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    Clinical Trial Results:
    Final Report: A Phase 3, Randomized, Placebo-Controlled, Observer-Blinded, Trial to Assess the Safety, Tolerability, and Immunogenicity of Bivalent rLP2086 Vaccine When Administered as a 3-Dose Regimen in Healthy Young Adults Aged greater than or equal to (>=) 18 to less than (<) 26 Years

    Summary
    EudraCT number
    		 2009-014492-46
    Trial protocol
    		 FI   PL   DK   ES  
    Global end of trial date
    13 Feb 2015

    Results information
    Results version number
    		 v1(current)
    This version publication date
    03 Aug 2016
    First version publication date
    03 Aug 2016
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    B1971016
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 NCT01352845
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 Alias: 6108A1-2004
    Sponsors
    Sponsor organisation name
    Pfizer, Inc.
    Sponsor organisation address
    235 E 42nd Street, New York, United States, NY 10017
    Public contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 800­718­1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Scientific contact
    Pfizer ClinicalTrials.gov Call Center, Pfizer Inc, 001 800­718­1021, ClinicalTrials.gov_Inquiries@pfizer.com
    Paediatric regulatory details
    Is trial part of an agreed paediatric investigation plan (PIP)
    No
    Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?
    No
    Results analysis stage
    Analysis stage
    Final
    Date of interim/final analysis
    02 Nov 2015
    Is this the analysis of the primary completion data?
    No
    Global end of trial reached?
    Yes
    Global end of trial date
    13 Feb 2015
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the immune response as measured by serum bactericidal assay using human complement (hSBA) performed with 4 primary Neisseria meningitidis serogroup B (MnB) test strains, 2 expressing a lipoprotein 2086 vaccine (LP2086) subfamily A protein and 2 expressing a LP2086 subfamily B protein, easured 1 month after the third vaccination with bivalent (recombinant lipoprotein) rLP2086. To evaluate the safety profile of bivalent rLP2086 compared to a control (saline), as measured by local reactions, systemic events, adverse events (AEs), serious adverse events (SAEs), newly diagnosed chronic medical conditions, medically attended adverse events, and immediate AEs.
    Protection of trial subjects
    The study was in compliance with the ethical principles derived from the Declaration of Helsinki and in compliance with all International Conference on Harmonization (ICH) Good Clinical Practice (GCP) Guidelines. All the local regulatory requirements pertinent to safety of trial subjects were followed.
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    03 May 2013
    Long term follow-up planned
    Yes
    Long term follow-up rationale
    		 Safety
    Long term follow-up duration
    		 6 Months
    Independent data monitoring committee (IDMC) involvement?
    Yes
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Canada: 361
    Country: Number of subjects enrolled
    Denmark: 451
    Country: Number of subjects enrolled
    Finland: 454
    Country: Number of subjects enrolled
    Poland: 83
    Country: Number of subjects enrolled
    Spain: 300
    Country: Number of subjects enrolled
    United States: 1644
    Worldwide total number of subjects
    3293
    EEA total number of subjects
    1288
    Number of subjects enrolled per age group
    In utero
    0
    Preterm newborn - gestational age < 37 wk
    0
    Newborns (0-27 days)
    0
    Infants and toddlers (28 days-23 months)
    0
    Children (2-11 years)
    0
    Adolescents (12-17 years)
    0
    Adults (18-64 years)
    3293
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 -

    Pre-assignment
    Screening details
    		 A total of 3304 subjects were randomized in this study, out of which 3293 subjects received vaccination.

    Period 1
    Period 1 title
    Overall Study (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Randomised - controlled
    Blinding used
    		 Double blind
    Roles blinded
    		 Subject, Investigator, Monitor, Data analyst, Assessor

    Arms
    Are arms mutually exclusive
    Yes

    Arm title
    		 Group 1 rLP2086
    Arm description
    		 Recombinant lipoprotein 2086 (rLP2086) vaccine on a 0-, 2-, 6- month schedule.
    Arm type
    		 Experimental

    Investigational medicinal product name
    Bivalent rLP2086
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 0.5 milliliter (mL) of rLP2086 at 0-, 2- and 6- month schedule.

    Arm title
    		 Group 2 Saline
    Arm description
    		 Saline on a 0-, 2-, 6- month schedule.
    Arm type
    		 Placebo

    Investigational medicinal product name
    Saline
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Injection
    Routes of administration
    Intramuscular use
    Dosage and administration details
    Subjects received 0.5 mL of saline at 0-, 2- and 6- month schedule.

    Number of subjects in period 1
    		Group 1 rLP2086 Group 2 Saline
    Started
    2471
    822
    Completed
    1800
    619
    Not completed
    671
    203
         Adverse event, serious fatal
    3
    -
         Consent withdrawn by subject
    48
    16
         No Longer Willing to Participate
    205
    58
         Adverse event, non-fatal
    22
    6
         Pregnancy
    27
    7
         Unspecified
    17
    7
         Lost to follow-up
    313
    92
         No Longer Meets Eligibility Criteria
    24
    11
         Protocol deviation
    12
    6

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    Group 1 rLP2086
    Reporting group description
    		 Recombinant lipoprotein 2086 (rLP2086) vaccine on a 0-, 2-, 6- month schedule.

    Reporting group title
    Group 2 Saline
    Reporting group description
    		 Saline on a 0-, 2-, 6- month schedule.

    Reporting group values
    		 Group 1 rLP2086 Group 2 Saline Total
    Number of subjects
    		 2471 822 3293
    Age categorical
    Units: Subjects
    Age Continuous |
    Units: Years
        arithmetic mean (standard deviation)
    		 21.47 ( 2.14 ) 21.52 ( 2.2 ) -
    Gender, Male/Female
    Units: Participants
        Female
    		 1452 482 1934
        Male
    		 1019 340 1359

    End points

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    End points reporting groups
    Reporting group title
    Group 1 rLP2086
    Reporting group description
    		 Recombinant lipoprotein 2086 (rLP2086) vaccine on a 0-, 2-, 6- month schedule.

    Reporting group title
    Group 2 Saline
    Reporting group description
    		 Saline on a 0-, 2-, 6- month schedule.

    Primary: Percentage of Subjects with (>=) 4 Fold Rise in Serum Bactericidal Assay Using Human Complement (hSBA) for 4 Primary Strains and Composite Response (hSBA >= Lower Limit of Quantification [LLOQ] for all 4 Primary Strains Combined): Group 1

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    End point title
    		 Percentage of Subjects with (>=) 4 Fold Rise in Serum Bactericidal Assay Using Human Complement (hSBA) for 4 Primary Strains and Composite Response (hSBA >= Lower Limit of Quantification [LLOQ] for all 4 Primary Strains Combined): Group 1 [1] [2]
    End point description
    Evaluable immunogenicity population: all eligible subjects randomized, who received correct investigational product, had pre/post vaccination blood drawn at pre-specified time points, had valid and determinate assay results for proposed analysis, received no prohibited treatment or prohibited vaccines, and had no major protocol violations. Here, N signifies subjects with valid and determinate hSBA titers for given strain at specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Primary
    End point timeframe
    One month after third bivalent rLP2086 vaccination
    Notes
    [1] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    [2] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    1723
    Units: Percentage of subjects
    number (confidence interval 95%)
        Composite hSBA response (N=1664)
    84.9 (83.1 to 86.6)
        PMB80 [A22] (N=1695)
    80.5 (78.6 to 82.4)
        PMB2001 [A56] (N=1642)
    90 (88.4 to 91.4)
        PMB2948 [B24] (N=1675)
    79.3 (77.3 to 81.2)
        PMB2707 [B44] (N=1696)
    79.6 (77.6 to 81.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Pre-specified Local Reactions (LRs) Within 7 Days After First Vaccination

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    End point title
    		 Percentage of Subjects Reporting Pre-specified Local Reactions (LRs) Within 7 Days After First Vaccination [3]
    End point description
    Safety population for first vaccination included all subjects who received the first dose of investigational product (rLP2086 or saline) and for whom safety information was available from first vaccination until prior to second vaccination.
    End point type
    Primary
    End point timeframe
    Within 7 days after first vaccination
    Notes
    [3] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2425
    798
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pain at injection site: Any
    84.2 (82.7 to 85.6)
    11.8 (9.6 to 14.2)
        Pain at injection site: Mild
    42.3 (40.3 to 44.3)
    10.7 (8.6 to 13)
        Pain at injection site: Moderate
    37.1 (35.1 to 39)
    1.1 (0.5 to 2.1)
        Pain at injection site: Severe
    4.8 (4 to 5.8)
    0 (0 to 0.5)
        Redness: Any
    13.8 (12.5 to 15.3)
    0.6 (0.2 to 1.5)
        Redness: Mild
    5.8 (4.9 to 6.8)
    0.5 (0.1 to 1.3)
        Redness: Moderate
    7.1 (6.1 to 8.2)
    0 (0 to 0.5)
        Redness: Severe
    0.9 (0.6 to 1.4)
    0.1 (0 to 0.7)
        Swelling: Any
    15.5 (14.1 to 17.1)
    0.6 (0.2 to 1.5)
        Swelling: Mild
    8.5 (7.4 to 9.7)
    0.3 (0 to 0.9)
        Swelling: Moderate
    6.8 (5.8 to 7.9)
    0.3 (0 to 0.9)
        Swelling: Severe
    0.2 (0.1 to 0.5)
    0.1 (0 to 0.7)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Pre-specified Local Reactions (LRs) Within 7 Days After Second Vaccination

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    End point title
    		 Percentage of Subjects Reporting Pre-specified Local Reactions (LRs) Within 7 Days After Second Vaccination [4]
    End point description
    Safety population for second vaccination included all subjects who received the second dose of investigational product (rLP2086 or saline) and for whom safety information was available from second vaccination until prior to third vaccination.
    End point type
    Primary
    End point timeframe
    Within 7 days after second vaccination
    Notes
    [4] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2076
    706
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pain at injection site: Any
    79.3 (77.5 to 81.1)
    7.8 (5.9 to 10)
        Pain at injection site: Mild
    42.2 (40.1 to 44.4)
    6.8 (5.1 to 8.9)
        Pain at injection site: Moderate
    32.7 (30.7 to 34.8)
    1 (0.4 to 2)
        Pain at injection site: Severe
    4.4 (3.6 to 5.4)
    0 (0 to 0.5)
        Redness: Any
    11.8 (10.4 to 13.3)
    0.3 (0 to 1)
        Redness: Mild
    4.6 (3.7 to 5.6)
    0.1 (0 to 0.8)
        Redness: Moderate
    6.3 (5.3 to 7.4)
    0 (0 to 0.5)
        Redness: Severe
    0.9 (0.6 to 1.4)
    0.1 (0 to 0.8)
        Swelling: Any
    14 (12.6 to 15.6)
    0.4 (0.1 to 1.2)
        Swelling: Mild
    7.7 (6.6 to 8.9)
    0.3 (0 to 1)
        Swelling: Moderate
    6 (5 to 7.1)
    0.1 (0 to 0.8)
        Swelling: Severe
    0.3 (0.1 to 0.7)
    0 (0 to 0.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Pre-specified Local Reactions (LRs) Within 7 Days After Third Vaccination

