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Original Investigation |

Effect of Varying Doses of a Monovalent H7N9 Influenza Vaccine With and Without AS03 and MF59 Adjuvants on Immune Response A Randomized Clinical Trial FREE

Lisa A. Jackson, MD, MPH1; James D. Campbell, MD, MS2; Sharon E. Frey, MD3; Kathryn M. Edwards, MD4; Wendy A. Keitel, MD5; Karen L. Kotloff, MD2; Andrea A. Berry, MD2; Irene Graham, MD3; Robert L Atmar, MD5; C. Buddy Creech, MD, MPH4; Isaac P. Thomsen, MD4; Shital M. Patel, MD5; Andres F. Gutierrez, MD5; Edwin L. Anderson, MD3; Hana M. El Sahly, MD5; Heather Hill, MS6; Diana L. Noah, PhD7; Abbie R. Bellamy, PhD6
[+] Author Affiliations
1Group Health Research Institute, Seattle, Washington
2Division of Infectious Disease and Tropical Pediatrics, Department of Pediatrics, Center for Vaccine Development, University of Maryland School of Medicine, Baltimore
3Division of Infectious Diseases, Allergy, and Immunology, Saint Louis University School of Medicine, St Louis, Missouri
4Vanderbilt Vaccine Research Program, Vanderbilt University Medical Center, Nashville, Tennessee
5Departments of Molecular Virology and Microbiology and Medicine, Baylor College of Medicine, Houston, Texas
6The EMMES Corporation, Rockville, Maryland
7Southern Research Institute, Birmingham, Alabama
JAMA. 2015;314(3):237-246. doi:10.1001/jama.2015.7916.
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Published online

Importance  Human infections with the avian influenza A(H7N9) virus were first reported in China in 2013 and continue to occur. Hemagglutinin H7 administered alone is a poor immunogen necessitating evaluation of adjuvanted H7N9 vaccines.

Objective  To evaluate the immunogenicity and safety of an inactivated H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations.

Design, Setting, and Participants  Double-blind, phase 2 trial at 5 US sites enrolled 980 adults aged 19 through 64 years from September 2013 through November 2013; safety follow-up was completed in January 2015.

Interventions  The H7N9 vaccine was given on days 0 and 21 at nominal doses of 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin with or without AS03 or MF59 adjuvant mixed on site.

Main Outcomes and Measures  Proportions achieving a hemagglutination inhibition antibody (HIA) titer of 40 or higher at 21 days after the second vaccination; vaccine-related serious adverse events through 12 months after the first vaccination; and solicited signs and symptoms after vaccination through day 7.

Results  Two doses of vaccine were required to induce detectable antibody titers in most participants. After 2 doses of an H7N9 formulation containing 15 µg of hemagglutinin given without adjuvant, with AS03 adjuvant, or with MF59 adjuvant, the proportion achieving an HIA titer of 40 or higher was 2% (95% CI, 0%-7%) without adjuvant (n = 94), 84% (95% CI, 76%-91%) with AS03 adjuvant (n = 96), and 57% (95% CI, 47%-68%) with MF59 adjuvant (n = 92) (P < .001 for comparison of the AS03 and MF59 schedules). The 2 schedules alternating AS03-and MF59-adjuvanted formulations led to lower geometric mean titers (GMTs) of (41.5 [95% CI, 31.7-54.4]; n = 92) and (58.6 [95% CI, 44.3-77.6]; n = 96) than the group induced by 2 AS03-adjuvanted formulations (n = 96) (103.4 [95% CI, 78.7-135.9]; P < .001) but higher GMTs than 2 doses of MF59-adjuvanted formulation (n = 94) (29.0 [95% CI, 22.4-37.6]; P < .001).

Conclusions and Relevance  The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.

Trial Registration  clinicaltrials.gov Identifier: NCT01942265

Figures in this Article

In March 2013 the first human infections with a novel avian influenza A(H7N9) virus were reported in China, and since that time hundreds of cases have been documented.1,2 Most infections are believed to result from poultry exposure, and no evidence of sustained person-to-person spread of H7N9 has yet been found, although limited person-to-person spread appears to have occurred.3 The potential for viral adaptation that would facilitate person-to-person transmission is a major concern.4,5

Previous experience with an inactivated H7N7 influenza vaccine indicated that hemagglutinin H7 is poorly immunogenic6 and that an adjuvanted formulation of an H7N9 vaccine would likely be required. Accordingly, the US National Institutes of Health rapidly initiated 2 companion clinical trials in the Vaccine and Treatment Evaluation Unit network to evaluate a monovalent H7N9 influenza vaccine (Sanofi Pasteur) mixed on site with the 2 adjuvants that are maintained in the US national prepandemic influenza vaccine stockpile. These adjuvants, AS03 (GlaxoSmithKline Biologicals) and MF59 (Novartis Vaccines and Diagnostics), have been shown to enhance the immune response to and improve the efficacy of other inactivated influenza vaccines.710

A report of data from the first study, which evaluated the H7N9 vaccine with and without MF59 adjuvant in healthy adults, has been published.11 We report the findings from the second study, also in healthy adults, that evaluated the H7N9 vaccine with and without AS03 adjuvant, as well as mixed vaccine schedules that included sequential administration of AS03- and MF59-containing formulations and of adjuvanted and unadjuvanted formulations.

Study Design and Participants

The protocol and informed consent forms were approved by the National Institute of Allergy and Infectious Diseases, Division of Microbiology and Infectious Diseases, the US Food and Drug Administration, and the institutional review boards of record for each of the participating study sites.

This randomized, double-blind, phase 2 study was designed to assess the immunogenicity and safety of 2 injections, administered 21 days apart, of an inactivated H7N9 influenza vaccine given with and without adjuvant. Study objectives were to assess the safety, reactogenicity, and immunogenicity of formulations containing 3 dose levels of hemagglutinin antigen combined with AS03, 1 dose level combined with MF59, and 2 dose levels without adjuvant. Participants were randomly assigned with equal probability to 1 of 10 study groups and received various formulations for the 2 study vaccinations (Figure 1). Upon enrollment, each participant was assigned a randomization number from the electronic data entry system that corresponded to a treatment on a randomization list available only to the unblinded study pharmacist and vaccine administrator.

