Abstract
Background
Individuals who receive allogeneic hematopoietic cell transplant (allo-HCT) are immunocompromised and at high risk of pneumococcal infections, especially in the months following transplant. This study evaluated the safety and immunogenicity of V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co., Inc., Rahway, NJ, USA), a 15-valent pneumococcal conjugate vaccine (PCV), when given to allo-HCT recipients.
Methods
Participants received 3 doses of V114 or PCV13 (Prevnar 13; Wyeth LLC) in 1-month intervals starting 3–6 months after allo-HCT. Twelve months after HCT, participants received either PNEUMOVAX 23 or a fourth dose of PCV (if they experienced chronic graft vs 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 was higher for V114 serotypes 22F and 33F. Study results support the use of V114 in allo-HCT recipients.
Clinical Trials Registration. clinicaltrials.gov (NCT03565900) and European Union at EudraCT 2018-000066-11.
Keywords: vaccine, pneumococcal, hematopoietic cell transplant, immunocompromised, safety
V114, a 15-valent pneumococcal conjugate vaccine, was well tolerated in allogeneic hematopoietic cell transplant recipients with a generally comparable safety profile to PCV13. Immune responses were induced to all 15 serotypes. Study results support V114 use in this at-risk population.
Graphical Abstract
Graphical Abstract.
This graphical abstract is also available at Tidbit: https://tidbitapp.io/tidbits/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
Allogeneic hematopoietic cell transplantation (allo-HCT) is an effective therapy for a variety of hematologic and immunologic conditions. Transplant recipients are at high risk of infection and associated complications, including high rates of disease due to Streptococcus pneumoniae [1–3]. Delayed immune reconstitution and complications like graft versus host disease (GVHD) further increase this risk while decreasing vaccine responses.
Studies have demonstrated that vaccination with pneumococcal conjugate vaccines (PCVs) after allo-HCT are immunogenic when given repeatedly starting as early as 3–6 months post-transplant [4–8]. Current guidelines for the prevention of pneumococcal disease in allo-HCT recipients include administration of a 3-dose PCV series starting 3 months post-transplant followed by vaccination with the 23-valent pneumococcal vaccine (PPSV23) at 1 year post-transplant. A fourth dose of PCV is recommended in individuals with GVHD as these persons are less likely to respond to unconjugated vaccines [9–13]. While limited data exist on the effectiveness of post–allo-HCT pneumococcal vaccination, data from a cohort of auto- and allo-HCT recipients with high (>90%) pneumococcal vaccine uptake after transplant suggest that the use of PCVs reduces the incidence of invasive pneumococcal disease (IPD) [14]. The few studies that have evaluated the safety and immunogenicity of PCVs in HCT recipients are smaller, mostly open-label, nonrandomized studies [4, 5, 8, 15–17].
V114 (VAXNEUVANCE; Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc., Rahway, NJ, USA [MSD]) is a 15-valent PCV approved in adults and children, containing all 13 serotypes in PCV13 (Prevnar 13; Wyeth LLC, marketed by Pfizer, New York, NY, USA) and epidemiologically important serotypes 22F and 33F [18–21] for expanded serotype coverage. Several studies have demonstrated the acceptable safety and immunogenicity profiles of V114 in immunocompetent adults and children [22–24], as well as in individuals with human immunodeficiency virus (HIV) or sickle cell disease [25, 26]. This study was designed to evaluate the safety, tolerability, and immunogenicity of V114 when given to individuals following allo-HCT.
METHODS
Study Design
This study was a phase 3, randomized, double-blind, comparator-controlled, multicenter clinical study that aimed to describe the safety, tolerability, and immunogenicity of V114 and PCV13 when administered as a 3-dose regimen in recipients of allo-HCT aged 3 years and older (protocol V114-022). It was conducted at 44 centers in 10 countries (Supplementary Table 1) from September 2018 to November 2021 (clinicaltrials.gov NCT03565900 and European Union at EudraCT 2018-000066-11).