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    End point title
    		 Percentage of Subjects Reporting Pre-specified Local Reactions (LRs) Within 7 Days After Third Vaccination [5]
    End point description
    Safety population for third vaccination included all subjects who received the third dose of investigational product (rLP2086 or saline) and for whom safety information was available from third vaccination until post third-vaccination blood draw.
    End point type
    Primary
    End point timeframe
    Within 7 days after third vaccination
    Notes
    [5] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    1823
    624
    Units: Percentage of subjects
    number (confidence interval 95%)
        Pain at injection site: Any
    80.4 (78.5 to 82.2)
    6.7 (4.9 to 9)
        Pain at injection site: Mild
    36.1 (33.9 to 38.4)
    6.4 (4.6 to 8.6)
        Pain at injection site: Moderate
    38.9 (36.6 to 41.2)
    0.3 (0 to 1.2)
        Pain at injection site: Severe
    5.3 (4.3 to 6.5)
    0 (0 to 0.6)
        Redness: Any
    17.1 (15.4 to 18.9)
    0.2 (0 to 0.9)
        Redness: Mild
    6.2 (5.1 to 7.4)
    0.2 (0 to 0.9)
        Redness: Moderate
    8.6 (7.3 to 9.9)
    0 (0 to 0.6)
        Redness: Severe
    2.3 (1.7 to 3.1)
    0 (0 to 0.6)
        Swelling: Any
    16.6 (14.9 to 18.4)
    0.3 (0 to 1.2)
        Swelling: Mild
    8.8 (7.6 to 10.2)
    0 (0 to 0.6)
        Swelling: Moderate
    7.2 (6.1 to 8.5)
    0.3 (0 to 1.2)
        Swelling: Severe
    0.5 (0.2 to 0.9)
    0 (0 to 0.6)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Systemic Events (SEs) and Antipyretic Use Within 7 Days After First Vaccination

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    End point title
    		 Percentage of Subjects Reporting Systemic Events (SEs) and Antipyretic Use Within 7 Days After First Vaccination [6]
    End point description
    Safety population for first vaccination included all subjects who received the first dose of investigational product (rLP2086 or saline) and for whom safety information was available from first vaccination until prior to second vaccination. Here, 'N' signifies subjects with known values reporting specific characteristic.
    End point type
    Primary
    End point timeframe
    Within 7 days after first vaccination
    Notes
    [6] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2425
    798
    Units: Percentage of subjects
    number (confidence interval 95%)
        Fever >=38 degrees C(N=2415, 796)
    2.4 (1.8 to 3)
    0.6 (0.2 to 1.5)
        Fever 38 to <38.5 degreesC(N=2415, 796)
    1.6 (1.1 to 2.2)
    0.4 (0.1 to 1.1)
        Fever 38.5 to<39 degrees C(N=2415, 796)
    0.7 (0.4 to 1.2)
    0 (0 to 0.5)
        Fever 39 to 40 degrees C (N=2415, 796)
    0 (0 to 0.2)
    0.3 (0 to 0.9)
        Fever >40 degrees C(N=2415, 796)
    0 (0 to 0.2)
    0 (0 to 0.5)
        Vomiting:Any(N=2425, 798)
    2.6 (2 to 3.3)
    2.1 (1.2 to 3.4)
        Vomiting:Mild(N=2425, 798)
    2.2 (1.6 to 2.8)
    2.1 (1.2 to 3.4)
        Vomiting:Moderate(N=2425, 798)
    0.4 (0.2 to 0.8)
    0 (0 to 0.5)
        Vomiting:Severe(N=2425, 798)
    0 (0 to 0.2)
    0 (0 to 0.5)
        Diarrhea:Any(N=2425, 798)
    12.7 (11.4 to 14.1)
    11.8 (9.6 to 14.2)
        Diarrhea:Mild(N=2425, 798)
    10.2 (9 to 11.5)
    9.8 (7.8 to 12)
        Diarrhea:Moderate(N=2425, 798)
    2.4 (1.8 to 3)
    1.9 (1.1 to 3.1)
        Diarrhea:Severe(N=2425, 798)
    0.2 (0.1 to 0.5)
    0.1 (0 to 0.7)
        Headache:Any(N=2425, 798)
    43.9 (41.9 to 45.9)
    36.2 (32.9 to 39.7)
        Headache:Mild(N=2425, 798)
    24.3 (22.6 to 26.1)
    22.1 (19.2 to 25.1)
        Headache:Moderate(N=2425, 798)
    17.9 (16.4 to 19.5)
    13.5 (11.2 to 16.1)
        Headache:Severe(N=2425, 798)
    1.6 (1.2 to 2.2)
    0.6 (0.2 to 1.5)
        Fatigue:Any(N=2425, 798)
    50.9 (48.9 to 52.9)
    39.8 (36.4 to 43.3)
        Fatigue:Mild(N=2425, 798)
    25.4 (23.7 to 27.2)
    23.2 (20.3 to 26.3)
        Fatigue:Moderate(N=2425, 798)
    22.1 (20.5 to 23.8)
    15.8 (13.3 to 18.5)
        Fatigue:Severe(N=2425, 798)
    3.4 (2.7 to 4.2)
    0.9 (0.4 to 1.8)
        Chills:Any(N=2425, 798)
    18.1 (16.5 to 19.7)
    9.8 (7.8 to 12)
        Chills:Mild(N=2425, 798)
    12 (10.8 to 13.4)
    8.1 (6.3 to 10.3)
        Chills:Moderate(N=2425, 798)
    4.9 (4.1 to 5.8)
    1.6 (0.9 to 2.8)
        Chills: Severe(N=2425, 798)
    1.1 (0.7 to 1.6)
    0 (0 to 0.5)
        Muscle pain:Any(N=2425,798)
    25.9 (24.1 to 27.6)
    14.5 (12.2 to 17.2)
        Muscle pain:Mild(N=2425,798)
    13 (11.7 to 14.4)
    9.6 (7.7 to 11.9)
        Muscle pain:Moderate(N=2425,798)
    11.3 (10 to 12.6)
    4.4 (3.1 to 6)
        Muscle pain:Severe(N=2425,798)
    1.6 (1.1 to 2.2)
    0.5 (0.1 to 1.3)
        Joint pain:Any(N=2425,798)
    19.6 (18.1 to 21.3)
    10.9 (8.8 to 13.3)
        Joint pain:Mild(N=2425,798)
    10.3 (9.1 to 11.6)
    6.9 (5.2 to 8.9)
        Joint pain:Moderate(N=2425,798)
    7.9 (6.8 to 9)
    3.5 (2.3 to 5)
        Joint pain: Severe(N=2425,798)
    1.4 (1 to 2)
    0.5 (0.1 to 1.3)
        Antipyretic medication(N=2425,798)
    13.4 (12.1 to 14.8)
    8.9 (7 to 11.1)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Systemic Events (SEs) and Antipyretic Use Within 7 Days After Second Vaccination

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    End point title
    		 Percentage of Subjects Reporting Systemic Events (SEs) and Antipyretic Use Within 7 Days After Second Vaccination [7]
    End point description
    Safety population for second vaccination included all subjects who received the second dose of investigational product (rLP2086 or saline) and for whom safety information was available from second vaccination until prior to third vaccination. Here, 'N' signifies subjects with known values reporting specific characteristic.
    End point type
    Primary
    End point timeframe
    Within 7 days after second vaccination
    Notes
    [7] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2076
    706
    Units: Percentage of subjects
    number (confidence interval 95%)
        Fever >=38 degrees C(N=2067, 705)
    1.2 (0.7 to 1.7)
    1 (0.4 to 2)
        Fever 38 to <38.5 degreesC(N=2067, 705)
    0.7 (0.4 to 1.1)
    0.6 (0.2 to 1.4)
        Fever 38.5 to<39 degrees C(N=2067, 705)
    0.4 (0.2 to 0.8)
    0.3 (0 to 1)
        Fever 39 to 40 degrees C (N=2067, 705)
    0.1 (0 to 0.3)
    0.1 (0 to 0.8)
        Fever >40 degrees C(N=2067, 705)
    0 (0 to 0.2)
    0 (0 to 0.5)
        Vomiting:Any(N=2076, 706)
    2.1 (1.5 to 2.8)
    1.6 (0.8 to 2.8)
        Vomiting:Mild(N=2076, 706)
    1.6 (1.1 to 2.3)
    1.3 (0.6 to 2.4)
        Vomiting:Moderate(N=2076, 706)
    0.5 (0.2 to 0.9)
    0.3 (0 to 1)
        Vomiting:Severe(N=2076, 706)
    0 (0 to 0.2)
    0 (0 to 0.5)
        Diarrhea:Any(N=2076, 706)
    8.6 (7.4 to 9.9)
    8.1 (6.2 to 10.3)
        Diarrhea:Mild(N=2076, 706)
    6.4 (5.3 to 7.5)
    4.7 (3.2 to 6.5)
        Diarrhea:Moderate(N=2076, 706)
    1.7 (1.2 to 2.4)
    2.8 (1.7 to 4.3)
        Diarrhea:Severe(N=2076, 706)
    0.5 (0.3 to 0.9)
    0.6 (0.2 to 1.4)
        Headache:Any(N=2076, 706)
    33.1 (31.1 to 35.2)
    24.9 (21.8 to 28.3)
        Headache:Mild(N=2076, 706)
    18.4 (16.8 to 20.1)
    13.6 (11.2 to 16.3)
        Headache:Moderate(N=2076, 706)
    13.3 (11.9 to 14.8)
    10.1 (7.9 to 12.5)
        Headache:Severe(N=2076, 706)
    1.4 (1 to 2.1)
    1.3 (0.6 to 2.4)
        Fatigue:Any(N=2076, 706)
    39.2 (37.1 to 41.3)
    27.3 (24.1 to 30.8)
        Fatigue:Mild(N=2076, 706)
    20.6 (18.8 to 22.4)
    13.9 (11.4 to 16.7)
        Fatigue:Moderate(N=2076, 706)
    16.4 (14.8 to 18)
    11.5 (9.2 to 14.1)
        Fatigue:Severe(N=2076, 706)
    2.2 (1.6 to 2.9)
    2 (1.1 to 3.3)
        Chills:Any(N=2076, 706)
    12.4 (11 to 13.9)
    8.5 (6.5 to 10.8)
        Chills:Mild(N=2076, 706)
    8.1 (7 to 9.4)
    6.9 (5.2 to 9.1)
        Chills:Moderate(N=2076, 706)
    3.5 (2.8 to 4.4)
    1.6 (0.8 to 2.8)
        Chills: Severe(N=2076, 706)
    0.8 (0.4 to 1.2)
    0 (0 to 0.5)
        Muscle pain:Any(N=2076, 706)
    15.6 (14 to 17.2)
    8.5 (6.5 to 10.8)
        Muscle pain:Mild(N=2076, 706)
    7.6 (6.5 to 8.8)
    5.8 (4.2 to 7.8)
        Muscle pain:Moderate(N=2076, 706)
    7.1 (6.1 to 8.3)
    2.3 (1.3 to 3.7)
        Muscle pain:Severe(N=2076, 706)
    0.8 (0.5 to 1.3)
    0.4 (0.1 to 1.2)
        Joint pain:Any(N=2076, 706)
    15.1 (13.6 to 16.7)
    6.5 (4.8 to 8.6)
        Joint pain:Mild(N=2076, 706)
    8.1 (7 to 9.3)
    3.7 (2.4 to 5.3)
        Joint pain:Moderate(N=2076, 706)
    6.2 (5.2 to 7.3)
    2.5 (1.5 to 4)
        Joint pain: Severe(N=2076, 706)
    0.9 (0.5 to 1.4)
    0.3 (0 to 1)
        Antipyretic medication(N=2076, 706)
    12.3 (10.9 to 13.8)
    7.6 (5.8 to 9.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting Systemic Events (SEs) and Antipyretic Use Within 7 Days After Third Vaccination

