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Trial registered on ANZCTR

Registration number

ACTRN12623001320640p

Ethics application status

Submitted, not yet approved

Date submitted

23/06/2023

Date registered

15/12/2023

Date last updated

15/12/2023

Date data sharing statement initially provided

15/12/2023

Type of registration

Prospectively registered

Titles & IDs

Public title

Effect of Inactivated Poliovirus Vaccine (IPV) on Mucosal Immunity: A Randomized, Controlled Trial in Cuba

Scientific title

Impact of IPV on mucosal immunity: A randomized controlled trial comparing nasopharyngeal and intestinal poliovirus shedding after bOPV challenge in IPV recipients with those not receiving IPV

Secondary ID [1]

None

Universal Trial Number (UTN)

Trial acronym

Linked study record

Health condition

Health condition(s) or problem(s) studied:

Poliomyelitis

Condition category

Condition code

Infection

Other infectious diseases

Intervention/exposure

Study type

Interventional

Description of intervention(s) / exposure

This is a two-armed study with an interventional (A) and a control arm (B). The intervention arm A will receive one full dose of Inactivated Poliovirus Vaccine (IPV) administered via intramuscular injection.
- IPV contents: 40 D antigen units of Type 1, 8 D antigen units of Type 2, and 32 D antigen units of Type 3 poliovirus.
- IPV Dose: 0.5 mL (full dose)
- Who will administer: local medical clinic nurse
- Where: at the local medical clinic
- When: between 6-8 months of age

All participants will receive the usual polio vaccines administered via routine immunization and national immunization days in Cuba (i.e., fractional-dose IPV administered intradermally at 4 and 8 months, one dose of bivalent oral poliovirus vaccine (bOPV) in the national immunization days). However, as a result of this study, administration of the second dose of fIPV will be delayed by 1 month.
- fIPV contents: IPV contents: 40 D antigen units of Type 1, 8 D antigen units of Type 2, and 32 D antigen units of Type 3 poliovirus.
- fIPV Dose: 0.1 mL (fractional dose)

Intervention code [1]

Treatment: Drugs

Comparator / control treatment

Control group receives no dose of inactivated poliovirus vaccine (IPV).

Participants in the control group will receive no intervention during the study. They will receive the usual polio vaccines administered via routine immunization and national immunization days in Cuba (i.e., fractional-dose IPV administered intradermally at 4 and 8 months, one dose of bOPV in the national immunization days). However, as a result of this study administration the second dose of fIPV will be delayed by 1 month.
- fIPV contents: IPV contents: 40 D antigen units of Type 1, 8 D antigen units of Type 2, and 32 D antigen units of Type 3 poliovirus.
- fIPV Dose: 0.1 mL (fractional dose)

Control group

Active

Outcomes

Primary outcome [1]

Difference in proportion (expressed as percentage) of nasopharyngeal shedding of poliovirus serotypes 1 and 3 (as a composite outcome) between arms A (interventional: full dose IPV) and B (control: no IPV). This data is generated through a cotton nasal/oral swab and analyzed via PCR.

Timepoint [1]

at 7- and 28-days post bOPV (1 month and 1 week post intervention, and 2 months post intervention).

Primary outcome [2]

Difference in proportion (expressed as percentage) of mucosal shedding of poliovirus serotypes 1 and 3 (as a composite outcome) between arms A (interventional: full dose IPV) and B (control: no IPV). This data is generated through a stool sample and analyzed via viral isolation in cell cultures (L20B and RD).

Timepoint [2]

at 7- and 28-days post bOPV (1 month and 1 week post intervention, and 2 months post intervention).

Secondary outcome [1]

Seroconversion for all three serotypes (as a composite outcome) in Arm A (Internventional: full dose IPV) and Arm B (control: no IPV). Participant data is collected as blood sample.

Timepoint [1]

4 and 8 weeks after interventional administration. 4 weeks after bOPV (2 months after intervention)

Secondary outcome [2]

Seroprevalence at the final visit of all three serotypes (as a composite outcome) by study arm. Seropositivity defined as log2 antibody titres >3. Participant data is collected as blood sample.

Timepoint [2]

8 weeks after enrollment (IPV administration in Arm A)

Secondary outcome [3]

Median titers of all three serotypes by study arm (as a composite outcome). Participant data is collected as blood sample.

