22F and 33F. Study results support use of V114 in allo-HCT recipients.
PICO Summary
Population
Adults and children who received allo-HCT 90 to 180 days prior to randomization, from 44 centres in 10 countries (n=274)
Intervention
3 doses of V114 pneumococcal conjugate vaccine in one-month intervals starting 3-6 months after transplant. For people who experienced chronic GvHD, a fourth dose of PNEUMOVAXTM 23 was given (n=139)
Comparison
Three doses of PCV13 in pneumococcal conjugate vaccine in one-month intervals starting 3-6 months after transplant. For people who experienced chronic GvHD, a fourth dose was given. (n=135)
Outcome
The proportions of participants with AEs and serious AEs were generally comparable between intervention groups, and the majority of AEs in both groups were of short duration and mild-to-moderate intensity. For both IgG GMCs and OPA GMTs, V114 was generally comparable to PCV13 for the 13 shared serotypes, and higher for serotypes 22F and 33F at Day 90.
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Antibody response after third dose of COVID-19 mRNA vaccination in allogeneic hematopoietic stem cell transplant recipients is comparable to that in healthy counterparts
Takagi, E., Terakura, S., Fujigaki, H., Okamoto, A., Miyao, K., Sawa, M., Morishita, T., Goto, T., Ozawa, Y., Nishida, T., et al
International journal of hematology. 2023
Abstract
To determine the efficacy of SARS-CoV-2 mRNA vaccination for allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients, we measured antibody titer serially in 92 allo-HSCT patients. Among the evaluable 87 patients, median age at vaccination was 53 years (range, 18-75). The average time between allo-HSCT and vaccination was 3.3 years (range, 0.5-15.7). One month after the second dose, 70 patients (80.5%) had a positive response, whereas 17 patients (19.5%) had a negative response (< 20 U/mL). Only patients older than 44 years had a negative response. Low IgM level was the only significant predictor of vaccine failure in elderly patients. When antibody response before and after the third vaccination was examined in 47 patients, antibodies increased significantly from a median of 18.3 U/mL to 312.6 U/mL (P < 0.01). The median antibody titer after the third vaccination of healthy individuals (n = 203) was 426.4 U/mL, which was comparable to that of patients (P = 0.2). The antibody titer after the third mRNA vaccination increased even in patients whose first two mRNA vaccinations failed. These findings suggest that allo-HSCT recipients should receive the mRNA vaccine regularly.
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Vaccine response after pneumococcal vaccination in allogeneic hematopoietic stem cell transplant recipients
Cheplowitz, H., Patel, N., Kim, A., Logan, C., Law, N., Koura, D., Haste, N., Medley, K., Trinh, J., Sanders, T., et al
Journal of oncology pharmacy practice : official publication of the International Society of Oncology Pharmacy Practitioners. 2023;:10781552231165733
Abstract
Current guidelines for vaccination in allogeneic hematopoietic stem cell transplant (HCT) recipients recommend initiation of pneumococcal vaccination series three to six months post-HCT, with most data supporting initiation at six months due to a more robust immune response. This single-center, retrospective, observational chart review aimed to evaluate the impact of initiating the pneumococcal vaccine series at three months post-HCT compared to six months post-HCT. The primary endpoints were defined as a percentage of patients with a serologic response of >1 and >1.3 µg/mL for over 50% of the defined serotypes. Outcomes showed no difference in immunologic response between the two groups.
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Successful SARS-CoV-2 mRNA Vaccination Program in Allogeneic Hematopoietic Stem Cell Transplant Recipients-A Retrospective Single-Center Analysis
Nikoloudis, A., Neumann, I. J., Buxhofer-Ausch, V., Machherndl-Spandl, S., Binder, M., Kaynak, E., Milanov, R., Nocker, S., Stiefel, O., Strassl, I., et al
Vaccines. 2023;11(10)
Abstract
(1) Background: mRNA COVID-19 vaccines are effective but show varied efficacy in immunocompromised patients, including allogeneic hematopoietic stem cell transplant (HSCT) recipients. (2) Methods: A retrospective study on 167 HSCT recipients assessed humoral response to two mRNA vaccine doses, using the manufacturer cut-off of ≥7.1 BAU/mL, and examined factors affecting non-response. (3) Results: Twenty-two percent of HSCT recipients failed humoral response. Non-responders received the first vaccine a median of 10.2 (2.5-88.9) months post-HSCT versus 35.3 (3.0-215.0) months for responders (p < 0.001). Higher CD19 (B cell) counts favored vaccination response (adjusted odds ratio (aOR) 3.3 per 100 B-cells/microliters, p < 0.001), while ongoing mycophenolate mofetil (MMF) immunosuppression hindered it (aOR 0.04, p < 0.001). By multivariable analysis, the time from transplant to first vaccine did not remain a significant risk factor. A total of 92% of non-responders received a third mRNA dose, achieving additional 77% seroconversion. Non-converters mostly received a fourth dose, with an additional 50% success. Overall, a cumulative seroconversion rate of 93% was achieved after up to four doses. (4) Conclusion: mRNA vaccines are promising for HSCT recipients as early as 3 months post-HSCT. A majority seroconverted after four doses. MMF usage and low B cell counts are risk factors for non-response.