Place holder to copy figure label and caption
Figure 1.
CONSORT Flow Diagram of Participants Through the Influenza A(H7N9) Vaccine Study

HIA indicates hemagglutination inhibition antibody.

aParticipant unable to comply with visit schedule.

bParticipant incarcerated.

Graphic Jump Location

Eligible participants were nonpregnant healthy persons or persons with controlled chronic illness who were aged 19 through 64 years and who provided written informed consent for study participation. Eligibility criteria are provided in the trial protocol (Supplement 1). Participants were enrolled at 5 US sites between September 18, 2013, and November 22, 2013, and were recruited from the broader communities at those sites. Study follow-up was completed on January 9, 2015.

The participants’ race and ethnicity were classified according to their self-reported responses. Ethnicity options were Hispanic or Latino and non-Hispanic or non-Latino. Race options were American Indian/Alaskan Native, Asian, native Hawaiian or other Pacific Islander, black or African American, and white. Race and ethnicity were assessed to track diversity of participants and permit ad hoc group-specific assessments of outcomes if needed.

Vaccine and Adjuvants

The study vaccine was a monovalent, inactivated, subvirion, preservative-free preparation of the influenza A/Shanghai/2/2013(H7N9) virus, propagated in embryonated chicken eggs, manufactured using a process similar to that used to produce the licensed seasonal influenza virus vaccine Fluzone (Sanofi Pasteur). The hemagglutinin antigen content of the vaccine lots used for this study was determined by reversed-phase high-performance liquid chromatography, instead of the traditional single radial immunodiffusion (SRID) assay, as official calibrated reagents for the SRID assay were not available at the time of bulk trial vaccine formulation. To accommodate potential variance between the high-performance liquid chromatography and SRID methods, the manufacturer elected to formulate the bulk vaccine at a concentration 50% higher than the target and the vaccine antigen contents later confirmed by SRID were approximately 50% higher than the target contents. Therefore, study vaccine formulations estimated to contain 3.75 µg, 7.5 µg, 15 µg, and 45 µg of hemagglutinin based on the target vaccine concentrations actually contained 5.75 µg, 11.5 µg, 22.5 µg, and 74.25 µg of hemagglutinin, respectively, as confirmed by SRID. In this report, we have maintained identification of study groups based on the intended hemagglutinin contents.

AS03 is an adjuvant system including α-tocopherol and squalene in an oil-in-water emulsion. The MF59 adjuvant is an oil-in-water emulsion composed of squalene stabilized by the addition of polysorbate 80 and sorbitan trioleate. The AS03 adjuvant contained 10.68 mg squalene per administered dose and the MF59 adjuvant contained 9.75 mg squalene per administered dose.

The study vaccine formulations were prepared by a research pharmacist at each of the study sites using supplied vials of influenza A(H7N9) vaccine containing an estimated 7.5 µg, 15 µg, or 30 µg of hemagglutinin per 0.5 mL. The adjuvanted formulations were prepared by injecting 0.5 mL of H7N9 vaccine followed by 0.5 mL of AS03 or MF59 adjuvant into a new, sterile 3 mL mixing vial under a laminar flow hood. A single 0.5 mL dose was then withdrawn from the mixture. All administered formulations had an injection volume of 0.5 mL, except the 45-µg unadjuvanted formulation, which was made up of 0.75 mL of vaccine containing 30 µg of hemagglutinin per 0.5 mL. All vaccines were injected intramuscularly in the deltoid by unblinded staff members who were not involved with subsequent participant follow-up.

Immunogenicity Assays

Blood samples were collected at baseline and at 8 and 21 days after each vaccination for testing by hemagglutination inhibition and microneutralization antibody assays using methods previously described.1113

Safety Outcomes

Safety and tolerability were evaluated by identification of serious adverse events and new chronic medical conditions through 12 months after the first vaccination; unsolicited adverse events through day 42; clinical safety laboratory adverse events 8 days after each vaccination; and, using a memory aid, solicited local and systemic signs and symptoms for 7 days after each vaccination. Unsolicited adverse events were identified by querying participants at the time of scheduled in-person and phone visits.

Statistical Analysis

The 2 co–primary immunologic end points included the proportion of participants who had a hemagglutination inhibition antibody (HIA) titer of 40 or higher and the proportion of participants who met the definition of seroconversion (4-fold or greater increase in HIA titer from a baseline titer of ≥10 or a titer after vaccination of ≥40 if the baseline titer was <10) 21 days after the second vaccination. Because nearly all participants were seronegative at baseline, these 2 end points were essentially identical and for simplicity only the primary end point of proportion with an HIA titer of 40 or higher is presented. As secondary end points, the proportion of participants with microneutralization antibody titer of 40 or higher, and HIA and microneutralization antibody geometric mean titers (GMTs) were also calculated, with titers below the limit of detection (titer <10) assigned a value of 5.

Comparisons were conducted to evaluate differences in response between study groups using a χ2 test to compare the percentage of participants with a titer of 40 or higher and a nonparametric Kruskal-Wallis test for comparisons of titer magnitude. Statistical significance was considered at a level of α = 0.05 and all tests were 2-sided. Analysis was performed using SAS (SAS Institute), version 9.3. As the study objective was to obtain preliminary estimates of immune response and trends between groups, analyses were not adjusted for multiple comparisons and because missing data were minimal, imputation was not performed.

As a prespecified analysis of factors potentially influencing immune response, a logistic regression model was fit to evaluate the association between covariates including study group, age (19-34, 35-49, and 50-64 years), sex, body mass index (BMI; calculated as weight in kilograms divided by height in meters squared; <30 vs ≥30), and receipt of seasonal influenza vaccine prior to enrollment (no receipt of either the 2012-2013 vaccine or the 2013-2014 vaccine vs prior receipt of either vaccine) with the outcome of an HIA titer of 40 or higher at 21 days after the second vaccination. A forward stepwise selection algorithm was used to determine which covariates to include in the final multivariable model. At each step independent variables were considered for addition or removal from the model at a significance level of α = 0.10. Model fit was assessed using residual χ2 and Hosmer-Lemeshow goodness-of-fit tests.