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    End point title
    		 Percentage of Subjects Reporting Systemic Events (SEs) and Antipyretic Use Within 7 Days After Third Vaccination [8]
    End point description
    Safety population for third vaccination included all subjects who received the third dose of investigational product (rLP2086 or saline) and for whom safety information was available from third vaccination until post third-vaccination blood draw. Here, 'N' signifies subjects with known values reporting specific characteristic.
    End point type
    Primary
    End point timeframe
    Within 7 days after third vaccination
    Notes
    [8] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    1823
    624
    Units: Percentage of subjects
    number (confidence interval 95%)
        Fever >=38 degrees C(N=1814, 621)
    2 (1.4 to 2.7)
    0.6 (0.2 to 1.6)
        Fever 38 to <38.5 degreesC(N=1814, 621)
    1.4 (0.9 to 2)
    0.5 (0.1 to 1.4)
        Fever 38.5 to<39 degrees C(N=1814, 621)
    0.4 (0.2 to 0.9)
    0.2 (0 to 0.9)
        Fever 39 to 40 degrees C (N=1814, 621)
    0.1 (0 to 0.4)
    0 (0 to 0.6)
        Fever >40 degrees C(N=1814, 621)
    0.1 (0 to 0.3)
    0 (0 to 0.6)
        Vomiting:Any(N=1823, 624)
    2 (1.4 to 2.7)
    1.4 (0.7 to 2.7)
        Vomiting:Mild(N=1823, 624)
    1.8 (1.2 to 2.5)
    1.1 (0.5 to 2.3)
        Vomiting:Moderate(N=1823, 624)
    0.2 (0.1 to 0.6)
    0.3 (0 to 1.2)
        Vomiting:Severe(N=1823, 624)
    0 (0 to 0.2)
    0 (0 to 0.6)
        Diarrhea:Any(N=1823, 624)
    7.5 (6.3 to 8.8)
    6.9 (5 to 9.2)
        Diarrhea:Mild(N=1823, 624)
    6.1 (5 to 7.3)
    5.3 (3.7 to 7.3)
        Diarrhea:Moderate(N=1823, 624)
    1.2 (0.8 to 1.8)
    1.3 (0.6 to 2.5)
        Diarrhea:Severe(N=1823, 624)
    0.2 (0 to 0.5)
    0.3 (0 to 1.2)
        Headache:Any(N=1823, 624)
    32.5 (30.4 to 34.7)
    21.6 (18.5 to 25.1)
        Headache:Mild(N=1823, 624)
    17.6 (15.9 to 19.4)
    12.5 (10 to 15.4)
        Headache:Moderate(N=1823, 624)
    13.3 (11.8 to 15)
    8.3 (6.3 to 10.8)
        Headache:Severe(N=1823, 624)
    1.6 (1.1 to 2.3)
    0.8 (0.3 to 1.9)
        Fatigue:Any(N=1823, 624)
    39.3 (37.1 to 41.6)
    24.5 (21.2 to 28.1)
        Fatigue:Mild(N=1823, 624)
    18.9 (17.2 to 20.8)
    13.1 (10.6 to 16)
        Fatigue:Moderate(N=1823, 624)
    18.8 (17 to 20.6)
    9.6 (7.4 to 12.2)
        Fatigue:Severe(N=1823, 624)
    1.6 (1.1 to 2.3)
    1.8 (0.9 to 3.1)
        Chills:Any(N=1823, 624)
    12.6 (11.1 to 14.2)
    6.4 (4.6 to 8.6)
        Chills:Mild(N=1823, 624)
    7.7 (6.5 to 9)
    4.3 (2.9 to 6.2)
        Chills:Moderate(N=1823, 624)
    4.2 (3.3 to 5.2)
    2.1 (1.1 to 3.5)
        Chills: Severe(N=1823, 624)
    0.8 (0.4 to 1.3)
    0 (0 to 0.6)
        Muscle pain:Any(N=1823, 624)
    16.9 (15.2 to 18.7)
    7.5 (5.6 to 9.9)
        Muscle pain:Mild(N=1823, 624)
    8.9 (7.7 to 10.3)
    4.5 (3 to 6.4)
        Muscle pain:Moderate(N=1823, 624)
    6.8 (5.7 to 8.1)
    2.9 (1.7 to 4.5)
        Muscle pain:Severe(N=1823, 624)
    1.2 (0.7 to 1.8)
    0.2 (0 to 0.9)
        Joint pain:Any(N=1823, 624)
    12.6 (11.1 to 14.2)
    5.3 (3.7 to 7.3)
        Joint pain:Mild(N=1823, 624)
    6.6 (5.5 to 7.9)
    2.9 (1.7 to 4.5)
        Joint pain:Moderate(N=1823, 624)
    5.4 (4.4 to 6.5)
    2.4 (1.4 to 3.9)
        Joint pain: Severe(N=1823, 624)
    0.6 (0.3 to 1.1)
    0 (0 to 0.6)
        Antipyretic medication(N=1823, 624)
    12.8 (11.3 to 14.5)
    6.6 (4.8 to 8.8)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After First Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After First Vaccination [9]
    End point description
    Safety population for first vaccination included all subjects who received the first dose of investigational product (rLP2086 or saline) and for whom safety information was available from first vaccination until prior to second vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after first vaccination
    Notes
    [9] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    8.62 (7.5 to 9.8)
    7.3 (5.6 to 9.3)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After Second Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After Second Vaccination [10]
    End point description
    Safety population for second vaccination included all subjects who received the second dose of investigational product (rLP2086 or saline) and for whom safety information was available from second vaccination until prior to third vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after second vaccination
    Notes
    [10] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2169
    733
    Units: Percentage of subjects
        number (confidence interval 95%)
    10.1 (8.9 to 11.4)
    10.1 (8 to 12.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After Third Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After Third Vaccination [11]
    End point description
    Safety population for third vaccination included all subjects who received the third dose of investigational product (rLP2086 or saline) and for whom safety information was available from third vaccination until post third-vaccination blood draw.
    End point type
    Primary
    End point timeframe
    Within 30 days after third vaccination
    Notes
    [11] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    1889
    649
    Units: Percentage of subjects
        number (confidence interval 95%)
    9.26 (8 to 10.7)
    7.24 (5.4 to 9.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After any Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Adverse Event (AE) Within 30 Days After any Vaccination [12]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    Within 30 days after any vaccination
    Notes
    [12] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    21.17 (19.6 to 22.8)
    18.86 (16.2 to 21.7)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Adverse Event (AE) During the Vaccination Phase

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    End point title
    		 Percentage of Subjects With at Least 1 Adverse Event (AE) During the Vaccination Phase [13]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 1 month after the third vaccination
    Notes
    [13] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    31.2 (29.4 to 33.1)
    31.14 (28 to 34.4)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After First Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After First Vaccination [14]
    End point description
    Safety population for first vaccination included all subjects who received the first dose of investigational product (rLP2086 or saline) and for whom safety information was available from first vaccination until prior to second vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after first vaccination
    Notes
    [14] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.24 (0.1 to 0.5)
    0.12 (0 to 0.7)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After Second Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After Second Vaccination [15]
    End point description
    Safety population for second vaccination included all subjects who received the second dose of investigational product (rLP2086 or saline) and for whom safety information was available from second vaccination until prior to third vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after second vaccination
    Notes
    [15] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2169
    733
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.23 (0.1 to 0.5)
    0 (0 to 0.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After Third Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After Third Vaccination [16]
    End point description
    Safety population for third vaccination included all subjects who received the third dose of investigational product (rLP2086 or saline) and for whom safety information was available from third vaccination until post third-vaccination blood draw.
    End point type
    Primary
    End point timeframe
    Within 30 days after third vaccination
    Notes
    [16] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    1889
    649
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.11 (0 to 0.4)
    0.15 (0 to 0.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After any Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Within 30 Days After any Vaccination [17]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    Within 30 days after any vaccination
    Notes
    [17] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.53 (0.3 to 0.9)
    0.24 (0 to 0.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) During the Follow-up Phase

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    End point title
    		 Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) During the Follow-up Phase [18]
    End point description
    Safety population: all subjects who had at least 1 dose of investigational product (rLP2086 or saline) for whom safety information was available from after post-vaccination 3 blood draw to 6 months after last study vaccination.
    End point type
    Primary
    End point timeframe
    From 1 month after third vaccination up to 6 months after the third vaccination
    Notes
    [18] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2067
    704
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.63 (0.3 to 1.1)
    0.71 (0.2 to 1.6)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) During the Vaccination Phase

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    End point title
    		 Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) During the Vaccination Phase [19]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 1 month after the third vaccination
    Notes
    [19] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.85 (0.5 to 1.3)
    0.73 (0.3 to 1.6)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Throughout the Study Period