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SARS-CoV-2 vaccination in the first year after allogeneic hematopoietic cell transplant: a prospective, multicentre, observational study
Hill, J. A., Martens, M. J., Young, J. H., Bhavsar, K., Kou, J., Chen, M., Lee, L. W., Baluch, A., Dhodapkar, M. V., Nakamura, R., et al
EClinicalMedicine. 2023;59:101983
Abstract
BACKGROUND The optimal timing for SARS-CoV-2 vaccines within the first year after allogeneic hematopoietic cell transplant (HCT) is poorly understood. METHODS We conducted a prospective, multicentre, observational study of allogeneic HCT recipients who initiated SARS-CoV-2 vaccinations within 12 months of HCT. Participants were enrolled at 22 academic cancer centers across the United States. Participants of any age who were planning to receive a first post-HCT SARS-CoV-2 vaccine within 12 months of HCT were eligible. We obtained blood prior to and after each vaccine dose for up to four vaccine doses, with an end-of-study sample seven to nine months after enrollment. We tested for SARS-CoV-2 spike protein (anti-S) IgG; nucleocapsid protein (anti-N) IgG; neutralizing antibodies for Wuhan D614G, Delta B.1.617.2, and Omicron B.1.1.529 strains; and SARS-CoV-2-specific T-cell receptors (TCRs). The primary outcome was a comparison of anti-S IgG titers at the post-V2 time point in participants initiating vaccinations <4 months versus 4-12 months after HCT using a propensity-adjusted analysis. We also evaluated factors associated with high-level anti-S IgG titers (≥2403 U/mL) in logistic regression models. FINDINGS Between April 22, 2021 and November 17, 2021, 175 allogeneic HCT recipients were enrolled in the study, of whom all but one received mRNA SARS-CoV-2 vaccines. SARS-CoV-2 anti-S IgG titers, neutralizing antibody titers, and TCR breadth and depth did not significantly differ at all tested time points following the second vaccination among those initiating vaccinations <4 months versus 4-12 months after HCT. Anti-S IgG ≥2403 U/mL correlated with neutralizing antibody levels similar to those observed in a prior study of non-immunocompromised individuals, and 57% of participants achieved anti-S IgG ≥2403 U/mL at the end-of-study time point. In models adjusted for SARS-CoV-2 infection pre-enrollment, SARS-CoV-2 vaccination pre-HCT, CD19+ B-cell count, CD4+ T-cell count, and age (as applicable to the model), vaccine initiation timing was not associated with high-level anti-S IgG titers at the post-V2, post-V3, or end-of-study time points. Notably, prior graft-versus-host-disease (GVHD) or use of immunosuppressive medications were not associated with high-level anti-S IgG titers. Grade ≥3 vaccine-associated adverse events were infrequent. INTERPRETATION These data support starting mRNA SARS-CoV-2 vaccination three months after HCT, irrespective of concurrent GVHD or use of immunosuppressive medications. This is one of the largest prospective analyses of vaccination for any pathogen within the first year after allogeneic HCT and supports current guidelines for SARS-CoV-2 vaccination starting three months post-HCT. Additionally, there are few studies of mRNA vaccine formulations for other pathogens in HCT recipients, and these data provide encouraging proof-of-concept for the utility of early vaccination targeting additional pathogens with mRNA vaccine platforms. FUNDING National Marrow Donor Program, Leukemia and Lymphoma Society, Multiple Myeloma Research Foundation, Novartis, LabCorp, American Society for Transplantation and Cellular Therapy, Adaptive Biotechnologies, and the National Institutes of Health.