The intention-to-treat (ITT) analysis subset included data for participants who received at least 1 dose of study vaccine and had valid hemagglutination inhibition assay results prior to vaccination and for at least 1 visit after vaccination. The per-protocol analysis subset included all participants in the ITT subset except those who did not receive both doses of study vaccine or who had major protocol deviations. Results of analyses of the 2 subsets were similar and only the ITT analyses are presented.

Prespecified interim analyses of the hemagglutination inhibition and microneutralization responses at each time point were evaluated in a subset of 25 participants per group (250 total participants) to provide information of potential public health relevance. Results of the interim analyses were not shared with study investigators, staff, or the trial statistician at the data coordinating center and did not influence the conduct of the study or the final analysis.

The sample size of approximately 100 participants per group was selected to obtain preliminary estimates of immunogenicity and safety in a time-critical manner and was not designed to test any specific null hypothesis.

Enrollment and Demographics

A total of 975 participants received the first dose of study vaccine. Demographic and baseline characteristics were similar across study groups (Table 1). Of those who received a first vaccination, 946 participants were included in the ITT analysis of the primary end point at 21 days following the second dose (Figure 1).

Table Graphic Jump LocationTable 1.  Demographic and Baseline Characteristics of All Participants Receiving the Influenza Vaccination
AS03- and MF59-Enhanced Responses

Ninety-nine percent of the ITT cohort lacked detectable baseline HIA and all with detectable antibody had a titer lower than 40 (Table 2). Observed responses after the first vaccination were low in all study groups.

Table Graphic Jump LocationTable 2.  Hemagglutination Inhibition and Microneutralization Antibody Responses Against Influenza A(H7N9) for Each Group in the ITT Population

On day 21 after dose 2, the highest hemagglutination inhibition GMTs were observed in groups given 2 doses of an AS03-adjuvanted vaccine (groups 1, 2, and 3) (Figure 2). Among those 3 groups, hemagglutinin antigen content was not associated with statistically significant differences in the proportion of participants with a titer of 40 or higher (91% [95% CI, 83%-96%] for group 1 vs 81% [95% CI, 71%-88%] for group 2 vs 84% [95% CI, 76%-91%] for group 3; P = .16) or GMT (107.1 [95% CI, 85.9-133.6] for group 1 vs 80.9 [95% CI, 60.7-107.7] for group 2 vs 103.4 [95% CI, 78.7-135.9] for group 3; P = .54). Administration of 2 doses of MF59-adjuvanted vaccine (group 8) led to significantly lower GMT and proportion with an HIA titer of 40 or higher at 21 days after dose 2 compared with administration of 2 doses of AS03-adjuvanted vaccine (group 3) (GMT: 29.0 [95% CI, 22.4-37.6] for group 8 vs 103.4 [95% CI, 78.7-135.9] for group 3; HIA titer ≥40: 57% [95% CI, 47%-68%] for group 8 vs 84% [95% CI, 76%-91%] for group 3; P < .001 for both comparisons).

Place holder to copy figure label and caption
Figure 2.
HIA Geometric Mean Titer by Time Point and Study Group in the ITT Population

HIA indicates hemagglutination inhibition antibody; ITT, intention-to-treat. Error bars indicate 95% CIs.

aThe No. of participants in each group indicate those who received vaccination as randomized. Four patients did not have data reported after vaccination and are not included in this analysis.

Graphic Jump Location

In evaluations of participants who received a mixed schedule that included an AS03-adjuvanted vaccine and an unadjuvanted vaccine, the proportion with an HIA titer of 40 or higher and the GMT after the second vaccination were significantly higher in the group that received the AS03-adjuvanted vaccine first (group 4) compared with the group that received the unadjuvanted vaccine first (group 5) (HIA titer ≥40: 63% [95% CI, 53%-73%] for group 4 vs 28% [95% CI, 19%-38%] for group 5; GMT: 43.1 [95% CI, 33.2-55.9] for group 4 vs 13.0 [95% CI, 10.3-16.5] for group 5; P < .001 for both comparisons). The groups that received only 1 AS03-adjuvanted vaccine (groups 4 and 5) had significantly lower GMTs and proportion with an HIA titer of 40 or higher than the comparison group that received 2 AS03-adjuvanted vaccines (group 3) (P < .001 for all comparisons of group 3 vs group 4 and group 3 vs group 5).

In evaluations of the 2 groups that received a mixed schedule including an AS03-adjuvanted vaccine and a MF59-adjuvanted vaccine (groups 6 and 7), there was a higher GMT at 21 days after dose 2 in group 7, which received MF59 followed by AS03 (58.6 [95% CI, 44.3-77.6] for group 7 vs 41.5 [95% CI, 31.7-54.4] for group 6; P = .03), but no significant difference in proportion with an HIA titer of 40 or higher (75% [95% CI, 65%-83%] for group 7 vs 70% [95% CI, 59%-79%] for group 6; P = .41). Responses to the mixed adjuvant schedules were significantly lower than responses to 2 doses of AS03-adjuvanted vaccine (group 6 and 7 combined vs group 3; for proportion with an HIA titer ≥40, P = .02 ; for GMT, P < .001) and were higher than to 2 doses of MF59-adjuvanted vaccine (group 6 and 7 combined vs group 8; for proportion with an HIA titer ≥40, P = .08; for GMT, P < .001).

Responses to an AS03-adjuvanted vaccine followed by an MF59-adjuvanted vaccine (group 6) were similar to responses to an AS03-adjuvanted vaccine followed by unadjuvanted vaccine (group 4), whereas responses to an unadjuvanted vaccine followed by an AS03-adjuvanted vaccine (group 5) were significantly lower than responses to an MF59-adjuvanted vaccine followed by an AS03-adjuvanted vaccine (group 7) (P < .001 for comparisons of GMT and an HIA titer ≥40). Administration of vaccine series containing at least 1 adjuvanted vaccine led to significantly higher GMTs and proportion with an HIA titer of 40 or higher than administration of 2 doses of unadjuvanted vaccine (P < .001 for comparison of groups 1 through 8 combined vs groups 9 and 10 combined). Among participants who received 2 doses of unadjuvanted vaccine, responses were low, but the GMT (P = .03) and proportion with an HIA titer of 40 or higher (P = .03) were significantly higher in the group given unadjuvanted vaccine with the higher hemagglutinin content (group 10).

