A cluster-randomised, non-inferiority trial of the impact of a two-dose compared to three-dose schedule of pneumococcal conjugate vaccination in rural Gambia: the PVS trial

Abstract

Background Pneumococcal conjugate vaccines (PCV) effectively prevent pneumococcal disease but the global impact of pneumococcal vaccination is hampered by the cost of PCV. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where PCV has been introduced with good disease control but where transmission of vaccine-type pneumococci persists. We are conducting a large cluster-randomised, non-inferiority, field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. Methods PVS is a prospective, cluster-randomised, non-inferiority, real-world field trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. the alternative ‘1 + 1’ schedule) compared to the standard schedule of three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. the standard ‘3 + 0’ schedule). The intervention will be delivered for 4 years. The primary endpoint is the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in children aged 2 weeks to 59 months with clinical pneumonia in year 4 of the trial. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoint will be masked. Sixty-eight geographic population clusters have been randomly allocated, in a 1:1 ratio, to each schedule and all resident infants are eligible for enrolment. All resident children less than 5 years of age are under continuous surveillance for clinical safety endpoints measured at 11 health facilities; invasive pneumococcal disease, radiological pneumonia, clinical pneumonia, and hospitalisations. Secondary endpoints include the population-level prevalence of nasopharyngeal vaccine-type pneumococcal carriage in years 2 and 4 and vaccine-type carriage prevalence in unimmunised infants aged 6–12 weeks in year 4. The trial includes components of mathematical modelling, health economics, and health systems research. Discussion Analysis will account for potential non-independence of measurements by cluster, comparing the population-level impact of the two schedules with interpretation at the individual level. The non-inferiority margin is informed by the ‘acceptable loss of effect’ of the alternative compared to the standard schedule. The secondary endpoints will provide substantial evidence to support the interpretation of the primary endpoint. PVS will evaluate the effect of transition from a standard 3+ 0 schedule to an alternative 1 + 1 schedule in a setting of high pneumococcal transmission. The results of PVS will inform global decision-making concerning the use of reduced-dose PCV schedules. Trial registration International Standard Randomised Controlled Trial Number 15056916. Registered on 15 November 2018.

Sustained impact of 10-valent pneumococcal conjugate vaccine on invasive pneumococcal disease in Kenya, 2011-2022

“…The low incidence of VT-IPD suggests minimal risk for a switch to a reduced dose schedule in Kenya, though this will be informed by emerging evidence on reduced dose PCV trials in settings such as The Gambia. 45 The NVT-IPD serotype distribution suggests that new-generation PCVs have the potential to enhance IPD control among children and adults. In late 2022, Kenya transitioned to use of the 10-valent Pneumosil™, which differs from Synflorix™ by two serotypes; Pneumosil™ includes serotypes 6A and 19A in place of serotypes 4 and 18C.…”

Pneumococcal vaccine schedules (PVS) study: a cluster-randomised, non-inferiority trial of an alternative versus standard schedule for pneumococcal conjugate vaccination—statistical analysis plan

“…The details of case ascertainment are found in the supplementary material and published protocol [ 5 ].…”

“…Unsolicited reactogenicity events within 7 days of a dose of PCV recorded at EPI clinics will be reported in each group [ 5 ]. Severe adverse reactions to doses of PCV will be reported for each group, specifically episodes of anaphylaxis and severe local reactions.…”

“…This statistical analysis plan follows the reporting guidelines described by Rodriguez et al [ 1 ] and the UK Clinical Research Collaboration Registered Clinical Trial Unit Statisticians’ Operational Group [ 2 ], as well as CONSORT guidelines for reporting cluster-randomised [ 3 ] and non-inferiority [ 4 ] trials. The trial protocol is available on the Trials website [ 5 ].…”

Impact of the COVID-19 pandemic on the coverage and timeliness of routine childhood vaccinations in the Gambia, 2015–2021

“…For children born in BHDSS from September 2019 until December 2021, timely Penta1 was considered as vaccination between 6 and 10 weeks of age (42–70 days). This modified definition for Penta1 in BHDSS was adopted due to the ongoing prospective, cluster-randomised, non-inferiority field trial of an alternative schedule for one dose of pneumococcal conjugate vaccines in this area from September 2019 39. This trial, conducted in collaboration between the MRC Unit The Gambia at LSHTM and the Gambian Ministry of Health, administers Penta1 at 6 weeks instead of the usual 2 months.…”