The study was designed to randomize approximately 300 participants (250 adults [age ≥18 y] and 50 children [ages ≥3 to <18 y]) in a 1:1 ratio to receive either a 3-dose series of V114 or PCV13 in 1-month intervals (study day 1, days 30–44, and 30–44 days following receipt of dose 2) starting 3–6 months after allo-HCT. At 12 months post–allo-HCT, the 3-dose PCV series was followed by either a single dose of PPSV23 (PNEUMOVAX 23; MSD) or, if the participant was diagnosed with chronic GVHD, a fourth dose of PCV (V114 or PCV13). Treatment allocation/randomization occurred centrally using an interactive response technology system and was stratified according to the following factors: (1) use of systemic steroids within 14 days of randomization, (2) age category (3 to <18 y, 18–49 y, or ≥50 y), and (3) haploidentical donor status. The study vaccines were managed, prepared, and administered by an unblinded pharmacist and/or other qualified study site personnel who were not involved in any participant assessments or other study procedures. All safety and immunogenicity assessments were conducted by blinded personnel, and the participant and/or participant's parent/legal representative were also blinded to the study vaccine received by the participant. The study was conducted in accordance with the principles of Good Clinical Practice and approved by the appropriate institutional review boards and regulatory agencies.
Participants
Eligible participants included those who (1) received allo-HCT 90 to 180 days prior to randomization for acute lymphoblastic or myeloid leukemia, chronic myeloid leukemia, Hodgkin's lymphoma, non-Hodgkin's lymphoma, myelodysplastic syndrome, myelofibrosis and myeloproliferative diseases, aplastic anemia, or sickle cell disease; (2) had a life expectancy of more than 12 months after allo-HCT; and (3) had stable engraftment. Written informed consent was obtained from each participant or parent/legal representative prior to any study procedure.
Key exclusion criteria were as follows: (1) 1 or more allo-HCT; (2) an allo-HCT with ex vivo graft manipulation, in vivo T-cell depletion with alemtuzumab, or haploidentical allo-HCT with high-dose anti-thymocyte globulin; (3) an allo-HCT for multiple myeloma or, in participants aged 18 years or older, any nonmalignant disease other than sickle cell disease or aplastic anemia; (4) persistent or relapsed primary disease after allo-HCT; (5) history of grade 3 or 4 GVHD; (6) history of culture-positive PD after allo-HCT; and (7) known hypersensitivity to any PCV components. Key prior/concomitant therapy that would result in exclusion included (1) chimeric antigen receptor T-cell therapy, checkpoint inhibitor therapy, or anti-CD20 therapy after allo-HCT; (2) pneumococcal vaccination after allo-HCT; (3) receipt of systemic steroids of more than 0.5 mg/kg/day for 14 or more days within 30 days prior to study vaccine administration; and (4) receipt of any vaccine within 14 days prior to administration of study vaccines.
Vaccines and Administration
V114 is a 15-valent PCV containing 2 µg of capsular polysaccharide from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, 23F, 22F, and 33F and 4 µg of serotype 6B conjugated to CRM197 carrier protein and adjuvanted with 125 µg of aluminum phosphate. PCV13 is a 13-valent PCV containing 2.2 µg of capsular polysaccharide from serotypes 1, 3, 4, 5, 6A, 7F, 9V, 14, 18C, 19A, 19F, and 23F and 4.4 µg of serotype 6B conjugated to CRM197 carrier protein and adjuvanted with 125 µg of aluminum phosphate. PPSV23 is a 23-valent pneumococcal vaccine containing 25 µg of capsular polysaccharides from serotypes 1, 2, 3, 4, 5, 6B, 7F, 8, 9N, 9V, 10A, 11A, 12F, 14, 15B, 17F, 18C, 19A, 19F, 20, 22F, 23F, and 33F with no carrier protein or adjuvant. Study vaccines were supplied as suspensions in prefilled syringes or single-dose vial and stored at 2–8◦C. A 0.5-mL intramuscular dose of V114, PCV13, or PPSV23 was administered, and participants were observed for 30 minutes postvaccination.
