Ibrahim Aldoss, MD *; Corinna La Rosa, PhD *; Lindsey R. Baden, MD *; Jeffrey Longmate, PhD; Ella J. Ariza-Heredia, MD; Wasima N. Rida, PhD; Chetan Raj Lingaraju, MS; Qiao Zhou, BS; Joy Martinez, MS; Teodora Kaltcheva, PhD; Andy Dagis, MS; Nicola Hardwick, PhD; Nicolas C. Issa, MD; Len Farol, MD; Auayporn Nademanee, MD; Monzr M. Al Malki, MD; Stephen Forman, MD; Ryotaro Nakamura, MD †; Don J. Diamond, PhD †; for the TRIPLEX VACCINE Study Group ‡
Acknowledgment: The authors thank the patients, nurses, technicians, research coordinators, and clinicians at all participating sites and the staff at the data safety monitoring and coordinating center, without whose support this trial could not have been conducted.
Financial Support: By grants 5R01 CA077544, 1ROI CA181045, P30 CA033572, P01 CA111412, and NCI-SAIC-Frederick 28XS061 from the National Cancer Institute (NCI) and U19 AI128913 from the The National Institute of Allergy and Infectious Diseases (NIAID) and by Helocyte. The NIAID Laboratory of Viral Diseases (Dr. Bernard Moss, director) provided MVA to COH under a Material Transfer Agreement. The following reagent was obtained through the National Institutes of Health (NIH) AIDS Reagent Program, Division of AIDS, NIAID, NIH: HCMV pp65 Peptide Pool (referred as pp65 library in the Supplement).
Disclosures: Dr. Aldoss reports trial support and personal fees from Helocyte outside the submitted work. Dr. La Rosa reports grants from COH and personal fees from Helocyte during the conduct of the study. Dr. Baden reports grants from the NCI/NIH/COH during the conduct of the study and grants from Ragon Institute, the NIAID of the NIH, and the Gates Foundation outside the submitted work. In addition, Dr. Baden is involved in HIV vaccine clinical trials conducted in collaboration with the NIH, HIV Vaccine Trials Network, International AIDS Vaccine Initiative, Crucell/Janssen, U.S. Military HIV Research Program, Gates Foundation, and Ragon Institute. Dr. Longmate reports grants from the NIH during the conduct of the study. Dr. Ariza-Heredia reports research grants from COH and Helocyte during the conduct of the study and from Merck and Oxford Immunotec outside the submitted work. Dr. Rida reports personal fees from Helocyte during the conduct of the study. Mr. Dagis reports salary support from Helocyte and grants from the NCI during the conduct of the study. Dr. Issa reports grants from GSK, Merck, Astellas, and AiCuris and personal fees from Akros Pharma outside the submitted work. Dr. Nakamura reports grants from the NCI and trial support from Helocyte during the conduct of the study, as well as personal fees from Merck, seminar support from Kyowa Kirin and Celgene, and lectureship support at a meeting from Alexion outside the submitted work. Dr. Diamond reports grants from the NIH and Helocyte during the conduct of the study; grants, personal fees, and equity via stock ownership from Helocyte outside the submitted work; and nonfinancial support from Pfizer outside the submitted work. In addition, Dr. Diamond has patents 8,580,276 and 9,675,689 with royalties paid to Helocyte. Authors not named here have disclosed no conflicts of interest. Disclosures can also be viewed at www.acponline.org/authors/icmje/ConflictOfInterestForms.do?msNum=M19-2511.
Editors' Disclosures: Christine Laine, MD, MPH, Editor in Chief, reports that her spouse has stock options/holdings with Targeted Diagnostics and Therapeutics. Darren B. Taichman, MD, PhD, Executive Editor, reports that he has no financial relationships or interests to disclose. Cynthia D. Mulrow, MD, MSc, Senior Deputy Editor, reports that she has no relationships or interests to disclose. Jaya K. Rao, MD, MHS, Deputy Editor, reports that she has stock holdings/options in Eli Lilly and Pfizer. Christina C. Wee, MD, MPH, Deputy Editor, reports employment with Beth Israel Deaconess Medical Center. Sankey V. Williams, MD, Deputy Editor, reports that he has no financial relationships or interests to disclose. Yu-Xiao Yang, MD, MSCE, Deputy Editor, reports that he has no financial relationships or interest to disclose.
