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High Rates of Seroprotection and Seroconversion to Vaccine-Preventable Infections in the Early Post-Autologous Stem Cell Transplant Period
Hall, V. G., Saunders, N. R., Klimevski, E., Tennakoon, G. S., Khot, A., Harrison, S., Worth, L. J., Yong, M. K., Slavin, M. A., Teh, B. W.
Open forum infectious diseases. 2023;10(10):ofad497
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Abstract
In patients early post-autologous stem cell transplant, seroprotection rates were high for Hemophilus influenzae type B and tetanus toxoid (70%-90%) but lower for Streptococcus pneumoniae (30%-50%) including after revaccination. There were high rates of seropositivity (67%-86%) to measles, mumps, and rubella and varicella zoster virus. Durability of protection requires assessment.
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Evaluation of Safety and Immunogenicity of a Recombinant Receptor-Binding Domain (RBD)-Tetanus Toxoid (TT) Conjugated SARS-CoV-2 Vaccine (PastoCovac) in Recipients of Autologous Hematopoietic Stem Cell Transplantation Compared to the Healthy Controls; A Prospective, Open-Label Clinical Trial
Barkhordar, M., Ahmadvand, M., Sharifi Aliabadi, L., Noorani, S. S., Bagheri Amiri, F., Janbabai, G., Sorouri, R., Asadi Milani, M., Vaezi, M.
Vaccines. 2023;11(1)
Abstract
Background: The urgent need for prompt SARS-CoV-2 immunization of hematopoietic stem cell transplant (HSCT) recipients in an endemic area raises many challenges regarding selecting a vaccine platform appropriate for HSCT recipients being economical for widespread use in developing countries. Methods: The trial is a prospective, single-group, open-label study to investigate the safety and serologic response of two doses of the recombinant receptor-binding domain (RBD)-Tetanus Toxoid (TT) conjugated SARS-CoV-2 vaccine (PastoCovac) early after autologous (auto) HSCT. For this reason, a total of 38 patients who completed the two-dose SARS-CoV-2 RBD-based vaccine between three to nine months after auto-HSCT and had an available anti-spike serologic test at three predefined time points of baseline and after the first and second doses and 50 healthy control individuals were included in the analysis. The primary outcome was defined as an increase in IgG Immune status ratio (ISR) to the cut-off value for the positive result (≥1.1) in the semiquantitative test. Findings: The median time between auto-HSCT and vaccination was 127 days. No participant reported any significant adverse effects (Grade 3). Pain at the injection site was the most common adverse event. The ISR increased significantly (p < 0.001) during the three-time point sampling for both patients and healthy control groups. In patients, the mean ISR increased from 1.39 (95% CI: 1.13-1.65) at baseline to 2.48 (1.93-3.03) and 3.73 (3.13-4.38) following the first and second dosages, respectively. In multivariate analysis, the higher count of lymphocytes [OR: 8.57 (95% CI: 1.51-48.75); p = 0.02] and history of obtaining COVID-19 infection before transplantation [OR: 6.24 (95% CI: 1.17-33.15); p = 0.03] remained the predictors of the stronger immune response following two doses of the RBD-TT conjugated vaccine. Moreover, we found that the immunogenicity of the COVID-19 vaccine shortly after transplantation could be influenced by pre-transplant COVID-19 vaccination. Interpretation: The RBD-TT conjugated SARS-CoV-2 vaccine was safe, highly immunogenic, and affordable early after autologous transplants. Funding: This work was mainly financed by the Hematology-Oncology-Stem Cell Transplantation Research Center (HORCSCT) of Tehran University and the Pasteur Institute of Iran.
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Homologous versus Heterologous prime-boost COVID-19 Vaccination in autologous hematopoietic stem cell transplantation recipients: a blinded randomized controlled trial
Sharifi Aliabadi, L., Karami, M., Barkhordar, M., Hashemi Nazari, S. S., Kavousi, A., Ahmadvand, M., Vaezi, M.