Safety Assessments
Participants were followed after each study vaccination for unsolicited and solicited adverse events (AEs). Postvaccination, participants or their parent/legal representative recorded daily body temperatures for either 5 days in adults or 7 days in pediatric participants and any complaints for 14 days postvaccination using an electronic Vaccination Report Card. The complaints were subsequently reviewed by the study investigators to determine if they met protocol-defined AE criteria and to assess seriousness, intensity, and causality to the study vaccine. Solicited AEs included injection-site AEs (pain, erythema, and swelling for adults and additionally induration for pediatric participants) collected for 5 days postvaccination for adults and 14 days postvaccination for pediatric participants and systemic AEs (myalgia, arthralgia, headache, and fatigue for adults and additionally urticaria for pediatric participants) collected for 14 days postvaccination for all participants. Serious AEs and deaths were collected for the length of the study.
Immunogenicity Assessments
Blood was collected prior to the first study vaccination and 30 days after the third PCV vaccination (day 90) as well as prior to and 30 days after vaccination with PPSV23 or a fourth PCV dose for the measurement of serotype-specific, anti-pneumococcal polysaccharide (PnPs) antibodies. Anti-PnP serotype-specific immunoglobulin G (IgG) for the 15 serotypes contained in V114 and the 13 serotypes contained in PCV13 was measured in sera using the pneumococcal electrochemiluminescence (PnECL) v2.0 assay, which was developed by MSD [27, 28]. A validated multiplex opsonophagocytic assay was used to assess serotype-specific, antibody-mediated killing activity.
Determination of Study Sample Size
The overall objective of the study was to generate safety and immunogenicity data with V114 in persons who have undergone allo-HCT and, as such, the safety and immunogenicity endpoints are descriptive. The sample size of approximately 125 adult participants per group was selected to achieve a reasonably sized safety database in this population. After study initiation, a pediatric cohort was added to enroll approximately 25 participants in each group following initiation of the V114 pediatric phase 3 program.
Analysis Populations
Safety analyses were conducted in the “all participants as treated” population, which consisted of all randomized participants who received at least 1 study vaccination. The “per protocol” population was the primary analysis population for immunogenicity data and consisted of all randomized participants without protocol deviations that may substantially affect results of the immunogenicity endpoints.
Safety Endpoints and Statistical Methods
The primary safety endpoint was to evaluate the safety and tolerability of 3 doses of V114 and PCV13 with respect to the proportion of participants with AEs. Secondary safety endpoints were to evaluate safety and tolerability of PPSV23 or a fourth dose of V114 or PCV13 with respect to the proportion of participants with AEs. The within-group 95% CIs were calculated based on the exact method by Clopper and Pearson [29].
Immunogenicity Endpoints and Statistical Methods
The primary immunogenicity endpoint was to evaluate the anti-PnP serotype-specific IgG geometric mean concentrations (GMCs) at day 90 for each vaccination group. The secondary objectives were to evaluate the anti-PnP serotype-specific opsonophagocytic activity (OPA) geometric mean titers (GMTs) at day 90 for each vaccination group, as well as OPA and IgG geometric mean fold rises (GMFRs) and the proportion of participants with a 4-fold or greater increase in antibody levels from baseline (day 1) to day 90. Exploratory immunogenicity endpoints were to evaluate anti-PnP serotype-specific IgG GMCs and OPA GMTs at 30 days following PPSV23 or 30 days following a fourth dose of V114 or PCV13. Point estimates and within-group 95% CIs were calculated by exponentiating the CIs of the mean of the natural log values based on the t-distribution. For continuous endpoints, the within-group 95% CIs were obtained by exponentiating the CIs of the mean of the natural log values based on the t-distribution. For dichotomous endpoints, the within-group 95% CIs were based on the exact method by Clopper and Pearson.
Analysis Software
All analyses were performed using SAS software, version 9.4, of the SAS System for Unix (copyright© 2012 SAS Institute, Inc).