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    End point title
    		 Percentage of Subjects With at Least 1 Serious Adverse Event (SAE) Throughout the Study Period [20]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 6 month after the third vaccination
    Notes
    [20] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    1.34 (0.9 to 1.9)
    1.34 (0.7 to 2.4)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After First Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After First Vaccination [21]
    End point description
    Safety population for first vaccination included all subjects who received the first dose of investigational product (rLP2086 or saline) and for whom safety information was available from first vaccination until prior to second vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after first vaccination
    Notes
    [21] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    3.89 (3.2 to 4.7)
    3.77 (2.6 to 5.3)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After Second Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After Second Vaccination [22]
    End point description
    Safety population for second vaccination included all subjects who received the second dose of investigational product (rLP2086 or saline) and for whom safety information was available from second vaccination until prior to third vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after second vaccination
    Notes
    [22] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2169
    733
    Units: Percentage of subjects
        number (confidence interval 95%)
    4.66 (3.8 to 5.6)
    4.91 (3.5 to 6.7)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After Third Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After Third Vaccination [23]
    End point description
    Safety population for third vaccination included all subjects who received the third dose of investigational product (rLP2086 or saline) and for whom safety information was available from third vaccination until until post third-vaccination blood draw.
    End point type
    Primary
    End point timeframe
    Within 30 days after third vaccination
    Notes
    [23] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    1889
    649
    Units: Percentage of subjects
        number (confidence interval 95%)
    5.03 (4.1 to 6.1)
    3.85 (2.5 to 5.6)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After any Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Medically Attended AE Within 30 Days After any Vaccination [24]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    Within 30 days after any vaccination
    Notes
    [24] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    10.93 (9.7 to 12.2)
    10.22 (8.2 to 12.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Medically Attended AE During the Vaccination Phase

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    End point title
    		 Percentage of Subjects With at Least 1 Medically Attended AE During the Vaccination Phase [25]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 1 month after the third vaccination
    Notes
    [25] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    19.22 (17.7 to 20.8)
    17.76 (15.2 to 20.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Medically Attended AE During the Follow-Up Phase

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    End point title
    		 Percentage of Subjects With at Least 1 Medically Attended AE During the Follow-Up Phase [26]
    End point description
    Safety population: all subjects who had at least 1 dose of investigational product (rLP2086 or saline) for whom safety information was available from after post-vaccination 3 blood draw to 6 months after last study vaccination.
    End point type
    Primary
    End point timeframe
    From 1 month after third vaccination up to 6 months after the third vaccination
    Notes
    [26] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2067
    704
    Units: Percentage of subjects
        number (confidence interval 95%)
    6.97 (5.9 to 8.2)
    6.68 (4.9 to 8.8)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting at Least 1 Medically Attended Adverse Event Throughout the Study Period

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    End point title
    		 Percentage of Subjects Reporting at Least 1 Medically Attended Adverse Event Throughout the Study Period [27]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 6 month after the third vaccination
    Notes
    [27] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    21.89 (20.3 to 23.6)
    21.17 (18.4 to 24.1)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After First Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After First Vaccination [28]
    End point description
    Safety population for first vaccination included all subjects who received the first dose of investigational product (rLP2086 or saline) and for whom safety information was available from first vaccination until prior to second vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after first vaccination
    Notes
    [28] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0 (0 to 0.1)
    0 (0 to 0.4)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After Second Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After Second Vaccination [29]
    End point description
    Safety population for second vaccination included all subjects who received the second dose of investigational product (rLP2086 or saline) and for whom safety information was available from second vaccination until prior to third vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 days after second vaccination
    Notes
    [29] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2169
    733
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.23 (0.1 to 0.5)
    0 (0 to 0.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After Third Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After Third Vaccination [30]
    End point description
    Safety population for third vaccination included all subjects who received the third dose of investigational product (rLP2086 or saline) and for whom safety information was available from third vaccination until post third-vaccination blood draw.
    End point type
    Primary
    End point timeframe
    Within 30 days after third vaccination
    Notes
    [30] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    1889
    649
    Units: Percentage of subjects
        number (confidence interval 95%)
    0 (0 to 0.2)
    0.15 (0 to 0.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After any Vaccination

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    End point title
    		 Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Within 30 Days After any Vaccination [31]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    Within 30 days after any vaccination
    Notes
    [31] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.2 (0.1 to 0.5)
    0.12 (0 to 0.7)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition During the Vaccination Phase

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    End point title
    		 Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition During the Vaccination Phase [32]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 1 month after the third vaccination
    Notes
    [32] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.32 (0.1 to 0.6)
    0.24 (0 to 0.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition During the Follow-Up Phase

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    End point title
    		 Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition During the Follow-Up Phase [33]
    End point description
    Safety population: all subjectts who had at least 1 dose of investigational product (rLP2086 or saline) for whom safety information was available from after post third-vaccination blood draw to 6 months after last study vaccination.
    End point type
    Primary
    End point timeframe
    From 1 month after third vaccination up to 6 months after the third vaccination
    Notes
    [33] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2067
    704
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.1 (0 to 0.3)
    0 (0 to 0.5)
    No statistical analyses for this end point

    Primary: Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Throughout the Study Period

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    End point title
    		 Percentage of Subjects With at Least 1 Newly Diagnosed Chronic Medical Condition Throughout the Study Period [34]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 6 month after the third vaccination the third vaccination
    Notes
    [34] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.4 (0.2 to 0.7)
    0.24 (0 to 0.9)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting at Least 1 Immediate Adverse Event (AE) After First Vaccination

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    End point title
    		 Percentage of Subjects Reporting at Least 1 Immediate Adverse Event (AE) After First Vaccination [35]
    End point description
    Safety population for first vaccination included all subjects who received the first dose of investigational product (rLP2086 or saline) and for whom safety information was available from first vaccination until prior to second vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 minutes after first vaccination
    Notes
    [35] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2471
    822
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.4 (0.2 to 0.7)
    0.6 (0.2 to 1.4)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting at Least 1 Immediate Adverse Event (AE) After Second Vaccination

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    End point title
    		 Percentage of Subjects Reporting at Least 1 Immediate Adverse Event (AE) After Second Vaccination [36]
    End point description
    Safety population for second vaccination included all subjects who received the second dose of investigational product (rLP2086 or saline) and for whom safety information was available from second vaccination until prior to third vaccination.
    End point type
    Primary
    End point timeframe
    Within 30 minutes after second vaccination
    Notes
    [36] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    2169
    733
    Units: Percentage of subjects
        number (confidence interval 95%)
    0 (0 to 0.3)
    0.4 (0.1 to 1.2)
    No statistical analyses for this end point

    Primary: Percentage of Subjects Reporting at Least 1 Immediate Adverse Event (AE) After Third Vaccination

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    End point title
    		 Percentage of Subjects Reporting at Least 1 Immediate Adverse Event (AE) After Third Vaccination [37]
    End point description
    Safety population for third vaccination included all subjects who received the third dose of investigational product (rLP2086 or saline) and for whom safety information was available from third vaccination until post third-vaccination blood draw.
    End point type
    Primary
    End point timeframe
    Within 30 minutes after third vaccination
    Notes
    [37] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    1889
    649
    Units: Percentage of subjects
        number (confidence interval 95%)
    0.1 (0 to 0.3)
    0 (0 to 0.6)
    No statistical analyses for this end point

    Primary: Number of Days Subjects Missed School or Work Due to AE During the Vaccination Phase

