Background: Cardiovascular disease (CVD) such as ischemic heart disease and stroke is the leading causes of death and disability globally with a growing burden in low and middle-income countries. A credible way of managing the incidence and prevalence of cardiovascular diseases is by reducing risk factors. This understanding has led to the development and recommendation for the clinical use of cardiovascular risk stratification tools. These tools enhance clinical decision-making. However, there is a lag in the implementation of these tools in most countries. This systematic review seeks to synthesise the current knowledge of the factors influencing the implementation of cardiovascular risk scoring in primary care settings.Methods: We searched bibliographic databases and grey literature for studies of any design relating to the topic. Titles, abstracts and full texts were independently assessed for eligibility by two reviewers. This was followed by quality assessment and data extraction. We analysed data using an integrated and best fit framework synthesis approach to identify these factors. Quantitative and qualitative forms of data were combined into a single mixed-methods synthesis. The Consolidated Framework for Implementation Research was used as the guiding tool and template for this analysis.Results: Twenty-five studies (cross-sectionaln= 12, qualitativen= 9 and mixed-methodsn= 4) were included in this review. Twenty (80%) of these were conducted in high-income countries. Only four studies (16%) included patients as participants. This review reports on a total of eleven cardiovascular risk stratification tools. The factors influencing the implementation of cardiovascular risk scoring are related to clinical setting and healthcare system (resources, priorities, practice culture and organisation), users (attributes and interactions between users) and the specific cardiovascular risk tool (characteristics, perceived role and effectiveness).Conclusions: While these findings bolster the understanding of implementation complexity, there exists limited research in the context of low and middle-income countries. Notwithstanding the need to direct resources in bridging this gap, it is also crucial that these efforts are in concert with providing high-quality evidence on the clinical effectiveness of using cardiovascular risk scoring to improve cardiovascular disease outcomes of mortality and morbidity.Trial registration: PROSPERO registration number: CRD42018092679.

Yellow fever (YF) remains a threat to global health, with an increasing number of major outbreaks in the tropical areas of the world over the recent past. In light of this, the Eliminate Yellow Fever Epidemics Strategy was established with the aim of protecting one billion people at risk of YF through vaccination by the year 2026. The current YF vaccine gives excellent protection, but its use is limited by shortages in supply due to the difficulties in producing the vaccine. There are good grounds for believing that alternative fractional dosing regimens can produce strong protection and overcome the problem of supply shortages as less vaccine is required per person. However, immune responses to these vaccination approaches are yet to be fully understood. In addition, published data on immune responses following YF vaccination have mostly quantified neutralising antibody titers. However, vaccine-induced antibodies can confer immunity through other antibody effector functions beyond neutralisation, and an effective vaccine is also likely to induce strong and persistent memory T cell responses. This review highlights the gaps in knowledge in the characterisation of YF vaccine-induced protective immunity in the absence or presence of neutralising antibodies. The assessment of biophysical antibody characteristics and cell-mediated immunity following YF vaccination could help provide a comprehensive landscape of YF vaccine-induced immunity and a better understanding of correlates of protective immunity.

Introduction: Yellow fever is endemic in specific regions of sub-Saharan Africa and the Americas, with recent epidemics occurring on both continents. The yellow fever vaccine is effective, affordable and safe, providing life-long immunity following a single dose vaccination. However, the vaccine production process is slow and cannot be readily scaled up during epidemics. This has led the World Health Organization (WHO) to recommend the use of fractional doses as a dose-sparing strategy during epidemics, but there are no randomized controlled trials of fractional yellow fever vaccine doses in Africa. Methods and analysis: We will recruit healthy adult volunteers, adults living with HIV, and children to a series of randomized controlled trials aiming to determine the immunogenicity and safety of fractional vaccine doses in comparison to the standard vaccine dose. The trials will be conducted across two sites; Kilifi, Kenya and Mbarara, Uganda. Recruited participants will be randomized to receive fractional or standard doses of yellow fever vaccine. Scheduled visits will include blood collection for serum and peripheral blood mononuclear cells (PBMCs) before vaccination and on various days – up to 2 years – post-vaccination. The primary outcome is the rate of seroconversion as measured by the plaque reduction neutralization test (PRNT50) at 28 days post-vaccination. Secondary outcomes include antibody titre changes, longevity of the immune response, safety assessment using clinical data, the nature and magnitude of the cellular immune response and post-vaccination control of viremia by vaccine dose. Ethics and dissemination: The clinical trial protocols have received approval from the relevant institutional ethics and regulatory review committees in Kenya and Uganda, and the WHO Ethics Review Committee. The research findings will be disseminated through open-access publications and presented at relevant conferences and workshops. Registration: ClinicalTrials.gov NCT02991495 (registered on 13 December 2016) and NCT04059471 (registered on 15 August 2019).