RESULTS
A total of 274 participants (14 children [3 to <18 y of age] and 260 adults [≥18 y old]) were enrolled and vaccinated with either V114 (n = 139) or PCV13 (n = 135). Enrollment was contingent on the adult cohort, with a plan to cease enrollment once 250 adults were enrolled. As a result, a lower-than-expected number of pediatric participants were enrolled. Of the vaccinated participants, 115 in the V114 group (82.7%) and 111 in the PCV13 group (80.4%) completed the study (Figure 1). Participant demographic and baseline characteristics were generally comparable between vaccination groups, including prior steroid use and haploidentical donor status (Table 1). Graft versus host disease at randomization was also reported in both groups (43.2% in the V114 group, 36.3% in the PCV13 group).
Figure 1.
Participant disposition. Abbreviation: PCV, pneumococcal conjugate vaccine.
Table 1.
Baseline Demographics and Clinical Characteristics
| V114 (n = 139) | PCV13 (n = 135) | Total (N = 274) | |
|---|---|---|---|
| Gender, n (%) | |||
| Male | 82 (59.0) | 74 (54.8) | 156 (56.9) |
| Female | 57 (41.0) | 61 (45.2) | 118 (43.1) |
| Age,a n (%) | |||
| 3 to <18 y | 8 (5.8) | 6 (4.4) | 14 (5.1) |
| ≥18 y | 131 (94.2) | 129 (95.6) | 260 (94.9) |
| Age, mean ± SD, y | |||
| 3 to <18 y | 10.3 ± 5.0 | 8.5 ± 4.0 | 9.5 ± 4.6 |
| ≥18 y | 50.2 ± 13.3 | 48.4 ± 16.7 | 49.3 ± 15.1 |
| Underlying disease, n (%) | |||
| Acute myeloid leukemia | 63 (45.3) | 52 (38.5) | 115 (42.0) |
| Myelodysplastic syndrome | 16 (11.5) | 29 (21.5) | 45 (16.4) |
| Acute lymphoblastic leukemia | 16 (11.5) | 26 (19.3) | 42 (15.3) |
| Myelofibrosis | 7 (5.0) | 4 (3.0) | 11 (4.0) |
| Chronic myeloid leukemia | 6 (4.3) | 4 (3.0) | 10 (3.6) |
| Other hematologic conditions | 32 (23.0) | 28 (20.7) | 60 (21.9) |
| Haploidentical donor status,a n (%) | |||
| Yes | 45 (32.4) | 43 (31.9) | 88 (32.1) |
| No | 94 (67.6) | 92 (68.1) | 186 (67.9) |
| Median time from allo-HCT to Day 1, d | 130.0 | 134.0 | … |
| Use of systemic steroids within 14 days of Day 1,a n (%) | |||
| Yes | 42 (30.2) | 36 (26.7) | 78 (28.5) |
| No | 97 (69.8) | 99 (73.3) | 196 (71.5) |
| History of GVHD at Day 1, n (%) | |||
| Yes | 60 (43.2) | 49 (36.3) | 109 (39.8) |
| No | 79 (56.8) | 86 (63.7) | 165 (60.2) |
Abbreviations: allo-HCT, allogeneic hematopoietic cell transplant; GVHD, graft versus host disease.
Study stratification factors.
Safety
During the study, most participants experienced 1 or more AEs. Due to different AE collection requirements in adults and children, safety outcomes in these cohorts were reported separately. The proportions of participants with systemic and serious AEs after any of the first 3 doses of study vaccine were comparable between intervention groups in both adults and children (Figure 2 and Supplementary Table 2). Adults in the V114 group had a numerically higher (>10-point difference between groups) proportion of solicited AEs, injection-site AEs, and vaccine-related systemic AEs after any of the first 3 doses compared with the PCV13 group. The majority of AEs in each group were of mild-to-moderate intensity (Figure 2A).
Figure 2.