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    End point title
    		 Number of Days Subjects Missed School or Work Due to AE During the Vaccination Phase [38]
    End point description
    Safety population included all the subjects who received at least 1 dose of the investigational product (rLP2086 or saline) and had safety data available. Here, number of subjects analyzed signifies subjects that were evaluable for this endpoint.
    End point type
    Primary
    End point timeframe
    From the first vaccination up to 1 month after the third vaccination
    Notes
    [38] - No statistical analyses have been specified for this primary end point. It is expected there is at least one statistical analysis for each primary end point.
    Justification: Only descriptive data was planned to be reported for this endpoint. 
    End point values
    		 Group 1 rLP2086 Group 2 Saline
    Number of subjects analysed
    167
    63
    Units: Days
        arithmetic mean (standard deviation)
    5.6 ( 10.75 )
    5.6 ( 13.26 )
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With hSBA Titers >= LLOQ for 10 Secondary Strains Before First Vaccination and 1 Month After Third Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 Percentage of Subjects With hSBA Titers >= LLOQ for 10 Secondary Strains Before First Vaccination and 1 Month After Third Bivalent rLP2086 Vaccination: Group 1 [39]
    End point description
    Evaluable immunogenicity population. Here, number of subjects analyzed signifies subjects with valid and determinate hSBA titers for the given strain. Here, N signifies subjects with valid and determinate hSBA titers for the given strain at the specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    Before first vaccination, 1 month after third vaccination
    Notes
    [39] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    300
    Units: Percentage of subjects
    number (confidence interval 95%)
        PMB3175[A29]:Before Vaccination 1 (N=280)
    31.1 (25.7 to 36.9)
        PMB3175[A29]:1 Month after Vaccination 3 (N=283)
    99.3 (97.5 to 99.9)
        PMB3010[A06]:Before Vaccination 1 (N=275)
    16 (11.9 to 20.9)
        PMB3010[A06]:1 Month after Vaccination 3 (N=275)
    92 (88.1 to 94.9)
        PMB3040[A07]:Before Vaccination 1 (N=274)
    55.8 (49.7 to 61.8)
        PMB3040[A07]:1 Month after Vaccination 3 (N=277)
    95.7 (92.6 to 97.7)
        PMB824[A12]: Before Vaccination 1 (N=278)
    5 (2.8 to 8.3)
        PMB824[A12]:1 Month after Vaccination 3 (N=275)
    71.3 (65.5 to 76.5)
        PMB1672[A15]:Before Vaccination 1 (N=279)
    37.3 (31.6 to 43.2)
        PMB1672[A15]:1 Month after Vaccination 3 (N=279)
    91.8 (87.9 to 94.7)
        PMB1989[A19]:Before Vaccination 1 (N=278)
    28.8 (23.5 to 34.5)
        PMB1989[A19]:1 Month after Vaccination 3 (N=284)
    95.8 (92.7 to 97.8)
        PMB1256[B03]:Before Vaccination 1 (N=277)
    11.2 (7.7 to 15.5)
        PMB1256[B03]:1 Month after Vaccination 3 (N=273)
    86.4 (81.8 to 90.3)
        PMB866[B09]:Before Vaccination 1 (N=277)
    23.5 (18.6 to 28.9)
        PMB866[B09]:1 Month after Vaccination 3 (N=274)
    77 (71.6 to 81.9)
        PMB431[B15]:Before Vaccination 1 (N=274)
    43.8 (37.8 to 49.9)
        PMB431[B15]:1 Month after Vaccination 3 (N=276)
    96.7 (93.9 to 98.5)
        PMB648[B16]:Before Vaccination 1 (N=270)
    21.9 (17.1 to 27.3)
        PMB648[B16]:1 Month after Vaccination 3 (N=273)
    78 (72.6 to 82.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With hSBA Titers >=1:4, >=1:8, >=1:16, >=1:32, >=1:64, >=1:128 for Each of the 10 Secondary Strains Before First Vaccination and 1 Month After the Third Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 Percentage of Subjects With hSBA Titers >=1:4, >=1:8, >=1:16, >=1:32, >=1:64, >=1:128 for Each of the 10 Secondary Strains Before First Vaccination and 1 Month After the Third Bivalent rLP2086 Vaccination: Group 1 [40]
    End point description
    Evaluable immunogenicity population. Here, number of subjects analyzed signifies subjects with valid and determinate hSBA titers for the given strain. Here, N signifies subjects with valid and determinate hSBA titers for the given strain at the specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    Before first vaccination, 1 month after third vaccination (Vac)
    Notes
    [40] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    300
    Units: Percentage of subjects
    number (confidence interval 95%)
        Before Vaccination 1: PMB3175[A29] 1:4 (N=280)
    32.9 (27.4 to 38.7)
        1 month after Vac 3: PMB3175[A29] 1:4 (N=283)
    99.3 (97.5 to 99.9)
        Before Vaccination 1: PMB3175[A29] 1:8 (N=280)
    31.1 (25.7 to 36.9)
        1 month after Vac 3: PMB3175[A29] 1:8 (N=283)
    99.3 (97.5 to 99.9)
        Before Vaccination 1: PMB3175[A29] 1:16 (N=280)
    27.9 (22.7 to 33.5)
        1 month after Vac 3: PMB3175[A29] 1:16 (N=283)
    98.9 (96.9 to 99.8)
        Before Vaccination 1: PMB3175[A29] 1:32 (N=280)
    16.1 (12 to 20.9)
        1 month after Vac 3: PMB3175[A29] 1:32 (N=283)
    96.8 (94 to 98.5)
        Before Vaccination 1: PMB3175[A29] 1:64 (N=280)
    5.7 (3.3 to 9.1)
        1 month after Vac 3: PMB3175[A29] 1:64 (N=283)
    80.9 (75.8 to 85.3)
        Before Vaccination 1: PMB3175[A29] 1:128 (N=280)
    2.1 (0.8 to 4.6)
        1 month after Vac 3: PMB3175[A29] 1:128 (N=283)
    53 (47 to 58.9)
        Before Vaccination 1: PMB3010[A06] 1:4 (N=275)
    18.9 (14.5 to 24)
        1 month after Vac 3: PMB3010[A06] 1:4 (N=275)
    92.4 (88.6 to 95.2)
        Before Vaccination 1: PMB3010[A06] 1:8 (N=275)
    17.5 (13.2 to 22.5)
        1 month after Vac 3: PMB3010[A06] 1:8 (N=275)
    92.4 (88.6 to 95.2)
        Before Vaccination 1: PMB3010[A06] 1:16 (N=275)
    16 (11.9 to 20.9)
        1 month after Vac 3: PMB3010[A06] 1:16 (N=275)
    92 (88.1 to 94.9)
        Before Vaccination 1: PMB3010[A06] 1:32 (N=275)
    10.5 (7.2 to 14.8)
        1 month after Vac 3: PMB3010 [A06] 1:32 (N=275)
    86.2 (81.5 to 90)
        Before Vaccination 1: PMB3010[A06] 1:64 (N=275)
    6.5 (3.9 to 10.1)
        1 month after Vac 3: PMB3010[A06] 1:64 (N=275)
    70.5 (64.8 to 75.9)
        Before Vaccination 1: PMB3010[A06] 1:128 (N=275)
    2.5 (1 to 5.2)
        1 month after Vac 3: PMB3010[A06] 1:128 (N=275)
    41.8 (35.9 to 47.9)
        Before Vaccination 1: PMB3040[A07] 1:4 (N=274)
    55.8 (49.7 to 61.8)
        1 month after Vac 3: PMB3040[A07] 1:4 (N=277)
    95.7 (92.6 to 97.7)
        Before Vaccination 1: PMB3040[A07] 1:8 (N=274)
    55.8 (49.7 to 61.8)
        1 month after Vac 3: PMB3040[A07] 1:8 (N=277)
    95.7 (92.6 to 97.7)
        Before Vaccination 1: PMB3040[A07] 1:16 (N=274)
    55.5 (49.4 to 61.5)
        1 month after Vac 3: PMB3040[A07] 1:16 (N=277)
    95.7 (92.6 to 97.7)
        Before Vaccination 1: PMB3040[A07] 1:32 (N=274)
    42.7 (36.8 to 48.8)
        1 month after Vac 3: PMB3040[A07] 1:32 (N=277)
    92.4 (88.6 to 95.2)
        Before Vaccination 1: PMB3040[A07] 1:64 (N=274)
    21.2 (16.5 to 26.5)
        1 month after Vac 3: PMB3040[A07] 1:64 (N=277)
    72.9 (67.3 to 78.1)
        Before Vaccination 1: PMB3040[A07] 1:128 (N=274)
    4 (2 to 7.1)
        1 month after Vac 3: PMB3040[A07] 1:128 (N=277)
    29.2 (24 to 35)
        Before Vaccination 1: PMB824[A12] 1:4 (N=278)
    10.4 (7.1 to 14.6)
        1 month after Vac 3: PMB824[A12] 1:4 (N=275)
    73.8 (68.2 to 78.9)
        Before Vaccination 1: PMB824[A12] 1:8 (N=278)
    8.3 (5.3 to 12.2)
        1 month after Vac 3: PMB824[A12] 1:8 (N=275)
    73.5 (67.8 to 78.6)
        Before Vaccination 1: PMB824[A12] 1:16 (N=278)
    5 (2.8 to 8.3)
        1 month after Vac 3: PMB824[A12] 1:16 (N=275)
    71.3 (65.5 to 76.5)
        Before Vaccination 1: PMB824[A12] 1:32 (N=278)
    2.2 (0.8 to 4.6)
        1 month after Vac 3: PMB824[A12] 1:32 (N=275)
    46.5 (40.5 to 52.6)
        Before Vaccination 1: PMB824[A12] 1:64 (N=278)
    0 (0 to 1.3)
        1 month after Vac 3: PMB824[A12] 1:64 (N=275)
    15.6 (11.6 to 20.5)
        Before Vaccination 1: PMB824[A12] 1:128 (N=278)
    0 (0 to 1.3)
        1 month after Vac 3: PMB824[A12] 1:128 (N=275)
    3.3 (1.5 to 6.1)
        Before Vaccination 1: PMB1672[A15] 1:4 (N=279)
    39.4 (33.7 to 45.4)
        1 month after Vac 3: PMB1672[A15] 1:4 (N=279)
    91.8 (87.9 to 94.7)
        Before Vaccination 1: PMB1672[A15] 1:8 (N=279)
    37.3 (31.6 to 43.2)
        1 month after Vac 3: PMB1672[A15] 1:8 (N=279)
    91.8 (87.9 to 94.7)
        Before Vaccination 1: PMB1672[A15] 1:16 (N=279)
    33.3 (27.8 to 39.2)
        1 month after Vac 3: PMB1672[A15] 1:16 (N=279)
    91.4 (87.5 to 94.4)
        Before Vaccination 1: PMB1672[A15] 1:32 (N=279)
    20.4 (15.9 to 25.6)
        1 month after Vac 3: PMB1672[A15] 1:32 (N=279)
    82.4 (77.5 to 86.7)
        Before Vaccination 1: PMB1672[A15] 1:64 (N=279)
    7.2 (4.4 to 10.9)
        1 month after Vac 3: PMB1672[A15] 1:64 (N=279)
    54.5 (48.4 to 60.4)
        Before Vaccination 1: PMB1672[A15] 1:128 (N=279)
    1.8 (0.6 to 4.1)
        1 month after Vac 3: PMB1672[A15] 1:128 (N=279)
    19 (14.6 to 24.1)
        Before Vaccination 1: PMB1989[A19] 1:4 (N=278)
    39.2 (33.4 to 45.2)
        1 month after Vac 3: PMB1989[A19] 1:4 (N=284)
    96.1 (93.2 to 98.1)
        Before Vaccination 1: PMB1989[A19] 1:8 (N=278)
    37.1 (31.4 to 43)
        1 month after Vac 3: PMB1989[A19] 1:8 (N=284)
    96.1 (93.2 to 98.1)
        Before Vaccination 1: PMB1989[A19] 1:16 (N=278)
    28.8 (23.5 to 34.5)
        1 month after Vac 3: PMB1989[A19] 1:16 (N=284)
    95.8 (92.7 to 97.8)
        Before Vaccination 1: PMB1989[A19] 1:32 (N=278)
    18.3 (14 to 23.4)
        1 month after Vac 3: PMB1989[A19] 1:32 (N=284)
    92.3 (88.5 to 95.1)
        Before Vaccination 1: PMB1989[A19] 1:64 (N=278)
    9 (5.9 to 13)
        1 month after Vac 3: PMB1989[A19] 1:64 (N=284)
    77.5 (72.2 to 82.2)
        Before Vaccination 1: PMB1989[A19] 1:128 (N=278)
    9 (5.9 to 13)
        1 month after Vac 3: PMB1989[A19] 1:128 (N=284)
    49.6 (43.7 to 55.6)
        Before Vaccination 1: PMB1256[B03] 1:4 (N=277)
    13 (9.3 to 17.5)
        1 month after Vac 3: PMB1256[B03] 1:4 (N=273)
    86.8 (82.2 to 90.6)
        Before Vaccination 1: PMB1256[B03] 1:8 (N=277)
    11.2 (7.7 to 15.5)
        1 month after Vac 3: PMB1256[B03] 1:8 (N=273)
    86.4 (81.8 to 90.3)
        Before Vaccination 1: PMB1256[B03] 1:16 (N=277)
    10.1 (6.8 to 14.3)
        1 month after Vac 3: PMB1256[B03] 1:16 (N=273)
    85.3 (80.6 to 89.3)
        Before Vaccination 1: PMB1256[B03] 1:32 (N=277)
    7.6 (4.8 to 11.4)
        1 month after Vac 3: PMB1256[B03] 1:32 (N=273)
    78.4 (73 to 83.1)
        Before Vaccination 1: PMB1256[B03] 1:64 (N=277)
    4.7 (2.5 to 7.9)
        1 month after Vac 3: PMB1256[B03] 1:64 (N=273)
    56.4 (50.3 to 62.4)
        Before Vaccination 1: PMB1256[B03] 1:128 (N=277)
    1.1 (0.2 to 3.1)
        1 month after Vac 3: PMB1256[B03] 1:128 (N=273)
    30.8 (25.3 to 36.6)
        Before Vaccination 1: PMB866[B09] 1:4 (N=277)
    24.5 (19.6 to 30.1)
        1 month after Vac 3: PMB866[B09] 1:4 (N=274)
    78.5 (73.1 to 83.2)
        Before Vaccination 1: PMB866[B09] 1:8 (N=277)
    23.5 (18.6 to 28.9)
        1 month after Vac 3: PMB866[B09] 1:8 (N=274)
    77 (71.6 to 81.9)
        Before Vaccination 1: PMB866[B09] 1:16 (N=277)
    18.8 (14.3 to 23.9)
        1 month after Vac 3: PMB866[B09] 1:16 (N=274)
    73.4 (67.7 to 78.5)
        Before Vaccination 1: PMB866[B09] 1:32 (N=277)
    11.9 (8.3 to 16.3)
        1 month after Vac 3: PMB866[B09] 1:32 (N=274)
    52.6 (46.5 to 58.6)
        Before Vaccination 1: PMB866[B09] 1:64 (N=277)
    4.7 (2.5 to 7.9)
        1 month after Vac 3: PMB866[B09] 1:64 (N=274)
    27.7 (22.5 to 33.4)
        Before Vaccination 1: PMB866[B09] 1:128 (N=277)
    1.1 (0.2 to 3.1)
        1 month after Vac 3: PMB866[B09] 1:128 (N=274)
    12.8 (9.1 to 17.3)
        Before Vaccination 1: PMB431[B15] 1:4 (N=274)
    44.9 (38.9 to 51)
        1 month after Vac 3: PMB431[B15] 1:4 (N=276)
    97.1 (94.4 to 98.7)
        Before Vaccination 1: PMB431[B15] 1:8 (N=274)
    43.8 (37.8 to 49.9)
        1 month after Vac 3: PMB431[B15] 1:8 (N=276)
    96.7 (93.9 to 98.5)
        Before Vaccination 1: PMB431[B15] 1:16 (N=274)
    41.2 (35.4 to 47.3)
        1 month after Vac 3: PMB431[B15] 1:16 (N=276)
    96.7 (93.9 to 98.5)
        Before Vaccination 1: PMB431[B15] 1:32 (N=274)
    23.7 (18.8 to 29.2)
        1 month after Vac 3: PMB431[B15] 1:32 (N=276)
    84.4 (79.6 to 88.5)
        Before Vaccination 1: PMB431[B15] 1:64 (N=274)
    8 (5.1 to 11.9)
        1 month after Vac 3: PMB431[B15] 1:64 (N=276)
    56.5 (50.4 to 62.5)
        Before Vaccination 1: PMB431[B15] 1:128 (N=274)
    1.5 (0.4 to 3.7)
        1 month after Vac 3: PMB431[B15] 1:128 (N=276)
    22.5 (17.7 to 27.9)
        Before Vaccination 1: PMB648[B16] 1:4 (N=270)
    24.4 (19.4 to 30)
        1 month after Vac 3: PMB648[B16] 1:4 (N=273)
    79.1 (73.8 to 83.8)
        Before Vaccination 1: PMB648[B16] 1:8 (N=270)
    21.9 (17.1 to 27.3)
        1 month after Vac 3: PMB648[B16] 1:8 (N=273)
    78 (72.6 to 82.8)
        Before Vaccination 1: PMB648[B16] 1:16 (N=270)
    18.9 (14.4 to 24.1)
        1 month after Vac 3: PMB648[B16] 1:16 (N=273)
    76.6 (71.1 to 81.5)
        Before Vaccination 1: PMB648[B16] 1:32 (N=270)
    11.9 (8.2 to 16.3)
        1 month after Vac 3: PMB648[B16] 1:32 (N=273)
    61.2 (55.1 to 67)
        Before Vaccination 1: PMB648[B16] 1:64 (N=270)
    7.4 (4.6 to 11.2)
        1 month after Vac 3: PMB648[B16] 1:64 (N=273)
    34.4 (28.8 to 40.4)
        Before Vaccination 1: PMB648[B16] 1:128 (N=270)
    1.9 (0.6 to 4.3)
        1 month after Vac 3: PMB648[B16] 1:128 (N=273)
    16.8 (12.6 to 21.8)
    No statistical analyses for this end point