The absolute values of titers detected by the microneutralization assay tended to be higher than those detected by the hemagglutination inhibition assay, but the patterns of response by study group were similar between the 2 assays (Table 2). Most of the specimens with undetectable titers by the hemagglutination inhibition assay had detectable titers by the microneutralization assay (eFigure in Supplement 2). The correlation between the 2 assays was higher for specimens with detectable titers by the hemagglutination inhibition assay.

Antibody Response by Age and by Prior Influenza Vaccination

In analyses stratified by age group, the 19-34 years age group achieved the highest HIA GMTs on day 21 after dose 2 (Table 3). Analyses stratified by prior receipt of seasonal influenza vaccine found generally higher GMTs and proportion with an HIA titer of 40 or higher at 21 days after dose 2 in the group that did not receive seasonal influenza vaccine (eTable 1 in Supplement 2).

Table Graphic Jump LocationTable 3.  HIA Responses 21 Days After the Second Dose of Influenza Vaccination by Study Group and Age Group in the ITT Population

In the logistic regression model using stepwise selection of covariates, older age and prior receipt of seasonal influenza vaccine were independently associated with a lower likelihood of achieving an HIA titer of 40 or higher after dose 2 and were retained, along with study group, in the final model. Results from the model suggest that participants in both older age groups were less likely to have an HIA titer of 40 or higher than participants in the youngest age group; for participants in the 35-49 years age group, the odds ratio (OR) was 0.62 (95% CI, 0.38-0.98), and, for participants in the 50-64 years age group, the OR was 0.53 (95% CI, 0.35-0.79). The model also suggested that participants who previously received seasonal influenza vaccine were less likely to have an HIA titer of 40 or higher than those who had not; OR, 0.37 (95% CI, 0.24-0.56).

Safety and Tolerability of the Vaccine Regimens

Of the 16 serious adverse events that were reported, 1 (myocardial infarction, reported 5 days after receipt of the second vaccination for a participant in group 4) was considered to be related to the study product. No new onset chronic medical conditions were considered to be related to vaccination. Overall, 43% of participants reported 1 or more nonserious adverse event; most were mild in severity and not related to the vaccine. Thirteen nonserious adverse events were graded severe, 1 of which (abdominal pain) was considered related to the vaccine. Clinical laboratory adverse events were infrequent and, when they occurred, were nearly always mild in severity (eTables 2 and 3 in Supplement 2).

Overall the administered vaccines were well tolerated. Solicited local signs and symptoms tended to be more frequently reported by participants who received a vaccine dose with adjuvant (eTable 4 in Supplement 2) and multivariable logistic regression modeling indicated participants who received a vaccine dose with adjuvant were significantly more likely to report local reactogenicity compared with those who received the vaccine without the any adjuvant (eg, for first vaccination, 595 of 680 participants [88%] for vaccine dose with adjuvant vs 164 of 295 participants [56%] for vaccine dose without adjuvant; P < .001). Participants who received a first vaccine dose with adjuvant were also significantly more likely to report a systemic reaction than those who received a dose without adjuvant (347 of 680 participants [51%] for vaccine dose with adjuvant vs 119 of 295 participants [40%] for vaccine dose without adjuvant; P = .01), but the rates were similar following the second vaccination.

The US national prepandemic influenza vaccine stockpile includes liquid formulations of AS03 and MF59 adjuvants to allow a flexible and accelerated pandemic response. Most clinical trials of adjuvanted influenza vaccines have evaluated formulations produced by a single manufacturer and some of those formulations combine the vaccine antigens and the adjuvant in the investigational product prior to release. In contrast, use of adjuvants from the stockpile would involve mixing unadjuvanted vaccine with stockpiled adjuvant at the point of use and would also likely include combining vaccine and adjuvants made by different manufacturers. In this study, we found that such on-site mixing of unadjuvanted vaccine from Sanofi Pasteur with AS03 and MF59 adjuvants from other manufacturers produced adjuvanted vaccine formulations that were well tolerated and that augmented the immune response to the H7 antigen.

We also found that a single dose of the inactivated H7N9 vaccine is poorly immunogenic, regardless of whether the formulation contains AS03 or MF59 adjuvant, and that a 2-dose schedule of unadjuvanted vaccine given 21 days apart is also poorly immunogenic. The greatest responses were seen after 2 doses of AS03-adjuvanted vaccine, which induced an HIA titer of 40 or higher in at least 81% of participants compared with 57% following 2 doses of MF59-adjuvanted vaccine and less than 10% following 2 doses of unadjuvanted vaccine. To our knowledge, this is the first head-to-head comparison of AS03 and MF59 adjuvants. These results imply that, of the options currently available utilizing adjuvants included in the national stockpile, based on the immune response data, AS03 should be considered a first-line adjuvant for strategies incorporating an inactivated H7N9 vaccine in adults. Use of AS03 adjuvant was also shown to permit dose-sparing of hemagglutinin antigen, with no significant difference in responses after the second dose among study groups 1 through 3.

We evaluated schedules alternating administration of AS03- and MF59-adjuvanted vaccines and those alternating adjuvanted and unadjuvanted vaccines. These schedules were evaluated to provide information on immune responses to patterns of vaccine administration that may occur if adjuvants are inconsistently available during a vaccination campaign. The best responses were seen following 2 doses of AS03-adjuvanted vaccine; however, if availability of AS03 is not sufficient to ensure consistent administration of 2 doses of AS03-adjuvanted vaccine, the response to a schedule including an AS03-adjuvanted vaccine as a first dose and an unadjuvanted vaccine as a second dose were comparable to schedules that alternated AS03- and MF59-containing vaccines. In contrast, a schedule that included a first dose of an unadjuvanted vaccine and a second dose of an AS03-adjuvanted vaccine led to significantly lower immune responses, indicating that initial priming with an adjuvanted formulation is optimal for a 2-dose schedule. If AS03 is not available, 2 doses of MF59-adjuvanted vaccine led to significantly higher titers than 2 doses of unadjuvanted vaccine.

