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Abstract Background This trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial. Methods The key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics. Discussion The findings from this study will provide the first experimental evidence for the efficacy of releasing male-Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter. Trial registration ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023.

Background: This trial is a parallel, two-arm, non-blinded cluster randomised controlled trial that is under way in Singapore, with the aim of measuring the efficacy of male Wolbachia-infected Aedes aegypti deployments in reducing dengue incidence in an endemic setting with all four dengue serotypes in circulation. The trial commenced in July 2022 and is expected to conclude in September 2024. The original study protocol was published in December 2022. Here, we describe amendments that have been made to the study protocol since commencement of the trial. Methods: The key protocol amendments are (1) addition of an explicit definition of Wolbachia exposure for residents residing in intervention sites based on the duration of Wolbachia exposure at point of testing, (2) incorporation of a high-dimensional set of anthropogenic and environmental characteristics in the analysis plan to adjust for baseline risk factors of dengue transmission, and (3) addition of alternative statistical analyses for endpoints to control for post hoc imbalance in cluster-based environmental and anthropogenic characteristics. Discussion: The findings from this study will provide the first experimental evidence for the efficacy of releasing male-Wolbachia infected mosquitoes to reduce dengue incidence in a cluster-randomised controlled trial. The trial will conclude in 2024 and results will be reported shortly thereafter. Trial registration: ClinicalTrials.gov, identifier: NCT05505682. Registered on 16 August 2022. Retrospectively registered. Last updated 11 November 2023. [ABSTRACT FROM AUTHOR]

Abstract Background The malaria incidence data from a malaria prevention study from the Rift Valley, Central Ethiopia, were reanalysed. The objective was to investigate whether including an administrative structure within the society, which may have required consideration in the protocol or previous analysis, would provide divergent outcomes on the effect measures of the interventions. Methods A cluster-randomized controlled trial lasting 121 weeks with 176 clusters in four groups with 6071 households with 34,548 persons was done: interventions combining indoor residual spraying (IRS) and insecticide-treated nets (ITNs), IRS alone, ITNs alone and routine use. The primary outcome was malaria incidence. A multilevel negative binomial regression model was employed to examine the impact of the kebele (smallest administrative unit) and the proximity of homes to the primary mosquito breeding sites as potential residual confounders (levels). The study also assessed whether these factors influenced the effect measures of the interventions. Results The study's initial findings revealed 1183 malaria episodes among 1059 persons, with comparable effects observed across the four intervention groups. In the reanalysis, the results showed that both ITN + IRS (incidence rate ratio [IRR] 0.63, P

Abstract Background Long-term reinforcement in the role of primary care and improvement the healthcare system as a whole requires the involvement of GPs in clinical research processes. However, many clinical studies fail due to failure to achieve sample population targets amongst GPs and their patients. This issue has been identified and discussed, but effective strategies to overcome it are still lacking. One of the reasons is that the positions, requirements, and experiences of GPs on participating in clinical research have hardly been examined up to now. Methods The years 2021 and 2022 saw three quantitative and qualitative surveys amongst GPs in Germany with the aim of shedding light on the attitudes, experiences, and potential issues regarding the involvement of primary care in clinical research projects and participation in cluster-randomised controlled trials (cRCTs) in a general sense. This overview summarises and abstracts conclusions gained from the exploratory series of studies and compares the results with the current research situation. From here, this contribution will then develop an approach towards optimising the integration of GPs into clinical research. Results Most of the GPs asked associated clinical research with opportunities and potential such as closing gaps in healthcare, using evidence-based instruments, optimising diagnostic and therapeutic management, and reinforcement of multiprofessional healthcare. Even so, many GPs unsure as to how far primary care in particular would stand to benefit from studies of this type in the long term. Respondents were also divided on willingness to participate in clinical research. GPs having already participated in Innovation Fund projects generally saw a benefit regarding intervention and cost–benefit relationship. However, some also reported major hurdles and stress factors such as excessive documentation and enrolment requirements, greater interference in practice routines, and sometimes poor integration into project processes such as in communication and opportunities to play an active role in the project. Conclusions Results from the studies presented provide indications as to how GPs perceive clinical research projects and cRCTs as a whole and from their existing project experience, and on the requirements that studies would have to meet for GPs to be willing to participate. In particular, making sure that clinical studies fully conform with GPs would play a major role; this especially applies to freedom to make medical decisions, limitation of documentation obligations, interference in regular practice routine, greater involvement in research planning, and long-term reinforcement in the role of primary care. Clinical research projects and cRCTs should be planned, designed, and communicated for clear and visible relevance to everyday primary care.