Frontiers in immunology. 2023;14:1237916
Abstract
BACKGROUND/PURPOSE Optimizing vaccine efficacy is of particular concern in patients undergoing hematopoietic stem cell transplantation (HSCT), which mainly have an inadequate immune response to primary SARS-CoV-2 vaccination. This investigation aimed to explore the potential prime-boost COVID-19 vaccination strategies following autologous (auto-) HSCT. METHODS In a randomized clinical trial, patients who had already received two primary doses of receptor-binding domain (RBD) tetanus toxoid (TT) conjugated SARS-CoV-2 vaccine during three to nine months after auto-HSCT were randomized to receive either a homologous RBD-TT conjugated or heterologous inactivated booster dose four weeks after the primary vaccination course. The primary outcome was comparing the anti-S IgG Immune status ratio (ISR) four weeks after the heterologous versus homologous booster dose. The assessment of safety and reactogenicity adverse events was considered as the secondary outcome. RESULTS Sixty-one auto-HSCT recipients were recruited and randomly assigned to receive either homologous or heterologous booster doses four weeks after the primary vaccination course. The mean ISR was 3.40 (95% CI: 2.63- 4.16) before the booster dose with a 90.0% seropositive rate. The ISR raised to 5.12 (95% CI: 4.15- 6.08) with a 100% seropositive rate after heterologous (P= 0.0064) and to 3.42 (95% CI: 2.67- 4.17) with a 93.0% seropositivity after the homologous booster doses (P= 0.96). In addition, the heterologous group suffered more AEs following the booster dosage than the homologous group, but this difference was not statistically significant (p = 0.955). In multivariable analysis, the prime-boost vaccination strategy (heterologous versus homologous), the level of ISR before the booster dose, and the length of time between auto-HSCT and booster dose were the positive predictors of serologic response to a booster dose. No serious adverse event is attributed to booster vaccination. CONCLUSION In patients who were primed with two SARS-CoV-2 vaccine doses during the first year after auto-HSCT, heterologous prime-boost COVID-19 vaccination with inactivated platform resulted in considerably enhanced serologic response and non-significantly higher reactogenicity adverse events than homologous RBD-TT conjugated prime-boost COVID-19 vaccination strategy.
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[Vaccination before and after autologous hematopoietic cell transplantation for autoimmune diseases: Guidances from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (MATHEC-SFGM-TC)]
Maria, A. T. J., Campidelli, A., Castilla-Llorente, C., Lansiaux, P., Marjanovic, Z., Pugnet, G., Torregrosa-Diaz, J. M., Terriou, L., Algayres, J. P., Urbain, F., et al
Bulletin du cancer. 2023
Abstract
The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) organized the 12th workshop on hematopoietic stem cell transplantation clinical practices harmonization procedures on September 2021 in Lille, France. In the absence of specific national or international recommendation, the French working group for autologous stem Cell transplantation in Auto-immune Diseases (MATHEC) proposed guidances for vaccinations of patients undergoing autologous hematopoietic stem cell transplantation for autoimmune disease, including in the context of SARS-Cov-2 pandemic.
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A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma
Qazilbash, M. H., Saini, N. Y., Cha, S. C., Wang, Z., Stadtmauer, E. A., Baladandayuthapani, V., Lin, H., Tross, B., Honhar, M., Rao, S. S., et al
Blood. 2022;139(9):1289-1301
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Editor's Choice
Abstract
We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.
PICO Summary
Population
Patients with newly diagnosed symptomatic MM with immunoglobulin G monoclonal protein, age ≤70 years, in two centres in USA (n=36)
Intervention
antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine (Id-KLH arm, n=16)
Comparison
Keyhole limpet hemocyanin (KLH) vaccine alone (KLH only arm, n=20)
Outcome
In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH.
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CMV Triplex vaccine to enhance adaptive NK and T-cell reconstitution after autologous hematopoietic cell transplantation
Rashidi, A., La Rosa, C., Curtsinger, J., Cao, Q., Zhou, Q., Lingaraju, C. R., Weisdorf, D. J., Cichocki, F., Miller, J. S., Diamond, D. J.