We found that older age and prior administration of seasonal influenza vaccine were independently associated with a decreased antibody response; findings that have also been reported from evaluations of the 2009 influenza A(H1N1) pandemic vaccines.1423 The results of this study are consistent with the companion study of H7N9 influenza vaccine in adults conducted in the Vaccine and Treatment Evaluation Unit network, which evaluated varying doses of the vaccine with or without the MF59 adjuvant,11 with both studies reporting that unadjuvanted vaccine was poorly immunogenic and that the MF59 adjuvant enhanced the immune response. Other reported evaluations of H7N9 influenza vaccines also support the need for adjuvanted formulations.24,25 Our unique evaluation of mixed adjuvant vaccination schedules suggests that, in an H7N9 vaccination campaign, sequential administration of formulations with different adjuvants, and possibly of mixed schedules including boosting with an unadjuvanted vaccine, could be considered in the event that such flexibility is needed.

The AS03 and MF59 adjuvants augmented the immune responses to 2 doses of an inactivated H7N9 influenza vaccine, with AS03-adjuvanted formulations inducing the highest titers. This study of 2 adjuvants used in influenza vaccine formulations with adjuvant mixed on site provides immunogenicity information that may be informative to influenza pandemic preparedness programs.

Corresponding Author: Lisa A. Jackson, MD, MPH, Group Health Research Institute, 1730 Minor Avenue, Ste 1600, Seattle, WA 98101 (jackson.l@ghc.org).

Author Contributions: Dr Jackson had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Jackson, Campbell, Keitel, Kotloff, Creech.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Jackson, Keitel, Anderson, Bellamy.

Critical revision of the manuscript for important intellectual content: Jackson, Campbell, Frey, Edwards, Keitel, Kotloff, Berry, Graham, Atmar, Creech, Thomsen, Patel, Gutierrez, Sahly, Hill, Noah.

Statistical analysis: Jackson, Bellamy.

Obtained funding: Jackson, Edwards, Keitel, Kotloff, Noah.

Administrative, technical, or material support: Jackson, Campbell, Frey, Keitel, Kotloff, Berry, Creech, Thomsen, Anderson, Noah.

Study supervision: Jackson, Campbell, Edwards, Keitel, Kotloff, Gutierrez, Sahly.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest. Dr Jackson reports receiving funding from Novavax for the conduct of a clinical trial of an unrelated vaccine. Dr Frey reports receiving funding from Novartis and from GlaxoSmithKline for the conduct of influenza vaccine trials. Dr Edwards reports receiving grant funding from Novartis for a study of an unrelated vaccine and serving on a data and safety monitoring board for a seasonal influenza vaccine made by Novartis. Dr Keitel reports serving as an unpaid advisor to ContraFect-flu antibodies and as an unpaid program reviewer for GlaxoSmithKline. Dr Kotloff reports receiving grant funding from Merck for an unrelated vaccine. Dr Creech reports receiving grant funding from Pfizer and from Novartis Vaccines for unrelated work. Dr El Sahly reports receiving grants to conduct clinical research from Protein Sciences Corp. No other disclosures were reported.

Funding/Support: This work was supported by federal funds from the National Institute of Allergy and Infectious Diseases, the National Institutes of Health, and the US Department of Health and Human Services (contracts HHSN272200800004C [Group Health], HHSN27220080000C [Vanderbilt University], HHSN272200800001C [University of Maryland], HHSN272200800002C [Baylor College of Medicine], HHSN272200800003C [Saint Louis University], HHSN2722012000031 and HHSN27200003 [Battelle and subcontractor Southern Research], and HHSN272200800013C [EMMES Corporation]). At the University of Maryland, partial support was also provided by additional funding sources, including grant M01-RR-016500 from the University of Maryland General Clinical Research Center and grant K12-RR-023250 from the National Center for Research Resources. The vaccine and adjuvants were provided by the US Department of Health and Human Services Biomedical Advanced Research and Development Authority from the national prepandemic influenza vaccine stockpile and were manufactured by Sanofi Pasteur (H7N9 vaccine), Novartis Vaccines (MF59 adjuvant), and GlaxoSmithKline (AS03 adjuvant).