Abstract Rationale The effectiveness of immunisation with pneumococcal conjugate vaccine (PCV) has been demonstrated in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in some countries. Reducing the cost of PCV programmes will facilitate further vaccine introductions and improve the sustainability of PCV in low-income countries when they transition from subsidised vaccine supply. We are conducting a large, population-level, cluster-randomised field trial (PVS) of an alternative reduced-dose schedule of PCV compared to the standard schedule. We are also conducting a nested sub-study at the individual level to investigate the immunogenicity of the two schedules and their effects on pneumococcal carriage acquisition (PVS-AcqImm). Methods and design PVS-AcqImm is a prospective, cluster-randomised trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months compared to the standard of three primary doses scheduled at 6, 10, and 14 weeks of age. Sub-groups within the alternative schedule group receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) concentrations of vaccine-type anti-pneumococcal IgG at 18 months of age, (b) proportions with yellow fever neutralising antibody titre ≥ 1:8 4 weeks after separate or co-administration of PCV and yellow fever vaccines, and (c) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 10–14 months of age. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoints is masked. Approximately equal numbers of participants are resident in each of 28 randomly allocated geographic clusters (14 clusters in each group); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Purpose This statistical analysis plan (SAP) describes the PVS-AcqImm cohort and follow-up criteria to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe the approach to analyses and how we will account for the effect of clustering. Defining the SAP prior to the conduct of analysis will avoid bias in analyses that may arise from prior knowledge of trial findings. Trial registration ISRCTN, ISRCTN7282161328. Registered on 28 November 2019. https://www.isrctn.com/ISRCTN72821613 . Protocol: MRCG SCC number 1670, LSHTM Ref 17683. Current protocol version: 6.0, 24 May 2021. Version: 1.0 (5 April 2023); SAP revisions—none.

Rationale: The effectiveness of immunisation with pneumococcal conjugate vaccine (PCV) has been demonstrated in many countries. However, the global impact of PCV is limited by its cost, which has prevented its introduction in some countries. Reducing the cost of PCV programmes will facilitate further vaccine introductions and improve the sustainability of PCV in low-income countries when they transition from subsidised vaccine supply. We are conducting a large, population-level, cluster-randomised field trial (PVS) of an alternative reduced-dose schedule of PCV compared to the standard schedule. We are also conducting a nested sub-study at the individual level to investigate the immunogenicity of the two schedules and their effects on pneumococcal carriage acquisition (PVS-AcqImm). Methods and design: PVS-AcqImm is a prospective, cluster-randomised trial of an alternative schedule of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months compared to the standard of three primary doses scheduled at 6, 10, and 14 weeks of age. Sub-groups within the alternative schedule group receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) concentrations of vaccine-type anti-pneumococcal IgG at 18 months of age, (b) proportions with yellow fever neutralising antibody titre ≥ 1:8 4 weeks after separate or co-administration of PCV and yellow fever vaccines, and (c) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 10–14 months of age. Participants and field staff are not masked to group allocation while measurement of the laboratory endpoints is masked. Approximately equal numbers of participants are resident in each of 28 randomly allocated geographic clusters (14 clusters in each group); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Purpose: This statistical analysis plan (SAP) describes the PVS-AcqImm cohort and follow-up criteria to be used in different analyses. The SAP defines the endpoints and describes how adherence to the interventions will be presented. We describe the approach to analyses and how we will account for the effect of clustering. Defining the SAP prior to the conduct of analysis will avoid bias in analyses that may arise from prior knowledge of trial findings. Trial registration: ISRCTN, ISRCTN7282161328. Registered on 28 November 2019. https://www.isrctn.com/ISRCTN72821613. Protocol: MRCG SCC number 1670, LSHTM Ref 17683. Current protocol version: 6.0, 24 May 2021. Version: 1.0 (5 April 2023); SAP revisions—none. [ABSTRACT FROM AUTHOR]

