Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial.
Journal
Annals of internal medicine
ISSN: 1539-3704
Titre abrégé: Ann Intern Med
Pays: United States
ID NLM: 0372351
Informations de publication
Date de publication:
03 03 2020
03 03 2020
Historique:
pubmed:
11
2
2020
medline:
1
9
2020
entrez:
11
2
2020
Statut:
ppublish
Résumé
Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT). To determine the safety and efficacy of Triplex. First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933). 3 U.S. HCT centers. 102 CMV-seropositive HCT recipients at high risk for CMV reactivation. Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens. The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection. A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients. The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial. No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia. National Cancer Institute and Helocyte.
Sections du résumé
Background
Triplex vaccine was developed to enhance cytomegalovirus (CMV)-specific T cells and prevent CMV reactivation early after hematopoietic stem cell transplant (HCT).
Objective
To determine the safety and efficacy of Triplex.
Design
First-in-patient, phase 2 trial. (ClinicalTrials.gov: NCT02506933).
Setting
3 U.S. HCT centers.
Participants
102 CMV-seropositive HCT recipients at high risk for CMV reactivation.
Intervention
Intramuscular injections of Triplex or placebo were given on days 28 and 56 after HCT. Triplex is a recombinant attenuated poxvirus (modified vaccinia Ankara) expressing immunodominant CMV antigens.
Measurements
The primary outcomes were CMV events (CMV DNA level ≥1250 IU/mL, CMV viremia requiring antiviral treatment, or end-organ disease), nonrelapse mortality, and severe (grade 3 or 4) graft-versus-host disease (GVHD), all evaluated through 100 days after HCT, and grade 3 or 4 adverse events (AEs) within 2 weeks after vaccination that were probably or definitely attributable to injection.
Results
A total of 102 patients (51 per group) received the first vaccination, and 91 (89.2%) received both vaccinations (46 Triplex and 45 placebo). Reactivation of CMV occurred in 5 Triplex (9.8%) and 10 placebo (19.6%) recipients (hazard ratio, 0.46 [95% CI, 0.16 to 1.4]; P = 0.075). No Triplex recipient died of nonrelapse causes during the first 100 days or had serious AEs, and no grade 3 or 4 AEs related to vaccination were observed within 2 weeks after vaccination. Incidence of severe acute GVHD after injection was similar between groups (hazard ratio, 1.1 [CI, 0.53 to 2.4]; P = 0.23). Levels of long-lasting, pp65-specific T cells with effector memory phenotype were significantly higher in Triplex than placebo recipients.
Limitation
The lower-than-expected incidence of CMV events in the placebo group reduced the power of the trial.
Conclusion
No vaccine-associated safety concerns were identified. Triplex elicited and amplified CMV-specific immune responses, and fewer Triplex-vaccinated patients had CMV viremia.
Primary Funding Source
National Cancer Institute and Helocyte.
Identifiants
pubmed: 32040960
pii: 2760880
doi: 10.7326/M19-2511
pmc: PMC9074089
mid: NIHMS1799505
doi:
Substances chimiques
Cytomegalovirus Vaccines
0
Banques de données
ClinicalTrials.gov
['NCT02506933']
Types de publication
Clinical Trial, Phase II
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
306-316Subventions
Organisme : NCI NIH HHS
ID : P30 CA033572
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA077544
