a cluster randomised non inferiority trial of the impact of a two dose compared to CORD-Papers-2022-06-02 (Version 1)

Title: 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 612 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. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s13063-021-05964-5.
Published: 2022-01-24
Journal: Trials
DOI: 10.1186/s13063-021-05964-5
DOI_URL: http://doi.org/10.1186/s13063-021-05964-5
Author Name: Mackenzie Grant A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mackenzie_grant_a
Author Name: Osei Isaac
Author link: https://covid19-data.nist.gov/pid/rest/local/author/osei_isaac
Author Name: Salaudeen Rasheed
Author link: https://covid19-data.nist.gov/pid/rest/local/author/salaudeen_rasheed
Author Name: Hossain Ilias
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hossain_ilias
Author Name: Young Benjamin
Author link: https://covid19-data.nist.gov/pid/rest/local/author/young_benjamin
Author Name: Secka Ousman
Author link: https://covid19-data.nist.gov/pid/rest/local/author/secka_ousman
Author Name: DAlessandro Umberto
Author link: https://covid19-data.nist.gov/pid/rest/local/author/dalessandro_umberto
Author Name: Palmu Arto A
Author link: https://covid19-data.nist.gov/pid/rest/local/author/palmu_arto_a
Author Name: Jokinen Jukka
Author link: https://covid19-data.nist.gov/pid/rest/local/author/jokinen_jukka
Author Name: Hinds Jason
Author link: https://covid19-data.nist.gov/pid/rest/local/author/hinds_jason
Author Name: Flasche Stefan
Author link: https://covid19-data.nist.gov/pid/rest/local/author/flasche_stefan
Author Name: Mulholland Kim
Author link: https://covid19-data.nist.gov/pid/rest/local/author/mulholland_kim
Author Name: Nguyen Cattram
Author link: https://covid19-data.nist.gov/pid/rest/local/author/nguyen_cattram
Author Name: Greenwood Brian
Author link: https://covid19-data.nist.gov/pid/rest/local/author/greenwood_brian
sha: 538e7ba2c7a8ef02d9b35ef8ee49752ab40a064c
license: cc-by
license_url: https://creativecommons.org/licenses/by/4.0/
source_x: PMC
source_x_url: https://www.ncbi.nlm.nih.gov/pubmed/
pubmed_id: 35073989
pubmed_id_url: https://www.ncbi.nlm.nih.gov/pubmed/35073989
pmcid: PMC8785014
pmcid_url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785014
url: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8785014/
has_full_text: TRUE
Keywords Extracted from Text Content: infants nasopharyngeal vaccinetype PVS reduced-dose nasopharyngeal vaccine-type children PHP\ASP.Net 9-valent 99,113 specimens human papillomavirus vaccine FWHDSS centre Harmonised Guideline GG/MRC alpha Human papilloma virus vaccine Vaccinators O 2 peripheral Synflorix® GG/ oral polio vaccine COVID-19 lower-chest wall h. St George's Non-typeable isolates free-call Measles-Mumps-Rubella [35] PCV13 vaccines PCV13-severe Fig. 4 SUSAR UK 1 + 1 clusters infants 1, 2, 3 Vaccine Fuladu West Health alpha= Epidemiologist Waroux hepatitis B E6(R2 MSSQL backend database PCV7/13 Plasma nasopharyngeal Front-end × Fig. 3 Children upper serotypes V EC blood individuals peripheral arterial serotype 1 S. pneumoniae SAEs non-vaccine type ISCTRN polio vaccine 3-5-year-olds AVPU Gambisara SCC Measles-Mumps-Rubella-Varicella [36] vaccines blood cultures Upper c NP carriage of VT mother Patients NVT pneumococcal CRF father thumbprints measles vaccine PCV13 [18 Serum NP specimen rotavirus SUSARs Bank 'low-income' DMC Blood SUSARS SADRs Tostan measlesrubella micrococcus OPV measles serotypes 1 PCV13 BCG PI bile NVT serotypes NP VT trial/future polio 1 + 1 IPD PCV9 18C min-and PCV13 vaccine patient 19F lumbar puncture 1+ 1 NP specimens Gambia Medicines Control Agency − EPI μl/ml pleural fluid Gambia Government/MRCG Joint Ethics Committee Head 178,510 (225 villages Fatoto 1 + 1 versus 3 + 0 2 + 1 ≥85 trialist patients 3 + 0 clusters was 6 2+ 1 3+ 0 gentamicin infants Koina PCV10 vaccine GSK vaccine March-7 PCV13 vaccine serotypes children ≤1.38 human 1 + 1alternative Gambia. Infants ethylhydrocupreine Gambia Government/MRC Joint Ethics Committee SADR 3 + 0 e-CRF eCRFs herd BHDSS participants § Basse. 4-6 PCV7 NVT pneumococci Oct-Dec haemoglobin plasma PCV10 vaccine colonies Janjanbureh SGUL pneumococci Streptococcus viridans Jan-Sept b) non-PCV13 vaccine serotypes − 5 NP swab joint latex lung aspirate IgG Gambia rotavirus vaccine pleural of~1500 NP NP swabs head, ICC= NP carriage of ID 7F, 9 V PVS ≤15 peripheral O 2 https://doi Bill GM EC Joint Global Health Trials Scheme Statistician SF IH EPI UD AP UK INV006724 patients infants BG org/10.1186/s13063-021 IO CN,