Background: Long-term reinforcement in the role of primary care and improvement the healthcare system as a whole requires the involvement of GPs in clinical research processes. However, many clinical studies fail due to failure to achieve sample population targets amongst GPs and their patients. This issue has been identified and discussed, but effective strategies to overcome it are still lacking. One of the reasons is that the positions, requirements, and experiences of GPs on participating in clinical research have hardly been examined up to now. Methods: The years 2021 and 2022 saw three quantitative and qualitative surveys amongst GPs in Germany with the aim of shedding light on the attitudes, experiences, and potential issues regarding the involvement of primary care in clinical research projects and participation in cluster-randomised controlled trials (cRCTs) in a general sense. This overview summarises and abstracts conclusions gained from the exploratory series of studies and compares the results with the current research situation. From here, this contribution will then develop an approach towards optimising the integration of GPs into clinical research. Results: Most of the GPs asked associated clinical research with opportunities and potential such as closing gaps in healthcare, using evidence-based instruments, optimising diagnostic and therapeutic management, and reinforcement of multiprofessional healthcare. Even so, many GPs unsure as to how far primary care in particular would stand to benefit from studies of this type in the long term. Respondents were also divided on willingness to participate in clinical research. GPs having already participated in Innovation Fund projects generally saw a benefit regarding intervention and cost–benefit relationship. However, some also reported major hurdles and stress factors such as excessive documentation and enrolment requirements, greater interference in practice routines, and sometimes poor integration into project processes such as in communication and opportunities to play an active role in the project. Conclusions: Results from the studies presented provide indications as to how GPs perceive clinical research projects and cRCTs as a whole and from their existing project experience, and on the requirements that studies would have to meet for GPs to be willing to participate. In particular, making sure that clinical studies fully conform with GPs would play a major role; this especially applies to freedom to make medical decisions, limitation of documentation obligations, interference in regular practice routine, greater involvement in research planning, and long-term reinforcement in the role of primary care. Clinical research projects and cRCTs should be planned, designed, and communicated for clear and visible relevance to everyday primary care. [ABSTRACT FROM AUTHOR]

Background: The malaria incidence data from a malaria prevention study from the Rift Valley, Central Ethiopia, were reanalysed. The objective was to investigate whether including an administrative structure within the society, which may have required consideration in the protocol or previous analysis, would provide divergent outcomes on the effect measures of the interventions. Methods: A cluster-randomized controlled trial lasting 121 weeks with 176 clusters in four groups with 6071 households with 34,548 persons was done: interventions combining indoor residual spraying (IRS) and insecticide-treated nets (ITNs), IRS alone, ITNs alone and routine use. The primary outcome was malaria incidence. A multilevel negative binomial regression model was employed to examine the impact of the kebele (smallest administrative unit) and the proximity of homes to the primary mosquito breeding sites as potential residual confounders (levels). The study also assessed whether these factors influenced the effect measures of the interventions. Results: The study's initial findings revealed 1183 malaria episodes among 1059 persons, with comparable effects observed across the four intervention groups. In the reanalysis, the results showed that both ITN + IRS (incidence rate ratio [IRR] 0.63, P < 0.001) and ITN alone (IRR 0.78, P = 0.011) were associated with a greater reduction in malaria cases compared to IRS (IRR 0.90; P = 0.28) or the control (reference) group. The combined usage of IRS with ITN yields better outcomes compared to the standalone use of ITN and surpasses the effectiveness of IRS in isolation. Conclusion: The findings indicate that implementing a combination of IRS and ITN and also ITN alone decrease malaria incidence. Furthermore, there was an observed synergistic impact when ITN and IRS were used in combination. Considering relevant social structures as potential residual confounders is of paramount importance. Trial registration: PACTR201411000882128 (08 September 2014). [ABSTRACT FROM AUTHOR]