Safety summary in (A) adult (n = 260) and (B) pediatric (n = 14) participants after any of the first 3 PCV doses. Stacked bar graphs on the right display solicited AEs by intensity. For injection-site swelling, erythema, and induration, intensity was assigned according to size as follows: mild events were those measuring 0 to ≤1 inch, moderate events were >1 to ≤3 inches, and severe events were >3 inches. Injection-site induration and urticaria were only solicited in pediatric participants. Abbreviations: AE, adverse event; P, PCV13; PCV, pneumococcal conjugate vaccine; V, V114. *Determined by the investigator to be related to the study vaccine.
The most common AEs reported were those solicited in the trial, including injection-site (pain, erythema, swelling) and systemic (myalgia, arthralgia, headache, fatigue) AEs. The 3 most common AEs after any of the first 3 PCV doses were injection-site pain, myalgia, and fatigue in adults and injection-site pain, injection-site swelling, and myalgia in children. The proportions of participants with individual solicited AEs by intensity are displayed in Figure 2. The majority of participants experienced AEs of mild-to-moderate intensity with a duration of 3 days or fewer (Figure 2 and Supplementary Table 3). The distribution of maximum body temperature measurements after vaccination were also comparable between vaccination groups, with most participants reporting a maximum temperature of 38.0°C or less (Supplementary Table 4).
At approximately 12 months post–allo-HCT, participants received either a single dose of PPSV23 (n = 164) or a fourth dose of PCV (n = 66) if there was a diagnosis of chronic GVHD (Figure 1). After PPSV23, the most common AEs in both groups were injection-site pain and myalgia. The majority of AEs in both groups were of mild-to-moderate intensity with a duration of 3 days or fewer (Supplementary Tables 5–7). Results were similar in participants who received a fourth PCV dose (Supplementary Tables 8–10).
Of all vaccinated participants, 32.4% experienced 1 or more serious AEs (28.8% in the V114 group, 36.3% in the PCV13 group). The proportions of participants with serious AEs after any of the first 3 PCV doses, PPSV23, or the fourth PCV dose were generally comparable between groups (Supplementary Tables 11–14). Two serious AEs were considered by the investigator to be related to a vaccine given in the study, one after V114 and one after PPSV23. One adult participant with a history of acute lymphoblastic leukemia and cutaneous GVHD discontinued the study 36 days after V114 dose 2 due to a serious AE of immune thrombocytopenic purpura. Another adult participant in the V114 group was hospitalized after experiencing pyrexia (39.5°C) 1 day after PPSV23 that lasted 2 days. In both cases, the conditions resolved with no further complications. Seventeen participants (8 in the V114 group, 9 in the PCV13 group) died during the study. None of the deaths were determined by the investigator to be related to the study vaccines. New-onset or worsening GVHD during the study was reported for 28.1% of participants in the V114 group and 40.0% of participants in the PCV13 group. Relapse or progression of underlying disease occurred in 10.8% and 11.9% of participants in the V114 and PCV13 groups, respectively.
Immunogenicity
Immunogenicity analyses were pooled for adults and children. At day 90, V114 induced immune responses comparable to PCV13 for the 13 shared serotypes and higher than PCV13 for serotypes 22F and 33F for both IgG GMCs (Figure 3) and functional antibodies (OPA) (Figure 4). Results were further supported by serotype-specific IgG and OPA GMFRs and the proportions of participants with a 4-fold or greater increase in serotype-specific antibody levels from baseline to day 90 (Supplementary Figures 1 and 2). V114 also induced immune responses as assessed by serotype-specific IgG GMCs at day 90 in participants stratified by steroid use within 14 days of the first study vaccination, haploidentical donor status, and age. Results observed in the subgroup analyses, as well as in participants with a history of GVHD, were generally consistent with the overall population (Supplementary Tables 15–22).
Figure 3.
Serotype-specific IgG GMCs at day 90 (30 days following dose 3) for all participants (adult and pediatric). The bar graph shows IgG GMCs with 95% CIs for V114 and PCV13 groups. Raw data are shown in the table to the right. V114 group: n = 105; PCV13 group: n = 86–88. Abbreviations: CI, confidence interval; GMC, geometric mean concentration; IgG, immunoglobulin G; PCV, pneumococcal conjugate vaccine.
Figure 4.