Timepoint [3]

4 and 8 weeks after enrollment (Arm A IPV administration at enrollment, bOPV challenge 1 month after enrollment).

Eligibility

Key inclusion criteria

1. Healthy infants born June-August 2023 (i.e, 6-8 months of age at time of enrolment in February 2024) residing in Camaguey province of Cuba
2. Over the 3rd percentile for height and weight
3. Resident of the study locality for more than or at least 5 months, with no plans to move
4. Previously received one dose of fIPV in primary series at 4 months of age
5. Parent/guardian consent for participation in the study and for samples collection

Minimum age

6 Months

Maximum age

8 Months

Sex

Both males and females

Can healthy volunteers participate?

Yes

Key exclusion criteria

1. Infant not fulfilling inclusion criteria
2. Contraindication for venepuncture
3. Having received bOPV or 2nd fIPV dose before enrolment
4. Acutely sick child or child requiring hospitalization. These children will be referred to the nearest medical facility equipped to handle the case at their own expense.
5. Diagnosis or suspicion in the subject or an immediate family member of congenital medical conditions (e.g., Down Syndrome); primary immunodeficiency disorder; chronic medical illness (e.g., renal, cardiac)
6. Infants of mothers below the legal age (<18 years) or with mental incapacity will not be eligible to participate.

Study design

Purpose of the study

Prevention

Allocation to intervention

Randomised controlled trial

Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)

"Allocation is not concealed"

Methods used to generate the sequence in which subjects will be randomised (sequence generation)

Permuted block randomization of sizes 2, 4 and 6 will be applied to produce the random sequence. The random sequence with serial number will be handed to the principal investigator. The parent or the study investigator had no discretion to opt for a particular study arm. The randomly allocated sequence will be handed over to the vaccine administrator who will check the sequence and administer the study vaccine as mentioned in the sequence.

Masking / blinding

Open (masking not used)

Who is / are masked / blinded?

Intervention assignment

Other design features

This study is open-labeled because the participants and the study investigators are not masked to the vaccines administered. However, the laboratory investigators at the PKI, who will be the outcome assessors, will be masked to the study arm allocation.

Phase

Not Applicable

Type of endpoint/s

Statistical methods / analysis

Recruitment

Recruitment status

Not yet recruiting

Date of first participant enrolment

Anticipated

8/01/2024

Actual

Date of last participant enrolment

Anticipated

Actual

Date of last data collection

Anticipated

Actual

Sample size

Target

400

Accrual to date

Final

Recruitment outside Australia

Country [1]

Cuba

State/province [1]

Camagüey Province

Funding & Sponsors

Funding source category [1]

Government body

Name [1]

World Health Organization

Address [1]

WHO Headquarters
Avenue Appia 20
1211
Geneva 27

Country [1]

Switzerland

Funding source category [2]

Government body

Name [2]

Ministry of Health, Cuba

Address [2]

4JR9+68J, La Habana, Cuba

Country [2]

Cuba

Primary sponsor type

Government body

Name

World Health Organization

Address

WHO Headquarters
Avenue Appia 20
1211
Geneva 27

Country

Switzerland

Secondary sponsor category [1]

Other Collaborative groups

Name [1]

Pedro Kouri Institute

Address [1]

Autopista Novia del Mediodía, KM 6 1/2, La Lisa, La Habana, 11400,

Country [1]

Cuba

Ethics approval

Ethics application status

Submitted, not yet approved

Ethics committee name [1]

Research Ethics Review Committee (WHO ERC)

Ethics committee address [1]

Av. Appia 20, 1202 Genève, Switzerland

Ethics committee country [1]

Switzerland

Date submitted for ethics approval [1]

12/05/2023

Approval date [1]

Ethics approval number [1]

Ethics committee name [2]

CEI-IPK

Ethics committee address [2]

2GPF+66V, La Habana, Cuba

Ethics committee country [2]

Cuba

Date submitted for ethics approval [2]

17/04/2023

Approval date [2]

Ethics approval number [2]

Summary

Brief summary

The current World Health Organization (WHO) outbreak response guidelines recommend use of oral poliovirus vaccines (OPVs) to interrupt transmission of poliovirus outbreaks  due to their ability to induce intestinal mucosal immunity. However, countries that exclusively use inactivated poliovirus vaccine (IPV) in their immunization schedules may be reluctant to reintroduction of OPV as it poses hurdles in both regulatory aspects and carries risk of seeding of vaccine-derived polioviruses (VDPVs). Additionally, the use of exclusive IPV was able to eliminate wild poliovirus in settings with higher sanitation and hygiene levels where oral-oral transmission dominates, likely through the induction of nasopharyngeal immunity.  