Abstract Background The cognitive benefits of early non-pharmacological approaches have been demonstrated in older adults with mild cognitive impairment (MCI). However, older adults living in nursing homes have more severe cognitive impairment problems and lower initiative and compliance to participate in complex interventions. Hence, it important to investigate more attractive and sustainable methods to prevent or delay cognitive decline. The present study adopts the self-determination theory (SDT) as a theoretical framework to innovatively develop an integrated art-based intervention for older adults with MCI in nursing homes in China and aims to evaluate its effects on cognitive function, mental health, and other health-related outcomes. Methods The study is a nursing home-based, cluster randomised controlled trial (RCT) that targets older adults (aged ≥ 60 years) with MCI in Fuzhou City, China. All nursing homes in the area covered by Fuzhou City are invited to participate. Eligible nursing homes are randomised to one of two groups: intervention group (receive a 14-week, 27-session intervention) and waitlist control group (receive the usual care). The SDT-based integrated creative art (SDTICA) program reasonably adopts the SDT as a theoretical framework to innovatively develop an integrated art-based intervention for older adults with MCI in nursing homes. The primary (global cognitive function and psychological indicator) and secondary (daily activity function, social function, and specific domains of cognitive function) outcomes will be measured at baseline, after the intervention, and during follow-up. Discussion This study aims to evaluate the effects of SDTICA program on neuropsychological outcomes in older adults with MCI and provide scientific evidence for art-based non-pharmacologic interventions in nursing homes, which may reduce dementia risk in older adults with MCI. Trial registration The trial was prospectively registered at the Chinese Clinical Trials Registry with the registration number ChiCTR2200061681 on 30 June 2022.

Abstract Background Dental service provision in the care home sector is poor, with little emphasis on prevention. Emerging evidence suggests that the use of Dental Care Professionals (dental therapists and dental nurses) as an alternative to dentists has the potential to improve preventive advice, the provision of care and access to services within care homes. However, robust empirical evidence from definitive trials on how to successfully implement and sustain these interventions within care homes is currently lacking. The aim of the study is to determine whether Dental Care Professionals could reduce plaque levels of dentate older adults (65 + years) residing in care homes. Methods This protocol describes a two-arm cluster-randomised controlled trial that will be undertaken in care homes across Wales, Northern Ireland and England. In the intervention arm, the dental therapists will visit the care homes every 6 months to assess and then treat eligible residents, where necessary. All treatment will be conducted within their Scope of Practice. Dental nurses will visit the care homes every month for the first 3 months and then three-monthly afterwards to promulgate advice to improve the day-to-day prevention offered to residents by carers. The control arm will be ‘treatment as usual’. Eligible care homes (n = 40) will be randomised based on a 1:1 ratio (20 intervention and 20 control), with an average of seven residents recruited in each home resulting in an estimated sample of 280. Assessments will be undertaken at baseline, 6 months and 12 months and will include a dental examination and quality of life questionnaires. Care home staff will collect weekly information on the residents’ oral health (e.g. episodes of pain and unscheduled care). The primary outcome will be a binary classification of the mean reduction in Silness-Löe Plaque Index at 6 months. A parallel process evaluation will be undertaken to explore the intervention’s acceptability and how it could be embedded in standard practice (described in a separate paper), whilst a cost-effectiveness analysis will examine the potential long-term costs and benefits of the intervention. Discussion This trial will provide evidence on how to successfully implement and sustain a Dental Care Professional-led intervention within care homes to promote access and prevention. Trial registration ISRCTN16332897 . Registered on 3 December 2021.