    Secondary: hSBA Geometric Mean Titers (GMTs) for Each of the 10 Secondary Strains Before First Vaccination and 1 Month After the Third Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 hSBA Geometric Mean Titers (GMTs) for Each of the 10 Secondary Strains Before First Vaccination and 1 Month After the Third Bivalent rLP2086 Vaccination: Group 1 [41]
    End point description
    Evaluable immunogenicity population. Here, number of subjects analyzed signifies subjects with valid and determinate hSBA titers for the given strain. Here, N signifies subjects with valid and determinate assay results for the given antigen or strain. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    Before first vaccination, 1 month after third vaccination
    Notes
    [41] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    300
    Units: Titers
    geometric mean (confidence interval 95%)
        PMB3175[A29]:Before Vaccination 1 (N=280)
    7.1 (6.4 to 8)
        PMB3175[A29]:1 Month after Vaccination 3 (N=283)
    96.3 (86.9 to 106.9)
        PMB3010[A06]:Before Vaccination 1 (N=275)
    10.3 (9.5 to 11.2)
        PMB3010[A06]:1 Month after Vaccination 3 (N=275)
    69.9 (61.8 to 79.1)
        PMB3040[A07]:Before Vaccination 1 (N=274)
    13.9 (12 to 16)
        PMB3040[A07]:1 Month after Vaccination 3 (N=277)
    60.4 (54.6 to 66.8)
        PMB824[A12]: Before Vaccination 1 (N=278)
    8.4 (8.2 to 8.6)
        PMB824[A12]:1 Month after Vaccination 3 (N=275)
    20.6 (18.8 to 22.6)
        PMB1672[A15]:Before Vaccination 1 (N=279)
    8 (7.1 to 9)
        PMB1672[A15]:1 Month after Vaccination 3 (N=279)
    43.1 (38.4 to 48.4)
        PMB1989[A19]:Before Vaccination 1 (N=278)
    12.1 (11.1 to 13.3)
        PMB1989[A19]:1 Month after Vaccination 3 (N=284)
    87.3 (77.7 to 98)
        PMB1256[B03]:Before Vaccination 1 (N=277)
    5.1 (4.7 to 5.6)
        PMB1256[B03]:1 Month after Vaccination 3 (N=273)
    49.8 (42.2 to 58.7)
        PMB866[B09]:Before Vaccination 1 (N=277)
    6.1 (5.5 to 6.7)
        PMB866[B09]:1 Month after Vaccination 3 (N=274)
    23.3 (19.9 to 27.1)
        PMB431[B15]:Before Vaccination 1 (N=274)
    9.1 (8.1 to 10.3)
        PMB431[B15]:1 Month after Vaccination 3 (N=276)
    49.4 (44.6 to 54.8)
        PMB648[B16]:Before Vaccination 1 (N=270)
    6.2 (5.5 to 6.9)
        PMB648[B16]:1 Month after Vaccination 3 (N=273)
    26.5 (22.8 to 30.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving Composite hSBA Titer >=Lower Limit of Quantitation for all 4 Primary Strains Before First Vaccination and 1 Month After Second Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 Percentage of Subjects Achieving Composite hSBA Titer >=Lower Limit of Quantitation for all 4 Primary Strains Before First Vaccination and 1 Month After Second Bivalent rLP2086 Vaccination: Group 1 [42]
    End point description
    Evaluable immunogenicity population. Here, N signifies subjects valid and determinate hSBA results on all 4 strains at the given time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    Before vaccination 1, 1 Month after Vaccination 2
    Notes
    [42] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    1723
    Units: Percentage of subjects
    number (confidence interval 95%)
        Before First Vaccination (N=1612)
    7.3 (6 to 8.6)
        1 Month after Vaccination 2 (N=1620)
    64.5 (62.1 to 66.8)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving at Least a 4-Fold Increase in hSBA Titer for Each of the 4 Primary Strains Before First Vaccination to 1 Month After the Second Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 Percentage of Subjects Achieving at Least a 4-Fold Increase in hSBA Titer for Each of the 4 Primary Strains Before First Vaccination to 1 Month After the Second Bivalent rLP2086 Vaccination: Group 1 [43]
    End point description
    Evaluable immunogenicity population. Here, N signifies subjects with valid and determinate hSBA titers for the given strain at both the specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    One month after second Bivalent rLP2086 vaccination
    Notes
    [43] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    1723
    Units: Percentage of subjects
    number (confidence interval 95%)
        PMB80[A22] (N=1679)
    66.9 (64.6 to 69.2)
        PMB2001[A56] (N=1637)
    85.9 (84.1 to 87.5)
        PMB2948[B24] (N=1658)
    67.9 (65.6 to 70.2)
        PMB2707[B44] (N=1686)
    55.5 (53.1 to 57.9)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With hSBA Titers >=1:4,>=1:8,>=1:16,>=1:32,>=1:64,>=1:128 for 4 Primary Test Strains Before First Vaccination, 1 Month After Second and Third Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 Percentage of Subjects With hSBA Titers >=1:4,>=1:8,>=1:16,>=1:32,>=1:64,>=1:128 for 4 Primary Test Strains Before First Vaccination, 1 Month After Second and Third Bivalent rLP2086 Vaccination: Group 1 [44]
    End point description
    Results for PMB80[A22] 1:16, PMB2001[A56] 1:8, PMB2948[B24] 1:8 and PMB2707[B44] 1:8 are reported under secondary endpoint ‘Percentage of Subjects With hSBA Titers >=LLOQ for 4 Primary Test Strains Before First Vaccination, 1 Month After Second and Third Bivalent rLP2086 Vaccination: Group 1’. Evaluable immunogenicity population. Here, N signifies subjects with valid and determinate hSBA titers for the given strain at the specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    Before Vaccination (Vac) 1, 1 Month after Vac 2, 3
    Notes
    [44] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    1723
    Units: Percentage of subjects
    number (confidence interval 95%)
        Before Vac 1: PMB80[A22] 1:4 (N=1704)
    42.1 (39.7 to 44.5)
        1 month after Vac 2: PMB80[A22] 1:4 (N=1697)
    86.2 (84.5 to 87.8)
        1 month after Vac 3: PMB80[A22] 1:4 (N=1714)
    94.3 (93.1 to 95.3)
        Before Vac 1: PMB80[A22] 1:8 (N=1704)
    38.8 (36.5 to 41.2)
        1 month after Vac 2: PMB80[A22] 1:8 (N=1697)
    85.7 (83.9 to 87.3)
        1 month after Vac 3: PMB80[A22] 1:8 (N=1714)
    94.1 (92.9 to 95.2)
        Before Vac 1: PMB80[A22] 1:32 (N=1704)
    19.7 (17.8 to 21.6)
        1 month after Vac 2: PMB80[A22] 1:32 (N=1697)
    71.2 (69 to 73.3)
        1 month after Vac 3: PMB80[A22] 1:32 (N=1714)
    85.5 (83.8 to 87.2)
        Before Vac 1: PMB80[A22] 1:64 (N=1704)
    9.6 (8.3 to 11.1)
        1 month after Vac 2: PMB80[A22] 1:64 (N=1697)
    49.9 (47.4 to 52.3)
        1 month after Vac 3: PMB80[A22] 1:64 (N=1714)
    64.4 (62.1 to 66.7)
        Before Vac 1: PMB80[A22] 1:128 (N=1704)
    3.4 (2.6 to 4.4)
        1 month after Vac 2: PMB80[A22] 1:128 (N=1697)
    29.9 (27.8 to 32.2)
        1 month after Vac 3: PMB80[A22] 1:128 (N=1714)
    41.7 (39.4 to 44.1)
        Before Vac 1: PMB2001[A56] 1:4 (N=1657)
    35.9 (33.6 to 38.3)
        1 month after Vac 2: PMB2001[A56] 1:4 (N=1701)
    97.8 (97 to 98.5)
        1 month after Vac 3: PMB2001[A56] 1:4 (N=1708)
    99.4 (98.9 to 99.7)
        Before Vac 1: PMB2001[A56] 1:16 (N=1657)
    30.4 (28.2 to 32.7)
        1 month after Vac 2: PMB2001[A56] 1:16 (N=1701)
    97.1 (96.1 to 97.8)
        1 month after Vac 3: PMB2001[A56] 1:16 (N=1708)
    99.2 (98.7 to 99.6)
        Before Vac 1: PMB2001[A56] ] 1:32 (N=1657)
    24.4 (22.3 to 26.5)
        1 month after Vac 2: PMB2001[A56] 1:32 (N=1701)
    92.8 (91.4 to 94)
        1 month after Vac 3: PMB2001[A56] 1:32 (N=1708)
    97.2 (96.4 to 98)
        Before Vac 1: PMB2001[A56] 1:64 (N=1657)
    16.4 (14.6 to 18.2)
        1 month after Vac 2 :PMB2001[A56] 1:64 (N=1701)
    80.8 (78.9 to 82.7)
        1 month after Vac 3 :PMB2001[A56] 1:64 (N=1708)
    90.5 (89 to 91.9)
        Before Vac 1: PMB2001[A56] 1:128 (N=1657)
    7.1 (5.9 to 8.5)
        1 month after Vac 2: PMB2001[A56] 1:128 (N=1701)
    56.6 (54.2 to 58.9)
        1 month after Vac 3: PMB2001[A56] 1:128 (N=1708)
    73.7 (71.5 to 75.7)
        Before Vac 1: PMB2948[B24] 1:4 (N=1696)
    35 (32.7 to 37.3)
        1 month after Vac 2: PMB2948[B24] 1:4 (N=1685)
    87.2 (85.5 to 88.7)
        1 month after Vac 3: PMB2948[B24] 1:4 (N=1702)
    95.8 (94.8 to 96.7)
        Before Vac 1: PMB2948[B24] 1:16 (N=1696)
    29.5 (27.3 to 31.7)
        1 month after Vac 2: PMB2948[B24] 1:16 (N=1685)
    83.7 (81.9 to 85.5)
        1 month after Vac 3: PMB2948[B24] 1:16 (N=1702)
    93.2 (91.9 to 94.3)
        Before Vac 1: PMB2948[B24] 1:32 (N=1696)
    18.1 (16.3 to 20)
        1 month after Vac 2: PMB2948[B24] 1:32 (N=1685)
    65.6 (63.3 to 67.8)
        1 month after Vac 3: PMB2948[B24] 1:32 (N=1702)
    75.1 (73 to 77.2)
        Before Vac 1: PMB2948[B24] 1:64 (N=1696)
    8.4 (7.1 to 9.8)
        1 month after Vac 2: PMB2948[B24] 1:64 (N=1685)
    40.4 (38 to 42.7)
        1 month after Vac 3: PMB2948[B24] 1:64 (N=1702)
    48.8 (46.4 to 51.2)
        Before Vac 1: PMB2948[B24] 1:128 (N=1696)
    3.3 (2.5 to 4.3)
        1 month after Vac 2: PMB2948[B24] 1:128 (N=1685)
    22.8 (20.9 to 24.9)
        1 month after Vac 3: PMB2948[B24] 1:128 (N=1702)
    27.8 (25.7 to 30)
        Before Vac 1: PMB2707[B44] 1:4 (N=1716)
    14.5 (12.8 to 16.2)
        1 month after Vac 2: PMB2707[B44] 1:4 (N=1693)
    71.5 (69.3 to 73.7)
        1 month after Vac 3: PMB2707[B44] 1:4 (N=1703)
    89.7 (88.1 to 91.1)
        Before Vac 1: PMB2707[B44] 1:16 (N=1716)
    7.8 (6.5 to 9.1)
        1 month after Vac 2: PMB2707[B44] 1:16 (N=1693)
    61 (58.6 to 63.3)
        1 month after Vac 3: PMB2707[B44] 1:16 (N=1703)
    83.3 (81.4 to 85)
        Before Vac 1: PMB2707[B44] 1:32 (N=1716)
    4.3 (3.4 to 5.4)
        1 month after Vac 2: PMB2707[B44] 1:32 (N=1693)
    41.9 (39.6 to 44.3)
        1 month after Vac 3: PMB2707[B44] 1:32 (N=1703)
    67.1 (64.8 to 69.3)
        Before Vac 1: PMB2707[B44] 1:64 (N=1716)
    2.3 (1.6 to 3.1)
        1 month after Vac 2: PMB2707[B44] 1:64 (N=1693)
    30.3 (28.1 to 32.6)
        1 month after Vac 3: PMB2707[B44] 1:64 (N=1703)
    49.8 (47.4 to 52.2)
        Before Vac 1: PMB2707[B44] 1:128 (N=1716)
    0.8 (0.4 to 1.3)
        1 month after Vac 2: PMB2707[B44] 1:128 (N=1693)
    21 (19.1 to 23)
        1 month after Vac 3: PMB2707[B44] 1:128 (N=1703)
    32.1 (29.9 to 34.4)
    No statistical analyses for this end point