Background: Yellow fever vaccine stocks have been insufficient to cover exceptional demands for outbreak response. Fractional dosing evidence is limited to the 17DD substrain vaccine. We assessed the immunogenicity and safety of one-fifth fractional dose compared to standard dose of each of the four WHO-prequalified yellow fever vaccines produced from three substrains. Methods: We conducted a randomized, double-blind, non-inferiority trial in Mbarara, Uganda and Kilifi, Kenya. 960 participants aged 18-59 years without previous yellow fever vaccination or infection were recruited from communities and randomized to receive one of four vaccines and to standard or fractional dosage. Vaccine was administered subcutaneously by unblinded nurse. Other study personnel and participants were blinded to vaccine allocation. Primary immunogenicity outcome, seroconversion, was measured in the per-protocol population; safety outcomes included all vaccinated participants. We defined non-inferiority as no more than 10% decrease in seroconversion in fractional compared to standard dose arms 28 days post-vaccination. Seroconversion was defined as ≥4-fold rise in neutralizing antibody titers measured by 50% plaque reduction neutralization test (PRNT ₅₀ ). ClinicalTrials.gov Identifier: NCT02991495 , following participants. Findings: Between 6 ^th November 2017 and 21 ^st February 2018, 960 participants, total sample goal, were randomized. The primary per-protocol analysis includes 899 participants, with 110 to 117 participants per arm. The absolute difference in seroconversion between fractional and standard doses by vaccine was 1.71% (95%CI: −2.60, 5.28), −0.90% (95%CI: −4.24, 3.13), 1.82% (95%CI: −2.75, 5.39), 0.0% (95%CI: −3.32, 3.29). Fractional doses from all four vaccines met the non-inferiority criterion. There were no safety concerns. Interpretation: These results support fractional dosing of all WHO-prequalified yellow fever vaccines for the general adult population for outbreak response in situations of vaccine shortage. Funding: The study was funded by Médecins Sans Frontières Foundation, Wellcome Trust (grant no. 092654) and the UK Department for International Development. Vaccines were donated in kind. Research in context: Evidence before this study: In July 2016, following major yellow fever (YF) outbreaks in two countries, WHO published a secretariat information paper including a review of studies assessing the immunogenicity of fractional doses of YF vaccines and recommended consideration of fractional doses to manage a vaccine shortage. Following this, fractional doses of YF vaccine produced by Bio-Manguinhos/Fiocruz (17DD substrain) were given to approximately 7.5 million non-pregnant adults and children ≥ 2 years of age in Kinshasa, Democratic Republic of Congo. The evidence base to support this action was limited to a single vaccine substrain and to a specific context. To broaden and simplify recommendations, WHO called for additional research to be conducted. We designed a trial to assess non-inferiority in seroconversion of fractional (one-fifth dose) versus standard dose for each of the four WHO-prequalified YF vaccines at 28 days post-vaccination in an adult population in Kenya and Uganda. We selected vaccine batches as close as possible to each manufacturer’s minimum release specification. Added value of this study: This is the first randomized controlled trial assessing all four WHO-prequalified YF vaccines, providing information on the immunogenicity and safety of fractional doses of the different vaccine substrains at 10 days, 28 days and one year post-vaccination. The results show that, at 28 days post-vaccination, most participants had high levels of neutralizing antibodies and that seroconversion rates in the fractional dose arms were non-inferior to standard dose for each of the four vaccines. Seroconversion rates and neutralizing antibodies remained high up to one year post-vaccination for both fractional and standard doses for all vaccines. These results are aligned with previous studies using the 17DD substrain vaccine but extend the evidence to randomized comparisons of all four vaccines and to a sub-Saharan Africa context. To our knowledge, this is the first trial assessing immunogenicity of fractional doses at 10 days post-vaccination. Implications of all the available evidence: Our study supports the use of one-fifth fractional doses of all four WHO-prequalified yellow fever vaccines for the general adult population and fills a critical knowledge gap to support WHO policy on the use of fractional dosing of yellow fever vaccine for outbreak response. The immunogenicity and safety of fractional dosing in children and specific populations, such as those living with HIV, is yet to be determined. Long-term studies are warranted to confirm the duration of protection.