Role of the Funders/Sponsors: The funders/sponsors participated in the design and monitoring of the study; and the review and approval of the manuscript. The funders/sponsors did not participate in the collection, management, analysis, and interpretation of the data; the preparation of the manuscript; or the decision to submit the manuscript for publication. The study product manufacturers had no role in the conduct of the study, analysis of the data, or preparation of this report.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: The investigators at the 5 National Institute of Allergy and Infectious Diseases Vaccine and Treatment Units thank the various groups that made this trial possible: Linda Lambert, PhD, Wendy L. Buchanan, BSN, MS, Valerie Riddle, MD, Soju Chang, MD, MPH, Rhonda Pikaart-Tautges, BSBA, BS, Suzanne Murray, RN, BSN, Richard Gorman, MD (National Institute of Allergy and Infectious Diseases); Michael O’Hara, PhD, Corrina Pavetto, MS, Bai Yeh, MBA, Vittoria Cioce, PhD, Karen Biscardi, MS (Biomedical Advanced Research and Development Authority); Jeanne S. Sheffield, MD, Robert A. Salata, MD, H. Cody Meissner, MD, Richard Webby, PhD, and Maria Deloria Knoll, PhD (data and safety monitoring board). We also thank each member of the study teams for their important contributions to the conduct of this clinical trial: Kathleen Koehler, RN, Thomas Pacatte, BSN, MSW, RN, Janice Tennant, MPH, RN, Sabrina DiPiazza, BSN, RN, Linda Eggemeyer, BSN, RN, Kathleen Geldmacher, RN, Sharon Irby-Moore, MPH, RN, Mary Margaret Donavan MSN, RN, Joan Siegner, MSN, RN, Karla Mosby, RN, Carol Duane, PhD, RN, Richard Nickel, RPh, Nicole Purcell, Maria Woodson (Saint Louis University); Nancy Greenberg, RN, MS, Ginny Cummings, CRNP, Robin Barnes, CRNP, Milagritos Tapia, MD, Mark Travassos, MD, Monica McArthur, MD, PhD, Barbara Jean Albert, MD, Mardi Reymann, BS, Inna Ruslanova, MS, Brenda Dorsey, BSN, MS, CCRP, Alyson Kwon, BA, CCRC, Kimberly Wilhelmi, RN, BSN, MS, Naya Komninou, BA, Sandra Getlein, RN, Nancy Wymer, RN, Linda Wadsworth, RN, Myounghee Lee, PharmD, PhD, CCRP, Gillian Freedman, BA, Stephen Yu, BS, Sana IqBal, BS, MS, and the expert nursing assistance (University of Maryland School of Medicine); Todd Callahan, MD, MPH, Leigh Howard, MD, MPH, Kalpana Manthiram, MD, Elizabeth Williams, MD, MPH, Ashley Chadha, MD, Kim Fortner, MD, Deborah Myers, Debbie Hunter, BSN, Gayle Johnson, RN, Shanda Phillips, BSN, Wendi McDonald, BSN, Sara Anderson, Julie Anderson, RN, Mary Jones, RN, Kevin Booth, MBA, Roberta Winfrey, Megan Baker, Amy Kinsey (Vanderbilt University); Tracey Lanford, RN, Celsa Tajonera, RN, Nanette Bond, PA, Janet Brown, RPh, JD, Connie Rangel, RN, Virginia Mancha, MA, Annette Nagel, RN, Pedro A. Piedra, MD, Kathy Bosworth, BA, Jesus Banay, BS, Kirtida Patel, BS, Sneha Thakar, BS, Yvette Rugeley, Gwen Bennett, BBA, Verna Manley, Richard Hamill, MD, Mark Udden, MD (Baylor College of Medicine); Barbara Carste, MPH, Maya Dunstan, MS, RN, Patty Starkovich, RN, Janice Suyehira, MD, Colin Fields, MD, John Dunn, MD, MPH, Joyce Benoit, RN, Joanne Greene, MBA, RN, Jennifer Gross, MS, RN, Michelle Hill, MS, RN, Steve Koets, RN, Rebecca Lederman, RN, Angel Mathis, MN, MPH, ARNP, Alyssa Spingola, MN, ARNP, Hallie Phillips. MEd, Tom Archer, PharmD, Joyce Liew, PharmD, Michael Witte, PharmD, Lawrence Madziwa, MS, Matt Nguyen, MPH, Patti Benson, MPH, Scott Caparelli, BS, Alisa Fairweather, BS, Sarah Kotowski, PhD, JoAnn Lorenzo, BS, Mihir Parikh, BS, and Christine Truong, BS (Group Health). No one received additional compensation for their contribution.

Gao  R, Cao  B, Hu  Y,  et al.  Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013;368(20):1888-1897.
PubMed   |  Link to Article
World Health Organization. WHO risk assessment of human infections with avian Influenza A(H7N9) virus. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/RiskAssessment_H7N9_23Feb20115.pdf?ua=1. Accessed May 4, 2015.
Qi  X, Qian  YH, Bao  CJ,  et al.  Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013: epidemiological investigation. BMJ. 2013;347:f4752.
PubMed   |  Link to Article
Zhang  Q, Shi  J, Deng  G,  et al.  H7N9 influenza viruses are transmissible in ferrets by respiratory droplet. Science. 2013;341(6144):410-414.
PubMed   |  Link to Article
Belser  JA, Gustin  KM, Pearce  MB,  et al.  Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice. Nature. 2013;501(7468):556-559.
PubMed   |  Link to Article