Extracted Text Content in Record: First 5000 Characters: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 vaccinetype 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 populationlevel 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 Despite the pneumococcus causing more childhood deaths than any single pathogen [2, 3] , global control of pneumococcal disease is hampered by the cost of pneumococcal conjugate vaccines (PCVs). In addition to the relatively high cost of several new vaccines that have recently been introduced in many low-income countries, expanded programmes on immunisation (EPI) face the additional challenge of schedules with increasing numbers of doses. Reducing the cost and complexity of EPI schedules would improve the flexibility, acceptability and sustainability of immunisation programmes. Low-income countries receive subsidised PCV through the GAVI Alliance, providing a co-payment of 0.15-0.30 USD per dose (increasing 15% per year in 'intermediate' countries) [4] . However, when countries' Gross National Income per capita exceeds the World Bank 'low-income' threshold of~1500 USD, they begin to transition from GAVI support. During transition, co-payments increase each year for 5 years to a final price set under the GAVI Advance Market Commitment (2.00-2.90 USD per dose) [5] . GAVI expenditure on PCV represents approximately half of its vaccine budget [6] . The importance of the cost of PCV was evident in The Gambia where its introduction, at 0.2 USD per dose, increased the national cost of the EPI programme by one third, with vaccine representing 91% of the total cost of introducing PCV [7] . Thus, a major determinant of the sustainability of pneumococcal vaccination in low-and middle-income countries is vaccine cost. Middle-income countries, ineligible for GAVI support, experience many child deaths due to pneumococcus but cost has precluded many from introducing PCV. EPI programmes in low-and middle-income countries are becoming more complicated and costly with the introduction of new vaccines. The addition of vaccines such as PCV, rotavirus vaccine, injectable polio vaccine, meningococcal group A conjugate, human papillomavirus vaccine, and typhoid conjugate challenges the implementation, acceptance, cold-chain capacity, and sustainability of EPIs. The difficulty of introducing such new vaccines has its biggest impact in low-and middle-income countries where the bu
Keywords Extracted from PMC Text: NP BHDSS polio NVT pneumococcal PCV10 vaccine 2–12 lumbar puncture CRF OPV Synflorix® NP swabs 19F × thumbprints Epidemiologist Head PCV13— CO2 PCV13 gentamicin PCV13 [18 Measles-Mumps-Rubella [35] human papillomavirus vaccine haemoglobin DMC ethylhydrocupreine 2+ 1 pneumococci eCRFs NP carriage of COVID-19 Bank ' Front-end serotype 1 human trialist oral polio vaccine Koina 1 + 1 patients Blood ageAge PCV13 vaccine serotypes PCV9 Non-typeable isolates Measles-Mumps-Rubella-Varicella [36] vaccines BCG Waroux individuals NP VT mother's Sabi Gambia Government/MRCG Joint Ethics Committee NP swab http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/ ≤15 pleural fluid colonies Fatoto SADRs EPI ' Patients EC's GSK vaccine measles vaccine PCV13 vaccines − serotypes Gambia Medicines Control Agency 's 7F, 9 V children patient infants Human papilloma virus vaccine PVS ≥85 PCV7 Vaccine Streptococcus viridans Gambisara latex Fig. 4 IgG NVT pneumococci NVT serotypes EC 2016/2017 3–5-year-olds blood cultures participants upper PCV10 e-CRF O2 alpha UK 3+ 0 2 + 1 guardians SAEs blood Gambia. Bansang RHDs ISCTRN Plasma Children SADR ID FWHDSS lower-chest wall free-call serotypes 1 SUSARS S. pneumoniae 1 + 1 clusters infants plasma PCVs 's father NP specimen herd St George's 9-valent hepatitis B curly brackets peripheral arterial b) non-PCV13 vaccine serotypes URR 1, 2, 3 language SCC SGUL low- μl/ml rotavirus vaccine PCV7/13 1+ 1 GG/MRC lung aspirate EPI polio vaccine nasopharyngeal Oct–Dec 2015 Basse. 3 + 0 ≤1.38 Gambia head, peripheral O2 rotavirus Vaccinators − 28–91 Harmonised Guideline micrococcus c Janjanbureh IPD Tostan SUSAR 18C DMC's h. MSSQL backend database Serum measles PCV13 vaccine NP specimens SUSARs PI Infants Gambia Government/MRC Joint Ethics Committee E6(R2 specimens 1 + 1 versus 3 + 0 PHP\ASP.Net joint bile vaccine 3 + 0 clusters was 6