    Secondary: hSBA Geometric Mean Titers (GMTs) for 4 Primary Test Strains Before First Vaccination, 1 Month After Second and Third Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 hSBA Geometric Mean Titers (GMTs) for 4 Primary Test Strains Before First Vaccination, 1 Month After Second and Third Bivalent rLP2086 Vaccination: Group 1 [45]
    End point description
    Evaluable immunogenicity population. Here, N signifies subjects with valid and determinate hSBA titers for the given strain at the specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    Before Vaccination (Vac) 1, 1 Month after Vac 2, 3
    Notes
    [45] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    1723
    Units: Titer
    geometric mean (confidence interval 95%)
        PMB80[A22]: Before Vac 1 (N=1704)
    12.8 (12.3 to 13.3)
        PMB80[A22]: 1 Month after Vac 2 (N=1697)
    49 (46.2 to 52.1)
        PMB80[A22]: 1 Month after Vac 3 (N=1714)
    74.3 (70.2 to 78.6)
        PMB2001[A56]: Before Vac 1 (N=1657)
    8.8 (8.3 to 9.3)
        PMB2001[A56]: 1 Month after Vac 2 (N=1701)
    114.3 (107.9 to 121)
        PMB2001[A56]: 1 Month after Vac 3 (N=1708)
    176.7 (167.8 to 186.1)
        PMB2948[B24]: Before Vac 1 (N=1696)
    7.6 (7.3 to 8)
        PMB2948[B24]: 1 Month after Vac 2 (N=1685)
    35.8 (33.7 to 38.2)
        PMB2948[B24]: 1 Month after Vac 3 (N=1702)
    49.5 (46.8 to 52.4)
        PMB2707[B44]: Before Vac 1 (N=1716)
    4.8 (4.7 to 4.9)
        PMB2707[B44]: 1 Month after Vac 2 (N=1693)
    22.6 (20.9 to 24.4)
        PMB2707[B44]: 1 Month after Vac 3 (N=1703)
    47.6 (44.2 to 51.3)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving at Least a 3-Fold Increase in hSBA Titer for 4 Primary Test Strains Before First Vaccination to 1 Month After Third Bivalent rLP2086 Vaccination

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    End point title
    		 Percentage of Subjects Achieving at Least a 3-Fold Increase in hSBA Titer for 4 Primary Test Strains Before First Vaccination to 1 Month After Third Bivalent rLP2086 Vaccination [46]
    End point description
    Data was not reported because 3-fold rise analyses was not performed as per change in planned analysis.
    End point type
    Secondary
    End point timeframe
    One month after third bivalent rLP2086 vaccination
    Notes
    [46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    0 [47]
    Units: Percentage of subjects
        number (confidence interval 95%)
    ( to )
    Notes
    [47] - Data not reported because 3-fold rise analyses was not performed as per change in planned analysis.
    No statistical analyses for this end point

    Secondary: Percentage of Subjects Achieving at Least a 2-Fold Increase in hSBA Titer for 4 Primary Test Strains Before First Vaccination to 1 Month After the Third Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 Percentage of Subjects Achieving at Least a 2-Fold Increase in hSBA Titer for 4 Primary Test Strains Before First Vaccination to 1 Month After the Third Bivalent rLP2086 Vaccination: Group 1 [48]
    End point description
    Evaluable immunogenicity population. Here, N signifies subjects with valid and determinate hSBA titers for the given strain at the specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    One month after third bivalent rLP2086 vaccination
    Notes
    [48] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    1723
    Units: Percentage of subjects
    number (confidence interval 95%)
        PMB80[A22]: 1 Month after Vac 3 (N=1695)
    89 (87.4 to 90.4)
        PMB2001[A56]: 1 Month after Vac 3 (N=1642)
    95.3 (94.2 to 96.3)
        PMB2948[B24]: 1 Month after Vac 3 (N=1675)
    87.1 (85.4 to 88.7)
        PMB2707[B44]: 1 Month after Vac 3(N=1696)
    81.8 (79.9 to 83.6)
    No statistical analyses for this end point

    Secondary: Percentage of Subjects With hSBA Titers >=LLOQ for 4 Primary Test Strains Before First Vaccination, 1 Month After Second and Third Bivalent rLP2086 Vaccination: Group 1