Transplantation and cellular therapy. 2022
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Editor's Choice
Abstract
BACKGROUND Cytomegalovirus (CMV) reactivation after hematopoietic cell transplantation (HCT) augments adaptive (CD56(dim)NKG2C(+)CD57(+)) NK and CMV-specific T cells, with potential anti-tumor effects. Our recent work found an association between higher abundance of adaptive NK cells after auto-HCT and lower risk of relapse in patients with multiple myeloma. Triplex vaccine is a recombinant modified vaccinia Ankara expressing immunodominant CMV antigens, which significantly enhanced CMV-specific T-cell immune responses in allo-HCT recipients. OBJECTIVE We evaluated whether 2 doses of the vaccine after auto-HCT in patients with lymphoma or myeloma improves reconstitution of adaptive NK and CMV-specific T cells. The primary endpoint was the number of adaptive NK cells at Day +100 (∼1 month after dose 2) relative to Day +28 (before dose 1). STUDY DESIGN We conducted a single-arm phase 2 clinical trial of 20 patients with lymphoma or myeloma undergoing auto-HCT. Two doses of the vaccine were given on days +28 and +56. RESULTS Adaptive NK cells increased in CMV-seronegative patients (p = 0.02), a rise that was more substantial than in unvaccinated historical CMV-seronegative cohorts (p = 0.03 comparing the rise between the two cohorts). There was also an increase in both CD4(+) and CD8(+) CMV-specific T cells in CMV-seronegative patients (p = 0.01) and CMV-specific CD8(+) effector T cells in CMV-seropositive patients (p = 0.03). CONCLUSIONS Triplex vaccine improved reconstitution of adaptive NK and CMV-specific T cells after auto-HCT in patients with lymphoma and myeloma. Further study is needed to determine the clinical impact of this modulation of immune response.
PICO Summary
Population
Patients undergoing autologous stem cell transplantation for lymphoma or myeloma (n=20)
Intervention
CMV-MVA Triplex Vaccine given as two doses on days 28 and 56
Comparison
unvaccinated historical CMV-seronegative cohorts
Outcome
Adaptive NK cells increased in CMV-seronegative patients, a rise that was more substantial than in unvaccinated historical CMV-seronegative cohorts. There was also an increase in both CD4(+) and CD8(+) CMV-specific T cells in CMV-seronegative patients and CMV-specific CD8(+) effector T cells in CMV-seropositive patients.
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Immunogenicity of SARS-CoV-2 vaccination in patients undergoing autologous stem cell transplantation. A multicentric experience
Autore, F., Stirparo, L., Innocenti, I., Papa, E., Marchesi, F., Togni, C., Mariani, S., Torrieri, L., Salvatori, M., Fazio, F., et al
Frontiers in oncology. 2022;12:897937
Abstract
COVID-19 disease has a strong impact on hematological patients; those receiving autologous hematopoietic stem cell transplantation (aHSCT) represent a particularly vulnerable group, in which the effectiveness of vaccination is very variable. Chiarucci et al. showed that patients affected by non-Hodgkin lymphoma (NHL) and treated with rituximab experienced a lower rate of immunization against SARS-CoV-2 (54%), as well as significantly lower IgG antibody titers. In our multicenter retrospective observational study, we included 82 patients who underwent aHSCT, divided into two groups: 58 patients vaccinated after aHSCT (group A) and 24 vaccinated before getting transplantation (group B). In group A, 39 (67%) patients had positive serology, and the rate of positivity increased with time after aHSCT. In the subgroup of patients with NHL, the administration of rituximab predicted negative serology, particularly when administered in the 6 months before vaccination (13% response rate). Patients affected by plasma cells had a higher rate of positivity (83% overall), independently of the time to aHSCT. In group B, no patient who initially showed positive serology became negative after transplantation, so the aHSCT did not affect the response to the vaccination. Our study confirmed the role of rituximab as a negative predictor of response to SARS-CoV-2 vaccination, whereas the conditioning and transplantation procedure itself seemed to be less important.
