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    Clinical Trial Results:
    Immunogenicity and safety study of a third measles mumps rubella (MMR-3) vaccine dose in healthy young adults in The Netherlands

    Summary
    EudraCT number
    		 2016-001104-36
    Trial protocol
    		 NL  
    Global end of trial date
    25 Mar 2020

    Results information
    Results version number
    		 v1(current)
    This version publication date
    12 Jul 2023
    First version publication date
    12 Jul 2023
    Other versions

    Trial information

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    Trial identification
    Sponsor protocol code
    IIV-291
    Additional study identifiers
    ISRCTN number
    		 -
    US NCT number
    		 -
    WHO universal trial number (UTN)
    		 -
    Other trial identifiers
    		 NTR: 5911, ABR: NL57282.094.16
    Sponsors
    Sponsor organisation name
    RIVM
    Sponsor organisation address
    PO Box 1, Bilthoven, Netherlands, 3720 BA
    Public contact
    Clinical Expertise Centre, RIVM, mensgebonden-onderzoek@rivm.nl
    Scientific contact
    Clinical Expertise Centre, RIVM, mensgebonden-onderzoek@rivm.nl
    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
    Interim
    Date of interim/final analysis
    14 Dec 2021
    Is this the analysis of the primary completion data?
    Yes
    Primary completion date
    25 Mar 2020
    Global end of trial reached?
    Yes
    Global end of trial date
    25 Mar 2020
    Was the trial ended prematurely?
    No
    General information about the trial
    Main objective of the trial
    To assess the effect of third dose of MMR in young adults 18-25 years of age on the development of mumps-specific serum VN antibody titers (against vaccine- and currently circulating wild-type mumps virus strains (genotype G)) and mumps-specific serum antibody IgG titers (including antibody avidity), 10 days, 4 weeks, 1 year and 3 years following vaccination.
    Protection of trial subjects
    Available data on the MMR-3 in young adults does not suggest any elevated frequency or unusual patterns of adverse events compared to the MMR-1 and MMR-2 immunizations given within the routine national immunization program (NIP). Participants who despite the advice become pregnant within 4 weeks after MMR vaccination, will be strongly recommended to consult a physician. The burden and risk of blood and saliva sampling is considered low. Blood collection could result in a small bruise at the location of injection, which will disappear within a few days. Collection of finger prick blood is regarded an adequate and safe alternative for full venous blood puncture. The applied lancet is easy to use, sterile and with a pricking needle which is designed to prevent exposure and re-use. Risk of infecting someone via the lancet is therefore very unlikely. The method has been successfully applied in a previous RIVM study, “Retrospective assessment of symptomatic and asymptomatic mumps virus infection: assessing attack rates and correlates of protection” (NL38042.041.11).
    Background therapy
    		 -
    Evidence for comparator
    		 -
    Actual start date of recruitment
    13 Oct 2016
    Long term follow-up planned
    No
    Independent data monitoring committee (IDMC) involvement?
    No
    Population of trial subjects
    Number of subjects enrolled per country
    Country: Number of subjects enrolled
    Netherlands: 147
    Worldwide total number of subjects
    147
    EEA total number of subjects
    147
    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)
    147
    From 65 to 84 years
    0
    85 years and over
    0

    Subject disposition

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    Recruitment
    Recruitment details
    		 Recruitment took place as of September 2016 among students (18-25 years of age), in the surroundings of Haarlem and Amsterdam, The Netherlands. Recruitment was via email, Facebook and flyers. First inclusion 13-10-2016, last inclusion 06-04-2017.

    Pre-assignment
    Screening details
    		 During a telephone call, check: Generally healthy? For woman: Are you (possibly) pregnant? Do you give breast feeding? Ever received a third BMR vaccination? Received two BMR vaccinations as a child (according to the Dutch National Immunization Program)? Participated in other trials with medication in the past 4 weeks?

    Period 1
    Period 1 title
    MMR-3 immunization (overall period)
    Is this the baseline period?
    		 Yes
    Allocation method
    Not applicable
    Blinding used
    		 Not blinded
    Blinding implementation details
    No blinding

    Arms
    Arm title
    		 MMR-3 immunization
    Arm description
    		 -
    Arm type
    		 Experimental

    Investigational medicinal product name
    M-M-RVAXPRO
    Investigational medicinal product code
    Other name
    Pharmaceutical forms
    Suspension for injection in pre-filled syringe
    Routes of administration
    Intramuscular use
    Dosage and administration details
    One dose (0.5 mL) contains: Measles virus1 Enders' Edmonston strain (live, attenuated) ………..….not less than 1x103 TCID50* Mumps virus1 Jeryl Lynn™ [Level B] strain (live, attenuated)……...…not less than 12.5x103 TCID50* Rubella virus2 Wistar RA 27/3 strain (live, attenuated) …………….….not less than 1x103 TCID50* *50% tissue culture infectious dose 1 produced in chick embryo cells. 2 produced in WI-38 human diploid lung fibroblasts. The vaccine may contain traces of recombinant human albumin (rHA). This vaccine contains a trace amount of neomycin. See section 4.3 of the SmPC.