Extracted PMC Text Content in Record: First 5000 Characters:Note: the numbers in curly brackets in this protocol refer to SPIRIT checklist item numbers [1]. The order of the items has been modified to group similar items (see http://www.equator-network.org/reporting-guidelines/spirit-2013-statement-defining-standard-protocol-items-for-clinical-trials/). Despite the pneumococcus causing more childhood deaths than any single pathogen [2, 3], global control of pneumococcal disease is hampered by the cost of pneumococcal conjugate vaccines (PCVs). In addition to the relatively high cost of several new vaccines that have recently been introduced in many low-income countries, expanded programmes on immunisation (EPI) face the additional challenge of schedules with increasing numbers of doses. Reducing the cost and complexity of EPI schedules would improve the flexibility, acceptability and sustainability of immunisation programmes. Low-income countries receive subsidised PCV through the GAVI Alliance, providing a co-payment of 0.15–0.30 USD per dose (increasing 15% per year in 'intermediate' countries) [4]. However, when countries' Gross National Income per capita exceeds the World Bank 'low-income' threshold of ~ 1500 USD, they begin to transition from GAVI support. During transition, co-payments increase each year for 5 years to a final price set under the GAVI Advance Market Commitment (2.00–2.90 USD per dose) [5]. GAVI expenditure on PCV represents approximately half of its vaccine budget [6]. The importance of the cost of PCV was evident in The Gambia where its introduction, at 0.2 USD per dose, increased the national cost of the EPI programme by one third, with vaccine representing 91% of the total cost of introducing PCV [7]. Thus, a major determinant of the sustainability of pneumococcal vaccination in low- and middle-income countries is vaccine cost. Middle-income countries, ineligible for GAVI support, experience many child deaths due to pneumococcus but cost has precluded many from introducing PCV. EPI programmes in low- and middle-income countries are becoming more complicated and costly with the introduction of new vaccines. The addition of vaccines such as PCV, rotavirus vaccine, injectable polio vaccine, meningococcal group A conjugate, human papillomavirus vaccine, and typhoid conjugate challenges the implementation, acceptance, cold-chain capacity, and sustainability of EPIs. The difficulty of introducing such new vaccines has its biggest impact in low- and middle-income countries where the burden of disease is greatest but resources are scarce. The Medical Research Council Unit The Gambia at London School of Hygiene & Tropical Medicine (MRCG at LSHTM) has a long history investigating the burden of pneumococcal disease and pneumococcal vaccination. In 2000–2004, a trial of a 9-valent PCV (PCV9) was conducted in Central and Upper River Regions (CRR and URR) of The Gambia. Vaccine efficacy in children aged 3–29 months was 37% against radiological pneumonia, 77% against vaccine-type (VT) invasive pneumococcal disease (IPD), and 16% against all-cause mortality [8]. In 2009, The Gambia introduced PCV7 into the routine EPI using a three-dose schedule without a booster dose (i.e. a '3 + 0' schedule). In 2011, PCV7 was replaced by PCV13. The Pneumococcal Surveillance Project (PSP) has documented the impact of PCV13 in the Basse Health & Demographic Surveillance System (BHDSS) in rural Gambia. Four to five years after the introduction of PCV7/13 the incidence of VT IPD had declined by 82%, with a 24% reduction in radiological pneumonia, and 61% reduction in severe hypoxic pneumonia in children aged 2–59 months [9, 10]. Eight years after the introduction of PCV7/13 the incidence of VT IPD in the 2–59 month age group has declined by 92% and radiological pneumonia has declined by 33% [11]. Before the introduction of PCV, PSP detected an average of 35 annual cases of VT IPD among children aged 2–59 months. In 2016, we detected six cases of VT IPD, and in 2017, we detected three. In 2016/2017, we detected zero cases of VT IPD among children in the first year of life. These data indicate that the introduction of PCV7/13 has now controlled VT IPD. It is now evident that following the introduction of PCV13, herd protection has developed in The Gambia. The annual count of VT IPD in older children in PSP was six to ten before the introduction of PCV13 in 2011. Following the introduction of PCV13 the annual case counts in 2015, 2016, and 2017 were four, one, and zero, respectively. In the 5–14 year age group, IPD incidence declined by 69% (95%CI, − 28–91%) and radiological pneumonia by 27% (95%CI, − 5–49%) [11]. Similar findings of the direct and herd effect of PCV are evident in Kenya [12, 13]. The prevalence of nasopharyngeal (NP) carriage of PCV13 VT in the BHDSS area before the introduction of vaccine was 47% in the under-5-year age group. In 2015 and 2017, the prevalence of vaccine types was 15% and 17%, respectively (author's own data). The downward trajectory of VT p
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