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    End point title
    		 Percentage of Subjects With hSBA Titers >=LLOQ for 4 Primary Test Strains Before First Vaccination, 1 Month After Second and Third Bivalent rLP2086 Vaccination: Group 1 [49]
    End point description
    Evaluable immunogenicity population. Here, N signifies subjects with valid and determinate hSBA titers for the given strain at the specified time point. This outcome measure was planned to be analyzed for Group 1 only.
    End point type
    Secondary
    End point timeframe
    Before Vaccination (Vac) 1, 1 Month after Vac 2, 3
    Notes
    [49] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
    Justification: Data was planned to be analysed only for Group 1 rLP2086.
    End point values
    		 Group 1 rLP2086
    Number of subjects analysed
    1723
    Units: Percentage of subjects
    number (confidence interval 95%)
        Before Vac 1: PMB80[A22] 1:16 (N=1704)
    33.6 (31.3 to 35.9)
        1 month after Vac 2: PMB80[A22] 1:16 (N=1697)
    84.7 (82.9 to 86.4)
        1 month after Vac 3: PMB80[A22] 1:16 (N=1714)
    93.5 (92.2 to 94.6)
        Before Vac 1: PMB2001[A56] 1:8 (N=1657)
    32.2 (29.9 to 34.5)
        1 month after Vac 2: PMB2001[A56] 1:8) (N=1701)
    97.4 (96.5 to 98.1)
        1 month after Vac 3: PMB2001[A56] 1:8 (N=1708)
    99.4 (98.9 to 99.7)
        Before Vac 1: PMB2948[B24] 1:8 (N=1696)
    33.1 (30.9 to 35.4)
        1 month after Vac 2: PMB2948[B24] 1:8 (N=1685)
    86.5 (84.7 to 88.1)
        1 month after Vac 3: PMB2948[B24] 1:8 (N=1702)
    95.1 (93.9 to 96)
        Before Vac 1: PMB2707[B44] 1:8 (N=1716)
    11 (9.6 to 12.6)
        1 month after Vac 2: PMB2707[B44] 1:8 (N=1693)
    68.3 (66.1 to 70.6)
        1 month after Vac 3: PMB2707[B44] 1:8 (N=1703)
    87.4 (85.8 to 89)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    AEs/SAEs: recorded from first vaccination through 6 months after third vaccination. Subjects recorded pre-specified reactogenicity events (local reactions, systemic events) in electronic diary within 7 days after first, second and third vaccination.
    Adverse event reporting additional description
    All AEs collected on case report form are shown below as having been collected via non-systematic assessment. All events reported via electronic diary (reactogenicity events) are shown below as having been collected via systematic assessment. Reactogenicity events are grouped by all severities and doses combined.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    18.0
    Reporting groups
    Reporting group title
    Group 1 rLP2086
    Reporting group description
    		 Recombinant lipoprotein 2086 (rLP2086) vaccine on a 0-, 2-, 6- month schedule.

    Reporting group title
    Group 2 Saline
    Reporting group description
    		 Saline on a 0-, 2-, 6- month schedule.

    Serious adverse events
    		 Group 1 rLP2086 Group 2 Saline
    Total subjects affected by serious adverse events
         subjects affected / exposed
    33 / 2471 (1.34%)
    11 / 822 (1.34%)
         number of deaths (all causes)
    3
    0
         number of deaths resulting from adverse events
    Injury, poisoning and procedural complications
    Road traffic accident
         subjects affected / exposed
    2 / 2471 (0.08%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 2
    0 / 0
    Craniocerebral injury
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Laceration
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Tendon injury
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Nervous system disorders
    Migraine
         subjects affected / exposed
    0 / 2471 (0.00%)
    2 / 822 (0.24%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 2
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Benign intracranial hypertension
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dystonia
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Multiple sclerosis
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    1 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Syncope
         subjects affected / exposed
    0 / 2471 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pregnancy, puerperium and perinatal conditions
    Abortion missed
         subjects affected / exposed
    2 / 2471 (0.08%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Abortion spontaneous
         subjects affected / exposed
    4 / 2471 (0.16%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 4
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ectopic pregnancy
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hyperemesis gravidarum
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    General disorders and administration site conditions
    Pyrexia
         subjects affected / exposed
    3 / 2471 (0.12%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    1 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Ear and labyrinth disorders
    Sudden hearing loss
         subjects affected / exposed
    0 / 2471 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastrointestinal disorders
    Abdominal pain upper
         subjects affected / exposed
    0 / 2471 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Colitis
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Gastritis
         subjects affected / exposed
    0 / 2471 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Hepatobiliary disorders
    Cholecystitis acute
         subjects affected / exposed
    0 / 2471 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Respiratory, thoracic and mediastinal disorders
    Asthma
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pulmonary embolism
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Psychiatric disorders
    Completed suicide
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 1
    0 / 0
    Depression
         subjects affected / exposed
    0 / 2471 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Dissociative disorder
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Eating disorder
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 3
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Suicide attempt
         subjects affected / exposed
    0 / 2471 (0.00%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 0
    0 / 3
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Intervertebral disc protrusion
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Infections and infestations
    Cystitis
         subjects affected / exposed
    1 / 2471 (0.04%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Appendicitis
         subjects affected / exposed
    2 / 2471 (0.08%)
    1 / 822 (0.12%)
         occurrences causally related to treatment / all
    0 / 2
    0 / 1
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Anal abscess
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Mastoiditis
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Otosalpingitis
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Pyelonephritis
         subjects affected / exposed
    1 / 2471 (0.04%)
    0 / 822 (0.00%)
         occurrences causally related to treatment / all
    0 / 1
    0 / 0
         deaths causally related to treatment / all
    0 / 0
    0 / 0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 Group 1 rLP2086 Group 2 Saline
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    2193 / 2471 (88.75%)
    567 / 822 (68.98%)
    Injury, poisoning and procedural complications
    Fall
         subjects affected / exposed
    31 / 2471 (1.25%)
    6 / 822 (0.73%)
         occurrences all number
    32
    6
    Ligament sprain
         subjects affected / exposed
    22 / 2471 (0.89%)
    11 / 822 (1.34%)
         occurrences all number
    23
    11
    Nervous system disorders
    Headache
         subjects affected / exposed
    55 / 2471 (2.23%)
    10 / 822 (1.22%)
         occurrences all number
    62
    10
    General disorders and administration site conditions
    Injection site pain
         subjects affected / exposed
    46 / 2471 (1.86%)
    6 / 822 (0.73%)
         occurrences all number
    50
    7
    Fatigue
         subjects affected / exposed
    12 / 2471 (0.49%)
    10 / 822 (1.22%)
         occurrences all number
    14
    10
    Vomiting - Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [1]
    130 / 2438 (5.33%)
    37 / 808 (4.58%)
         occurrences all number
    130
    37
    Fever >=38.0 degrees C -Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [2]
    108 / 2432 (4.44%)
    14 / 807 (1.73%)
         occurrences all number
    108
    14
    Diarrhea-Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [3]
    497 / 2438 (20.39%)
    158 / 808 (19.55%)
         occurrences all number
    497
    158
    Headache - Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [4]
    1440 / 2438 (59.06%)
    391 / 808 (48.39%)
         occurrences all number
    1440
    391
    Fatigue -Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [5]
    1576 / 2438 (64.64%)
    411 / 808 (50.87%)
         occurrences all number
    1576
    411
    Chills - Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [6]
    697 / 2438 (28.59%)
    133 / 808 (16.46%)
         occurrences all number
    697
    133
    Muscle pain -Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [7]
    916 / 2438 (37.57%)
    170 / 808 (21.04%)
         occurrences all number
    916
    170
    Joint pain -Any (reactogenicity event)
    alternative dictionary used: Systemic Events 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [8]
    723 / 2438 (29.66%)
    136 / 808 (16.83%)
         occurrences all number
    723
    136
    Skin and subcutaneous tissue disorders
    Redness -Any (reactogenicity event)
    alternative dictionary used: Local Reactions 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [9]
    537 / 2438 (22.03%)
    8 / 808 (0.99%)
         occurrences all number
    537
    8
    Pain at injection site - Any (reactogenicity event)
    alternative dictionary used: Local Reactions 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [10]
    2184 / 2438 (89.58%)
    147 / 808 (18.19%)
         occurrences all number
    2184
    147
    Swelling -Any (reactogenicity event)
    alternative dictionary used: Local Reactions 0.0
    alternative assessment type: Systematic
         subjects affected / exposed [11]
    612 / 2438 (25.10%)
    8 / 808 (0.99%)
         occurrences all number
    612
    8
    Infections and infestations
    Upper respiratory tract infection
         subjects affected / exposed
    98 / 2471 (3.97%)
    29 / 822 (3.53%)
         occurrences all number
    112
    31
    Nasopharyngitis
         subjects affected / exposed
    77 / 2471 (3.12%)
    33 / 822 (4.01%)
         occurrences all number
    89
    37
    Urinary tract infection
         subjects affected / exposed
    45 / 2471 (1.82%)
    10 / 822 (1.22%)
         occurrences all number
    49
    12
    Gastroenteritis
         subjects affected / exposed
    33 / 2471 (1.34%)
    12 / 822 (1.46%)
         occurrences all number
    35
    13
    Pharyngitis
         subjects affected / exposed
    37 / 2471 (1.50%)
    10 / 822 (1.22%)
         occurrences all number
    41
    11
    Tonsillitis
         subjects affected / exposed
    19 / 2471 (0.77%)
    11 / 822 (1.34%)
         occurrences all number
    23
    13
    Bronchitis
         subjects affected / exposed
    12 / 2471 (0.49%)
    10 / 822 (1.22%)
         occurrences all number
    13
    10
    Notes
    [1] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [2] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [3] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [4] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [5] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [6] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [7] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [8] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [9] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [10] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.
    [11] - The number of subjects exposed to this adverse event is less than the total number of subjects exposed for the reporting group. These numbers are expected to be equal.
    Justification: Here number of subjects exposed signifies subjects reporting yes for at least 1 day or no for all days.

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    18 Sep 2012
    1) Events were to be reported throughout the study from the signing of the ICD up to the study end (Visit 6:final telephone contact). 2) Non-serious AEs were to be reported from the signing of the ICD to up to Visit 5 (postvaccination 3 blood draw).
    24 Jan 2013
    1) Serious adverse events occurring to a subject after the active reporting period has ended should be reported to the sponsor if the investigator becomes aware of them; at a minimum, all serious events that the investigator believed had at least a reasonable possibility of being related to study drug were to be reported to the sponsor.

    Interruptions (globally)
    Were there any global interruptions to the trial? No

    Limitations and caveats
    Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.
    None reported
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