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Trial registered on ANZCTR


Registration number
ACTRN12623000137695
Ethics application status
Approved
Date submitted
30/01/2023
Date registered
9/02/2023
Date last updated
9/02/2023
Date data sharing statement initially provided
9/02/2023
Type of registration
Prospectively registered

Titles & IDs
Public title
Measuring and strengthening immunity to measles in young adults fully immunised in childhood - single arm challenge study
Scientific title
Measuring and strengthening immunity to measles in young adults fully immunised in childhood - single arm challenge study
Secondary ID [1] 308835 0
none
Universal Trial Number (UTN)
Trial acronym
MAXXED MeaslesvAXXroutEsofDelivery
Linked study record
ACTRN12623000130662 is a randomised controlled trial of 3 methods of administration of MMR vaccine to seronegative young adults who received two doses of MMR vaccine in childhood. The challenge study will administer MMR vaccine by aerosol using the vibrating mesh nebuliser as for ACTRN12623000130662. The outcomes of interest are changes in antibody and identification of measles vaccine virus in oral fluid by PCR - both considered potential markers of insufficient immunity to prevent infection

Health condition
Health condition(s) or problem(s) studied:
Waning measles immunity in vaccinated young adults 328794 0
Immune health 328795 0
Condition category
Condition code
Public Health 325804 325804 0 0
Other public health
Inflammatory and Immune System 325805 325805 0 0
Normal development and function of the immune system

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Name
Administration of MMR by nebulised aerosol to seropositive previously vaccinated young adults

Why
This study will examine antibody responses and ability to identify measles vaccine virus in oral fluid in young adults with varying levels of seropositivity as a proxy for likely infection if exposed to wild measles virus.

What
Measles-Mumps-Rubella (MMR) vaccine (Priorix GSK) https://www.medsafe.govt.nz/profs/Datasheet/p/Priorixvac.pdf
will be administered using a vibrating mesh nebuliser manufactured by Aerogen Ltd (Ireland).
The Aerogen ultra nebuliser with solo vibrating mesh will create an aerosol of reconstituted freeze dried measles, mumps and rubella live attenuated virus with the appropriate particle size for inhalation into the lung. The device is light and handheld. Following instructions, the participant will inhale the vaccine mist using the mouthpiece via slow, natural breathing.

Who
Trained registered nurses will administer the MMR vaccine via Aerogen nebuliser. The study nurse will assess appropriate aerosol formation and during administration will monitor for completeness of inhaled dose. This is well within the scope of practice for trained registered nurses and specific training videos are available, supplemented by tailored instructions from the manufacturers.

How
Delivery of 0.3 mL aerosolised MMR vaccine during a face-to-face visit using the device as described above by the staff as described above to consenting eligible participants.

Where
The intervention will be delivered in a clinical setting in two locations - a student health service in Dunedin and a clinical research centre at the University of Auckland, both of which have all the required infrastructure for delivery of vaccines

When and how much
Administration of aerosolized MMR vaccine will occur once with four subsequent study visits for biological sampling, the last at 28-31 days after vaccine administration.

How well
Study nurses will monitor vaccine administration and record whether all visible fluid in the nebuliser chamber has been aerosolised. Measurement of immune responses by antibody assays in serum and detection of measles vaccine virus in oral fluid by PCR will be performed on the biological samples.
Delivery of vaccine and monitoring of adverse reactions by study staff in the two sites .
Intervention code [1] 325279 0
Treatment: Devices
Comparator / control treatment
This single arm challenge study will measure immune responses (Measles IgG antibody by MicroImmune Assay (MIA) and presence of measles vaccine virus in oral fluid by PCR) against baseline antibody measured prior to MMR administration.
Control group
Uncontrolled

Outcomes
Primary outcome [1] 333646 0
Measles antibody will be measured by Micro Immune Assay (MIA) at 4 timepoints after MMR vaccine administration. For measles, a four-fold rise in serum antibody post administration of MMR vaccine by aerosol will be considered likely to indicate a level of immune response consistent with that expected following "take" or infection by the measles vaccine virus.
Timepoint [1] 333646 0
28 days post MMR
Primary outcome [2] 333647 0
Detection of measles vaccine virus by PCR in oral fluid post MMR by aerosol
Timepoint [2] 333647 0
at 3-4, 7 and 14 days post aerosol delivery of MMR
Secondary outcome [1] 417853 0
Any change in serum antibody post MMR aerosol administration
Timepoint [1] 417853 0
3-4, 7 and 14 and 28-42 days post aerosol delivery of MMR

Eligibility
Key inclusion criteria
* Seropositive: Antibody above threshold for positivity of the Diasorin or BioPlex assay (for Dunedin and Auckland diagnostic labs, respectively) for both of measles and mumps antibodies and not required to have a dose of MMR vaccine by University of Otago or University of Auckland Screening and Immunisation Policies
* Capable and willing to give written informed consent
* Residing in Dunedin or Auckland
* Able and willing to participate for the duration of the study visits and follow-up
* Willing to provide verifiable identification at study entry and follow-up visits
* Daily access to an internet-connected device (smart phone, tablet, laptop or PC) and willing to complete an electronic diary post vaccination.
Minimum age
17 Years
Maximum age
50 Years
Sex
Both males and females
Can healthy volunteers participate?
Yes
Key exclusion criteria
Contraindications to MMR as specified in the NZ Immunisation Handbook. These include:
• proven anaphylaxis to the vaccine or vaccine component (eg, neomycin or gelatin)
• significant immunocompromise: impaired cell-mediated immunity, including untreated malignancy, type 1 interferon receptor (IFNAR) signalling pathway defects, immunosuppressive drug therapy, including high-dose steroids, receiving high-dose radiotherapy, HIV infection with severely impaired T cell immunity
• another live vaccine, including Bacillus Calmette-Guérin (BCG), within the previous 4 weeks
• pregnant women – pregnancy should be avoided for four weeks after immunization
• participants pregnant during study participation may complete follow-up.
• intravenous immunoglobulin or blood transfusion during the preceding 11 months