Data Sharing Statement: The following data will be made available with publication: complete deidentified patient data set (available from Dr. Diamond; e-mail, email@example.com). The following supporting documents will be made available with publication: informed consent form (available from Dr. Diamond; e-mail, firstname.lastname@example.org). These data will be made available with no restrictions.
Corresponding Author: Don J. Diamond, PhD, Professor, Department of Hematology and Hematopoietic Cell Transplantation, City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010; e-mail, email@example.com.
Current Author Addresses: Drs. Aldoss, La Rosa, Longmate, Kaltcheva, Hardwick, Farol, Nademanee, Al Malki, Forman, Nakamura, and Diamond; Mr. Lingaraju; Ms. Zhou; Ms. Martinez; and Mr. Dagis: City of Hope Comprehensive Cancer Center, 1500 East Duarte Road, Duarte, CA 91010.
Drs. Baden and Issa: Brigham and Women's Hospital, 75 Francis Street, Boston, MA 02115.
Dr. Ariza-Heredia: The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Unit 1460, Houston, TX 77030.
Dr. Rida: 1129 North Illinois Street, Arlington, VA 22205.
Dr. Hardwick: Janssen Infectious Diseases & Vaccines, 50-100 Holmers Farm Way, High Wycombe HP12 4DP, United Kingdom.
Author Contributions: Conception and design: J. Longmate, R. Nakamura, D.J. Diamond.
Analysis and interpretation of the data: I. Aldoss, C. La Rosa, L.R. Baden, J. Longmate, W.N. Rida, C.R. Lingaraju, R. Nakamura, D.J. Diamond.
Drafting of the article: C. La Rosa, L.R. Baden, J. Longmate, W.N. Rida, R. Nakamura, D.J. Diamond.
Critical revision of the article for important intellectual content: C. La Rosa, L.R. Baden, J. Longmate, W.N. Rida, C.R. Lingaraju, R. Nakamura, D.J. Diamond.
Final approval of the article: I. Aldoss, C. La Rosa, L.R. Baden, J. Longmate, E.J. Ariza-Heredia, W.N. Rida, C.R. Lingaraju, Q. Zhou, J. Martinez, T. Kaltcheva, A. Dagis, N. Hardwick, N.C. Issa, L. Farol, A. Nademanee, M.M. Al Malki, S. Forman, R. Nakamura, D.J. Diamond.
Provision of study materials or patients: I. Aldoss, L.R. Baden, N.C. Issa, L. Farol, A. Nademanee, M.M. Al Malki, S.J. Forman, R. Nakamura, D.J. Diamond.
Statistical expertise: J. Longmate, W.N. Rida, A. Dagis.
Obtaining of funding: D.J. Diamond.
Administrative, technical, or logistic support: Q. Zhou, C.R. Lingaraju, J. Martinez, T. Kaltcheva, N. Hardwick.
Collection and assembly of data: I. Aldoss, C. La Rosa, L.R. Baden, E.J. Ariza-Heredia, C.R. Lingaraju, Q. Zhou, R. Nakamura.
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.
Aldoss I, La Rosa C, Baden LR, et al, for the TRIPLEX VACCINE Study Group. Poxvirus Vectored Cytomegalovirus Vaccine to Prevent Cytomegalovirus Viremia in Transplant Recipients: A Phase 2, Randomized Clinical Trial. Ann Intern Med. 2020;:. [Epub ahead of print 11 February 2020]. doi: https://doi.org/10.7326/M19-2511
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Published: Ann Intern Med. 2020.
Infectious Disease, Multi-Organ Failure and Sepsis, Prevention/Screening, Pulmonary/Critical Care, Vaccines/Immunization.
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Print ISSN: 0003-4819 | Online ISSN: 1539-3704
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