Clinical trial NCT04078997: An Evaluation of PCV13 Vaccine Schedules, Comparing Impact of 2+1 vs 3+0 on Pneumococcal Carriage in Blantyre, Malawi
Official title: Pneumococcal Conjugate Vaccine 13 (PCV13) Schedule Change From 3+0 to 2+1 to Accelerate Reduction in Pneumococcal Vaccine Serotype Carriage in Blantyre, Malawi: an Effectiveness Study
Study type: OBSERVATIONAL
Overall status: RECRUITING
Conditions: 13-valent Pneumococcal Vaccine
Streptococcus Pneumoniae
Keywords: Pneumococcal carriage
Pneumococcal conjugate vaccine
Vaccine schedule
Evaluation
Children
Herd immunity
Malawi
Lead sponsor: University of Liverpool
Sponsor class: OTHER
Collaborators: name: Malawi-Liverpool-Wellcome Trust Clinical Research Programme
name: Ministry of Health, Malawi
name: Blantyre District Health Office
name: UNICEF
name: World Health Organization
name: University College, London
name: Liverpool School of Tropical Medicine
First posted: 2019-09-06
Enrollment: 5900
Sex: ALL
Minimum age (years): 15
Maximum age (years): 40
Standard ages: CHILD
ADULT
Accepts healthy volunteers: yes
Observational model: ECOLOGIC_OR_COMMUNITY
Time perspective: CROSS_SECTIONAL
Sampling method: PROBABILITY_SAMPLE
Study population: PCV13-vaccinated,15-24 months of age: Recruitment at randomly selected households within each of the catchment areas (zones) of the 20 selected health centers.

PCV13-vaccinated, 9 months of age: Recruitment will take place at MoH EPI vaccination centers.

PCV13-vaccinated, 5-10 years of age: Recruitment from six selected six schools: three located centrally in each of the 3+0 zones, and three in the 2+1 zones.

PCV13-unvaccinated HIV-infected adults on ART 18 - 40 years old: Recruitment from the Queen Elizabeth Central Hospital (QECH), Lighthouse ART clinic in Blantyre.

Brief summary: Pneumococcal conjugate vaccines (PCV) have been shown to be effective against invasive pneumococcal disease (IPD; including pneumococcal meningitis and sepsis) and all-cause mortality among young children when introduced into infant expanded programs on immunization (EPI). Colonization of the nasopharynx by Streptococcus pneumoniae is a necessary prerequisite to pneumococcal disease. Critically important to the population impact of PCV is therefore reducing vaccine serotype (VT) carriage prevalence, and therefore reducing both disease and onward transmission to vulnerable individuals. Thus, as well as protecting the vaccinated individual (direct protection), PCV confers indirect protection (herd immunity) to unvaccinated populations and to vaccinated individuals who have insufficient protective immunity.

While the ability of PCVs to induce herd immunity has been strong enough to control pneumococcal carriage in industrialized countries, such benefits have not been as marked in low-income countries. Carriage surveillance in Blantyre, Malawi from 4 to 7 years post-vaccine implementation shows persistent VT carriage. With the exception of South Africa, most sub-Saharan African countries, including Malawi, have introduced PCV using a 3+0 schedule. Whether the WHO-approved 2+1 schedule will maximize vaccine-induced protection has been identified as a research gap by the WHO. In this context, the Malawian Ministry of Health (MoH) and the National Immunizations Technical Advisory Committee (NITAG) are seeking evidence of adequate superiority of a 2+1 schedule to inform a change to the current Malawi EPI schedule.

HYPOTHESIS: Prolonging the period of vaccine-induced protection with a booster vaccine dose at 9 months will extend the period of low VT carriage, hence providing longer direct vaccine-induced protection as well as boosting the indirect herd immunity effect.

METHOD: The MoH will implement an evaluation, comparing a 2+1 to the current 3+0 PCV13 vaccine schedule in Blantyre District. This will use a pragmatic health centre-based randomization protocol, implemented within the scope of the EPI programme. This MoH-led change will be evaluated in partnership with the Malawi Liverpool Wellcome Trust Clinical Research Programme. Community carriage surveillance will be undertaken at 15 and 33 months after the introduction of the 2+1 schedule.

