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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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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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Improved serologic responses to DTaP over Tdap vaccination in adult hematopoietic cell transplant recipients
Xu, B., Gordillo, C. A., Delille, E. M., Malandrakis, S., Assal, A., Mapara, M. Y., Reshef, R.
European journal of haematology. 2023
Abstract
BACKGROUND Hematopoietic cell transplantation (HCT) recipients have reduced antibody titers to tetanus, diphtheria, and pertussis. Tdap is approved for revaccinating adult HCT recipients in the United States, whereas DTaP is not approved in this population. To our knowledge, no studies to date have compared responses to DTaP versus Tdap in adult HCT patients. We conducted a retrospective study comparing responses to DTaP versus Tdap vaccines in otherwise similar adult HCT patients in order to determine if one of these vaccines elicits superior antibody responses. METHODS We evaluated 43 allogeneic and autologous transplant recipients as a combined cohort and as separate subsets for vaccine specific antibody titers and proportion of strong vaccine responders. Subset analysis focused on the autologous transplant recipients. RESULTS Higher median antibody titers were found to all vaccine components among DTaP recipients (diphtheria p = .021, pertussis p = .020, tetanus p = .007). DTaP recipients also had more strong responders to diphtheria and pertussis (diphtheria p = .002, pertussis p = .006). Among the autologous HCT recipient subset, there were more strong responders to diphtheria (p = .036). CONCLUSIONS Our data shows that post-HCT vaccination with DTaP leads to higher antibody titers and more strong responders, which suggests that DTaP is more effective than Tdap in HCT recipients.
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Immunogenicity of a 5-dose pneumococcal vaccination schedule following allogeneic hematopoietic stem cell transplantation
Garcia Garrido, H. M., Haggenburg, S., Schoordijk, M. C. E., Meijer, E., Tanck, M. W. T., Hazenberg, M. D., Rutten, C. E., de Bree, G. J., Nur, E., Meek, B., et al
American journal of hematology. 2022
Abstract
The optimal schedule of pneumococcal vaccination after allogeneic hematopoietic stem cell transplantation (allo-HSCT) remains controversial. The objective of this study was to investigate the immunogenicity of a 5-dose pneumococcal vaccination schedule in adult allo-HSCT recipients with and without immunosuppressive therapy. In this prospective cohort study, allo-HSCT recipients received four doses of the 13-valent pneumococcal conjugate vaccine (PCV13) and one dose of the 23-valent pneumococcal polysaccharide vaccine (PPSV23) starting 4-6 months after allo-HSCT. PCV13 was administered at T0, T1, T2 and T8 (T= months from enrollment) and PPSV23 at T10. Serum was collected at T0, T4, T8, T10 and T12 and IgG levels were measured for all 24 vaccine serotypes by immunoassay. The primary outcome was overall seroprotection at T12 defined as an IgG concentration ≥ 1.3μg/mL for 17/24 vaccine serotypes in allo-HCST recipients with and without immunosuppressive therapy at baseline. Secondary outcomes were serotype specific seroprotection, and dynamics of IgG levels. We included 89 allo-HSCT recipients in the final analysis. Overall seroprotection was 47% (15/32) for patients without immunosuppressive therapy at baseline versus 24% (11/46) for patients with immunosuppressive therapy (p=0.03). Seroprotection was higher for PCV13 serotypes (78% and 54% respectively; p=0.03), and lower for PPSV23-unique serotypes (28% and 13% respectively; p=0.1). IgG concentrations increased significantly over time for all 24 serotypes. Concluding, although immunogenicity of PCV13 serotypes was reasonable, the poor response to PPSV23 serotypes resulted in an insufficient overall response to pneumococcal vaccination for allo-HSCT recipients. Research into vaccination strategies with higher-valent T-cell dependent pneumococcal vaccines is needed. This article is protected by copyright. All rights reserved.
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Immunogenicity and safety of the meningococcal B recombinant (4CMenB) vaccine in allogeneic hematopoietic cell transplantation recipients
Robin, C., Redjoul, R., Terrade, A., Deghmane, A. E., Cabanne, L., Cordonnier, C., Taha, M. K.
