Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients: an international, multicentre, randomised, double-blind, placebo-controlled trial

V212 Protocol 001 Trial Team

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23 Citations (Scopus)

Abstract

Background: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. Methods: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34). Findings: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI −5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5–26·6; p<0·0001). Interpretation: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. Funding: Merck & Co., Inc.

Original languageEnglish (US)
Pages (from-to)2116-2127
Number of pages12
JournalThe Lancet
Volume391
Issue number10135
DOIs
StatePublished - May 26 2018

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Herpes Zoster Vaccine
Chickenpox Vaccine
Inactivated Vaccines
Stem Cells
Vaccines
Placebos
Transplants
Herpes Zoster
Transplant Recipients
Antigens
Transplantation
Medical Laboratory Personnel
Combined Vaccines
Safety
Human Herpesvirus 3
Chickenpox
South America
Opportunistic Infections

ASJC Scopus subject areas

  • Medicine(all)

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Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients : an international, multicentre, randomised, double-blind, placebo-controlled trial. / V212 Protocol 001 Trial Team.

In: The Lancet, Vol. 391, No. 10135, 26.05.2018, p. 2116-2127.

Research output: Contribution to journalArticle

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abstract = "Background: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. Methods: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95{\%} CI be higher than 25{\%} for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34). Findings: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44{\%}) of patients in the vaccine consistency lot group, 35 (33{\%}) in the high-antigen lot group, and 220 (39{\%}) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4{\%}] in the vaccine consistency lot group, and 29 [5{\%}] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8{\%}) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21{\%}) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8{\%} (95{\%} CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33{\%}] of 657 vs 181 [33{\%}] of 554; risk difference 0·2{\%}, 95{\%} CI −5·1 to 5·5) and serious vaccine-related adverse events (five [1{\%}] vs five [1{\%}]; risk difference 0·1{\%}, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29{\%}] vs 36 [7{\%}]; risk difference 22·6{\%}, 95{\%} CI 18·5–26·6; p<0·0001). Interpretation: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. Funding: Merck & Co., Inc.",
author = "{V212 Protocol 001 Trial Team} and Winston, {Drew J.} and Mullane, {Kathleen M.} and Cornely, {Oliver A.} and Boeckh, {Michael J.} and Brown, {Janice Wes} and Pergam, {Steven A.} and Igoris Trociukas and Pavel Ž{\'a}k and Craig, {Michael D.} and Papanicolaou, {Genovefa A.} and Velez, {Juan D.} and Jens Panse and Kimberly Hurtado and Fernsler, {Doreen A.} and Stek, {Jon E.} and Lei Pang and Su, {Shu Chih} and Yanli Zhao and Chan, {Ivan S.F.} and Kaplan, {Susan S.} and Janie Parrino and Ingi Lee and Zoran Popmihajlov and Annunziato, {Paula W.} and Ann Arvin and Basso, {A. C.} and P. Bonvehi and S. Cerana and Dictar, {M. O.} and P. Campbell and G. Playford and J. Sasadeusz and J. Maertens and X. Poire and D. Sellesag and R. Schots and K. Theunissen and E. Willems and Alves, {R. S.} and Camargo, {J. F.C.} and Castro, {N. S.} and {Maria Fogliatto}, L. and O. Rodrigo and F. Courture and A. McGeer and M. Miller and Combariza, {J. F.} and Sossa, {C. L.} and Velez, {J. D.} and C. Freytes",
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doi = "10.1016/S0140-6736(18)30631-7",
language = "English (US)",
volume = "391",
pages = "2116--2127",
journal = "The Lancet",
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TY - JOUR

T1 - Inactivated varicella zoster vaccine in autologous haemopoietic stem-cell transplant recipients

T2 - an international, multicentre, randomised, double-blind, placebo-controlled trial

AU - V212 Protocol 001 Trial Team

AU - Winston, Drew J.

AU - Mullane, Kathleen M.

AU - Cornely, Oliver A.

AU - Boeckh, Michael J.

AU - Brown, Janice Wes

AU - Pergam, Steven A.

AU - Trociukas, Igoris

AU - Žák, Pavel

AU - Craig, Michael D.

AU - Papanicolaou, Genovefa A.

AU - Velez, Juan D.

AU - Panse, Jens

AU - Hurtado, Kimberly

AU - Fernsler, Doreen A.

AU - Stek, Jon E.

AU - Pang, Lei

AU - Su, Shu Chih

AU - Zhao, Yanli

AU - Chan, Ivan S.F.

AU - Kaplan, Susan S.

AU - Parrino, Janie

AU - Lee, Ingi

AU - Popmihajlov, Zoran

AU - Annunziato, Paula W.

AU - Arvin, Ann

AU - Basso, A. C.

AU - Bonvehi, P.

AU - Cerana, S.

AU - Dictar, M. O.

AU - Campbell, P.

AU - Playford, G.

AU - Sasadeusz, J.

AU - Maertens, J.

AU - Poire, X.