The primary endpoint will be VT carriage prevalence among children 15-24 months of age 36 months after schedule change. Other targeted study groups will include children aged 5-10 years who have received PCV13 on a 3+0 schedule, children aged 9 months who have received PCV13 in either a 3+0 or a 2+0 schedule, and HIV-infected adults aged 18-40 years receiving ART and PCV13-unvaccinated.

EXPECTED FINDINGS: Data will inform NITAG decisions on national vaccine policy, with implications at a national, regional and global level.

Detailed description: STUDY TYPE: Pragmatic health center-based evaluation to compare effectiveness of a MoH-mandated structured PCV13 schedule change from 3+0 to 2+1 dosing in a high disease burden setting in Malawi PROBLEM: Streptococcus pneumoniae is a leading cause of childhood pneumonia, meningitis, and bacteremia in sub-Saharan Africa. Pneumococcal conjugate vaccines (PCV) the commonest pneumococcal serotypes have been shown to be effective against pneumococcal meningitis and sepsis, so-called invasive pneumococcal disease (IPD), pneumonia, and all-cause mortality among young children when introduced into infant expanded programs on immunization (EPI). Colonization of the nasopharynx by Streptococcus pneumoniae is a necessary prerequisite to pneumococcal disease. Critically important to the population impact of PCV is therefore reducing vaccine serotype (VT) carriage prevalence, and therefore reducing both disease and onward transmission to vulnerable individuals. Thus, as well as protecting the vaccinated individual (direct protection), PCV confers indirect protection (herd immunity) to unvaccinated populations and to vaccinated individuals who have insufficient protective immunity.

While the ability of PCVs to induce herd immunity has been strong enough to control pneumococcal carriage and disease in industrialized countries, such benefits have not been as marked in low-income countries. In Malawi, the introduction of the PCV13 achieved an approximate 70% reduction in IPD among vaccinated children, and an estimated 35% fall in all-cause mortality among vaccinated children. However, carriage surveillance 4 to 7 years post-vaccine implementation shows persistent VT carriage. Data suggests that most of the vaccine's direct benefit occurs in the first 12 months of life, further suggesting that vaccine-induced protection against pneumococcal disease and colonization wanes rapidly under the current 3+0 schedule. With the exception of South Africa, most sub-Saharan African countries, including Malawi, have introduced PCV using a 3+0 schedule (doses at 6, 10, and 14 weeks of age). Whether the 2+1 schedule (6, 10 weeks and 9 months of age) will maximize vaccine-induced protection has been identified as a research gap by the WHO. There is a dearth of head-to-head studies directly comparing these two schedules. In this context, the Malawian Ministry of Health (MoH) and the National Immunizations Technical Advisory Committee (NITAG) are seeking evidence of adequate superiority of a 2+1 schedule to inform a change to the current Malawi EPI schedule.

HYPOTHESIS: Prolonging the period of vaccine-induced protection with a booster vaccine dose at 9 months will extend the period of low VT carriage, hence providing longer direct vaccine-induced protection as well as boosting the indirect herd immunity effect.

METHOD: The MoH will implement a 2+1 PCV13 vaccine schedule change in Blantyre District. A comparison with the ongoing 3+0 schedule will use a pragmatic health centre-based randomization protocol, with 10 centres continuing with the current 3+0 and 10 implementing the WHO-approved 2+1 schedule. This change will be implemented within the scope of the EPI, subjected to EPI standard procedures for delivery, monitoring, and assessment. This MoH-led change will be evaluated as part of a longstanding partnership with the Malawi Liverpool Wellcome Trust Clinical Research Programme. Researchers will undertake two population based pneumococcal carriage surveys in these 20 health centre catchment areas, at 15 and 33 months after the introduction of the 2+1 schedule.

PRIMARY OUTCOME: VT carriage prevalence among children 15-24 months of age 36 months after schedule change.

SECONDARY OUTCOMES: VT carriage prevalence among children 5-10 years old, among HIV infected adults 18-40 years, add among children 9 months old. Others include prevalence of multiple serotype carriage, and completeness of 3 doses PCV13.