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2022
Abstract
OBJECTIVES Despite a high risk of invasive meningococcal (Men) disease, there is no published data on any MenB vaccine after hematopoietic cell transplantation (HCT). We investigated the immunogenicity and safety of the 4CMenB recombinant vaccine (Bexsero®) in adult HCT recipients. METHODS Patients were eligible from 6 months post-HCT to receive 2 4CMenB doses at 2 months interval. Sera were collected at baseline, 1 month after the second dose, and 12 months after enrollment. The serum bactericidal activity (SBA) using human complement (hSBA) was assessed against fHbp, NadA, PorAP1.4 and NHBA antigens. The vaccine response was defined by one criteria for one vaccine antigen: (1) In patients with a hSBA titer < 4 at baseline: a titer > 4; (2) In patients with a hSBA titer > 4 at baseline: at least a x4 increase. RESULTS 40 patients were included at a median of 2.14 (0.57-13.03) years post-transplant. At baseline, most patients (32/40 80%) had hSBA titers < 4 for all vaccine antigens. After 2 vaccine doses, the proportion of patients with a titer > 4 was significantly increased for fHbp (23/40 57.5%), NadA (25/40 62.5%), and PorA (31/40 77.5%) but not for NHBA for which only 6/40 (15%) patients responded. 36/40 (90%) patients were responders to > 1 antigen. However, 9 months later, only 23/37 (62.2%) patients were still seroprotected. No severe adverse event was observed. CONCLUSION The response rate of 90% for >1 vaccine antigen and our safety data supports the 4CMenB vaccination of HCT recipients from 6 months after transplant with 2 doses. CLINICAL TRIALS REGISTRATION Clinicaltrials.gov, NCT03509051.
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Immunogenicity of three versus four doses of 13-valent pneumococcal conjugate vaccine followed by 23-valent pneumococcal polysaccharide vaccine in allogeneic haematopoietic stem cell transplantation recipients: a multicentre randomised controlled trial
Okinaka, K., Akeda, Y., Inamoto, Y., Fuji, S., Ito, A., Tanaka, T., Kurosawa, S., Kim, S. W., Tanosaki, R., Yamashita, T., et al
Clinical microbiology and infection : the official publication of the European Society of Clinical Microbiology and Infectious Diseases. 2022
Abstract
OBJECTIVE This multicentre, phase 2, randomised, controlled study of allogeneic haematopoietic stem cell transplantation (allo-HSCT) recipients compared the immunogenicity of two anti-pneumococcal vaccine regimens: four doses of 13-valent pneumococcal conjugate vaccine (PCV13) followed by 23-valent pneumococcal polysaccharide vaccine (PPSV23) (3+1+1 experimental group), and three doses of PCV13 followed by PPSV23 (3+0+1 group). METHODS Allo-HSCT recipients without active graft-versus-host disease (GVHD) at enrolment were eligible. The primary endpoint was the IgG response rate (≥0.20 mg/mL) for all eight measured serotypes at 5 months after the PPSV23 booster. RESULTS Seventy-two recipients were randomised, and seventy recipients who received over one PCV13 dose were analysed. The mean ages were 47.2 years (standard deviation, [SD] 14.4) in the 3+1+1 group (n=35) and 49.0 years (SD 14.3) in the 3+0+1 group (n=35). There was no significant difference in the overall IgG response rate at 5 months after the PPSV23 booster between the 3+1+1 and 3+0+1 groups (100% [26/26] versus 93% [27/29], respectively, relative risk [RR] 1.07, 95% confidence interval [CI] 0.97-1.19). This rate was higher immediately before the PPSV23 booster in the 3+1+1 group (100% [26/26] versus 81% [21/26], respectively, RR 1.24, 95% CI, 1.03-1.49), but this difference disappeared 1 month after the PPSV23 booster (100% [26/26] versus 97% [28/29], respectively, RR 1.04, 95% CI, 0.97-1.11). No serious adverse events leading to study dropout occurred. CONCLUSIONS We were not able to determine the efficacy of the experimental arm based on the IgG response rate at 5 months after the PPSV23 booster in allo-HSCT recipients.
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Changes in vaccination strategies contribute to the development of invasive pneumococcal disease in allogeneic hematopoietic stem cell transplantation recipients: a retrospective study for promoting vaccination
Konishi, T., Sekiya, N., Otsuka, Y., Konuma, R., Wada, A., Adachi, H., Kishida, Y., Nagata, A., Yamada, Y., Noguchi, Y., et al
International journal of hematology. 2021
Abstract
Allogeneic hematopoietic stem cell transplantation (allo-HSCT) recipients are at high risk of developing invasive pneumococcal disease (IPD) with substantial morbidity and mortality. Pneumococcal polysaccharide vaccine (PPSV23) and pneumococcal conjugate vaccine (PCV13) are the primary prevention strategy. The difference between the Japanese and international guidelines is limited except when to start PCV13. However, Japanese data regarding the incidence of IPD after allo-HSCT that include vaccination status are limited. Therefore, we aimed to study the clinical characteristics of patients with IPD following allo-HSCT, focusing on unvaccinated patients. We retrospectively reviewed allo-HSCT recipients between April 2005 and December 2018 at Komagome Hospital. Among 1,091 recipients, 11 (1008/100,000 recipients) developed 13 episodes of IPD. The median period from the first allo-HSCT to the first IPD episode was 686 days (10-3040 days). Ten patients developed IPD before vaccination, and seven of these unvaccinated patients with late-onset IPD were ineligible for vaccination based on domestic guidelines. Although appropriate treatments resulted in a good short-term prognosis, most episodes of IPD developed in unvaccinated allo-HSCT recipients. Our data support the promotion of better adherence to the current guidelines and the importance of pneumococcal vaccination even years after allo-HSCT to protect against late-onset IPD.