AU - Sellesag, D.

AU - Schots, R.

AU - Theunissen, K.

AU - Willems, E.

AU - Alves, R. S.

AU - Camargo, J. F.C.

AU - Castro, N. S.

AU - Maria Fogliatto, L.

AU - Rodrigo, O.

AU - Courture, F.

AU - McGeer, A.

AU - Miller, M.

AU - Combariza, J. F.

AU - Sossa, C. L.

AU - Velez, J. D.

AU - Freytes, C.

PY - 2018/5/26

Y1 - 2018/5/26

N2 - Background: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. Methods: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34). Findings: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI −5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5–26·6; p<0·0001). Interpretation: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. Funding: Merck & Co., Inc.

AB - Background: Recipients of autologous haemopoietic stem-cell transplants (auto-HSCT) have an increased risk of herpes zoster and herpes zoster-related complications. The aim of this study was to establish the efficacy and safety of an inactivated varicella zoster vaccine for the prevention of herpes zoster after auto-HSCT. Methods: In this randomised, double-blind, placebo-controlled phase 3 trial, participants were recruited from 135 medical centres (ie, stem-cell transplant centres and hospitals) in North America, South America, Europe, and Asia. Patients were eligible if they were aged 18 years or older, scheduled to receive an auto-HSCT within 60 days of enrolment, and had a history of varicella infection or were seropositive for antibodies to varicella zoster virus, or both. Exclusion criteria included a history of herpes zoster within the previous year of enrolment, and intended antiviral prophylaxis for longer than 6 months after transplantation. Participants were randomly assigned according to a central randomisation schedule generated by the trial statistician, to receive either the inactivated-virus vaccine from one of three consistency lots, a high-antigen lot, or placebo, stratified by age (<50 vs ≥50 years) and intended duration of antiviral prophylaxis after transplantation (≤3 months vs >3 to ≤6 months). Participants, investigators, trial staff, and the funder's clinical and laboratory personnel were masked to group assignment. Participants were given four doses of inactivated vaccine or placebo, with the first dose 5–60 days before auto-HSCT, and the second, third, and fourth doses at about 30, 60, and 90 days after transplantation. The primary efficacy endpoint was the incidence of herpes zoster, confirmed by PCR or adjudication by a masked clinical committee, or both, assessed in all participants randomly assigned to the vaccine consistency lot group or placebo group who received at least one dose of vaccine and had auto-HSCT. Safety was assessed in all randomised participants who received at least one dose of vaccine and had follow-up data. A prespecified vaccine efficacy success criterion required the lower bound of the 95% CI be higher than 25% for the relative reduction of the hazard ratio of herpes zoster infection in participants given the vaccine from one of the consistency lots compared with those given placebo. This trial is registered on ClinicalTrials.gov (NCT01229267) and EudraCT (2010–020150–34). Findings: Between Dec 7, 2010, and April 25, 2013, 560 participants were randomly assigned to the vaccine consistency lot group, 106 to the high-antigen lot group, and 564 to the placebo group. 249 (44%) of patients in the vaccine consistency lot group, 35 (33%) in the high-antigen lot group, and 220 (39%) in the placebo group discontinued before study end, mostly because of death or withdrawal. 51 participants were excluded from the primary efficacy endpoint analyses because they did not undergo auto-HSCT or were not vaccinated, or both (22 [4%] in the vaccine consistency lot group, and 29 [5%] in the placebo group). Mean follow-up for efficacy was 2·4 years (SD 1·3) in the vaccine consistency lot group and 2·3 years (SD 1·3) in the placebo group. 42 (8%) of 538 participants in the vaccine consistency lot group (32·9 per 1000 person-years) and 113 (21%) of 535 in the placebo group (91·9 per 1000 person-years) had a confirmed case of herpes zoster. The estimated vaccine efficacy was 63·8% (95% CI 48·4–74·6), meeting the pre-specified success criterion. For the combined vaccine groups versus the placebo group, the proportion of patients with serious adverse events (216 [33%] of 657 vs 181 [33%] of 554; risk difference 0·2%, 95% CI −5·1 to 5·5) and serious vaccine-related adverse events (five [1%] vs five [1%]; risk difference 0·1%, −1·4 to 1·1) were similar. Vaccine-related injection-site adverse events occurred more frequently in participants given vaccine than those given placebo (191 [29%] vs 36 [7%]; risk difference 22·6%, 95% CI 18·5–26·6; p<0·0001). Interpretation: This study shows for the first time in a large phase 3 trial that early vaccination of auto-HSCT recipients during the peri-transplant period can be effective for the prevention of an opportunistic infection like herpes zoster and that the vaccine is well tolerated. Funding: Merck & Co., Inc.

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U2 - 10.1016/S0140-6736(18)30631-7

DO - 10.1016/S0140-6736(18)30631-7

M3 - Article

AN - SCOPUS:85047299325

VL - 391

SP - 2116

EP - 2127

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 10135

ER -