Background: The cognitive benefits of early non-pharmacological approaches have been demonstrated in older adults with mild cognitive impairment (MCI). However, older adults living in nursing homes have more severe cognitive impairment problems and lower initiative and compliance to participate in complex interventions. Hence, it important to investigate more attractive and sustainable methods to prevent or delay cognitive decline. The present study adopts the self-determination theory (SDT) as a theoretical framework to innovatively develop an integrated art-based intervention for older adults with MCI in nursing homes in China and aims to evaluate its effects on cognitive function, mental health, and other health-related outcomes. Methods: The study is a nursing home-based, cluster randomised controlled trial (RCT) that targets older adults (aged ≥ 60 years) with MCI in Fuzhou City, China. All nursing homes in the area covered by Fuzhou City are invited to participate. Eligible nursing homes are randomised to one of two groups: intervention group (receive a 14-week, 27-session intervention) and waitlist control group (receive the usual care). The SDT-based integrated creative art (SDTICA) program reasonably adopts the SDT as a theoretical framework to innovatively develop an integrated art-based intervention for older adults with MCI in nursing homes. The primary (global cognitive function and psychological indicator) and secondary (daily activity function, social function, and specific domains of cognitive function) outcomes will be measured at baseline, after the intervention, and during follow-up. Discussion: This study aims to evaluate the effects of SDTICA program on neuropsychological outcomes in older adults with MCI and provide scientific evidence for art-based non-pharmacologic interventions in nursing homes, which may reduce dementia risk in older adults with MCI. Trial registration: The trial was prospectively registered at the Chinese Clinical Trials Registry with the registration number ChiCTR2200061681 on 30 June 2022. [ABSTRACT FROM AUTHOR]

Abstract Background Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial. Methods PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative ‘1+1’ schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard ‘3+0’ schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements. Discussion Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules. Trial registration International Standard Randomised Controlled Trial Number 72821613 .

Background: Many children would benefit from a diet richer in vegetables and fruit. 'Flavour School' is a programme of 'sensory food education', which aims to increase children's confidence and curiosity in exploring foods and flavours, especially vegetables and fruit. This study will conduct a cluster-randomised controlled trial to assess the outcomes of the Flavour School programme in primary school children aged 4-7 years.Methods: Four hundred plus children from 4+ schools will either complete the Flavour School programme (experimental group) or have no intervention with normal school teaching (control group), cluster-randomised within-schools, by school class. Baseline data collection will consist of video recorded behavioural observation during a tasting activity, and post-intervention data collection will repeat this activity after the experimental group have completed the intervention. Process measures will be assessed using a teacher engagement feedback questionnaire.Discussion: This study will provide causal data on the efficacy of a sensory food education intervention for increasing children's confidence and curiosity in exploring foods and flavours, especially vegetables and fruit. This new knowledge will help educators and policy makers to make evidence based decisions on uptake of sensory food education.Trial Registration: ISRCTN: 40249947 Date assigned 17 March 2020 Last edited 22 September 2021 Version 1.2 Trial Acronym OASES (Outcomes Assessment of Sensory Education in Schools). [ABSTRACT FROM AUTHOR]