Couch  RB, Patel  SM, Wade-Bowers  CL, Niño  D.  A randomized clinical trial of an inactivated avian influenza A (H7N7) vaccine. PLoS One. 2012;7(12):e49704.
PubMed   |  Link to Article
Tetsutani  K, Ishii  KJ.  Adjuvants in influenza vaccines. Vaccine. 2012;30(52):7658-7661.
PubMed   |  Link to Article
Nolan  T, Roy-Ghanta  S, Montellano  M,  et al.  Relative efficacy of AS03-adjuvanted pandemic influenza A(H1N1) vaccine in children: results of a controlled, randomized efficacy trial. J Infect Dis. 2014;210(4):545-557.
PubMed   |  Link to Article
McElhaney  JE, Beran  J, Devaster  JM,  et al; Influence65 study group.  AS03-adjuvanted vs nonadjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect Dis. 2013;13(6):485-496.
PubMed   |  Link to Article
Vesikari  T, Knuf  M, Wutzler  P,  et al.  Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med. 2011;365(15):1406-1416.
PubMed   |  Link to Article
Mulligan  MJ, Bernstein  DI, Winokur  P,  et al; DMID 13-0032 H7N9 Vaccine Study Group.  Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant: a randomized clinical trial. JAMA. 2014;312(14):1409-1419.
PubMed   |  Link to Article
Noah  DL, Hill  H, Hines  D, White  EL, Wolff  MC.  Qualification of the hemagglutination inhibition assay in support of pandemic influenza vaccine licensure. Clin Vaccine Immunol. 2009;16(4):558-566.
PubMed   |  Link to Article
Keitel  WA, Dekker  CL, Mink  C,  et al.  Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults. Vaccine. 2009;27(47):6642-6648.
PubMed   |  Link to Article
Jackson  LA, Chen  WH, Stapleton  JT,  et al.  Immunogenicity and safety of varying dosages of a monovalent 2009 H1N1 influenza vaccine given with and without AS03 adjuvant system in healthy adults and older persons. J Infect Dis. 2012;206(6):811-820.
PubMed   |  Link to Article
Greenberg  ME, Lai  MH, Hartel  GF,  et al.  Response to a monovalent 2009 influenza A (H1N1) vaccine. N Engl J Med. 2009;361(25):2405-2413.
PubMed   |  Link to Article
Roman  F, Vaman  T, Gerlach  B, Markendorf  A, Gillard  P, Devaster  JM.  Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: preliminary report of an observer-blind, randomised trial. Vaccine. 2010;28(7):1740-1745.
PubMed   |  Link to Article
Plennevaux  E, Sheldon  E, Blatter  M, Reeves-Hoché  MK, Denis  M.  Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of 2 randomised controlled phase 2 trials. Lancet. 2010;375(9708):41-48.
PubMed   |  Link to Article
Andrews  NJ, Walker  WT, Finn  A,  et al.  Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and nonadjuvanted whole virion H1N1 (2009) pandemic influenza vaccines. Vaccine. 2011;29(45):7913-7919.
PubMed   |  Link to Article
Ohfuji  S, Fukushima  W, Deguchi  M,  et al.  Immunogenicity of a monovalent 2009 influenza A (H1N1) vaccine among pregnant women: lowered antibody response by prior seasonal vaccination. J Infect Dis. 2011;203(9):1301-1308.
PubMed   |  Link to Article
Langley  JM, Frenette  L, Chu  L,  et al.  A randomized, controlled noninferiority trial comparing A(H1N1)pmd09 vaccine antigen, with and without AS03 adjuvant system, co-administered or sequentially administered with an inactivated trivalent seasonal influenza vaccine. BMC Infect Dis. 2012;12:279.
PubMed   |  Link to Article
Peeters  M, Regner  S, Vaman  T, Devaster  JM, Rombo  L.  Safety and immunogenicity of an AS03-adjuvanted A(H1N1)pmd09 vaccine administered simultaneously or sequentially with a seasonal trivalent vaccine in adults 61 years or older: data from 2 multicentre randomised trials. Vaccine. 2012;30(45):6483-6491.
PubMed   |  Link to Article
Roy-Ghanta  S, Van der Most  R, Li  P, Vaughn  DW.  Responses to A(H1N1)pdm09 influenza vaccines in participants previously vaccinated with seasonal influenza vaccine: a randomized, observer-blind, controlled study. J Infect Dis. 2014;210(9):1419-1430.
PubMed   |  Link to Article
Uno  S, Kimachi  K, Kei  J,  et al.  Effect of prior vaccination with a seasonal trivalent influenza vaccine on the antibody response to the influenza pandemic H1N1 2009 vaccine: a randomized controlled trial. Microbiol Immunol. 2011;55(11):783-789.
PubMed   |  Link to Article
Bart  SA, Hohenboken  M, Della Cioppa  G, Narasimhan  V, Dormitzer  PR, Kanesa-Thasan  N.  A cell culture-derived MF59-adjuvanted pandemic A/H7N9 vaccine is immunogenic in adults. Sci Transl Med. 2014;6(234):234ra55.
PubMed   |  Link to Article
Fries  LF, Smith  GE, Glenn  GM.  A recombinant viruslike particle influenza A (H7N9) vaccine. N Engl J Med. 2013;369(26):2564-2566.
PubMed   |  Link to Article