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Bacillus Calmette-Guerin (BCG) Vaccine-associated Complications in Immunodeficient Patients Following Stem Cell Transplantation
NaserEddin, A., Dinur-Schejter, Y., Shadur, B., Zaidman, I., Even-Or, E., Averbuch, D., Shamriz, O., Tal, Y., Shaag, A., Warnatz, K., et al
Journal of clinical immunology. 2020;:1-16
Abstract
PURPOSE Bacillus Calmette-Guerin (BCG) is a live attenuated vaccine with the potential of causing severe iatrogenic complications in patients with primary immunodeficiency diseases (PID) before and after hematopoietic stem cell transplantation (HSCT). We aim to investigate risk factors of post-HSCT BCG-related complications in PID patients. METHODS A retrospective analysis of pediatric PID patients who had received the BCG vaccine and underwent HSCT at Hadassah-Hebrew University Medical Center, between 2007 and 2019. RESULTS We found 15/36 (41.67%) patients who developed post-HSCT BCG-related complications. The most significant risk factor for developing BCG-related complications was T cell deficiency (47.6% of the non-complicated vs 83.3% of the BCGitis and 100% of the BCGosis groups had T cell lymphopenia, p = 0.013). None of the chronic granulomatous patients developed BCG-related manifestation post-transplant. Among T cell-deficient patients, lower NK (127 vs 698 cells/μl, p = 0.04) cell counts and NK-SCID were risk factors for ongoing post-HSCT BCGosis, as was pretransplant disseminated BCGosis (33.3% of patients with BCGosis vs none of the non-BCGosis patients, p = 0.04). Immune reconstitution inflammatory syndrome (IRIS) was observed in 3/5 patients with Omenn syndrome. Prophylactic antimycobacterial treatment was not proven effective. CONCLUSION BCG vaccination can cause significant morbidity and mortality in the post-transplant T cell-deficient patient, especially in the presence of pre-transplant disease. Taking a detailed medical history prior to administering, the BCG vaccine is crucial for prevention of this complication.
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Long-term pneumococcal vaccine immunogenicity following allogeneic hematopoietic stem cell transplantation
Langedijk, A. C., van Aalst, M., Meek, B., van Leeuwen, E. M. M., Zeerleder, S., Meijer, E., Hazenberg, M. D., Grobusch, M. P., Goorhuis, A.
Vaccine. 2018
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Full text
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Editor's Choice
Abstract
Infection with Streptococcus pneumoniae is a life-threatening, but vaccine preventable complication in patients with allogeneic hematopoietic stem cell transplantation (allo-HSCT). The international consensus on post allo-HSCT immunization schedules, starting 3-6months after HSCT, focuses on short-term immunogenicity while long-term immunogenicity is not well characterized. The current Dutch immunization schedule, which starts at 12months post allo-HSCT, was developed as a result of concerns on the coverage of long-term immunogenicity in international guidelines. We recently encountered two cases of allo-HSCT recipients who developed invasive pneumococcal disease (IPD) despite adequate revaccinations, which led us to question the immunogenicity of pneumococcal vaccinations in this patient group, and whether the currently existing vaccination schedules are appropriate. We included allo-HSCT recipients, vaccinated from one year after transplantation, and tested antibody responses to pneumococcal vaccination. We also performed a systematic review. Antibody concentrations were measured in 42 of 103 (41%) patients, with a response rate of 85% to PCV13 and 62% to PPSV23-unique serotypes. In six relevant studies, protection rates varied between 64 and 98%. Antibody responses in early and late vaccination schedules were similar, but adequate antibody responses were maintained better after late vaccination. Therefore, we propose a vaccination schedule that combines the advantages of early and late vaccination. This new schedule has been introduced since March 2018 in the two academic hospitals in Amsterdam, The Netherlands.
PICO Summary
Population
103 allo-HSCT recipients; 42 pts had antibody concentrations measured
Intervention
‘Late’ schedule pneumococcal vaccination >1 year after transplantation
Comparison
Systematic review evidence used to compare ‘early’ and ‘late’ vaccination schedule
Outcome
Response rate of 85% to PCV13 and 62% to PPSV23-unique serotypes. Antibody responses in early and late vaccination schedules were similar, but adequate antibody responses were maintained better after late vaccination.
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The immunogenicity of 7-valent pneumococcal conjugate vaccine (PCV7) in adult bone marrow transplant patients
MacIntyre, C. R., Katelaris, A. L., Ridda, I., Chughtai, A. A., Moa, A., Barnes, M., Kabir, M., Bradstock, K.
British Journal of Haematology. 2018;181(6):860-863