    Number of subjects in period 1
    		MMR-3 immunization
    Started
    147
    day 10 after MMR-3 immunization
    132
    4 weeks following MMR-3 immunization
    147
    1 year following MMR-3 immunization
    134
    3 years following MMR-3 immunization
    119
    Completed
    119
    Not completed
    28
         Not participating in the 3 years extension
    15
         Moved to another region or country
    12
         Lost to follow-up
    1

    Baseline characteristics

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    Baseline characteristics reporting groups
    Reporting group title
    MMR-3 immunization
    Reporting group description
    		 -

    Reporting group values
    		 MMR-3 immunization Total
    Number of subjects
    		 147 147
    Age categorical
    Units: Subjects
        In utero
    		 0 0
        Preterm newborn infants (gestational age < 37 wks)
    		 0 0
        Newborns (0-27 days)
    		 0 0
        Infants and toddlers (28 days-23 months)
    		 0 0
        Children (2-11 years)
    		 0 0
        Adolescents (12-17 years)
    		 0 0
        Adults (18-64 years)
    		 147 147
        From 65-84 years
    		 0 0
        85 years and over
    		 0 0
    Age continuous
    Units: years
        arithmetic mean (full range (min-max))
    		 22.4 (18 to 25) -
    Gender categorical
    Units: Subjects
        Female
    		 79 79
        Male
    		 68 68

    End points

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    End points reporting groups
    Reporting group title
    MMR-3 immunization
    Reporting group description
    		 -

    Subject analysis set title
    Pre-MMR-3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This trial contains one arm. In order to create multiple arms for the statistical analysis of the primary endpoint, each time point will be defined as one arm.

    Subject analysis set title
    10 days post-MMR-3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This trial contains one arm. In order to create multiple arms for the statistical analysis of the primary endpoint, each time point will be defined as one arm.

    Subject analysis set title
    4 weeks post-MMR-3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This trial contains one arm. In order to create multiple arms for the statistical analysis of the primary endpoint, each time point will be defined as one arm.

    Subject analysis set title
    1 year post-MMR-3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This trial contains one arm. In order to create multiple arms for the statistical analysis of the primary endpoint, each time point will be defined as one arm.

    Subject analysis set title
    3 years post-MMR-3
    Subject analysis set type
    		 Per protocol
    Subject analysis set description
    This trial contains one arm. In order to create multiple arms for the statistical analysis of the primary endpoint, each time point will be defined as one arm.