Figures

Place holder to copy figure label and caption
Figure 1.
CONSORT Flow Diagram of Participants Through the Influenza A(H7N9) Vaccine Study

HIA indicates hemagglutination inhibition antibody.

aParticipant unable to comply with visit schedule.

bParticipant incarcerated.

Graphic Jump Location
Place holder to copy figure label and caption
Figure 2.
HIA Geometric Mean Titer by Time Point and Study Group in the ITT Population

HIA indicates hemagglutination inhibition antibody; ITT, intention-to-treat. Error bars indicate 95% CIs.

aThe No. of participants in each group indicate those who received vaccination as randomized. Four patients did not have data reported after vaccination and are not included in this analysis.

Graphic Jump Location

Tables

Table Graphic Jump LocationTable 1.  Demographic and Baseline Characteristics of All Participants Receiving the Influenza Vaccination
Table Graphic Jump LocationTable 2.  Hemagglutination Inhibition and Microneutralization Antibody Responses Against Influenza A(H7N9) for Each Group in the ITT Population
Table Graphic Jump LocationTable 3.  HIA Responses 21 Days After the Second Dose of Influenza Vaccination by Study Group and Age Group in the ITT Population

References

Gao  R, Cao  B, Hu  Y,  et al.  Human infection with a novel avian-origin influenza A (H7N9) virus. N Engl J Med. 2013;368(20):1888-1897.
PubMed   |  Link to Article
World Health Organization. WHO risk assessment of human infections with avian Influenza A(H7N9) virus. http://www.who.int/influenza/human_animal_interface/influenza_h7n9/RiskAssessment_H7N9_23Feb20115.pdf?ua=1. Accessed May 4, 2015.
Qi  X, Qian  YH, Bao  CJ,  et al.  Probable person to person transmission of novel avian influenza A (H7N9) virus in Eastern China, 2013: epidemiological investigation. BMJ. 2013;347:f4752.
PubMed   |  Link to Article
Zhang  Q, Shi  J, Deng  G,  et al.  H7N9 influenza viruses are transmissible in ferrets by respiratory droplet. Science. 2013;341(6144):410-414.
PubMed   |  Link to Article
Belser  JA, Gustin  KM, Pearce  MB,  et al.  Pathogenesis and transmission of avian influenza A (H7N9) virus in ferrets and mice. Nature. 2013;501(7468):556-559.
PubMed   |  Link to Article
Couch  RB, Patel  SM, Wade-Bowers  CL, Niño  D.  A randomized clinical trial of an inactivated avian influenza A (H7N7) vaccine. PLoS One. 2012;7(12):e49704.
PubMed   |  Link to Article
Tetsutani  K, Ishii  KJ.  Adjuvants in influenza vaccines. Vaccine. 2012;30(52):7658-7661.
PubMed   |  Link to Article
Nolan  T, Roy-Ghanta  S, Montellano  M,  et al.  Relative efficacy of AS03-adjuvanted pandemic influenza A(H1N1) vaccine in children: results of a controlled, randomized efficacy trial. J Infect Dis. 2014;210(4):545-557.
PubMed   |  Link to Article
McElhaney  JE, Beran  J, Devaster  JM,  et al; Influence65 study group.  AS03-adjuvanted vs nonadjuvanted inactivated trivalent influenza vaccine against seasonal influenza in elderly people: a phase 3 randomised trial. Lancet Infect Dis. 2013;13(6):485-496.
PubMed   |  Link to Article
Vesikari  T, Knuf  M, Wutzler  P,  et al.  Oil-in-water emulsion adjuvant with influenza vaccine in young children. N Engl J Med. 2011;365(15):1406-1416.
PubMed   |  Link to Article
Mulligan  MJ, Bernstein  DI, Winokur  P,  et al; DMID 13-0032 H7N9 Vaccine Study Group.  Serological responses to an avian influenza A/H7N9 vaccine mixed at the point-of-use with MF59 adjuvant: a randomized clinical trial. JAMA. 2014;312(14):1409-1419.
PubMed   |  Link to Article
Noah  DL, Hill  H, Hines  D, White  EL, Wolff  MC.  Qualification of the hemagglutination inhibition assay in support of pandemic influenza vaccine licensure. Clin Vaccine Immunol. 2009;16(4):558-566.
PubMed   |  Link to Article
Keitel  WA, Dekker  CL, Mink  C,  et al.  Safety and immunogenicity of inactivated, Vero cell culture-derived whole virus influenza A/H5N1 vaccine given alone or with aluminum hydroxide adjuvant in healthy adults. Vaccine. 2009;27(47):6642-6648.
PubMed   |  Link to Article
Jackson  LA, Chen  WH, Stapleton  JT,  et al.  Immunogenicity and safety of varying dosages of a monovalent 2009 H1N1 influenza vaccine given with and without AS03 adjuvant system in healthy adults and older persons. J Infect Dis. 2012;206(6):811-820.
PubMed   |  Link to Article
Greenberg  ME, Lai  MH, Hartel  GF,  et al.  Response to a monovalent 2009 influenza A (H1N1) vaccine. N Engl J Med. 2009;361(25):2405-2413.
PubMed   |  Link to Article
Roman  F, Vaman  T, Gerlach  B, Markendorf  A, Gillard  P, Devaster  JM.  Immunogenicity and safety in adults of one dose of influenza A H1N1v 2009 vaccine formulated with and without AS03A-adjuvant: preliminary report of an observer-blind, randomised trial. Vaccine. 2010;28(7):1740-1745.
PubMed   |  Link to Article
Plennevaux  E, Sheldon  E, Blatter  M, Reeves-Hoché  MK, Denis  M.  Immune response after a single vaccination against 2009 influenza A H1N1 in USA: a preliminary report of 2 randomised controlled phase 2 trials. Lancet. 2010;375(9708):41-48.
PubMed   |  Link to Article
Andrews  NJ, Walker  WT, Finn  A,  et al.  Predictors of immune response and reactogenicity to AS03B-adjuvanted split virion and nonadjuvanted whole virion H1N1 (2009) pandemic influenza vaccines. Vaccine. 2011;29(45):7913-7919.
PubMed   |  Link to Article
Ohfuji  S, Fukushima  W, Deguchi  M,  et al.  Immunogenicity of a monovalent 2009 influenza A (H1N1) vaccine among pregnant women: lowered antibody response by prior seasonal vaccination. J Infect Dis. 2011;203(9):1301-1308.
PubMed   |  Link to Article
Langley  JM, Frenette  L, Chu  L,  et al.  A randomized, controlled noninferiority trial comparing A(H1N1)pmd09 vaccine antigen, with and without AS03 adjuvant system, co-administered or sequentially administered with an inactivated trivalent seasonal influenza vaccine. BMC Infect Dis. 2012;12:279.
PubMed   |  Link to Article
Peeters  M, Regner  S, Vaman  T, Devaster  JM, Rombo  L.  Safety and immunogenicity of an AS03-adjuvanted A(H1N1)pmd09 vaccine administered simultaneously or sequentially with a seasonal trivalent vaccine in adults 61 years or older: data from 2 multicentre randomised trials. Vaccine. 2012;30(45):6483-6491.
PubMed   |  Link to Article
Roy-Ghanta  S, Van der Most  R, Li  P, Vaughn  DW.  Responses to A(H1N1)pdm09 influenza vaccines in participants previously vaccinated with seasonal influenza vaccine: a randomized, observer-blind, controlled study. J Infect Dis. 2014;210(9):1419-1430.
PubMed   |  Link to Article
Uno  S, Kimachi  K, Kei  J,  et al.  Effect of prior vaccination with a seasonal trivalent influenza vaccine on the antibody response to the influenza pandemic H1N1 2009 vaccine: a randomized controlled trial. Microbiol Immunol. 2011;55(11):783-789.
PubMed   |  Link to Article
Bart  SA, Hohenboken  M, Della Cioppa  G, Narasimhan  V, Dormitzer  PR, Kanesa-Thasan  N.  A cell culture-derived MF59-adjuvanted pandemic A/H7N9 vaccine is immunogenic in adults. Sci Transl Med. 2014;6(234):234ra55.
PubMed   |  Link to Article
Fries  LF, Smith  GE, Glenn  GM.  A recombinant viruslike particle influenza A (H7N9) vaccine. N Engl J Med. 2013;369(26):2564-2566.
PubMed   |  Link to Article
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Multimedia

Supplement 1.

Trial Protocol

Supplemental Content
Supplement 2.

eTable 1. Hemagglutination inhibition antibody responses 21 days after the second vaccination by study group and by prior receipt of seasonal influenza vaccine

eTable 2. Safety clinical hematologic laboratory adverse events and severity for tests performed 8 days after each vaccination

eTable 3. Clinical safety hematologic laboratory adverse event severity grading

eTable 4. Proportion of participants with solicited systemic or local signs and symptoms by vaccination and study group

eFigure. Correlation of hemagglutination inhibition and microneutralization antibody titer at 8 and 21 days after the second vaccination, with the symbols indicating the number and type of adjuvants received for the two study vaccinations

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