POPULATION: Children who are aged 15-24 months, residents of Blantyre District, and who have received PCV13 in either a 3+0 or a 2+1 schedule (recruited from households); Children aged 5-10 years who have received PCV13 on a 3+0 schedule (recruited from schools); children aged 9 months, who have received PCV13 in either a 3+0 or a 2+0 schedule (recruited from health centres at routine 9-month visit); HIV-infected adults aged 18-40 years receiving ART and PCV13-unvaccinated (recruited from the Queen Elizabeth Central Hospital (QECH) HIV/ART Clinic) EXPECTED FINDINGS: Data will inform NITAG decisions on national vaccine policy, with implications at a national, regional and global level. Results will be disseminated through peer-reviewed publications, scientific conferences, and other relevant stakeholder and policymakers' meetings. This work will strengthen collaboration between relevant government and academic institutions, provide research training for MoH staff and early-career researchers.

Eligibility criteria: INCLUSION CRITERIA

PCV13-vaccinated children, 15-24 months of age (schedule 2+1 or 3+1):

* Aged between 15-24 month
* Permanent resident in Blantyre District
* Parent/legal guardian consent for the child to have a NP swab taken
* Evidence of having received a full schedule of PCV13 vaccination recorded in the health passport and which schedule given

PCV13-vaccinated children, 9 months of age (schedule 2+0 or 3+0):

* Aged 9 months
* Permanent resident in Blantyre District
* Parent/legal guardian consent for the child to have a NP swab taken
* Evidence of having received either a full 3+0 schedule or both primary doses (at approximately 6 and 14 weeks of age) of the 2+1 schedule of PCV13 vaccination recorded in the health passport

PCV13-vaccinated children, 5-10 years of age (schedule 3+0):

* Aged between 5-10 years
* Parent/legal guardian consent for the child to have a NP swab taken
* If the child is ≥8 years old, child assent to have a NP swab taken
* Either verbal or documented evidence of having received primary immunization with PCV

PCV13-unvaccinated HIV-infected adults on ART 18 - 40 years of age:

• Aged 18-40 years

EXCLUSION CRITERIA:

For all participants:

* Current TB treatment
* Pneumonia hospitalization \<14 days before study enrolment
* Terminal illness

For Children:

* No parental/legal guardian consent
* No child assent (children aged \>8 years old)
* Having received antibiotic treatment \<14 days before study enrolment

For Adults:

* Unable or unwilling to provide consent
* Prior vaccination with pneumococcal vaccine

Primary outcomes:
measure: Vaccine-type pneumococcal carriage prevalence among children 15-24 months old
timeFrame: 36 months after 2+1 vaccine schedule implementation
Secondary outcomes:
measure: Vaccine-type pneumococcal carriage prevalence among children 5-10 years old
timeFrame: 36 months after 2+1 vaccine schedule implementation
measure: Vaccine-type pneumococcal carriage prevalence among HIV infected adults 18-40 years old
timeFrame: 36 months after 2+1 vaccine schedule implementation
measure: Vaccine-type pneumococcal carriage prevalence among children 9 months old
timeFrame: 9 months after 2+1 vaccine schedule implementation
measure: Prevalence of multiple pneumococcal serotype carriage
timeFrame: 36 months after 2+1 vaccine schedule implementation
measure: Proportion of children receiving a full 3-dose PCV13 vaccination schedule
timeFrame: 36 months after 2+1 vaccine schedule implementation
Other outcomes:
Locations:
city: Blantyre
country: Malawi
facility: Malawi-Liverpool-Wellcome Research Programme
state: Chichiri
Study officials:
affiliation: University College, London
name: Robert Heyderman, PhD
role: PRINCIPAL_INVESTIGATOR
affiliation: Malawi-Liverpool-Wellcome Trust Clinical Research Programme
name: Stephen Gordon, PhD
role: STUDY_CHAIR
References:
citation: Swarthout TD, Ibarz-Pavon A, Kawalazira G, Sinjani G, Chirombo J, Gori A, Chalusa P, Bonomali F, Nyirenda R, Bulla E, Brown C, Msefula J, Banda M, Kachala J, Mwansambo C, Henrion MY, Gordon SB, French N, Heyderman RS. A pragmatic health centre-based evaluation comparing the effectiveness of a PCV13 schedule change from 3+0 to 2+1 in a high pneumococcal carriage and disease burden setting in Malawi: a study protocol. BMJ Open. 2021 Jun 17;11(6):e050312. doi: 10.1136/bmjopen-2021-050312.