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Immunogenicity of anti-SARS-CoV-2 Comirnaty vaccine in patients with lymphomas and myeloma who underwent autologous stem cell transplantation
Salvini, M., Maggi, F., Damonte, C., Mortara, L., Bruno, A., Mora, B., Brociner, M., Mattarucchi, R., Ingrassia, A., Sirocchi, D., et al
Bone marrow transplantation. 2021;:1-3
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Adjuvanted recombinant zoster vaccine in adult autologous stem cell transplant recipients: polyfunctional immune responses and lessons for clinical practice
Stadtmauer, E. A., Sullivan, K. M., El Idrissi, M., Salaun, B., Alonso Alonso, A., Andreadis, C., Anttila, V. J., Bloor, A. J., Broady, R., Cellini, C., et al
Human vaccines & immunotherapeutics. 2021;:1-11
Abstract
Immunocompromised individuals, particularly autologous hematopoietic stem cell transplant (auHSCT) recipients, are at high risk for herpes zoster (HZ). We provide an in-depth description of humoral and cell-mediated immune (CMI) responses by age (protocol-defined) or underlying disease (post-hoc) as well as efficacy by underlying disease (post-hoc) of the adjuvanted recombinant zoster vaccine (RZV) in a randomized observer-blind phase III trial (ZOE-HSCT, NCT01610414). 1846 adult auHSCT recipients were randomized to receive a first dose of either RZV or placebo 50-70 days post-auHSCT, followed by the second dose at 1-2 months (M) later. In cohorts of 114-1721 participants, at 1 M post-second vaccine dose: Anti-gE antibody geometric mean concentrations (GMCs) and median gE-specific CD4[2+] T-cell frequencies (CD4 T cells expressing =2 of four assessed activation markers) were similar between 18-49 and =50-year-olds. Despite lower anti-gE antibody GMCs in non-Hodgkin B-cell lymphoma (NHBCL) patients, CD4[2+] T-cell frequencies were similar between NHBCL and other underlying diseases. The proportion of polyfunctional CD4 T cells increased over time, accounting for 79.6% of gE-specific CD4 T cells at 24 M post-dose two. Vaccine efficacy against HZ ranged between 42.5% and 82.5% across underlying diseases and was statistically significant in NHBCL and multiple myeloma patients. In conclusion, two RZV doses administered early post-auHSCT induced robust, persistent, and polyfunctional gE-specific immune responses. Efficacy against HZ was also high in NHBCL patients despite the lower humoral response.
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Long-term survivors following autologous haematopoetic stem cell transplantation have significant defects in their humoral immunity against vaccine preventable diseases, years on from transplant
Colton, H., Greenfield, D. M., Snowden, J. A., Miller, P. D. E., Morley, N. J., Wright, J., Darton, T. C., Evans, C. M., de Silva, T. I.
Vaccine. 2021;39(34):4778-4783
Abstract
Current international guidelines recommend routinely vaccinating haematopoetic stem cell transplant (HSCT) recipients. Despite significant infection-related mortality following autologous HSCT, routine vaccination programmes (RVP) completion is poor. For recovered HSCT recipients, it is uncertain whether catch-up vaccination remains worthwhile years later. To determine potential susceptibility to vaccine preventable infections, we measured antibody titres in 56 patients, a median of 7 years (range 0-29) following autologous HSCT, who had not completed RVP. We found that almost all participants had inadequate titres against diphtheria (98.2%) and pneumococcal infection (100%), and a significant proportion had inadequate titres against measles (34.5%). Of those subsequently vaccinated according to available guidelines, many mounted adequate serological responses. These data suggest a pragmatic catch-up approach for autologous HSCT recipients who have not completed RVP is advisable, with universal vaccination against some pathogens (e.g. Streptococcus pneumoniae and diphtheria) and serologically-guided approaches for others (e.g. measles and varicella zoster virus).