There is a limited number of studies that analyse nasopharyngeal mucosal immunity related to IPV: 4 interventional studies and 1 observational study during an outbreak in the USA. Furthermore, the studies have many limitations including undetectable virus in nasopharyngeal washings, interference with natural exposure to poliovirus and small sample sizes. Following a literature review conducted on the impact of IPV on mucosal immunity, the SAGE Polio Working Group recommended that a clinical trial is conducted to generate evidence on the impact of IPV on nasopharyngeal shedding, which can inform policy on the use of IPV-only outbreak responses in settings where oral-oral transmission dominates. 

Cuba provides a unique setting in which to evaluate the serological immunity because of the absence of wild polioviruses since 1962 and its unique strategy for administering OPV in annual campaigns.  Poliomyelitis was eliminated from Cuba in the early 1960s.  Since then, OPV has been administered to children through biannual NIDs.  Each NID round lasts approximately one week during February and May, targeting all children aged greater than one month and less than 3 years with two doses of bOPV.  OPV is not available at any other time of the year. In addition, previous studies in Cuba have shown that the attenuated Sabin virus contained in OPV disappears rapidly from the population after the second round of NIDs.  For these reasons, the potential for “contamination” of the study arms by circulating OPV-like strains is minimized if not eliminated.

Cuba was selected as study country because it is the only country in the world that satisfies two conditions: 1) OPV is administered exclusively in annual campaigns (leaving approximately 7 months of OPV-free environment) and 2) IPV is administered at 14 weeks of age but may be delayed up to 4 months of age. This fits well with the design of the study which seeks to understand viral shedding after poliovirus exposure (through an OPV challenge dose) in IPV-vaccinated children. Cuba is using fractional IPV administered intradermally at 4 and 8 months of age in their routine immunisation (RI) program.

Trial website

Trial related presentations / publications

Public notes

Contacts

Principal investigator

Name

Prof Sonia Resik

Address

Tropical Medicine Institute Pedro Kourí
2GPF+66V, La Habana, Cuba

Country

Cuba

Phone

+537 2553550

Fax

sresik@ipk.sld.cu

Contact person for public queries

Name

Sonia Resik

Address

Tropical Medicine Institute Pedro Kourí
2GPF+66V, La Habana, Cuba

Country

Cuba

Phone

+537 2553550

Fax

sresik@ipk.sld.cu

Contact person for scientific queries

Name

Sonia Resik

Address

Tropical Medicine Institute Pedro Kourí
2GPF+66V, La Habana, Cuba

Country

Cuba

Phone

+537 2553550

Fax

sresik@ipk.sld.cu

Data sharing statement

Will individual participant data (IPD) for this trial be available (including data dictionaries)?

Yes

What data in particular will be shared?

All the names and personal information regarding any individual will be kept confidential and data sets will be kept anonymous for analysis. Identifying data will not be used in any publications, reports, or media, in any manner which could identify an individual participant. Individual data of published results only can be made available upon request.

When will data be available (start and end dates)?

After last study follow-ups (estimated May 2024) study data will be available. Data will then be securely stored for 3 years at IPK (estimated end date May 2027) - only accessible by the Principal Investigator, Dr. Sonia Resik.

Available to whom?

individual data of published results only can be made publicly available upon request.

Available for what types of analyses?

Statistical analyses (meta-analyses, seroprevalence, percent shedding, median titres, statistical significance, risk analysis, sociodemographic variables, etc)

How or where can data be obtained?

Data can be made available upon request by emailing the principal investigator Dr. Sonia Resik (sresik@ipk.sld.cu).

What supporting documents are/will be available?

Doc. No.	Type	Email
19527	Study protocol	sresik@ipk.sld.cu
19528	Informed consent form	sresik@ipk.sld.cu
19529	Ethical approval	sresik@ipk.sld.cu
19530	Data dictionary	sresik@ipk.sld.cu

Results publications and other study-related documents

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Trial Review

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