Study design
Purpose of the study
Prevention
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The main statistical analysis is aimed at identifying the pre-vaccine serum antibody (Ab) level that discriminates between subjects who have a 4-fold rise in serum Ab after challenge with aerosolised measles vaccine and those that do not.. After the baseline serology test, participating subjects will have antibody re-measured by microimmune assay (MIA) at RIVM for their pre-vaccine and post-vaccine sample, with the MIA assay results used to construct a receiver operated curve (ROC). We will use the Youden, nearest, and Liu methods, which give different weights to sensitivity and specificity, to calculate maximum area under the curve in order to identify the most appropriate pre-vaccine antibody level for discrimination between responders and non-responders.
Power and sample size:
Over the two years 2022-23, we anticipate that ~ 900 students will be available for recruitment, with 450 in the lowest 50% of measles seropositives from whom we will seek to recruit 100 in year 1 (25 in each of 4 quartiles of the eligible cohort). If a 4-fold increase in
titre is seen in 50% of recruits, for a given selected pre-vaccine threshold as measured by the MIA assay, we need 78 students to estimate an area under the ROC curve of 0.8 with a precision (half width of 95% CI) of 0.1. If the proportion with a 4-fold rise is 75%, this increases to 124 and if it is only 25%, we need 79 recruits. Thus, allowing for 10% dropout, and given our capacity to adjust our analysis plans for year 2 based on year 1 results, 100 students in the first year should provide adequate sample size to meet this aim over the full study period.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
23/02/2023
Actual
Date of last participant enrolment
Anticipated
30/07/2024
Actual
Date of last data collection
Anticipated
26/08/2024
Actual
Sample size
Target
100
Accrual to date
Final
Recruitment outside Australia
Country [1] 25240 0
New Zealand
State/province [1] 25240 0
Otago and Auckland

Funding & Sponsors
Funding source category [1] 313059 0
Government body
Name [1] 313059 0
Health Research Council
Country [1] 313059 0
New Zealand
Primary sponsor type
University
Name
University of Otago
Address
Professor Richard Blaikie
Research and Enterprise
Centre for Innovation
87 St David St
Dunedin 9054
Country
New Zealand
Secondary sponsor category [1] 314747 0
None
Name [1] 314747 0
Address [1] 314747 0
Country [1] 314747 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312311 0
Health and Disability Ethics Committees (HDECs): Northern A
Ethics committee address [1] 312311 0
Ministry of Health
Health and Disability Ethics Committees
133 Molesworth Street
Thorndon
Wellington 6011
Ethics committee country [1] 312311 0
New Zealand
Date submitted for ethics approval [1] 312311 0
02/11/2022
Approval date [1] 312311 0
10/01/2023
Ethics approval number [1] 312311 0
13681

Summary
Brief summary
In settings such as Australia and New Zealand where measles elimination has been achieved for a decade or more due to sustained high MMR vaccine coverage, cases of measles in young adults who have two documented MMR doses in childhood is increasingly being documented in association with waning measles antibody levels.
Because delivery of measles vaccine virus (MVV) by aerosol directly to the respiratory tract mimics the mode of infection for wild measles virus (WMV), as it infects the same lung cells, a challenge study using aerosolised MVV, with well-standardised serological measures pre and post exposure among subjects with a well-defined range of prior antibody levels, is suitable for use in identifying a threshold above which MVV replication sufficient to induce a 4-fold serum antibody rise is not seen, using a receiver operated characteristic (ROC) curve approach.
The study will use aerosolised delivery of a single 0.3 mL dose of Priorix Measles-Mumps_Rubella vaccine (MMR; GSK) to simulate exposure to wild-type measles virus in young adults previously immunised in childhood whose serum measles antibodies are above the currently used antibody threshold for seropositivity to evaluate whether a presumptive correlate of protection can be identified.
The working hypothesis is the aerosolised MMR vaccine will simulate exposure to wild measles virus and our data will allow calculation of accurate thresholds of measles antibody required pre-exposure to protect against measles infection on exposure.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 124202 0
Prof Peter McIntyre
Address 124202 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
3rd Floor Children's Pavilion
201 Great King Street
Dunedin 9016
Country 124202 0
New Zealand
Phone 124202 0
+64212814242
Fax 124202 0
Email 124202 0
peter.mcintyre@otago.ac.nz
Contact person for public queries
Name 124203 0
Prof Peter McIntyre
Address 124203 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
3rd Floor Children's Pavilion
201 Great King Street
Dunedin 9016
Country 124203 0
New Zealand
Phone 124203 0
+64212814242
Fax 124203 0
Email 124203 0
peter.mcintyre@otago.ac.nz
Contact person for scientific queries
Name 124204 0
Prof Peter McIntyre
Address 124204 0
Department of Women's and Children's Health
Dunedin School of Medicine
University of Otago
3rd Floor Children's Pavilion
201 Great King Street
Dunedin 9016
Country 124204 0
New Zealand
Phone 124204 0
+64212814242
Fax 124204 0
Email 124204 0
peter.mcintyre@otago.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This can be re-considered when we have all trial results available


What supporting documents are/will be available?

Doc. No.TypeCitationLinkEmailOther DetailsAttachment
18146Ethical approval    385286-(Uploaded-26-01-2023-17-35-54)-Study-related document.pdf



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
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