Serotype-specific OPA GMTs at day 90 (30 days following dose 3) for all participants (adult and pediatric). The bar graph shows OPA GMTs with 95% CIs for V114 and PCV13 groups. Raw data are shown in the table to the right. V114 group: n = 89–92; PCV13 group: n = 65–68. Abbreviations: CI, confidence interval; GMT, geometric mean titer; OPA, opsonophagocytic activity; PCV, pneumococcal conjugate vaccine.
Immunogenicity was further assessed before and after either PPSV23 or the fourth PCV dose. PPSV23 induced immune responses to the 15 serotypes shared with V114 when given following either V114 or PCV13 (Supplementary Figures 3 and 4). Increases in serotype-specific IgG GMCs and GMFRs to all study vaccine serotypes were also observed in both groups following a fourth PCV dose (Supplementary Figures 3 and 5).
DISCUSSION
Following allo-HCT, individuals are highly vulnerable to infectious disease and subsequent infection-related mortality [30]. Strategies to prevent infection through vaccination are critical to shorten the window of susceptibility and increase survival for this vulnerable population. This study demonstrates the safety, tolerability, and immunogenicity of V114 following allo-HCT, which has the potential to reduce the remaining burden of IPD [31, 32].
V114 was generally well tolerated in all participants throughout the vaccination series and comparable to recipients of PCV13, with the majority of solicited AEs experienced being of mild-to-moderate intensity and short duration. The proportions of adult participants who experienced solicited AEs after any V114 dose were generally comparable to PCV13 for all except injection-site pain, injection-site swelling, and myalgia, which were numerically higher in the V114 group, but mild-to-moderate in intensity and of short duration. The results observed in the planned subgroup analyses were generally consistent with the overall population. New-onset or worsening GVHD occurred in 28.1% of V114 recipients and 40.0% of PCV13 recipients; however, the clinical significance of this is unknown. Overall, the safety profile of V114 was consistent with the safety of other PCVs in this population [4–6, 8].
Following the recommended immunization schedule, a 3-dose series of V114 starting 3–6 months after allo-HCT elicited robust quantitative and qualitative immune responses as evidenced by serotype-specific IgG GMCs and OPA GMTs to all 15 serotypes. Due to delayed B-cell reconstitution after transplant [9], PPSV23 is recommended at least 1 year after transplant to broaden serotype coverage. Vaccination with PPSV23 following V114 was well tolerated and comparable to vaccination with PPSV23 following PCV13. In addition, the study demonstrates that PPSV23 or a fourth dose of PCV (in recipients with chronic GVHD) increased serotype-specific antibody levels at 1 year following transplant. These data suggest that serotype-specific immunity can be maintained with these vaccines at 1 year following transplant in the presence or absence of chronic GVHD. In addition, an advantage of V114 in this regimen is the higher immune response induced against serotypes 22F and 33F during the post-transplant window that is sustained following PPSV23.
This study has limitations. While the study enrolled a substantial number of participants with the risk condition of interest, the cohort size was insufficient for hypothesis testing of immunogenicity endpoints between groups or for the assessment of infrequently occurring AEs. Several factors contributed to low enrollment of pediatric participants, such as a later start of the pediatric V114 phase 3 program as compared with the adult one, the generally lower number of pediatric HCTs performed annually and the coronavirus disease 2019 (COVID-19) pandemic [33]. Certain populations of transplant recipients were excluded from the study. Vaccine effectiveness and persistence of antibody levels following booster were not evaluated. A 20-valent PCV is approved for use in the general adult population, [34] but has not been assessed in this population and was not available as a comparator for this study.
The results of this study demonstrate that V114 is well tolerated in allo-HCT recipients, with a safety profile generally comparable to PCV13. V114 was immunogenic in the 3-dose series, as well as at 1 year post-transplant. These results support the use of V114 as well as V114 followed by PPSV23 in recipients of allo-HCT.
Supplementary Data
Supplementary materials are available at Clinical Infectious Diseases online. Consisting of data provided by the authors to benefit the reader, the posted materials are not copyedited and are the sole responsibility of the authors, so questions or comments should be addressed to the corresponding author.