Background: Dental service provision in the care home sector is poor, with little emphasis on prevention. Emerging evidence suggests that the use of Dental Care Professionals (dental therapists and dental nurses) as an alternative to dentists has the potential to improve preventive advice, the provision of care and access to services within care homes. However, robust empirical evidence from definitive trials on how to successfully implement and sustain these interventions within care homes is currently lacking. The aim of the study is to determine whether Dental Care Professionals could reduce plaque levels of dentate older adults (65 + years) residing in care homes.Methods: This protocol describes a two-arm cluster-randomised controlled trial that will be undertaken in care homes across Wales, Northern Ireland and England. In the intervention arm, the dental therapists will visit the care homes every 6 months to assess and then treat eligible residents, where necessary. All treatment will be conducted within their Scope of Practice. Dental nurses will visit the care homes every month for the first 3 months and then three-monthly afterwards to promulgate advice to improve the day-to-day prevention offered to residents by carers. The control arm will be 'treatment as usual'. Eligible care homes (n = 40) will be randomised based on a 1:1 ratio (20 intervention and 20 control), with an average of seven residents recruited in each home resulting in an estimated sample of 280. Assessments will be undertaken at baseline, 6 months and 12 months and will include a dental examination and quality of life questionnaires. Care home staff will collect weekly information on the residents' oral health (e.g. episodes of pain and unscheduled care). The primary outcome will be a binary classification of the mean reduction in Silness-Löe Plaque Index at 6 months. A parallel process evaluation will be undertaken to explore the intervention's acceptability and how it could be embedded in standard practice (described in a separate paper), whilst a cost-effectiveness analysis will examine the potential long-term costs and benefits of the intervention.Discussion: This trial will provide evidence on how to successfully implement and sustain a Dental Care Professional-led intervention within care homes to promote access and prevention.Trial Registration: ISRCTN16332897 . Registered on 3 December 2021. [ABSTRACT FROM AUTHOR]

Background: Pneumococcal conjugate vaccines (PCVs) effectively prevent pneumococcal disease, but the global impact of pneumococcal vaccination is hampered by its cost. The evaluation of reduced dose schedules of PCV includes measurement of effects on immunogenicity and carriage acquisition compared to standard schedules. The relevance and feasibility of trials of reduced dose schedules is greatest in middle- and low-income countries, such as The Gambia, where the introduction of PCV resulted in good disease control but where transmission of vaccine-type pneumococci persists. We designed a large cluster-randomised field trial of an alternative reduced dose schedule of PCV compared to the standard schedule, the PVS trial. We will also conduct a sub-study to evaluate the individual-level effect of the two schedules on carriage acquisition, immunogenicity, and co-administration of PCV with yellow fever vaccine, the PVS-AcqImm trial.Methods: PVS-AcqImm is a prospective, cluster-randomised trial of one dose of PCV scheduled at age 6 weeks with a booster dose at age 9 months (i.e. alternative '1+1' schedule) compared to three primary doses scheduled at 6, 10, and 14 weeks of age (i.e. standard '3+0' schedule). Sub-groups within the alternative schedule group will receive yellow fever vaccine separately or co-administered with PCV at 9 months of age. The primary endpoints are (a) rate of nasopharyngeal vaccine-type pneumococcal acquisition from 9 to 14 months of age, (b) geometric mean concentration of vaccine-type pneumococcal IgG at 18 months of age, and (c) proportions with yellow fever neutralising antibody titre ≥8 four weeks after administration of yellow fever vaccine. Participants and field staff will not be masked to group allocation while the measurement of laboratory endpoints will be masked. Approximately equal numbers of participants will be resident in each of 28 geographic clusters (14 clusters in alternative and standard schedule groups); 784 enrolled for acquisition measurements and 336 for immunogenicity measurements.Discussion: Analysis will account for potential non-independence of measurements by cluster and so interpretation of effects will be at the individual level (i.e. a population of individuals). PVS-AcqImm will evaluate whether acquisition of vaccine-type pneumococci is reduced by the alternative compared to the standard schedule, which is required if the alternative schedule is to be effective. Likewise, evidence of superior immune response at 18 months of age and safety of PCV co-administration with yellow fever vaccine will support decision-making regarding the use of the alternative 1+1 schedule. Acquisition and immunogenicity outcomes will be essential for the interpretation of the results of the large field trial comparing the two schedules.Trial Registration: International Standard Randomised Controlled Trial Number 72821613 . [ABSTRACT FROM AUTHOR]