    Primary: Anti-mumps, -measles, and -rubella serum antibody levels

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    End point title
    		 Anti-mumps, -measles, and -rubella serum antibody levels
    End point description
    RU/mL (MuV IgG) IU/mL (MeV IgG, RuV IgG) ND50 (MuV), 50% virus neutralization dose measured against the JL mumps virus vaccine strain as well as against the mumps virus outbreak strain (genotype G).
    End point type
    Primary
    End point timeframe
    Baseline, day 0 of MMR-3 immunization Four weeks post MMR-3 immunization (22-36 days) One year post MMR-3 immunization (332-392 days) Three years post MMR-3 immunization (1012-1157 days)
    End point values
    		 Pre-MMR-3 4 weeks post-MMR-3 1 year post-MMR-3 3 years post-MMR-3
    Number of subjects analysed
    147
    147
    134
    119
    Units: RU/mL, ND50, IU/mL, see description
    geometric mean (confidence interval 95%)
        MuV IgG
    186 (163 to 211)
    306 (273 to 343)
    255 (224 to 290)
    228 (200 to 259)
        ND50 to MuV JL strain
    88.8 (72.6 to 109)
    119.3 (99.4 to 143)
    101.8 (84.6 to 123)
    93.8 (76.7 to 115)
        ND50 to MuV G strain
    65.3 (54.0 to 78.9)
    88.4 (74.8 to 104)
    82.8 (70.4 to 97.5)
    82.8 (67.9 to 101)
        MeV IgG
    0.69 (0.59 to 0.80)
    1.23 (1.10 to 1.38)
    1.04 (0.92 to 1.17)
    0.87 (0.76 to 1.00)
        RuV IgG
    36.7 (32.4 to 41.6)
    111 (100 to 122)
    64.8 (58.1 to 72.5)
    49.0 (43.6 to 55.2)
    Attachments
    		 Figure 3_35062794
    Statistical analysis title
    		 MuV IgG pre- versus 4 weeks post-MMR-3
    Statistical analysis description
    IgG antibody levels to mumps virus prior to and after a third measles-mumps-rubella vaccine dose. Geometric mean IgG concentrations, with 95% confidence interval. Differences in antibody levels between time points were analyzed with two-tailed Wilcoxon matched-pairs signed-rank test. Observed significant differences were in line with the results of the model fit. Subjects in this analysis = 147, with each 2 time points for comparison.
    Comparison groups
    Pre-MMR-3 v 4 weeks post-MMR-3
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 MuV FRNT JL strain pre- versus 4 weeks post-MMR-3
    Statistical analysis description
    Virus neutralizing antibody levels to mumps virus JL strain prior to and after a third measles-mumps-rubella vaccine dose. ND50 titers, with 95% confidence interval. Differences in antibody levels between time points were analyzed with two-tailed Wilcoxon matched-pairs signed-rank test. Observed significant differences were in line with the results of the model fit. Subjects in this analysis = 147, with each 2 time points for comparison.
    Comparison groups
    4 weeks post-MMR-3 v Pre-MMR-3
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 MuV FRNT G strain pre- versus 4 weeks post-MMR-3
    Statistical analysis description
    Virus neutralizing antibody levels to mumps virus G strain prior to and after a third measles-mumps-rubella vaccine dose. ND50 titers, with 95% confidence interval. Differences in antibody levels between time points were analyzed with two-tailed Wilcoxon matched-pairs signed-rank test. Observed significant differences were in line with the results of the model fit. Subjects in this analysis = 147, with each 2 time points for comparison.
    Comparison groups
    Pre-MMR-3 v 4 weeks post-MMR-3
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 MeV IgG pre- versus 4 weeks post-MMR-3
    Statistical analysis description
    IgG concentrations to measles virus prior to and after a third measles-mumps-rubella vaccine dose. Geometric mean IgG concentrations, with 95% confidence interval. Differences in antibody levels between time points were analyzed with two-tailed Wilcoxon matched-pairs signed-rank test. Observed significant differences were in line with the results of the model fit. Subjects in this analysis = 147, with each 2 time points for comparison.
    Comparison groups
    Pre-MMR-3 v 4 weeks post-MMR-3
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval
    Statistical analysis title
    		 RuV IgG pre- versus 4 weeks post-MMR-3
    Statistical analysis description
    IgG concentrations to rubella virus prior to and after a third measles-mumps-rubella vaccine dose. Geometric mean IgG concentrations, with 95% confidence interval. Differences in antibody levels between time points were analyzed with two-tailed Wilcoxon matched-pairs signed-rank test. Observed significant differences were in line with the results of the model fit. Subjects in this analysis = 147, with each 2 time points for comparison.
    Comparison groups
    Pre-MMR-3 v 4 weeks post-MMR-3
    Number of subjects included in analysis
    294
    Analysis specification
    Pre-specified
    Analysis type
    		 other
    P-value
    		 < 0.05
    Method
    		 Wilcoxon (Mann-Whitney)
    Confidence interval

    Secondary: Adverse Events (AEs) recorded in subjects diaries following receipt of MMR-3

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    End point title
    		 Adverse Events (AEs) recorded in subjects diaries following receipt of MMR-3
    End point description
    MedDRA version 26.0. Assessed solicited local symptoms were: Vaccination site reaction (= any occurrence of the symptoms), Vaccination site pain, Vaccination site erythema and Vaccination site swelling (all cases were <20 mm). Regardless of intensity grade. Assessed systemic symptoms were: Post vaccination systemic reaction (= any systemic reaction), Post vaccination fever*, Rash (any rash, not further specified), Salivary gland enlargement, Arthralgia and Myalgia. *defined as body temperature of 38 degrees Celsius or higher. No cases >39.5 degrees Celsius were reported. Number of subjects evaluated: Local symptoms, N=121 Overall, N=71 Female, N=50 Male Systemic symptoms, N=101 Overall, N=60 Female, N=41 Male
    End point type
    Secondary
    End point timeframe
    Local, AEs recorded d 0-3 after MMR-3 receipt. Systemic, AEs recorded d 0-28 after MMR-3 receipt.
    End point values
    		 MMR-3 immunization
    Number of subjects analysed
    121 [1]
    Units: NA
        Vaccination site reaction
    21
        Vaccination site pain
    15
        Vaccination site erythema
    8
        Vaccination site swelling
    6
        Post vaccination systemic reaction
    33
        Post vaccination fever
    4
        Rash
    3
        Arthralgia and myalgia
    16
        Salivary gland enlargement
    18
    Attachments
    		 Local and systemic reaction by gender
    Notes
    [1] - "Local: N=121 Overall, N=71 Female, N=50 Male Systemic: N=101 Overall, N=60 Female, N=41 Male"
    No statistical analyses for this end point