Supplementary Material
Contributor Information
Marissa Wilck, Merck & Co., Inc., Rahway, New Jersey, USA.
Oliver A Cornely, Institute of Translational Research, Cologne Excellence Cluster on Cellular Stress Responses In Aging-Associated Diseases (CECAD); Department of Internal Medicine, Center for Integrated Oncology Aachen Bonn Cologne Duesseldorf (CIO ABCD), Germany; Excellence Center for Medical Mycology (ECMM); Clinical Trials Centre Cologne (ZKS Köln), Faculty of Medicine and University Hospital Cologne, Cologne, Germany; German Centre for Infection Research (DZIF), Partner Site Bonn-Cologne, Cologne, Germany.
Catherine Cordonnier, Centre Hospitalier Universitaire Henri Mondor, Haematology and Cellular Therapy Department, Créteil and University Paris-Est Créteil, Créteil, France, FR.
Juan Diego Velez, Fundacion Valle del Lili, Cali, Colombia.
Per Ljungman, Karolinska University Hospital and Karolinska Institutet, Stockholm, Sweden.
Johan Maertens, University Hospitals Leuven, Leuven, BE.
Dominik Selleslag, AZ St Jan, Brugge, BE.
Kathleen M Mullane, University of Chicago, Department of Medicine, Chicago, Illinois.
Samir Nabhan, Instituto de Cancer e Transplante de Curitiba ICTR, Curitiba, Puerto Rico.
Qiuxu Chen, Merck & Co., Inc., Rahway, New Jersey, USA.
Ron Dagan, The Shraga Segal Dept. of Microbiology, Immunology and Genetics, Faculty of Health Sciences of the Ben-Gurion University of the Negev, Beer-Sheva, Israel.
Peter Richmond, School of Medicine, University of Western Australia, Perth, Australia.
Caroline Daus, Merck & Co., Inc., Rahway, New Jersey, USA.
Kateasha Geddie, Merck & Co., Inc., Rahway, New Jersey, USA.
Gretchen Tamms, Merck & Co., Inc., Rahway, New Jersey, USA.
Tina Sterling, Merck & Co., Inc., Rahway, New Jersey, USA.
Shrita M Patel, Merck & Co., Inc., Rahway, New Jersey, USA.
Tulin Shekar, Merck & Co., Inc., Rahway, New Jersey, USA.
Luwy Musey, Merck & Co., Inc., Rahway, New Jersey, USA.
Ulrike K Buchwald, Merck & Co., Inc., Rahway, New Jersey, USA.
Notes
Author Contributions. Conception, design, or planning of the study: M. W., P. L., T. Sterling, G. T., U. K. B., C. C., L. M., and T. Shekar. Acquisition of data: C. D., O. A. C., P. L., K. M. M., S. N., D. S., J. D. V., K. G., and T. Shekar. Analysis of data: M. W., C. D., U. K. B., C. C., Q. C., L. M., and T. Shekar. Interpretation of data: M. W., O. A. C., R. D., P. L., J. M., S. N., U. K. B., C. C., P. R., Q. C., L. M., S. M. P., and T. Shekar. Drafting of the manuscript: M. W., U. K. B., C. C., K. G., and T. Shekar. All authors critically reviewed or revised the manuscript for important intellectual content and approved the final version.
Acknowledgments. The authors thank the participants and their families, study staff, and investigators in the V114-022 study group for their contributions. Medical writing support was provided by Timothy J. Chapman and editorial support was provided by Karyn Davis (both of MSD). A full list of study investigators can be found in Supplementary Table 23.
Financial support. This work was supported by MSD.
Data sharing. The data-sharing policy, including restrictions, of Merck, Sharp & Dohme LLC, a subsidiary of Merck & Co, Inc., Rahway, NJ, USA, is available at http://engagezone.msd.com/ds_documentation.php. Requests for access to the clinical study data can be submitted through the Engage Zone site or via e-mail to dataaccess@merck.com.
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