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA181045
Pays : United States
Investigateurs
Lindsey R Baden
(LR)
Nicholas C Issa
(NC)
Ibrahim Aldoss
(I)
Monzr M Al Malki
(MM)
Don J Diamond
(DJ)
Len J Farol
(LJ)
Stephen Forman
(S)
Nicola Hardwick
(N)
Teodora Kaltcheva
(T)
Corinna La Rosa
(C)
Chetan Raj Lingaraju
(CR)
Joy Martinez
(J)
Auayporn Nademanee
(A)
Ryotaro Nakamura
(R)
Qiao Zhou
(Q)
Andy Dagis
(A)
Jeffrey Longmate
(J)
Wasima N Rida
(WN)
Ella J Ariza-Heredia
(EJ)
Esther Arbona Haddad
(EA)
Alisha Pandit
(A)
Jennifer Drake
(J)
Lupe Duarte
(L)
Thomas Morrison
(T)
Tania Paris
(T)
Cynthia Slape
(C)
Joycelynne Palmer
(J)
Gloria Araujo
(G)
Yadira Lobo
(Y)
Références
J Infect Dis. 2012 Apr 15;205(8):1294-304
pubmed: 22402037
J Clin Oncol. 2005 Oct 1;23(28):7199-206
pubmed: 16192604
J Exp Med. 2005 Apr 4;201(7):1031-6
pubmed: 15795239
Virology. 2008 Aug 1;377(2):379-90
pubmed: 18538366
Bone Marrow Transplant. 2019 Jun;54(6):911-912
pubmed: 30401966
Front Immunol. 2016 Nov 17;7:507
pubmed: 27909435
Hematol Oncol Clin North Am. 2011 Feb;25(1):151-69
pubmed: 21236396
Leuk Res. 2014 Oct;38(10):1184-90
pubmed: 25127690
Blood. 2016 Dec 8;128(23):2624-2636
pubmed: 27760756
Blood. 2001 Sep 1;98(5):1358-64
pubmed: 11520783
Lancet Infect Dis. 2012 Apr;12(4):290-9
pubmed: 22237175
J Exp Med. 2017 Mar 6;214(3):651-667
pubmed: 28130404
Biol Blood Marrow Transplant. 2015 Dec;21(12):2192-2202
pubmed: 26260678
Curr Opin Hematol. 2012 Jul;19(4):324-35
pubmed: 22517587
Blood. 2016 May 19;127(20):2427-38
pubmed: 26884374
J Infect Dis. 2008 Aug 15;198(4):536-43
pubmed: 18590456
Cytotherapy. 2002;4(1):49-54
pubmed: 11953041
Hematol Oncol Stem Cell Ther. 2017 Dec;10(4):233-238
pubmed: 28641094
Transpl Infect Dis. 2015 Jun;17(3):361-70
pubmed: 25850900
Biol Blood Marrow Transplant. 2012 Nov;18(11):1687-99
pubmed: 22683614
Lancet Haematol. 2016 Feb;3(2):e87-98
pubmed: 26853648
J Pathol. 2015 Jan;235(2):288-97
pubmed: 25205255
Biol Blood Marrow Transplant. 2009 Oct;15(10):1143-238
pubmed: 19747629
Blood. 2019 Feb 21;133(8):867-877
pubmed: 30573634
Clin Infect Dis. 2017 Jan 1;64(1):87-91
pubmed: 27682069
Mediterr J Hematol Infect Dis. 2019 Jan 01;11(1):e2019001
pubmed: 30671207
Curr Opin Hematol. 2014 Nov;21(6):466-9
pubmed: 25159712
Cell. 2014 Nov 6;159(4):814-28
pubmed: 25417158
J Exp Med. 2005 Sep 5;202(5):673-85
pubmed: 16147978
J Infect Dis. 2006 Nov 15;194(10):1410-21
pubmed: 17054071
Biol Blood Marrow Transplant. 2005 Nov;11(11):890-902
pubmed: 16275592
Blood. 2001 Mar 1;97(5):1232-40
pubmed: 11222365
Bone Marrow Transplant. 2011 Nov;46(11):1437-43
pubmed: 21243030
Transpl Immunol. 2009 Mar;20(4):238-42
pubmed: 19032982
Blood. 2017 Jan 5;129(1):114-125
pubmed: 27760761
Blood. 2006 Aug 15;108(4):1406-12
pubmed: 16614242
Blood. 2010 Sep 9;116(10):1655-62
pubmed: 20508161
Cytometry B Clin Cytom. 2008 Jul;74(4):211-20
pubmed: 18454493
J Infect Dis. 2011 Dec 1;204(11):1663-71
pubmed: 22021622
PLoS One. 2008;3(11):e3634
pubmed: 18982061
Expert Rev Vaccines. 2018 Oct;17(10):889-911
pubmed: 30246580
Biol Blood Marrow Transplant. 2019 Apr;25(4):771-784
pubmed: 30562587
Blood. 2009 Jun 18;113(25):6465-76
pubmed: 19369230
Antimicrob Agents Chemother. 2015 Oct;59(10):6588-93
pubmed: 26259791
J Infect Dis. 2013 Jun 15;207(12):1888-97
pubmed: 23482644
N Engl J Med. 2017 Dec 21;377(25):2433-2444
pubmed: 29211658
Lancet Haematol. 2016 Mar;3(3):e119-27
pubmed: 26947200
Clin Cancer Res. 2017 Nov 15;23(22):6833-6845
pubmed: 28855356
Blood. 2014 Jun 5;123(23):3664-71
pubmed: 24744269