    Secondary: Anti-mumps serum antibody levels, 10 days post MMR-3

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    End point title
    		 Anti-mumps serum antibody levels, 10 days post MMR-3
    End point description
    Serum from fingerprick blood. The amount of serum was low. GMC's were not measured, FRNT to MuV JL strain was measured and remaining serum was used for FRNT to MuV G strain.
    End point type
    Secondary
    End point timeframe
    Ten days post MMR-3 immunization (9-15 days days)
    End point values
    		 MMR-3 immunization
    Number of subjects analysed
    123
    Units: ND50
    geometric mean (confidence interval 95%)
        FRNT to MuV JL strain, 10d post-MMR-3, (N=123)
    132.6 (107.1 to 164.1)
        FRNT to MuV G strain, 10d post-MMR-3, (N=73)
    90.76 (67.35 to 122.3)
    No statistical analyses for this end point

    Adverse events

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    Adverse events information
    Timeframe for reporting adverse events
    SAEs and SUSARs < 4 weeks after immunization. AEs occurring directly after immunization (up until day 14). Local and systemic reactions recorded in the diary day 0-14.
    Adverse event reporting additional description
    There were no SAEs and SUSARs. Elective hospital admissions were excluded from SAE reporting.
    Assessment type
    		 Non-systematic
    Dictionary used for adverse event reporting
    Dictionary name
    		 MedDRA
    Dictionary version
    26.0
    Reporting groups
    Reporting group title
    MMR-3 immunization
    Reporting group description
    		 AE's were recorded of N=147 participants when spontaneously reported to the study team. The diary entries were not complete. N=121, D1-4 complete (local reactions). N=101, D1-14 complete (systemic reactions).

    Serious adverse events
    		 MMR-3 immunization
    Total subjects affected by serious adverse events
         subjects affected / exposed
    0 / 147 (0.00%)
         number of deaths (all causes)
    0
         number of deaths resulting from adverse events
    0
    Frequency threshold for reporting non-serious adverse events: 1%
    Non-serious adverse events
    		 MMR-3 immunization
    Total subjects affected by non serious adverse events
         subjects affected / exposed
    59 / 147 (40.14%)
    Injury, poisoning and procedural complications
    Post vaccination fever
         subjects affected / exposed
    4 / 147 (2.72%)
         occurrences all number
    4
    General disorders and administration site conditions
    Malaise
         subjects affected / exposed
    6 / 147 (4.08%)
         occurrences all number
    6
    Vaccination site erythema
         subjects affected / exposed
    8 / 147 (5.44%)
         occurrences all number
    8
    Vaccination site haematoma
         subjects affected / exposed
    6 / 147 (4.08%)
         occurrences all number
    6
    Vaccination site pain
         subjects affected / exposed
    15 / 147 (10.20%)
         occurrences all number
    15
    Vaccination site swelling
         subjects affected / exposed
    6 / 147 (4.08%)
         occurrences all number
    6
    Vessel puncture site haematoma
         subjects affected / exposed
    5 / 147 (3.40%)
         occurrences all number
    5
    Gastrointestinal disorders
    Salivary gland enlargement
         subjects affected / exposed
    18 / 147 (12.24%)
         occurrences all number
    18
    Skin and subcutaneous tissue disorders
    Rash
         subjects affected / exposed
    3 / 147 (2.04%)
         occurrences all number
    3
    Musculoskeletal and connective tissue disorders
    Arthralgia
         subjects affected / exposed
    5 / 147 (3.40%)
         occurrences all number
    5
    Myalgia
         subjects affected / exposed
    16 / 147 (10.88%)
         occurrences all number
    16

    More information

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    Substantial protocol amendments (globally)
    Were there any global substantial amendments to the protocol? Yes
    Date
    Amendment
    11 Jul 2019
    Extension of the follow-up period from 1 year to 3 years after vaccination. An extra blood sample (by fingerprick) will be taken 3 years after MMR-3 vaccine receipt, to provide information on the duration of protection to mumps virus infection following vaccination.

    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.
    No results: Mumps, Measles and Rubella IgG antibody concentrations and avidity measured at day 10 following MMR-3 (not enough serum in the fingerprick samples). Mumps IgG and IgA antibody concentrations in saliva (too low/undetectable).

    Online references
    http://www.ncbi.nlm.nih.gov/pubmed/31112277
    http://www.ncbi.nlm.nih.gov/pubmed/33269296
    http://www.ncbi.nlm.nih.gov/pubmed/34211021
    http://www.ncbi.nlm.nih.gov/pubmed/35062794
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